2007 – Volume 32, Issue 3

CONTENTS

Research Articles

PREPARATION AND CHARACTERIZATION OF BSA-LOADED ALGINATE MICROSPHERES
Meltem ÇETİN*, İmran VURAL**, Yılmaz ÇAPAN**, A. Atillâ HINCAL**
* Atatürk University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 25240, Erzurum, Turkey.
** Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100, Ankara, Turkey.

Pages, 103-107 Abstract I PDF (412 KB)

PASSIVE AND IONTOPHORETIC DELIVERY OF SILDENAFIL THROUGH THE SKIN
Sibel İLBASMIŞ TAMER*, Tuncer DEĞİM*
* Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Etiler, Ankara, Turkey

Pages, 109-119 Abstract I PDF (445 KB)

EVALUATION OF INORGANIC COMPOUNDS OF ERICA L. SPECIES (ERICACEAE) NATIVE TO TURKEY
Ayşegül GÜVENÇ*, Gülsen KENDİR*, Ayşe EKEN**, Ahmet AYDIN**
* Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100, Ankara, TURKEY

Pages, 121-125 Abstract I PDF (459 KB)

ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES OF SOME QUERCUS SPECIES GROWING IN TURKEY
Didem ŞÖHRETOĞLU*, Melike EKİZOĞLU**, Ekrem KILIÇ**, M. Koray SAKAR*
* Hacettepe University, Faculty of Pharmacy, Department of Pharmacognosy, Ankara, Turkey
** Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Ankara, Turkey

Pages, 127-130 Abstract I PDF (322 KB)

Invited Review

CHALLENGES IN THE SMALL-SCALE PREPARATION OF RADIOPHARMACEUTICALS – A EUROPEAN PERSPECTIVE
Clemens DECRISTOFORO*, **
* Clinical Department of Nuclear Medicine, Medical University Innsbruck, Austria
** Radiopharmacy Committee of the European Association of Nuclear Medicine

Pages, 131-138 Abstract I PDF (462 KB)

Scientific Review

COLLAGEN AND COLLAGEN DISORDERS
Açelya YALOVAÇ *, N. Nuray ULUSU**
* Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, 06100 Ankara, Turkey
** Hacettepe University, Faculty of Medicine, Department of Biochemistry, 06100 Ankara, Turkey

Pages, 139-144 Abstract I PDF (330 KB)

Journal of Pharmaceutical SciencesSaturday September 1st, 2007Tuesday February 20th, 2018

Nanomaterials Marvels: Transformative Advancements in Biomedicine, Drug Delivery, and Pharmaceutical Analysis

Amaresh PRUSTY*°, Sasmita Kumari PADHİ**

SUMMARY

Nanoparticles are solid colloidal particles ranging in size from 10 to 1000 nm having high surface area-to-volume ratio which allows them for efficient interaction with biological systems. Nanoparticles offer many benefits in comparison to larger particles such as increased surface-to-volume ratio and increased magnetic properties. Nanomaterials hold the potential to revolutionize critical domains like Biomedicine, Drug Delivery, and Pharmaceutical Analysis. These particles can be functionalized with specific molecules to target diseased cells or tissues, enhancing the efficacy of drugs while minimizing side effects. For instance, gold nanoparticles conjugated with antibodies can be used for targeted cancer therapy, delivering therapeutic agents directly to tumor cells. Similarly, drugs encapsulated within nanoparticles can be protected from premature degradation and released in a controlled manner at the target site improving their drug solubility, and enhance cellular uptake, leading to better therapeutic effect in treatment strategies. Polymeric nanoparticles, liposomes, and micelles are some examples of commonly used nanocarriers for drug delivery. Nanomaterials are finding increasing applications in pharmaceutical analysis and can be employed as highly sensitive detection probes for drugs, metabolites, and biomarkers. Additionally, nanomaterials can be used for the separation and purification of biomolecules, facilitating accurate and efficient analysis. This review explores different types of nano material’s used exploring their new advances and applications in biomedicine, drug delivery, and pharmaceutical analysis. As research
continues to overcome current challenges, nanomaterials unique properties hold immense promise for revolutionizing healthcare and improving patient outcomes.

Key Words: Biomedicine, Nanoparticles, Carbon nanotubes, Drug Delivery.

An Overview of Synthetic Derivatives of Thiazole and Their Role in Therapeutics

Manoj KASHYAP*, Muslek Uddin MAZUMDER**°, Pooja PATOWARY***, Apurba TALUKDAR****, Bhargab Jyoti SAHARIAH*****, Manish MAJUMDER******

SUMMARY

Thiazole derivatives have attracted much attention in medicinal chemistry due to their diverse pharmacological activities. This study provides an overview of the latest synthetic derivatives of thiazole and their therapeutic applications. Innovative methodologies have been adopted to enhance the structural diversity and optimize the pharmacological properties of thiazolebased compounds. These synthetic derivatives exhibit a broad spectrum of therapeutic activities, and understanding the essential features responsible for the observed pharmacological effects has been pivotal in structureactivity relationship studies. Drug development efforts have focused on modulating thiazole derivatives for improved bioavailability, selectivity, and reduced toxicity. This abstract highlights the potential of thiazole derivatives in targeting specific biological activity, paving the way for developing innovative therapeutic agents. Thiazole moiety as a heterocyclic compound was studied for its different pharmacological actions. The derivatives obtained from thiazole have diverse therapeutic actions along with antimicrobial activity, antitubercular activity, antidiabetic activity,
anticonvulsant, anti-inflammatory actions, and antitumor activities. The mechanism of actions of all these activities is also studied by the researcher to provide scientific evidence and validation of their actions. Utilization of synthetic chemistry for exploration of various pharmacological potential of thiazole derivatives will lead the future pharmacologists to a newer dimension for new drug discovery and also these derivatives can be further optimized for the development of alternative options for the treatment of various diseases. The versatility of thiazole scaffolds presents promising opportunities for discovering new drugs with enhanced efficacy and improved pharmacokinetic profiles. As researchers continue to delve into the synthesis and pharmacological evaluation of thiazole derivatives, their significance in modern drug design and therapy becomes increasingly evident.

Key Words: Thiazole, heterocyclic, antitubercular, antimicrobial, anti-inflammatory.

Innovative Approaches in Mirtazapine Delivery: Pharmacokinetic Simulations, Immediate Release to Controlled-Release Tablets, Formulation Optimization via D-optimal Mixture Design

Srk Raju SAGIRAJU*°, Pankaj Kumar SHARMA**, Jaya SHARMA***

SUMMARY

This research study describes the formulation and evaluation of Mirtazapine Controlled-Release (CR) Tablets, intended to improve therapeutic efficacy and patient compliance. Utilizing pharmacokinetic data from the USFDA-approved Remeron Immediate-Release (IR) Tablets, we constructed a plasma profile curve and calculated the following pharmacokinetic parameters Cmax, T max, AUC, Vd, and Ke. The principle of superposition method was employed to simulate steady-state plasma concentrations (Css), establishing target Css max and Css min values. These targets guided the development of our controlled-release formulation, which was designed to achieve a zero-order release mechanism.
The dose and release rate of the proposed controlled-release tablets were precisely adjusted to meet the targeted Css max and Css min concentrations. Our formulation strategy utilized different hydrophilic polymers such as HPMC, Carbopol, and Polyethylene oxide to create a robust ER matrix, we employed D Optimal Mixture Design to optimize the concentration of these three critical formulation variables. Dissolution studies were conducted in different media such as 0.01 N HCl, pH 4.5 Acetate buffer, and pH 6.8 Phosphate buffer for 14 hours to evaluate the rate, extent, and drug release kinetics. The successful simulation of plasma concentrations, followed by adjustments of dose, release rate, and
subsequent optimization of formulation variables using the Design of experiments yielded a CR tablet that meets the pharmacokinetic endpoints set by the IR reference. This innovative approach to Mirtazapine CR tablet formulation could significantly enhance patient compliance by providing a more consistent and controlled drug delivery system.

Key Words: Pharmacokinetic Simulations, Principle of superposition, Zero-Order release and absorption model. IR to CR conversions, Fluctuation index, Steady-state plasma concentration prediction.

The Local Anesthetic Activity of 4-(Naphthalen-1-yloxy)But-2-yn-1- yl)-Containing Piperidine Derivatives in Experimental Animal Models

Malika KHAIITOVA*°, Yelena SYCHEVA**°, Vasiliy TRUBACHEV***, Elmira SATBAYEVA****, Valentina YU*****, Talgat NURGOZHIN******, Edgaras STANKEVIČIUS*******, Yeskendir GASSANOV********, Zauresh UTELBAYEVA*********, Khaidar TASSIBEKOV**********

SUMMARY

Piperidine derivatives are of interest to researchers considering piperidines as an effective scaffold for the synthesis of new compounds. This research aimed to investigate the acute toxicity and local anesthetic activity of new synthesized 4-(Naphthalen-1-yloxy)but-2-yn-1-yl)-containing piperidine derivatives as inclusion complexes with β-cyclodextrin. Moreover, there was hydrogen or 3-methoxyphenyl in position 1 of the substituent at the nitrogen atom of the piperidine
ring. The acute toxicity tests were performed on outbred laboratory mice by subcutaneous injection of increasing concentrations of the test solutions. The initial investigation of local anesthetic activity during infiltration anesthesia was performed on guinea pigs using the Bulbring & Wajda animal model. An in-depth study of the efficacy of the most active compound was performed on a model of infiltration anesthesia of the rabbit’s abdominal wall by determining the threshold of nociception during electrical stimulation. The new studied piperidine derivatives are low-toxic substances, which are confirmed by the results of an acute toxicity study. At the stage of the primary study of local anesthetic activity during infiltration anesthesia on the experimental Bulbring and Wajda model, the LAS-251 compound showed the greatest activity, surpassing the reference drugs in terms of anesthesia index, duration of full anesthesia and total duration of action. At the stage of in-depth study, despite a longer latency period, LAS-251 has a local anesthetic effect longer than procaine and is slightly inferior to lidocaine. Results of the present study are promising because complex
1-(4-(naphthalen-1-yloxy)but-2-yn-1-yl)-4-phenylpiperidine (LAS- 251) with cyclodextrin showed high local anesthetic activity. The new piperidine derivative is future-oriented for prospective studies of other types of anesthesia as a potential medicinal substance for therapeutic use in the future.

Key Words: Piperidine derivatives, local anesthetic activity, acute toxicity, infiltration anesthesia

Metabolomic Studies in Girls With Central and Peripheral Precocious Puberty

Aylin BALCI OZYURT*, Tuba REÇBER**, Emirhan NEMUTLU***, Ayse Derya BULUS****, Sedef KIR*****, Belma KOCER-GUMUSEL******°, Pinar ERKEKOGLU*******°

* ORCID:0000-0002-0060-271X: Hacettepe University, Faculty of Pharmacy, Department of Toxicology, Ankara, Turkey; Bahçeşehir University, School of Pharmacy, Department of Toxicology, İstanbul, Turkey
** ORCID: 0000-0001-8257-7628: Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
*** ORCID: 0000-0002-7337-6215: Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
**** ORCID: 0000-0003-2865-4420: The Ministry of Health, Keçiören Training and Research Hospital, Pediatric Endocrinology Clinics, Ankara, Turkey
***** ORCID: 0000-0003-1322-1665: Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
****** ORCID: 0000-0003-4311-2291: Lokman Hekim University, Faculty of Pharmacy, Department of Toxicology, Ankara, Turkey
******* ORCID: 0000-0003-4713-7672: Hacettepe University, Faculty of Pharmacy, Department of Toxicology, Ankara, Turkey

° Corresponding Author;Pınar ERKEKOĞLU
Phone: 0312 305 2178, e-mail: erkekp@yahoo.com, erkekp@hacettepe.edu.tr

° Corresponding Author; Belma KOCER-GUMUSEL
Phone: 0312 502 8558, e-mail: belmagumusel@yahoo.com, belma.gumusel@lokmanhekim.edu.tr

SUMMARY

Precocious puberty (PP) is the beginning of secondary sexual characteristics before eight years of age in girls. “Central precocious puberty (CPP)” occurs due to early activation of the hypothalamuspituitary- gonad axis. “Peripheral precocious puberty (PPP)” is a rarer, and different condition that sidelines the hypothalamuspituitary- gonad (HPG) axis, and it depends on the peripheral causes. Metabolomics is the identification, and quantitation small molecule metabolites (<1000 Da) in a certain period. This study aimed to determine the plasma, and urinary metabolic profiles of girls, who were diagnosed with CPP (n=50) or PPP (n=47), and compare their results to control group (n=50). Metabolomics analysis was performed by using gas chromatography-mass spectrometry. After the complex chromatograms were deconvoluted, and aligned, the metabolites were identified using retention index libraries. The results were evaluated statistically using univariate, and multivariate analysis. Binary compressions were performed between groups, and metabolites from amino acids were found to be significantly different between the groups. These alterations in metabolites are suggested for potential biomarkers of PP; however, more comprehensive studies are needed to verify these data, and for validation. In the future, the metabolic alterations underlying different diseases, particularly those of endocrine origin, should be evaluated with mechanistic toxicological studies. This will help the researchers to develop new therapy options, particularly for PP.

Key Words: Central precocious puberty, gas chromatography-mass spectrometry, metabolomics, peripheral precocious puberty.

In Silico and In Vitro Anticancer Effects of Caffeic Acid Phenethyl Ester on Pancreatic Adenocarcinoma Cells

Zübeyde TANRIVERDİ*, Burak KUZU**, Ergül EYOL***, Fuat KARAKUŞ****°

* ORCID:0000-0002-1170-181X: Independent Researcher, Gaziantep/Türkiye.
** ORCID: 0000-0002-7305-7177: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Van Yuzuncu Yil University, 65080 Tuşba-Van/Türkiye.
*** ORCID: 0009-0000-3699-6725: Independent Researcher, Mannheim /Germany.
**** ORCID: 0000-0002-5260-3650: Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Van Yuzuncu Yil University, 65080 Tuşba-Van/Türkiye.

° Corresponding Author; Fuat Karakuş
Tel.: +90 432 444 5065 Extension: 2118, E-mail:fuatkarakus@yyu.edu.tr

SUMMARY

Pancreatic adenocarcinoma is an aggressive and fatal malignancy due to the lack of early diagnosis and poor therapeutic response. At this point, determining the anticancer potential of non-toxic natural compounds is essential. Caffeic acid phenethyl ester is a bioactive compound with different activities. In this study, the toxicity of caffeic acid phenethyl ester was estimated by in silico methods in 14 pancreatic cancer cells, and its anticancer activity was evaluated in rat adenocarcinoma cells. According to the in silico results, caffeic acid phenethyl ester had anticancer properties without causing severe toxicity. Subsequently, we investigated the effects of caffeic acid phenethyl ester on rat pancreatic cancer (ASML) cells. Caffeic acid phenethyl ester reduced ASML cell viability by up to 27% in a dose- (5, 10, 20, 40, and 80 μM) and time-dependent (24, 48, and 72h) manner. In the scratch assay, only 80 µM caffeic acid phenethyl ester statistically considerably inhibited ASML cell migration at 24 h. On the other hand, at 48 hours, all doses of caffeic acid phenethyl ester statistically remarkably decreased cell migration. Caffeic acid phenethyl ester also decreased ASML colony numbers at 5 µM and 10 µM compared to the control and completely suppressed colony formation at ≥ 20 µM. Our results revealed that caffeic acid phenethyl ester showed anticancer potential against human and mouse pancreatic cancer cells in silico and significantly inhibited the viability, migration, and colony formation of ASML cells in vitro.

Key Words: pancreatic cancer, caffeic acid phenethyl ester, ASML cells, anticancer activity, cytotoxicity.

Association of Inflammatory Parameters with Survival in Gastric Cancer Patients Underwent Subtotal and Total Gastrectomy

Bercis Imge UCAR*°, Muhammed Alperen TAŞ**, Hüseyin Emre ARSLAN***, Mehmet Fatih EKICI****, Sezgin ZEREN*****

* ORCID: 0000-0003-0229-5589, Department of General Surgery, Faculty of Medicine, Kutahya Health Sciences University, 43000 Kutahya
** ORCID: 0000-0002-4060-121X, Department of General Surgery, Faculty of Medicine, Kutahya Health Sciences University, 43000 Kutahya
*** ORCID: 0000-0002-3937-825X, Department of General Surgery, Faculty of Medicine, Kutahya Health Sciences University, 43000 Kutahya
**** ORCID: 0000-0002-3937-825X, Department of General Surgery, Faculty of Medicine, Kutahya Health Sciences University, 43000 Kutahya
***** ORCID: 0000-0002-9342-1706, Department of General Surgery, Faculty of Medicine, Kutahya Health Sciences University, 43000 Kutahya

° Corresponding Author; Bercis Imge UCAR
Phone: +902742316660, e-mail: bercis.imge@gmail.com

SUMMARY

This study aimed to assess the differences in inflammatory markers and modified Glasgow prognostic score (mGPS) among patients diagnosed with gastric cancer who underwent subtotal or total gastrectomy and to evaluate the diagnostic performance of these markers in predicting prognosis. The study included 103 patients diagnosed with gastric cancer who had undergone subtotal (n:48) or total gastrectomy (n:55). The inflammatory indices were respectively calculated as follows: neutrophil to lymphocyte ratio (NLR) = neutrophil count/lymphocyte count, platelet to lymphocyte ratio (PLR) = platelet count/lymphocyte count, systemic immune-inflammatory index (SII) = platelet count × neutrophil count/ lymphocyte count, C-reactive protein (CRP) to albumin ratio (CAR) = CRP / albumin levels. The mGPS was determined using established criteria based on CRP and albumin levels. The endpoint was the 3-year survival outcomes for all patients. The mean age of the patients included in the study was 65.9±9.7 years, and the vast majority were male (68.9%). The results of the inflammatory indices were not statistically significant between the subtotal and total gastrectomy groups. Multiple Cox regression analysis showed that elevated SII (HR = 1.12, p < 0.001) were independent predictors of the 3-year mortality. In predicting the 3-year mortality, SII demonstrated superior diagnostic performance compared to other inflammatory indices (Area under the curve: 0.843, Sensitivity: 90.5%, and Specificity = 67.1%). SII could be an essential screening tool for predicting long-term prognosis, regardless of the surgical procedure in patients with gastric cancer who have undergone subtotal and total gastrectomy.

Key Words: Gastric cancer, gastrectomy, inflammation, prognosis.

Drug Administration via Feeding Tube in Intensive Care Unit: A Cross-Sectional Study

Nursel SÜRMELİOĞLU*°, Yaren İLERİ**, Murat GÜNDÜZ***, Dilek ÖZCENGİZ****

* ORCID:0000-0001-7758-7100, Department of Clinical Pharmacy, Faculty of Pharmacy, Çukurova University, Adana, Türkiye, e-mail: nurselisci@gmail.com
** ORCID:0009-0008-1014-3474, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, İstanbul, Türkiye, e-mail: yarenileri01@gmail.com
*** ORCID:0000-0003-0006-8796, Department of Anesthesia and Reanimation, Faculty of Medicine, Çukurova University, Adana, Türkiye, e-mail: hmuratgunduz@gmail.com
**** ORCID:0000-0002-2598-0127, Department of Anesthesia and Reanimation, Faculty of Medicine, Çukurova University, Adana, Türkiye, e-mail: dilekozcengiz@gmail.com

° Corresponding Author; Nursel SÜRMELİOĞLU
Phone: +905330546901, e-mail: nurselisci@gmail.com

SUMMARY

The aim of this study was to evaluate the appropriateness of the administration of drugs in critically ill patients receiving enteral feeding support. This prospective, observational, and descriptive study was conducted in the reanimation unit of a university hospital. A clinical pharmacist on the intensive care team evaluated the drug administration of enterally fed patients at daily visits. The necessary interventions for incorrect drug administration via the feeding tube
detected in the patient’s treatment were reported to the responsible physician. Thirty patients who met the relevant criteria between December, 6 and April,1 2022 were included in the study. Fifteen (50%) of the patients were female, and the mean age of all patients was calculated as 49.16±20.23. It was determined that 76% of the patients received nutritional support via feding tube. The appropriateness of 74 drugs, 36 of which were different, administered
via the feeding tube of these patients was evaluated. Thirty-three of the 36 medications were in solid dosage form Most of the drugs administrated by tube (94.6%) were in dose form appropriate for tube administration, whereas 17.56% of the administration method was incorrect. Unlike the recommendations, solid dosage forms are primarily applied in drug administrations made via feeding tubes. It is thought that the creation of algorithms that can be used in clinical
practice for the correct method of administering the limited number of drugs available for application will contribute to the effectiveness and safety of the treatment.

Key Words: Enteral nutrition, feeding tube, drug administration, drug-related problems.

NLRP3 Expression in Peripheral Blood Mononuclear Cells of Patients with Rheumatoid Arthritis

Sezen Yılmaz SARIALTIN*°, Orhan KÜÇÜKŞAHIN**, Cemil NURAL***, Leyla Didem KOZACI****, Pınar KAYGIN*****, Gülçin GÜLER ŞİMŞEK******, Serpil OĞUZTÜZÜN*******, Tülay ÇOBAN ********

* ORCID: 0000-0002-8387-4146: Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkiye
** ORCID: 0000-0003-4530-2304: Division of Rheumatology, Department of Internal Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkiye
*** ORCID: 0000-0002-7867-7615: Department of Biochemistry, Hatay Training and Research Hospital, Hatay, Turkiye
**** ORCID: 0000-0001-5422-1640: Department of Medical Biochemistry, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkiye
***** ORCID: 0000-0003-0127-1753: Department of Biology, Faculty of Art and Sciences, Kırıkkale University, Kırıkkale, Turkiye
****** ORCID: 0000-0001-7710-4631: Department of Pathology, Gülhane Training and Research Hospital, University of Health Sciences, Ankara, Turkiye
******* ORCID: 0000-0002-5892-3735: Department of Biology, Faculty of Art and Sciences, Kırıkkale University, Kırıkkale, Turkiye
******** ORCID: 0000-0002-9696-6613: Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkiye

° Corresponding Author;Sezen YILMAZ SARIALTIN
Phone: +903122033121, e-mail: sezen.yilmaz@ankara.edu.tr

SUMMARY

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by painful, swollen, and inflamed joints. Individual, genetic, and environmental factors influence the development of the disease, which causes involvement not only in the joints but also in other extra-articular tissues. However, the etiopathogenesis of the disease has not yet been fully elucidated. NLRP3, a crucial component of the innate immune system, may contribute to recurrent and
chronic inflammation, resulting in inflammation-related diseases. Therefore, we aimed to examine the expression pattern of NLRP3 in peripheral blood mononuclear cells isolated from patients with RA using immunocytochemical approaches in this study. Our findings demonstrated that NLRP3 expression was significantly increased in patients with RA compared to the healthy controls (p<0.01). The highest expression among the patient groups was observed in the active period cases, and this expression considerably increased compared to the control group (p<0.01). Patients in the remission period possessed the lowest expression among the patient groups. Since female gender is considered an independent risk factor for the disease, the effect of gender on expressions was also investigated. NLRP3 was expressed at higher levels in female patients than in males; however, this difference was not significant (p>0.05). The expression patterns of the patient and control groups suggest that NLRP3 may be involved in the development and progression of the disease. To our knowledge, our study is the first research investigating NLRP3 expression profile in peripheral
blood mononuclear cells obtained from patients with RA using immunocytochemical approaches. The results of our study highlight significant aspects. However, further research using more sensitive methods with a larger number of cases is required to assess the function of NLRP3 in RA and to provide a deeper insight into the mechanism.

Key Words: Inflammasome, inflammation, NLRP3, rheumatoid arthritis.

Gene Delivery to Triple-Negative Breast Cancer Cells by Folic Acid-Polyethyleneimine Polyplexes

Devrim DEMIR-DORA *,**,***º

* ORCID: 0000-0002-6610-2507, Department of Medical Pharmacology, Faculty of Medicine, Akdeniz University, Antalya, Turkey,
** ORCID: 0000-0002-6610-2507, Department of Gene and Cell Therapy, Health Sciences Institute, Akdeniz University, Antalya, Turkey
*** ORCID: 0000-0002-6610-2507, Department of Medical Biotechnology, Health Sciences Institute, Akdeniz University, Antalya, Turkey

° Corresponding Author; Devrim DEMİR-DORA
Phone: +90-532-4133477, e-mail: dedemir@yahoo.com

SUMMARY

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. It lacks hormonal and growth factor receptors commonly expressed by other types of breast cancer, making it difficult to treat by conventional treatments. Although gene therapy might be a therapeutic option, delivery of genes into TNBC cells is still an obstacle. In this study, it was aimed to overcome this obstacle by folic acid (FA) conjugated polyplex formulations to target the folate receptor, which has been reported to be overexpressed in TNBC cells. Non-covalent complexes of FA and linear polyethyleneimine (LPEI) polyplexes (FA-LPEI polyplexes) were prepared at six different ratios. After characterization studies, cytotoxicity and transfection ability were evaluated. Conjugation of FA by increasing amounts of LPEI polyplexes increased the size from 204.1 to 469.8 nm. Their PDI values were between 0.31-0.51, and zeta potentials were positive. After treatment with polyplex formulations, cell viability decreased significantly, starting from 3:1(w/w) LPEI:pDNA ratio and from 3:3:1 (w/w/w) FA:LPEI:pDNA ratio. Cell viability decreased below 70%, only above the 5:1 (w/w) LPEI:pDNA ratio. Adding of FA to polyplex formulations reversed the cytotoxicity of P3, P4, and P5 formulations. Although LV-RFP pDNA was delivered successfully into 4T1 cells by all formulations, fluorescent microscope images
showed that the optimal formulations were FA-P3 and FA-P4. This gene delivery system, generated by the non-covalent conjugation of FA to polyplexes, increased the uptake and decreased the cytotoxicity of LPEI polyplexes. Non-covalent complexes of FA-PEI polyplexes represent promising delivery systems in gene therapy, directed against cancer cells expressing folate receptors.

Key Words: Triple-negative breast cancer, gene therapy, delivery system, folic acid, polyethyleneimine, polyplex

Synthesis of Some Novel Schiff Base Derivative 5-Substituted-4-Amino-1,2,4-Triazole-3-one Compounds with Potential Lipase Inhibition Activity

Yaren KAHVECİ*, İnci Selin DOĞAN**°, Şeyda KANBOLAT***, Bahittin KAHVECİ****

* ORCID: 0000-0002-4709-2278, Hacettepe University, Faculty of Pharmacy, Ankara, Turkey
** ORCID:: 0000-0003-4949-1747, Karadeniz Technical University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Trabzon, Turkey
*** ORCID:: 0000-0001-7261-7067, Karadeniz Technical University, Faculty of Pharmacy, Department of Biochemistry, Trabzon, Turkey
**** ORCID:: 0000-0001-7394-0552, Karadeniz Technical University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Trabzon, Turkey

° Corresponding Author;Assoc. Prof.Dr. İnci Selin DOĞAN
Phone: 0532 609 28 85, E-mail: isdogan@ktu.edu.tr, selinci@gmail.com

SUMMARY

In this study, 5 new Schiff base compounds containing triazole-imidazole rings were synthesized. Compounds containing this binary system have been realized for heterocyclic imine derivative compounds. According to literature information, these obtained compounds are expected to have potential biological activities such as anticonvulsant and antimicrobial activities. In the first step of the synthesis, iminoster derivative compounds (1a-e) were obtained from aryl/alkyl nitrile compounds by the Pinner method. In the second step, ester ethoxycarbonyl derivative compounds (2a-e) were obtained by the reaction of aryl/alkyl iminoester (1a-e) compounds with ethoxycarbonyl hydrazine compound. The resulting ester ethoxycarbonyl hydrazones were reacted with hydrazine hydrate, and the corresponding triazole-amine (3a-e) compounds were obtained using the method given in the literature. In the original step of the study, the 5-substituted-4-amino-1,2,4-triazol-3-one compounds (3a-e) were reacted with 4-imidazole carboxyaldehyde and five new Schiff bases 4-{[((1H-imidazol-4-yl)methylene]amino}-5-substituted-2,4-dihydro-3H-1,2,4-triazole-3-one compounds (4a-e) were obtained. A series of 5 new 5-substituted-4-{[(1H-imidazol-4-yl)methylene]amino}- 2,4-dihydro-3H-1,2,4-triazole-3-one (4a-e) were synthesized, and their physical properties and IR, 1H-NMR, and 13C-NMR spectral analyses were performed to elucidate the structures of the compounds. The pancreatic lipase enzyme inhibition activities of the obtained new Schiff base compounds were investigated. They showed average activity against the positive control “Orlistat”.

Key Words: Iminoester, Schiff base, triazole-imidazole, ester ethoxycarbonyl hydrazones, pancreatic lipase enzyme inhibition

Phase Transformation of Anhydrous to Dihydrate Carbamazepine: Preparation and Comparative Characterization

Kamlesh WADHER*°, Vaishnavi RAUT**, Keshav HIRAVE***, Sagar TRIVEDI****, Milind UMEKAR*****

* ORCID:0000-0002-3782-3380, Department of Pharmaceutics, Smt. KishoritaiBhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India 441002.
** ORCID: 0009-0002-2936-1849,Department of Pharmaceutics, Smt. KishoritaiBhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India 441002.
*** ORCID: 0000-0001-5673-3105 ,Department of Pharmaceutics, Smt. KishoritaiBhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India 441002.
**** ORCID: 0000-0001-6764-0019,Department of Pharmaceutics, Department of Pharmaceutical Sciences, RashtrasantTukadoji Maharaj Nagpur University Campus, Nagpur, India
***** ORCID: 0000-0002 2170-0896,Department of Pharmaceutics, Smt. KishoritaiBhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India 441002.

° Corresponding Author; Prof. Kamlesh Wadher
Mob. No. +91 9960099619, Email ID: kamleshwadher@gmail.com

SUMMARY

Carbamazepine, an anticonvulsant drug is one of the suitable active compounds for the study of crystal and polymorphism. Hydrate formation or dehydration of a given hydrate may affect the overall performance of the ultimate formulations and it has been estimated that more than 30 % available active drug compound can form a hydrate. The anhydrous form of the compound always shows higher aqueous solubility and dissolution parameters as compared to hydrates. This ultimately led to improved bioavailability when the rate limiting step for the absorption is dissolution rate. The purpose of the present investigation was to compare various techniques for the formation of Carbamazepine dihydrate from anhydrates and also to discriminate crystal forms of Carbamazepine by Melting point, FTIR, DSC, Powder X-ray diffractometry analysis, NMR, scanning electron microscopy, solubility and intrinsic dissolution testing. Carbamazepine phase transformation of solid state occurs when exposed to the environmental condition, which can affect the performance of the drug and the formulations.

Key Words: Carbamazepine, dihydrate, solubility, intrinsic dissolution rate, polymorphism,

Interpretable QSAR Modelling for QSAR-Based Virtual Screening of 3H-Thiazolo[4,5-b] pyridin-2-one Derivatives as Potential Antioxidant Drug Candidates

Olena KLENINA*°

* Orcid ID: 0000-0002-8946-3698, Department of General, Bioinorganic, Physical and Colloidal Chemistry, Faculty of Pharmacy, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine; Departament of Chemistry and Biochemistry, Faculty of Pharmacy, University San Pablo-CEU, Urbanización Montepríncipe, 28668 Boadilla del Monte, España

° Corresponding Author; Olena Klenina
Phone: +380 980 519 298, E-mail: olena_klenina@yahoo.com

SUMMARY
A quantitative structure-activity relationship (QSAR) study has been carried out for 32 N3 substituted 3H-thiazolo[4,5-b] pyridin-2-one derivatives as potential antioxidant drug candidates. The genetic algorithm (GA) and multiple linear regression analysis (MLRA) were used as appropriate techniques for descriptor selection and correlation model generation. The four best regressions for predicting the ability to scavenge the DPPH radical were generated as threeparameter QSAR models with the highest statistical characteristics and predictive power. It was shown that a set of 2D, 3D, and Molecular properties descriptors play a crucial role in antioxidant activity enhancement. Small hydrophilic molecules with the minimal distance of specific atoms and fragments from the center of mass, neglectable electronic density redistribution between the distant atoms, and molecules keeping strong symmetry of electronegative
atoms along the 1st principal component axe exhibit higher activity. Validation parameters of the generated models allow us to state that they satisfy the statistical requirements for their goodness-of-fitting with no current overfitting. The predictive ability of the constructed models was assessed with both internal and external validation approaches and estimated with the leave-one-out and leave-groupout cross-validation coefficients (Q2LOO and Q2 LGO). The values of Q2 LOO (0.7060  0.7480) and Q2 LGO (0.6647  0.7711) are reasonable, showing that the models are significant and robust to predict the free radical scavenging activity of the compounds from both training and validation sets. Applicability domain-defining technique was employed in the obtained models, and indicated that most structures were adequately represented by the chemical space of the models.

Key Words: 3H-thiazolo[4,5-b]pyridin-2-one, QSAR, multiple linear regression (MLR), antioxidant activity, applicability domain

Synthesis and Biological Evaluation of Novel Paracetamol-Triazole Conjugates

Necla KULABAŞ*, Merve GÜRBOĞA**, Özlem BİNGÖL ÖZAKPINAR***, Jianyang LIU****, Per-Johan JAKOBSSON*****, Özkan DANIŞ******, Ayşe OGAN*******, İlkay KÜÇÜKGÜZEL********°

* ORCID: 0000-0003-2273-5094, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Başıbüyük, İstanbul, Türkiye
** ORCID: 0000-0003-4614-7094, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Başıbüyük, İstanbul, Türkiye
*** ORCID: 0000-0003-0287-563, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Başıbüyük, İstanbul, Türkiye
**** ORCID: 0000-0002-8683-1109, Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden
***** ORCID: 0000-0001-7665-9715, Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden
****** ORCID: 0000-0003-1781-0520, Department of Chemistry, Faculty of Science, Marmara University, İstanbul, Türkiye
******* ORCID: 0000-0002-8973-9762, Department of Chemistry, Faculty of Science, Marmara University, İstanbul, Türkiye
******* ORCID: 0000-0002-7188-1859 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Fenerbahçe University, Ataşehir, İstanbul, Türkiye

° Corresponding Author; İlkay KÜÇÜKGÜZEL
Tel: +90 216 910 1907 , E-mail: kucukguzel@hotmail.com, ilkay.kucukguzel@fbu.edu.tr

SUMMARY

Some new triazole containing acetamide derivatives 9-20 using paracetamol as starting material were synthesized, and their structures were verified by FTIR, NMR (1H and 13C) and mass spectral data. Compounds 9-20 were tested against five human cancer cell lines (lung cancer A549, chronic myelogenous leukemia K562, breast cancer MCF-7, prostate cancer PC-3, neuroblastoma SH-SY5Y cell lines) for in vitro cytotoxic activities. They were also evaluated their cytotoxic effect on mouse embryonic fibroblast cells (NIH/3T3) to define selectivity by MTT assay. Additionally, we evaluated the potential mPGES-1 and COX-1/2 inhibitory effect of twelve target compounds 9-20. While none of the synthesized compounds exhibited significant inhibition against both cancer cells and mPGES-1 as well as COX-1/2, it was determined that they were not cytotoxic against healthy cells, too. Finally, ADMET properties of newly synthesized compounds were estimated using in silico methods.

Key Words: Paracetamol, 1,2,4-triazole, cancer, mPGES-1, COX-1/2.

Development and Characterization of Nanofiber Strip Containing Sertraline for Buccal Application

Kutsal ÖZCAN*, Eylül Su SARAL ACARCA**, Sibel ILBASMIS-TAMER***°

* ORCID: 0000-0001-5047-7251: Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, Türkiye, Faculty of Pharmacy, Department of Pharmaceutical Technology, Karadeniz Technical University, Trabzon, Turkey
** ORCID: 0000-0002-6497-1645: Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
*** ORCID: 0000-0003-0361-7105: Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, Türkiye

° Corresponding Author; Sibel İLBASMIŞ TAMER
Phone: 0 312 202 3056, E-mail: ilbasmis@gazi.edu.tr, ilbasm@yahoo.com

SUMMARY

Sertraline is one of the selective serotonin reuptake inhibitors indicated in major depressive disorder. Schizophrenia is a mental disorder with frequent depressive symptoms. Sertraline is thought to be useful for the treatment of depressive symptoms in schizophrenia. The objective of this study is to formulate sertraline-containing nanofiber strips produced by the electrospinning process, that can be easily dispersed by the buccal route, suitable for the use of schizophrenia patients. Here, various ratios (5%,7.5%, and 10%) of polyvinyl pyrrolidone (PVP) polymer solutions were prepared, and electrical conductivity, viscosity, and surface tension characterization studies were performed on polymer solutions. After characterization studies, a polymer solution containing 5% PVP was selected to prepare nanofibers. Nanofibers were obtained using the electrospinning method, each strip containing 5 mg sertraline. It was observed that the chosen
optimum formulation nanofiber had an average particle diameter of 371-439 nm in the SEM image. Tensile strength and elongation at break percentage values of 5% PVP-sertraline nanofibers values were 0.449±0.284 (Mpa) and 22.6±3.66 (%), respectively. The loading capacity and encapsulation efficiency of the formulation are 4.53±0.31% and 79.61±10.56%, respectively. In vitro drug dissolution studies showed that sertraline-containing buccal nanofibers conformed to the Hixson-Crowell kinetic model.

Key Words: Nanofiber, electrospinning, sertraline, polyvinyl pyrrolidone (PVP), buccal strip

Evaluation of The Effect of Topotecan, Carvacrol, Epigallocatechin Gallate and Their Combination on Apoptotic Process in Neuroblastoma and Astrocyte Cells

Çağatay OLTULU*°, Melek AKINCI**, Elvan BAKAR***

* ORCID: 0000-0002-6051-3479, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Trakya University, Edirne, Turkey.
** ORCID: 0000-0003-3879-4232, Department of Pharmacology, Faculty of Pharmacy, Trakya University, Edirne, Turkey.
*** ORCID: 0000-0001-5703-3469, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Trakya University, Edirne, Turkey.

° Corresponding Author: Çağatay OLTULU
Phone: +90 (284) 235 01 80, E-mail: cagatayo@trakya.edu.tr

SUMMARY

Neuroblastoma is a sympathetic nervous system cancer. Neuroblastoma most commonly affects children under five years of age and is the most common solid tumor in childhood. Topotecan is a topoisomerase 1 inhibitor. Carvacrol and epigallocatechin gallate are naturally derived substances with anticancer, antioxidant, and apoptotic properties. Our study aimed to evaluate the effects of topotecan, carvacrol, epigallocatechin gallate, topotecan+carvacrol, and topotecan+ epigallocatechin gallate combinations on the apoptotic signaling pathway. IC50 values were determined in neuroblastoma and healthy astrocyte cells using the MTT assay. Apoptotic mRNA expressions (topoisomerase 1 and 2, p53, BCL2, BAX, caspase 9, caspase 3, IL1, TNFα) in astrocytes and neuroblastoma cells at the neuroblastoma IC50 dose were analyzed using quantitative realtime PCR. Topotecan and carvacrol did not exhibit selective cytotoxic effects between healthy astrocytes and neuroblastoma cells. However, we found that the combination of topotecan+ epigallocatechin gallate and topotecan+carvacrol with epigallocatechin gallate showed selective cytotoxic effects on the neuroblastoma cell line compared to astrocyte cells. The obtained mRNA results can be interpreted as the initiation of apoptosis in neuroblastoma cells in the topotecan, carvacrol, epigallocatechin gallate, and topotecan+epigallocatechin gallate groups.
Further studies are needed to investigate this matter in more detail.

Key Words: Topotecan, carvacrol, epigallocatechin gallate, apoptosis, cytotoxicity

Design and Assessment of a Microemulsion-Based Transdermal Drug Delivery System for Meloxicam; Examination of Formulation Ingredients

Anayatollah SALIMI*, Ramin NOORAFROOZ**, Maryam FOULADI***, Saeed Mohammad SOLEYMANI****º

* ORCID: 0000-0003-1505-7969, Department of Pharmaceutics, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran., Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz,
** ORCID: 0000-0000-0000-0000, Department of Pharmaceutics, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
*** ORCID: 0000-0000-0000-0000, Department of Pharmaceutics, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
**** ORCID: 0000-0003-1462-3930, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

° Corresponding Author; Saeed Mohammad SOLEYMANI
Telephone number: +98-21-66355959,Email Address: mamsoloni@gmail.com

SUMMARY

The goal of creating meloxicam-loaded microemulsion formulations was to increase meloxicam permeability through the skin. Using pseudo-ternary phase diagram construction and full factorial design, eight formulations with three independent variables (water percent, oil percent, and surfactant/co-surfactant percent) were selected to be prepared. This research evaluated the formulation’s characteristics, including droplet size, viscosity, and release profile. FT-IR and DSC techniques were also utilized to investigate the effect of microemulsion components on rat abdomen skin, and the permeability of meloxicam-loaded microemulsions via rat abdomen skin was also evaluated by calculating permeability parameters such as Jss, Dapp, Tlag, ERflux, ERD, and ERP. When compared to a saturated aqueous solution of meloxicam as a reference, the findings showed that all microemulsion (ME) formulations considerably increased meloxicam permeability through rat skin. Water percent had a direct and significant relationship with Jss, and oil percent had a direct and significant relationship with Dapp, according to analysis regression. ME components also caused alterations in the skin’s lipoprotein bilayers, which might enhance formulation permeability through the skin.

Key Words: Meloxicam, Microemulsion, Formulation, NSAID, Permeability

The Role of Radiopharmaceuticals in the Bone Metastases Therapy

Hümeyra BATTAL*, Suna ERDOĞAN**°

* ORCID: 0000-0003-1588-7735, Hacettepe University Faculty of Pharmacy, Department of Radiopharmacy, 06100, Ankara
** ORCID: 0000-0003-4634-0097, Hacettepe University Faculty of Pharmacy, Department of Radiopharmacy, 06100, Ankara

° Corresponding Author; Suna Erdoğan
Tel: 0312 305 2152/2196, Fax: 0312 311 47 77, e-posta: serdogan@hacettepe.edu.tr

SUMMARY

Cancer, having high morbidity and mortality rates, has become a significant public health problem in recent years, and it is the second leading cause of death after heart disease in the world. Metastases are one of the most serious complications of cancer and bone metastases are detected in 2/3 of metastatic cancer cases. Therapy approaches in bone metastases can be classified as surgery, bisphosphonates, radiotherapy, and radionuclide therapy. Radionuclide therapy using alpha and beta-emitting radionuclides is more selective and effective than other local and systemic treatment methods, and this feature provides superiority over other therapeutic methods. Radionuclide therapy is used in bone metastasis to reduce pain, to kill tumor cells, to prolong life span, and to improve quality of life. In recent years, alpha-emitting radiopharmaceuticals [such as Radium-223 (Ra-223) chloride] and beta-emitting radiopharmaceuticals [such as Strontium-89 (Sr-89) chloride, Lutetium-177 (Lu-177) labeled Ethylenediamine Tetra Methylene Phosphonic Acid (EDTMP), Samarium-153 (Sm-153) labeled EDTMP] are introduced in the clinic for especially the treatment of painful bone metastases and on the other hand new radiopharmaceutical development studies also continue intensively, like Actinium-225 labeled prostate-specific membrane antigen-617 (Ac-225-PSMA). Number of studies are proven that using radionuclide therapy in bone metastases improves the patient’s general health, reduces pain and the risk of pathological fractures, and increases survival. This review presents an overview of radionuclide therapy used in bone metastases. In this context, following the general information about radiopharmaceuticals, the importance of radiopharmaceuticals used in bone metastases therapy is explained with experimental and clinical studies examples.

Key Words: Cancer, Bone Metastases, Radionuclide Therapy, Radiopharmaceutical

Thirdhand Smoke Exposure and Its Toxicological Impacts: A Review on Target Organ-Based Studies

Kübra KOLCİ*, Sena Nur GARİPKUŞ**, Rengin REİS***º

* ORCID: 0000-0003-4228-6564, Acıbadem Mehmet Ali Aydınlar University, Faculty of Pharmacy, Department of Toxicology, Atasehir/ Istanbul, Turkey
** ORCID: 0000-0002-8110-0112, Acıbadem Mehmet Ali Aydınlar University, Faculty of Pharmacy, Department of Toxicology, Atasehir/ Istanbul, Turkey
*** ORCID: 0000-0002-3484-2201, Acıbadem Mehmet Ali Aydınlar University, Faculty of Pharmacy, Department of Toxicology, Atasehir/ Istanbul, Turkey

° Corresponding Author; Rengin Reis
e-mail: rengin.reis@acibadem.edu.tr
Phone number: +90 216 500 42 59

SUMMARY

Thirdhand smoke (THS) is a newly described environmental health hazard that might be defined as residual cigarette smoke that occurs due to the accumulation of toxins of second-hand smoke (SHS) in the smoking environment. In addition, the chemicodynamic of THS may alter due to the interaction with other gases and chemicals in the environment. THS may cause serious health outcomes in the lungs, liver, skin, heart, and nervous system as well. Hence, it is thought to represent a major health hazard for people, particularly children, who are exposed to THS, where they interact more frequently with these surfaces exposed to THS via hand-to-mouth transfer. In the present study, it was aimed to summarize the proposed toxicity mechanisms based on in vitro and in vivo studies based on target organ toxicity. In this study, it is aimed to review the toxicity mechanisms of THS based on in vitro and in vivo studies on target organ toxicity. Recent studies reported that THS might induce unwanted effects in the respiratory, cardiovascular, nervous, hematopoietic, and skeletal systems and skin. Literature data indicated that THS-mediated oxidative damage and an increase in inflammatory response may play an important role in the pathogenesis of cardiovascular and neurobehavioral diseases, especially the target organ lung. In the future, THS might be defined as a preventable environmental risk factor. Therefore, further studies on THS are needed to define its toxicity mechanism as well as increase social awareness and legal regulations.

Key Words: Thirdhand smoke, cigarette, oxidative stress, lung, nicotine

Validation Of Rp-Hplc Uv Method for Determination Ketoconazole in Rabbit Plasma: an Application to The Pharmacokinetic Study

Viviane ANNISA*, Teuku Nanda SAIFULLAH SULAIMAN**, Akhmad KHARIS NUGROHO***, Agung ENDRO NUGROHO****°

* ORCID: 0000-0003-4035-7306, Program Doctoral Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
** ORCID: 0000-0001-6733-0221, Departement of Pharmaceutics, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
*** ORCID: 0000-0003-4277-5413, Departement of Pharmaceutics, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
**** ORCID: 0000-0002-1785-4008, Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia

° Corresponding Author; Agung Endro Nugroho
Address: Yogyakarta, Indonesia, Phone: +62 85643929723, E-mail: nugroho_ae@ugm.ac.id

SUMMARY

The validated method for determining ketoconazole in plasma rabbit is not yet reported. The HPLC-UV method is simple, rapid, cost-effective, sensitive, and only requires a small blood sampling. The chromatographic system used a mobile phase consist of NaH2PO4:Acetonitrile (30:70) and stationary phase as a reversedphase C18 column (250 x 4.6 mm, 5 μm) at a flow rate of 1 ml/min and detection wavelength of 240 nm, and the retention time of about 5 minutes for ketoconazole and 11 min for itraconazole
as internal standard. The peak of ketoconazole can separate from other peaks and has no interference from the diluent, indicating this method was selective to detect ketoconazole. The calibration curve presented linearity in the 0.05-8 μg/ml with R2=0.9969, which
showed good linearity. Precision and accuracy of the method were obtained. The result is 9.47 %diff and 10.13-12.08 RSD% for LLOQ and 0.59-3.94 %diff and 1.82-13.56 %RSD <20% for low, medium, and high levels. The LLOQ in this method is 0.05 μg/mL. Plasma stability under storage in a freezer (-200C) for three days was studied. The validated analytical method was successfully applied to determine the pharmacokinetics parameter of KTZ after a single oral administration.

Key Words: Chromatography, imidazole, plasma, pharmacokinetic, validation method

Toxicological Evaluations of Smilax myosotiflora Methanol Extract and its Effect on Testosterone Level of Male Rats in Subacute Study

Rasmaizatul Akma ROSDI*, Mohd Dasuki SUL’AIN**°, Deny Susanti DARNIS***, Bibi Nur Bazlini BAHARUN****, Nur FATIHAH AHMAD***** & Wan Rosli Wan ISHAK******

* ORCID: 0000-0002-0630-9303, Biomedicine Program, School of Health Sciences, Universiti Sains Malaysia (Health Campus), 16100 Kubang Kerian, Kelantan, Malaysia
** ORCID: 0000-0002-0063-7648, Biomedicine Program, School of Health Sciences, Universiti Sains Malaysia (Health Campus), 16100 Kubang Kerian, Kelantan, Malaysia
*** ORCID: 0000-0002-5345-1150, Department of Chemistry, Kulliyyah of Science, International Islamic University of Malaysia, 25200 Kuantan, Pahang, Malaysia
**** ORCID: 0000-0002-0947-9746,Biomedicine Program, School of Health Sciences, Universiti Sains Malaysia (Health Campus), 16100 Kubang Kerian, Kelantan, Malaysia
***** ORCID: 0000-0002-1164-9492,Biomedicine Program, School of Health Sciences, Universiti Sains Malaysia (Health Campus), 16100 Kubang Kerian, Kelantan, Malaysia
****** ORCID: 0000-0001-7650-0499, Nutrition and Dietetics Program, School of Health Sciences, Universiti Sains Malaysia (Health Campus), 16100 Kubang Kerian, Kelantan, Malaysia

° Corresponding Author; Mohd Dasuki SUL’AIN,

Telephone: +609-767 7581, Fax: +609 767 7515, Email: drdasuki@usm.my

SUMMARY

S. myosotiflora A. DC., the horny little devil, is a tropical creeping plant which popularly consumed as a male aphrodisiac, energy booster, and lumbago reliever in the old traditional medicine. The scientific studies showed that the plant able to increase sexual behaviors and testosterone levels in male rats. However, its toxicity effect still remained unknown. Therefore, this study aimed to investigate the toxicity effects of S. myosotiflora methanol extract (SMME) through in vitro and in vivo studies. The SMME was subjected to the brine shrimp lethality test (BSLT) to determine the LC50. Acute and subacute toxicity studies according to the Limit Test of OECD guidelines no. 425 and 407 were carried out through oral gavage accordingly. It was found that the LC50 of SMME was 674.4ppm while its LD50 via acute test was more than 5000 mg/kg. Neither sign of toxicity nor significant difference in food intake, weight gain, gross necropsy, hematological and biochemical analyses, and histological evaluation were recorded between the subacute of control and treated groups except the levels of AST and testosterone in male and sodium and triglycerides in female rats. The increase of testosterone in male rats might occur through a specific pathway as the SMME did not increase the hormone level in the female’s. According to Globally Harmonized System (GHS) classification, SMME in this study can be classified as Category 5 (Safe) and nontoxic. Data from this study can be served as a primary predictive guide for future research in assessing the efficiency and safety of S. myosotiflora consumption for human trials.

Key Words: Smilax myosotiflora, aphrodisiac, acute, subacute, toxicity, BSLT.

Determination of Antioxidant Activity of Salvia sclarea L. and Its Inhibitory Effects on Acetylcholinesterase and Monoamine Oxidase A

Yasemin Yücel YÜCEL*°, Ebru ÖZDEMİR NATH**

* ORCID: 0000-0002-6595-6850, Department of Biochemistry, Faculty of Pharmacy, Altınbaş University, İstanbul, Türkiye.
**ORCID: 0000-0002-0250-9084, Natural Products Research and Development Center (DÜAGEM), Altınbaş University, İstanbul, Türkiye.

° Corresponding Author;Yasemin Yücel Yücel
Phone: + 90 532 653 71 00, E-mail: yasemin.yucel@altinbas.edu.tr

SUMMARY

Over the past two to three decades, there has been a significant increase in research focused on the treatment of neurodegenerative disorders. In this study, our aim was to determine some biological activities of the ethanolic and methanolic extracts of Salvia sclarea L. The extracts were first assessed for their capacity to scavenge DPPH radicals, then their total phenolic content (TPC) were determined. Afterward, the extracts were evaluated for their effects on acetylcholinesterase (AChE) and monoamine oxidase-A (MAO-A). These two enzymes play a crucial role in the treatment of neurodegenerative disorders. It has been found that, the DPPH activity of the methanolic extract was higher than that of ethanolic extracts; while TPC was higher for the ethanolic extract. For AChE, the IC50 values for ethanolic extract and methanolic extract were 0,27±0,005 mg/mL and 1,19±0,037 mg/mL, respectively. And for MAO-A, the IC50 values for ethanolic extract and methanolic extract were 6,53±0,72 mg/ mL and 3,03±0,05 mg/mL, respectively. As the result of this study, the antioxidant property of Salvia sclarea was determined, and it was observed that this property changed in accordance with the total phenolic content of the plant. It has been shown that the extracts have inhibitory effects on both enzymes. This means, the obtained data are promising for further drug development studies.

Key Words: Salvia sclarea L., DPPH, total phenolic content, acetylcholinesterase, monoamine oxidase-A, neurodegenerative disorders.

Antibiofilm Effect of Moringa oleifera Leaf Extract Against Staphylococcus aureus, Cytotoxicity, Biochemical aspects, Anti-Inflammatory potential, and Interference on the Activity of Antimicrobial Drugs

Lorena Kimberly Silva ALCÂNTARA*, Luiz Felipe CARREIRO MACHADO**, Isabela Penna CERAVOLO***, Renan Martins DOS SANTOS****, Marcus Vinícius DIAS-SOUZA*****°

* Orcid ID: 0000-0001-6218-1503, Pitágoras College, Ipatinga, MG, Brazil.
** Orcid ID: 0000-0002-7474-7452, Pitágoras College, Ipatinga, MG, Brazil.
*** Orcid ID: 0000-0002-1374-2703, René Rachou Institute, FIOCRUZ MINAS, Belo Horizonte, MG, Brazil.
**** Orcid ID: 0000-0002-6689-1972, Central Pharmaceutical Group, Ipatinga, MG, Brazil and Integrated Pharmacology and Drug Interactions Research Group (GPqFAR), Brazil.
***** Orcid ID: 0000-0001-5723-5095 Pitágoras College, Ipatinga, MG, Brazil, and Integrated Pharmacology and Drug Interactions Research Group (GPqFAR), Brazil.

° Corresponding Author; Marcus Vinícius Dias-Souza
Phone: +5531987063642, E-mail: souzamvd@gmail.com

SUMMARY

There is a growing technical difficulty in treating infectious diseases due to bacterial resistance to antimicrobial drugs, such as biofilm formation. Here we provide evidence of the antimicrobial potential of the hydroethanolic extract of Moringa oleifera leaves, traditionally used to treat disorders like cardiovascular and endocrine diseases, on clinical isolates of Staphylococcus aureus. The plant extract was chemically characterized using classic techniques and by ultraperformance liquid chromatography (UPLC). We carried out minimum inhibitory concentration tests, minimal bactericidal concentration and minimal biofilm eradication concentration tests. Moreover, we tested the anti-inflammatory potential and assessed the toxicity of the extract on buffalo green monkey (BGM) cells. We also investigated the effects of combining the extract with clinically relevant antimicrobial drugs (i.e., synergistic or antagonistic interactions). The extract was active at 8 g/mL and 16 g/mL for planktonic cells and biofilms, respectively. Its anti-inflammatory potential was confirmed, and it lacked cytotoxicity. No significant interference of the extract on antimicrobial drugs was observed. Flavonoids, tannins, proteins, carbohydrates and vitamin C were detected in the extract. Our data open doors for further studies with isolated molecules of the extract in order to conduct in vivo antimicrobial tests.

Key Words: Moringa oleifera, Staphylococcus aureus, antimicrobial, biofilms.

The Potency of Beligo Seeds (Benincasa hispida (Thunb.) Cogn.) as Antihyperlipidemic in L-NAMEinduced Hyperlipidemic Rats

Nur ALIM*°, Haerani RASYID**, Agussalim BUKHARI***, Natsir DJIDE****, Sartini*****, Rusman HASANUDDIN******

* ORCID: 0000-0002-3575-9573, Makassar Islamic University, Department of Pharmacy, Mathematic and Natural Science Faculty, Makassar, Indonesia
**ORCID: 0000-0001-7404-2973, Hasanuddin University, Doctoral Program, Medicine Faculty, Makassar, Indonesia
*** ORCID: 0000-0002-6340-8615, Hasanuddin University, Doctoral Program, Medicine Faculty, Makassar, Indonesia
**** ORCID: 0000-0001-9224-5782, Hasanuddin University, Department of Pharmacy, Pharmacy Faculty, Makassar, Indonesia
***** ORCID: 0000-0001-8155-4467, Hasanuddin University, Department of Pharmacy, Pharmacy Faculty, Makassar, Indonesia
****** ORCID: 0000-0003-1473-8754, Makassar Islamic University, Department of Pharmacy, Mathematic and Science Faculty, Makassar, Indonesia

° Corresponding Author;Nur Alim
Tel. +62 0411 588167, 590023, e.mail: nuralim1983@yahoo.com

SUMMARY

Beligo or Bligo is the name of Benincasa hispida (Thunb.) Cogn. in Indonesian, empirically used in the treatment of cholesterol and hypertension. The part of the plant used is the seeds. This study aimed to determine the antihyperlipidemic activity of beligo seeds
in hyperlipidemic rats induced by L-NAME. The method of this study, male Wistar albino rats (n = 25) were measured for their initial levels of total cholesterol (TC), high density lipoprotein (HDL), triglyceride (TG), very low density lipoprotein (VLDL) and
low density lipoprotein (LDL) using a human analyzer (Thermo Scientific Indico®). All rats were induced by L-NAME 40 mg/kg body weight (BW) for four weeks and then the TC, HDL, TG, VLDL, and LDL levels were measured again. After the discontinuation of
L-NAME administration, the treatment was carried out and all rats were divided into five groups consisting of group I as negative control which was given sodium carboxy methyl celulose (CMC) 1%; groups II, III, and IV were given beligo seeds ethanol extract (BSEE) each dose of 100 mg/kg BW, 200 mg/kg BW, 300 mg/kg BW; and group V as the positive control group which was given Simvastatin 10 mg/kg BW. The results showed that the beligo seeds ethanol extract (BSEE) had an antihyperlipidemic activity where doses of 100 mg/kg BW, 200 mg/kg BW, and 300 mg/kg BW could significantly reduce levels of TC, TG, LDL, and VLDL (p<0 .05) and significantly increased HDL levels (p<0.05).

Key Words: Benincasa hispida (Thunb.) Cogn., Hyperlipidemic, L-NAME, Lipid profile

Evaluation of Mechanical and Mucoadhesive Properties of Polyvinyl Alcohol Nanofibers As Vaginal Drug Delivery System

Sinem SAAR*, Fatmanur TUĞCU-DEMİRÖZ **°

* ORCID: 0000-0001-6892-5497, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06330- Etiler, Ankara, TURKEY
** ORCID: 0000-0002-9468-3329, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06330- Etiler, Ankara, TURKEY

° Corresponding Author; Fatmanur TUĞCU-DEMİRÖZ
Phone: +903122023043; Fax: +903122127958; e-mail: fatmanur@gazi.edu.tr

SUMMARY

Electrospinning is a versatile and inexpensive technique to produce nanofibers. Nanofibers can be an excellent alternative to classical dosage forms in vaginal applications due to high surface area/volume ratio, high encapsulation efficiency, and mucoadhesive properties. Polyvinyl alcohol (PVA) is a biocompatible, easily degradable, and flexible polymer with mucoadhesive properties used in industrial, commercial, and medical applications. The scope of this study is to characterize electrospun nanofibers produced with different PVA types for vaginal use. PVA nanofibers were produced using the electrospinning method. Nanofiber formulations were prepared by dissolving PVA in dimethylformamide (DMF): distilled water (1:1) solvent system. Nanofibers were produced with three different types of PVA at 5%, 7.5%, and 10% concentrations. The surface tension, viscosity, and conductivity properties of the polymer mixtures were measured for the electrospinning process and these parameters were found suitable for nanofiber production. While the viscosity increased with increasing polymer concentration, the surface tension values were found to be close to each other since the solvent system was the same. The mechanical and mucoadhesive properties of nanofibers were examined and compared. Mucoadhesive and mechanical properties of nanofiber formulations differed depending on molecular weight and electrospinning process. The nanofiber formulations produced with Polyviol 13/140 were found suitable for vaginal applications in terms of their mechanical and mucoadhesive properties. PVA nanofibers can be a good alternative as a drug delivery system in vaginal applications.

Key Words: Nanofiber, Polyvinyl alcohol, Vaginal application, Electrospinning.

An Ethnomedicine Study of Traditional Healers as Joint Pain Therapy in Bantul District, Yogyakarta

Retno WIDYOWATI*°, Neny PURWITASARI**, Wiwied EKASARI***, Mangestuti AGIL****, Ram Kumar SAHU*****, Zalza Billa AROSA******, Irawati SHOLIKHAH*******

* ORCID: 0000-0002-6166-1289, Airlangga University, Faculty of Pharmacy, Department of Pharmaceutical Sciences, 60115, Surabaya, Indonesia
** ORCID: 0000-0003-0817-7065, Airlangga University, Faculty of Pharmacy, Department of Pharmaceutical Sciences, 60115, Surabaya, Indonesia
*** ORCID: 0000-0003-3163-5829, Airlangga University, Faculty of Pharmacy, Department of Pharmaceutical Sciences, 60115, Surabaya, Indonesia
**** ORCID: 0000-0002-2300-9214, Airlangga University, Faculty of Pharmacy, Department of Pharmaceutical Sciences, 60115, Surabaya, Indonesia
***** ORCID: 0000-0001-5671-6591, Assam University, Department of Pharmaceutical Sciences, 788011, Assam, India
****** ORCID: : 0000-0002-8274-0322, Airlangga University, Faculty of Pharmacy, Undergraduate Progam, 60115, Surabaya, Indonesia
******* ORCID: 0000-0002-0124-8302, Airlangga University, Faculty of Sains and Technology, Department of Chemistry, 60115, Surabaya, Indonesia

° Corresponding Author: Retno WIDYOWATI
Tel. +6281615886978, e.mail: rr-retno-w@ff.unair.ac.id

SUMMARY

Joint pain is a sign of disorders of the musculoskeletal system. In joint pain, there is usually discomfort, swelling, inflammation, and stiffness that cause movement restrictions. Bantul is the district with the lowest prevalence of joint disease in Yogyakarta, Indonesia. It related to the community culture in using traditional herbs to treat the disease. This study aims to determine the types of plants, the process of making traditional herbal medicine, and ways to use herbs to treat joint pain complaints. Traditional knowledge about using local plants was collected through field surveys. The 48 healers from 3 hamlets in Bantul District were found by snowball sampling technique and 47 traditional herbal medicines were recorded as being applied for joint pain treatment. Among traditional herbal medicines are identified that they use 33 plants belonging to 18 families, and the most widely used family is Zingiberaceae. Raw materials were detected to process by washing, boiling, pounding, grinding, pulverizing, and squeezing and used orally and topically (compress). This study showed that most of people in the Bantul District still depend on medicinal plants to treat diseases. Nevertheless, there are only a few traditional healers. There is a great danger that traditional knowledge will soon be lost because the young generation is not concerned about continuing this custom.

Key Words: Traditional herbs, joint pain, Kiringan, Mangunan, Kunden

The Effect of Troxerutin Intraperitoneal Consumption on the Symptoms of Morphine Withdrawal Syndrome in Male Mice

Nasrin Hosseinzad MANIE*, Ramin Ghasemi SHAYAN**o

* ORCID: 0000-0001-6895-4271, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran,
** ORCID: 0000-0002-7850-0756, Radiology Department, Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran,

° Corresponding Author;Ramin Ghasemi Shayan
raminghasemi1377@gmail.com, +989145755109

SUMMARY

Chronic morphine use is associated with increased oxidative stress and inflammatory factors. Troxerutin is a natural bioflavonoid containing antioxidant effects that could relieve morphine withdrawal syndrome. The aim is to experiment with the effects of troxerutin on morphine dependence in mice. Troxerutin was prepared in three doses (50, 100, and 200 mg/kg) via a normal saline solution. The experiment was performed in five groups of 7 mice. One group received eight days of increasing doses (10, 20, 30, 40, 50, and 60 mg/kg) of morphine subcutaneously with normal saline (10 ml/kg) intraperitoneal, one group received only normal saline, and the other three groups received three different doses of troxerutin solved in normal saline with morphine. On the ninth day, withdrawal symptoms were recorded after the naloxone injection and blood samples were examined. Consequently, the total withdrawal score in 50 mg/kg was p<0.001***, and in the 100 mg/kg Troxerutin-morphine group was p<0.01**, significantly lower than the morphine-saline group. Antioxidant tests showed a significant increase in the level of Total Antioxidant Capacity (TAC) (p<0.001***) and a decrease in the level of Malondialdehyde (MDA) of serum (p<0.001***) in all three doses of troxerutin. In the locomotion test, no significant motility dysfunction or paralysis was observed in mice after using troxerutin. (All P>0.05). Briefly, Troxerutin reduces the symptoms of morphine
withdrawal syndrome. The results of antioxidant tests declared that troxerutin possibly due to its antioxidant properties, increases the level of TAC and decreases the level of MDA in the serum of mice.

Key Words: Morphine, troxerutin, withdrawal syndrome, dependence, MDA, TAC

Investigation of Dimethoate Toxicity in Rat Brain and Protective Effect of Laurocerasus officinalis Roem. Fruit Extract Against Oxidative Stress, DNA Damage, and Apoptosis

Burcu ÜNLÜ ENDİRLİK*, Elçin BAKIR**, Arzu Hanim YAY***, Fazile Cantürk TAN****, Ayşe BALDEMİR KILIÇ*****, Ayşe EKEN******°

* ORCID: 0000-0001-5960-1036, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
** ORCID: 0000-0001-5333-8273, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
*** ORCID: 0000-0002-0541-8372, Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
**** ORCID: 0000-0002-0747-2209, Department of Biophysics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
***** ORCID: 0000-0003-2473-4837, Department of Pharmaceutical Botany, Gülhane Faculty of Pharmacy, University of Health Sciences, Ankara, Turkey
****** ORCID: 0000-0003-4830-5770, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey

° Corresponding Author; Ayşe Eken
Phone: 035220766-28325, E-mail: aeken@erciyes.edu.tr

SUMMARY

Dimethoate is an organophosphate insecticide that is used globally on a wide scale in agriculture. It was associated with numerous negative health effects in many studies. The brain is one of the target organs for dimethoate exposure. The present study aimed to evaluate the subchronic (60 days) toxicity of dimethoate (7 mg/kg body weight) by investigating its oxidative stress, DNA damage, apoptosis-inducing effects, and histopathological changes in brain tissue of rats. We also aimed to analyze the protective effects of Laurocerasus officinalis Roem. (cherry laurel) fruit extract. To evaluate oxidative stress, malondialdehyde (MDA) levels, as well as superoxide dismutase (Cu-Zn SOD), glutathione peroxidase (GPx), and catalase (CAT) antioxidant enzymes activities, were calculated. Experimental results demonstrated that dimethoate treatment increased MDA and decreased Cu-Zn SOD, GPx, and CAT enzyme activities, suggesting its potency as an oxidative stress inducer in rat brain tissues. Furthermore, comet and TUNEL assay results showed that dimethoate stimulated DNA damage and apoptosis. Administration of cherry laurel extracts protected against dimethoate-induced oxidative stress, DNA damage, and apoptosis. The findings of the current study are important in terms of demonstrating the beneficial effects of L. officinalis extract against dimethoate toxicity in the brain, considering the sensitivity of this organ to oxidative stress and
extensive usage of dimethoate.

Key Words: Dimethoate, neurotoxicity, Laurocerasus officinalis Roem., in vivo, DNA damage, oxidative stress

Evaluation of Phytochemical Contents and Biological Activities of Salvia officinalis and Salvia triloba Grown with Organic Farming

Burçin ÖZÜPEK*, Sultan PEKACAR**, Didem DELİORMAN ORHAN***°

* ORCID:0000-0003-2159-9860, Gazi Üniversitesi, Eczacılık Fakültesi, Farmakognozi Ana Bilim Dalı, 06510, Ankara, Türkiye,
** ORCID:0000-0002-7782-9832 , Gazi Üniversitesi, Eczacılık Fakültesi, Farmakognozi Ana Bilim Dalı, 06510, Ankara, Türkiye
*** ORCID:0000-0003-3916-4048, Gazi Üniversitesi, Eczacılık Fakültesi, Farmakognozi Ana Bilim Dalı, 06510, Ankara, Türkiye

° Corresponding Author; Didem Deliorman Orhan
Tel. +90 3122023173, Fax: +90 3122023173, e.mail: didem@gazi.edu.tr, didemdeliorman@gmail.com

SUMMARY

Salvia officinalis L., known as medicinal sage, and Salvia triloba L., known as Anatolian sage, belong to the Lamiaceae family and are species that usually grow in the Mediterranean region. In this study, it was aimed to evaluate the in vitro antidiabetic, antiobesity and antioxidant potentials of the extracts prepared by infusion technique from S. officinalis and S. triloba has grown by organic farming methods. In addition, the effects of the extracts on the pancreatic cholesterol esterase enzyme were also investigated.The Reverse Phase- High Performance Liquid Chromatography (HPLC) technique was used to analyze the phytochemical contents of the extracts. At a concentration of 2 mg/mL, S. officinalis inhibited 64.69% ± 0.23, S. triloba 47.78 ± 2.11% on the α-glucosidase enzyme. Only S. triloba had an inhibitory effect on α-amylase and pancreatic lipase enzyme. On the pancreatic cholesterol esterase enzyme, inhibition values of S. triloba extract at all tested concentrations was found higher than S. officinalis extract. It was observed that the S. officinalis extract had the highest reducing power potential. The metal chelating capacity of both extracts at a concentration of 2 mg/mL was calculated as 100%. It was concluded that the ABTS radical scavenging activity of the extracts increased in a dose-dependently manner. The amounts of rosmarinic acid and hesperidin were found higher in S. officinalis extract than in S. triloba extract by Reverse Phase-HPLC technique. The presence of hesperidin in S. triloba was detected for the first tim in this study. These findings considering it was concluded that activityguided isolation and in vivo activity studies should be performed because these two species grown the organic farming methods have potent α-glucosidase enzyme inhibitory and antioxidant effects.

Keywords: Antioxidant, enzyme inhibition, phytochemistry, Reverse phase-HPLC, Salvia officinalis, Salvia triloba

Development and Evaluation of Nanostructured Lipid Carriers for Transdermal Delivery of Ketoprofen

Thulasi SATHYANARAYANANA*, Preethi SUDHEER**°, Elsa JACOB***, Merlin Mary SABU****

* ORCID:0000-0002-5126-5813, Department of Pharmaceutics, Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram post, Varthur Hobli, Bangalore- 560035, India
** ORCID:0000-0002-7041-8993, Department of Pharmaceutics, Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram post, Varthur Hobli, Bangalore- 560035, India
*** ORCID:0000-0003 -4890-6867, Department of Pharmacy practice, Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram post, Varthur Hobli, Bangalore- 560035, India
**** ORCID:0000-0002-4052-4533, Department of Pharmacy practice, Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram post, Varthur Hobli, Bangalore- 560035, India

° Corresponding Author; Dr. Preethi Sudheer
Email: preetisudheer@gmail.com, Phone: 919449822912

SUMMARY

Ketoprofen is a nonsteroidal anti-inflammatory drug that displays significant gastrointestinal side effects when administered via the oral route and has a low skin permeation profile. The objective of the present work is to utilise nanostructured lipid carriers (NLCs) as a carrier system for the transdermal delivery of ketoprofen. NLCs were prepared via hot homogenisation technique using beeswax, carnauba wax, glyceryl monostearate (solid lipids), linseed oil (liquid lipid) and poloxamer188 (surfactant) and optimized using custom design via JMP. The responses evaluated were drug entrapment efficiency, particle size and drug release profile. The experimental design was evaluated for model fit with the assistance of variance analysis. The optimum formulations were characterized for particle size, zeta potential, scanning electron microscopy (SEM), differential scanning colorimetry, Fourier transform infrared spectrum (FTIR) and also drug content, entrapment efficiency, in-vitro drug release, and exvivo drug release profile was studied. The drug loading efficiency between the formulation ranges between 34±0.03-95.06±0.01%. The drug release from the formulations over a 24 h study was found to be 80%±0.09 to 95%±0.06. The maximum desirability was found to be 0.91. The optimum formulation showed a mean particle size of 425.8nm and a zeta potential of -45mV. SEM results revealed slightly agglomerated particles with uneven surfaces. The ex-vivo skin permeation of NLC optimized patch formulation exhibited a higher flux and permeability coefficient than the pure drug patch formulation, and marketed gel (2.5%w/w) FTIR spectra assured the chemical and physical compatibility. Transdermal delivery of ketoprofen via NLCs would be a promising approach for improving skin permeation.

Key Words: Ketoprofen, permeation, NLC, skin, oils, optimization, ex-vivo, flux

Caffeine May Improve the Chemotherapeutic Effect of Docetaxel by Inducing Unfolded Protein Response and Autophagy in Breast Cancer Cells

Yalcin ERZURUMLU*°, Deniz CATAKLI**, Hatice Kubra DOGAN***, Esra AYDOGDU****

* ORCID: 0000-0001-6835-4436, Suleyman Demirel University, Department of Biochemistry, Faculty of Pharmacy, Isparta, Turkey
** ORCID: 0000-0001-7327-5396, Suleyman Demirel University, Department of Pharmacology, Faculty of Medicine, Isparta, Turkey
*** ORCID: 0000-0002-6061-1300, Suleyman Demirel University, Department of Bioengineering, Institute of Science, Isparta, Turkey
**** ORCID: 0000-0003-0666-2067, Suleyman Demirel University, Department of Pharmaceutical Research and Development, Institute of Health Sciences, Isparta, Turkey

° Corresponding Author; Yalcin ERZURUMLU
Tel. +90 0246 311 0345 / +90 544 88 78 439, e.mail:yalcin.erzurumlu@gmail.com, yalcinerzurumlu@sdu.edu.tr

SUMMARY

Breast cancer is the most frequently diagnosed cancer type among women. Chemotherapeutic agents are widely used in the treatment of breast cancer, but acquired drug resistance limits their effectiveness. Therefore, there is a continuing need for more effective treatment approaches with fewer side effects. Caffeine is one of the naturally occurring xanthines in coffee beans, caffeine is the most commonly used psychoactive substance worldwide. Numerous studies have highlighted the health benefits of coffee consumption, including reducing the risk of heart disease and certain cancers. Docetaxel is a second-generation antineoplastic agent of the taxane family and is widely used in the treatment of numerous cancers such as breast cancer. Herein, we evaluated the effect of caffeine and its combination with docetaxel on MCF-7 breast cancer cells. To test the effect of caffeine and its combination with docetaxel, we evaluated the autophagy, ubiquitin-proteasome system (UPS), unfolded protein response (UPR) signaling and apoptosis-related protein levels by immunoblotting. Cell viability was measured by WST-1 method. Morphological alterations in cells were evaluated in microscopical examinations. We found that caffeine remarkably induced UPR signaling, accelerated autophagic flux, and UPS-dependent protein turnover. Co-administration of caffeine and docetaxel strongly diminished the viability of MCF-7 cells by expanding the cytotoxic effect of docetaxel through accelerating the UPS-dependent protein turnover, induction of UPR and autophagy and apoptotic protein levels in a dose-dependent manner. Our results suggest that caffeine supplementation with docetaxel may expand the chemotherapeutic efficiency of docetaxel in breast cancer.

Key Words: Autophagy, Apoptosis, Breast cancer, Caffeine, Unfolded Protein Response, Docetaxel

Development and Validation of an HPLC Method for Simultaneous Determination of Miconazole Nitrate and Chlorhexidine Digluconate in Chitosan-Based Gel Formulations

Ece TÜRKMEN*, Selin PARMAKSIZ**, Mustafa ÇELEBİER***, Sevda ŞENEL****°

* ORCID: 0000-0003-0365-2306, Hacettepe University, Department of Pharmaceutical Technology, Ankara, Turkey
** ORCID: 0000-0002-3798-7537, Hacettepe University, Department of Pharmaceutical Technology, Ankara, Turkey
*** ORCID: 0000-0001-7712-5512, Hacettepe University, Department of Pharmaceutical Technology, Ankara, Turkey
**** ORCID: 0000-0002-1467-3471, Hacettepe University, Department of Analytical Chemistry, Ankara, Turkey

° Corresponding Author; Sevda Şenel
Tel. +90 312 310 12 41, Fax: + 90 312 310 09 06, e.mail: ssenel@hacettepe.edu.tr

SUMMARY

Miconazole nitrate (MN) and chlorhexidine digluconate (CHX) are the commonly used antimicrobials for topical treatment of dermal infections. Combination of antimicrobials has been investigated to enhance the efficacy of the treatment. Gel formulations based on bioadhesive polymers are preferred for delivery of these drugs. Chitosan is a promising bioadhesive polymer due to its penetration enhancing, antimicrobial and tissue healing properties. Yet, most of the gel-based formulations present analytical challenges during testing the drug content. It was aimed to develop an HPLC method for simultaneous determination of MN and CHX in chitosan-based gel formulations. Different solvent combinations were investigated for extraction of drugs from the gels. HPLC conditions such as mobile phase, flow rate, run time, column temperature and wavelength were explored. The method was validated according to ICH guideline Q2(R1). MN and CHX were extracted in solvent composition same with the mobile phase. The method was employed on ACE-C8 column at 40°C by isocratic elution using the mobile phase consisting of methanol:phosphate (75:25 v/v) buffer (containing triethylamine). Flow rate was 1 mL/min. The drugs were detected at 254 nm (CHX) and 230 nm (MN). Linearity was obtained between 5 to 80 μg/
mL for both drugs. LOD and LOQ obtained for CHX were 1.61 and 4.87 µg/mL, for MN: 1.06 and 3.21 µg/mL, respectively. A new validated HPLC method was developed for simultaneous determination of CHX and MN in chitosan-based gels, with 98 to 102% recovery, without any interference with the excipients.

Key Words: HPLC method, simultaneous analysis, miconazole nitrate, chlorhexidine digluconate, chitosan gel, validation

Central Composite Design for the Development of Trimetazidine Dihydrochloride-Loaded Fast Dissolving Film

Swapnil S. CHOPADE*°, Mangesh A. PAWAR**, Popat S. KUMBHAR***, Arehalli S. MANJAPPA****, John I. DISOUZA*****, Santosh A. PAYGHAN******°, Jagruti L. DESAI*******

* ORCID: 0000-0001-6173-6343 ,Tatyasaheb Kore College of Pharmacy, Warananagar (MS, India)
** ORCID: 0000-0002-0108-3149, Tatyasaheb Kore College of Pharmacy, Warananagar (MS, India)
*** ORCID: 0000-0002-0108-3149, Tatyasaheb Kore College of Pharmacy, Warananagar (MS, India)
**** ORCID: 0000-0002-8576-6608, Tatyasaheb Kore College of Pharmacy, Warananagar (MS, India)
***** ORCID: 0000-0002-8576-6608, Tatyasaheb Kore College of Pharmacy, Warananagar (MS, India)
****** ORCID: 0000-0002-0653-6784, Vasantidevi Patil Institute of Pharmacy, Kodoli (MS, India).
******* ORCID: 0000-0001-7147-5861, Ramanbhai Patel College of Pharmacy, Gujarat (GJ, India)

° Corresponding Author;
1. Dr. Santosh A. Payghan, Email: santos14july@gmail.com
2. Mr. Swapnil S. Chopade, Phone: 02328 223526, Fax: 02328 223501, Email: swapnilchopade.tkcp@gmail.com

SUMMARY

A fast-dissolving dosage form is an approach used to improve therapeutic efficacy and bioavailability by avoiding the first-pass metabolism of the drug carrier. Besides, the approach causes rapid drug absorption from the pre-gastric area which may outcome in the quick inception of action. Trimetazidine dihydrochloride (TDC) is an anti-anginal drug, and there is a prerequisite to provide fast onset of action to treat angina. Therefore, the present work aimed to prepare and evaluate fast-dissolving oral films (FDOFs) of TDC to provide fast onset of action. The FDOF is prepared by using the solvent casting method, and it was optimized by employing a central composite statistical design (CCD). The two independent variables such as HPMC K4M (X1) and PEG 400 (X2) are the film-forming polymers that are evaluated at three levels. The dependent variables such as folding endurance (Y1), disintegration time (Y2), and % drug release (Y3). The formulation was prepared and optimized. The batch F-4 showed the least disintegration time (19 s) and the highest drug release (98.55±7.90%). Moreover, the ex-vivo mucus permeation study disclosed better permeation and satisfying physicochemical properties compared to plain drug solution. It was concluded that the prepared formulation could be a novel dosage form to improve drug delivery and patient compliance.

Key Words: Anti-anginal, CCD, ex-vivo permeation, fast dissolving oral film, solvent casting method, trimetazidine dihydrochloride

Assessment of Anxiety and Burden on Caregivers for Haemodialysis Patients in Southern Punjab, Pakistan

Hina RAZA*, Memona NASIR**, Zarmina RASHID***, Rahat SHAMIM****, Bushra ALAM*****, Amjad KHAN***** , Shabnam NAZIR******°

* ORCID: 0000-0002-4733-4089, Bahauddin Zakariya University Faculty of Pharmacy Multan Pakistan
** ORCID: 0000-0003-3069-4990, Bahauddin Zakariya University Faculty of Pharmacy Multan Pakistan
*** ORCID: 0000-0002-6537-6864, The Women University Department of Pharmacy Multan Pakistan
**** ORCID: 0000-0003-3897-9421, University of Punjab Punjab University College of Pharmacy,Lahore Pakistan
***** ORCID: 0000-0002-1274-9233, Kohat University of Science and Technology Department of Pharmacy, Kohat Pakistan
****** ORCID: 0000-0002-4121-4400, Kohat University of Science and Technology Department of Pharmacy, Kohat Pakistan
******* ORCID: 0000-0001-6543-0931, Kohat University of Science and Technology Department of Pharmacy, Kohat Pakistan

° Corresponding Author; Shabnam NAZIR
Email: Shabnammunirmalik@yahoo.com

SUMMARY

The aim of this work was to assess anxiety and depression experienced by unpaid caregivers of chronic hemodialysis patients suffering from end-stage renal failure (ESRF). The evaluation of factors influencing anxiety and depression and caregiving burden was performed. In the present study, non-paid primary caregivers (218 study participants) of patients with ESRF receiving hemodialysis, who were providing care (minimum 6 months and up to 5 years) were interviewed by using the Aga Khan University Anxiety and Depression Scale (AKUADS) and the carer’s burden of peritoneal dialysis patients (CSCDP) questionnaire. According to the scoring of AKUADS, 90.4% of caregivers were found to be experiencing significant anxiety and depression. From the assessment of demographic factors collected using the AKUAD scale, it was found that the female was more in number (44%), wedded (72.01%), with a mean life span of 38.5 ± 2 (standard error) years, and have monthly income below average. The main relationships of caregivers with patients were life partners (38%) and parents (18.2%). The highest depression levels were found in mothers as attendants (67%), caregivers of age less than 30 years (22 %), and caregivers of elderly patients (87%). The outcome of this study has revealed a need to plan policies to support unpaid caregivers as well as patients.

Key Words: Caregiver, anxiety, depression, hemodialysis, objective burden, subjective burden

Ifosfamide-Loaded Cubosomes: An Approach to Potentiate Cytotoxicity against MDA-MB-231 Breast Cancer Cells

Popat S. KUMBHAR*° , Vishvajit M. KHADE**, Varsha S. KHADAKE***, Pradnya S. MARALE****, Arehalli S. MANJAPPA*****, Sameer J. NADAF******, Vijay M. KUMBAR*******, Durgacharan A. BHAGWAT********, Ravindra A. MARATHE*********, John I. DISOUZA**********°

* ORCID: 0000-0002-6753-239X, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, India, 416113
** ORCID: 0000-0002-7522-8400, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, India, 416113
*** ORCID: 0000-0003-3623-6595, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, India, 416113
**** ORCID: 0000-0003-2633-5928, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, India, 416113
***** ORCID: 0000-0002-8576-6608, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, India, 416113
****** ORCID: 0000-0002-7132-1886, Sant Gajanan Maharaj College of Pharmacy, Mahagaon, Gadhinglaj, Maharashtra, India
******* ORCID: 0000-0001-6261-1665, Dr. Prabhakar Kore Basic Science Research Centre, KLE Academy of Higher Education & Research, Belagavi, India
******** ORCID: 0000-0002-3993-8851, Bharati Vidyapeeth College of Pharmacy, Kolhapur 416013, Maharashtra, India
********* ORCID: 0000-0002-9807-7932, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, India, 416113
********** ORCID: 0000-0002-0180-7266, Bharati Vidyapeeth (Deemed to be University), Yashwantrao Mohite Institute of Management, Karad

° Corresponding Author;
1. Dr. John I. Disouza
Phone: 02328 223526, Fax: 02328 223501
Email: jidisouza@tkcpwarana.ac.in

2. Mr. Popat S. Kumbhar
Phone: 02328 223526, Fax: 02328 223501
Email: pskumbhar@tkcpwarana.ac.in

SUMMARY

Ifosfamide (IFS) is proven efficacious against breast cancer, an enormously diagnosed cancer across the globe. However, the clinical efficacy of IFS is limited owing to its hydrophilicity, less stability, and dose-dependent toxicities. Therefore, the primary goal of the present research was to develop IFS-loaded cubosomes with improved anticancer efficacy and reduced dose-dependent toxicities. The IFScubosomes were optimized using a 32factorial design based on IFS content and zeta potential. The optimized cubosomal dispersion was further assessed for particle size, in vitro IFS release, hemolysis, cytotoxicity, cellular uptake, and physical stability. The optimized IFS-cubosomal dispersion exhibited maximum IFS content (89.75±4.3%) and better zeta potential value (-40.0±1.6 mV), and size in nanometer. Moreover, IFS-cubosomes retarded IFS release (about 91 %) 12 h than plain IFS solution (>99 % within 2 h). The IFS-cubosomes displayed lower hemolysis (3.7±0.79%) towards human RBCs. Besides, the in vitro cytotoxicity of IFS-cubosomes was noticed to be substantially higher (IC50: 0.64±0.08 μM) than plain IFS solution (IC50: 1.46±0.21 μM) against multi-drug resistant (MDR) breast cancer (MDA-MB-231) cells. The 4’,6-diamidino-2-phenylindole (DAPI) staining revealed the death of IFS-cubosomes treated cells mainly by apoptosis. The cubosomes showed increased uptake by cancer cells. Furthermore, IFS-cubosomes were found to be more stable at refrigeration temperature than at room temperature. Thus, IFS-cubosomes could be a novel avenue in the treatment of breast cancer with improved anticancer efficacy and reduced toxicity. However, further in vivo investigations are desired to validate these claims.

Key Words: Breast cancer, ifosfamide, cubosomes, haemolysis, cytotoxicity, cellular uptake.

The Relative Bioavailability Study of Two Cefdinir Formulations in Healthy Males Under Fasting Conditions

Fırat YERLİKAYA*°, Aslıhan ARSLAN**, Özlem ATİK***, Seda KOZAN****, Ahmet
PARLAK*****, Meltem ÖZEL KARATAŞ******, Onursal SAĞLAM*******, Peri AYTAÇ********

* ORCID: 0000-0003-4648-3258, Elixir İlaç Araştırma ve Geliştirme AŞ, Ankara, Turkey, Department of Pharmaceutical Technology, Faculty of Pharmacy, Lokman Hekim University, Ankara, Turkey
** ORCID: 0000-0002-3520-608X, Elixir İlaç Araştırma ve Geliştirme AŞ, Ankara, Turkey
*** ORCID: 0000-0001-7867-6316, İ.E. Ulagay İlaç Sanayii Türk A.Ş. (Istanbul, Turkey)
**** ORCID: 0000-0003-3925-0317, İ.E. Ulagay İlaç Sanayii Türk A.Ş. (Istanbul, Turkey)
***** ORCID: 0000-0002-4921-0004, İ.E. Ulagay İlaç Sanayii Türk A.Ş. (Istanbul, Turkey)
****** ORCID: 0000-0001-9226-2603, İ.E. Ulagay İlaç Sanayii Türk A.Ş. (Istanbul, Turkey)
******* ORCID: 0000-0002-1421-6633, Novagenix Biyoanalitik İlaç Ar-Ge Merkezi San. ve Tic. AŞ, Ankara, Turkey
******** ORCID: 0000-0002-9985-3382, Novagenix Biyoanalitik İlaç Ar-Ge Merkezi San. ve Tic. AŞ, Ankara, Turkey

° Corresponding Author; Fırat YERLİKAYA
Telephone: +90532609463; E-mail: firat.yerlikaya@elixirlabs.com.tr;

SUMMARY

A new oral formulation of cefdinir, Cefdinir 600 mg tablets has been developed and, in this study, its relative bioavailability has been compared with another oral solid dosage form, Cefdinir 300 mg Capsules, which is already on the market. An open-label, randomized, two-period, cross-over relative bioavailability study has been conducted with healthy males under fasting conditions in compliance with Good Clinical Practice (GCP) principles. A single
dose of the novel tablet formulation of 600 mg cefdinir has been compared to two doses of Cefdinir 300 mg Capsules (two capsules at once) regarding pharmacokinetic properties. The comparison study was performed as a single-center clinical study, and blood samples of the participants were withdrawn at specified time points, before and after dosing. The plasma concentrations and pharmacokinetic properties of two cefdinir formulations were assessed from the collected samples by using a validated LC-MS/MS analytical method. The relative bioavailability of the new formulation has been shown, and both products were introduced as safe.

Keywords: Bioavailability, cefdinir, cephalosporin, GCP

Glycosides Isolated from Leaf Extract of Phyllanthus muellerianus (Kuntze) Excell (Phyllanthaceae) Upregulated Cell-mediated Innate Immunity

Martha. N. OFOKANSI*, Ogechukwu N. ISIOGUGU**, Ikechukwu E PETER***,
Matthias O. AGBO****°, Festus B.C. OKOYE*****, Peter A. AKAH******

* ORCID: 0000-0001-7660-6800, Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, 410001, Enugu State Nigeria.
** ORCID: 0000-0003-4285-9860, Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, 410001, Enugu State Nigeria.
*** ORCID: 0000-0003-1223-582X, Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, 410001, Enugu State Nigeria.
**** ORCID: 0000-0001-8210-306X, Natural Products Chemistry Unit, Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, 410001, Enugu State Nigeria.
***** ORCID: 0000-0001-8414-2329, Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, PMB 2025 Awka, Anambra State Nigeria.
****** ORCID: 0000-0002-5064-1522, Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, 410001, Enugu State Nigeria.

° Corresponding Author; Matthias Onyebuchi Agbo
Phone: +234 8162661991; e.mail: matthias.agbo@unn.edu.ng

SUMMARY

Intracellular pathogens are mainly eliminated by cell-mediated immunity from phagocytic cells like neutrophils, macrophages, and monocytes. Tannin glycosides, 1-O-galloyl-6-O-luteoyl- α-D-glucopyranoside (1) and 3-O-methylellagic acid 3’-O-α- rhamnopyranoside (2) were isolated from the ethyl acetate fraction (EF) of the methanol leaf extract of Phyllanthus muellerianus. Structures of the isolated compounds were elucidated by 1H-NMR and by mass spectroscopy. Effects of the isolated compounds on the phagocytic competence of macrophages and neutrophils using in vitro models were evaluated. Tannin glycosides 1 and 2 significantly (p<0.05) increased both phagocytic ability and intracellular killing capacity of neutrophils. Present study established that tannin glycosides stimulated cell-mediated innate immunity by increasing the phagocytic function of neutrophils and thus may be helpful to both the clinical and prophylactic treatment of intracellular microbial infections.

Key Words: Glycosides, cell-mediated immunity, phagocytosis,
neutrophils, macrophages.

Use of Biodegradable Natural and Synthetic Polymers in Wound Dressing

Sümeyra PANCUR*, Erem BİLENSOY **, Sema ÇALIŞ ***°

* ORCID: 0000-0001-6585-3635, Hacettepe Üniversitesi, Farmasötik Teknoloji Anabilim Dalı, 06100, Ankara
**ORCID: 0000-0003-3911-6388, Hacettepe Üniversitesi, Farmasötik Teknoloji Anabilim Dalı, 06100, Ankara
***ORCID: 0000-0003-1778-5142, Hacettepe Üniversitesi, Farmasötik Teknoloji Anabilim Dalı, 06100, Ankara

º Corresponding Author: Sema Çalış
Tel. +90 312 305 3011, Fax: +90 312 310 0906
e.posta: scalis@hacettepe.edu.tr

SUMMARY

Wound healing is an extremely complex process consists of hemostasis, inflammation, cell proliferation and scar tissue remodeling phases. Delay or disruption of this process causes not only important health problems which impair the quality of patients’ life but also a socioeconomic burden for health systems. Thus various wound dressing designs are being developed that can meet the needs for different wound types and healing phases in order to ensure effective wound management. Natural or synthetic biodegradable polymers with adaptable flexible properties are considered as alternative biomaterials for wound healing applications. While natural polymers are preferred due to their biocompatibility, similarity to the extracellular matrix and cellular interactions, synthetic degradable polymers are widely used because of their low immunogenicity and ability to be synthesized in line with determined specifications. Wound dressings made of biodegradable polymers do not require a second procedure for removal. Also minimizing contact with the wound area in the treatment reduces the risk of infection and increases patient compliance. Polymeric wound dressings which play an active role in wound healing by keeping the wound environment moist and preventing the formation of microbial biofilms, could be in alginate, hydrogel or hydrocolloid structure, film or foam form. Also there are tissue engineering products made of polymeric scaffolds which keratinocytes and fibroblast cells are cultured on. In this article, the properties of biodegradable polymers used in wound dressings and their role in wound healing are summarized; ffilm, foam, hydrogel, hydrocolloid, alginate dressings and tissue engineered skin substitutes are reviewed and commercialized biodegradable polymeric wound dressings have been mentioned.

Key Words: Wound healing, wound management, biodegradable polymers, natural and synthetic polymers, bioactive wound dressings.

The Effects of Gender in Neurological Disorders: A Special Focus on Autism Spectrum Disorders and Thiomersal Toxicity

Selinay Başak ERDEMLİ-KÖSE*, Aylin BALCI ÖZYURT**, Anil YİRÜN***, Pınar ERKEKOĞLU****º

* ORCID: 0000-0001-8986-585X, Burdur Mehmet Akif Ersoy University, Faculty of Arts and Sciences, Department of Chemistry, Burdur, Turkey
** ORCID: 0000-0002-0060-271X, Hacettepe University Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Ankara, Turkey
*** ORCID: 0000-0002-4050-8832, Çukurova University Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Adana, Turkey
**** ORCID: 0000-0003-4713-7672, Hacettepe University Vaccine Institute Department of Vaccine Technology, Ankara, Turkey

º Corresponding Author: Pinar Erkekoglu
Tel: 0 312 309 29 58 Fax: 0 312 311 47 77
E-mail: erkekp@yahoo.com; erkekp@hacettepe.edu.tr

SUMMARY

Estrogen and testosterone serve as the main sex hormones in humans. In addition, they have many different functions in terms of metabolic, and body defense. Gender differences lead to various social, economic, physiological, and pathological outcomes. Gender differences may also cause different toxicokinetics for metalslike mercury.Mercury exposure is suggested to cause neurological disorders. Thiomersal which is one of the most widely used
preservatives particularly in vaccines, consists of approximately 50% mercury by weight. Autism spectrum disorders (ASD) have been associated with thiomersal exposure from vaccines in the last decades. Recent studies show that the incidence of ASD is higher in boys compared to girls. However, studies and discussions continue in this area. It is thought that this situation may be related to the difference in the toxicokinetics of mercury in different genders.
There are concerns that ASD in girls may have a distinct phenotype than boys. The studies are now focused on whether there is an overlook due to the difficulty of diagnosing in females or it is more common in males due to physiological and hormonal reasons or not. In this review, we evaluated the frequency of ASD in different genders, the association between thiomersal and ASD and whether thiomersal exposure from vaccines could be an underlying factor of ASD in boys or not.

Key Words: Autism, gender, neurodevelopmental disorders, mercury, thiomersal

Phytochemical Analysis and Screening of Acetylcholinesterase and Carbonic Anhydrase I and II Isoenzymes Inhibitory Effect of Heptaptera triquetra (Vent.) Tutin Root

Ayşe ÇİÇEK KAYA*, Hilal ÖZBEK**, Hafize YUCA***°, Gülderen YILMAZ****, Zeynebe BİNGÖL*****, Cavit KAZAZ******, İlhami GÜLÇİN*******, Zühal GÜVENALP********

* ORCID: 0000-0002-3012-1669, Department of Pharmacognosy, Faculty of Pharmacy, Ataturk University, Erzurum, 25240, Turkey
** ORCID: 0000-0002-2378-1896, Department of Pharmacognosy, Faculty of Pharmacy, Ataturk University, Erzurum, 25240, Turkey
*** ORCID: 0000-0002-0857-4776, Department of Pharmacognosy, Faculty of Pharmacy, Ataturk University, Erzurum, 25240, Turkey
**** ORCID: 0000-0002-6569-4766, Department of Pharmaceutical Botany, Faculty of Pharmacy, Ankara University, 06100, Turkey
***** ORCID: 0000-0003-3373-779X, Vocational School of Health Services, Tokat Gaziosmanpasa University, Tokat, 60250, Turkey
****** ORCID: 0000-0002-5249-0895, Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum, 25240, Turkey
******* ORCID: 0000-0001-5993-1668, Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum, 25240, Turkey
******** ORCID: 0000-0002-8803-8147, Department of Pharmacognosy, Faculty of Pharmacy, Ataturk University, Erzurum, 25240, Turkey

° Corresponding Author; Hafize YUCA
Phone: +90 442 231 52 50, Fax: +90 442 231 52 01, E-mail: hafize.yuca@atauni.edu.tr

SUMMARY

Alzheimer’s disease (AD) is characterized by progressive memory loss, deterioration of other cognitive functions, and inability to perform activities of daily living. Inhibiting the acetylcholinesterase (AChE) enzyme causes Ach accumulation in cholinergic synapses. This situation is expected to increase cognitive functions. Carbonic anhydrase enzymes (CAs) are ubiquitous in all living organisms. They have crucial physiological and pathological roles. CA inhibitors (CAIs) bind to catalytic zinc ions in the active site of CA isoenzymes and block their activity. The clinical use of CAIs had been established as antiglaucoma, anticonvulsant agents, diuretics, and anti-obesity drugs, in managing mountain sickness, gastric and duodenal ulcers, neurological disorders, osteoporosis, and tumors. To evaluate the bioactive profile of Heptaptera triquetra root, isolation studies, AChE, and human carbonic anhydrase (hCA) I and II inhibitory activities were performed. According to isolation studies, one fatty acid, coniferyl palmitate (1); four sesquiterpene coumarins, umbelliprenin (2), badrakemin acetate (4), colladonin (5), karatavicinol (6); and two sterols, stigmasterol (3a), β-sitosterol (3b) were isolated. All isolated compounds showed high potency against all enzymes (except badrakemin acetate for AChE) compared to standards. Umbelliprenin (2) with an IC50 value of 31.500 nM against hCA I, colladonin (5) with an IC50 value of 36.473 nM against hCA II and stigmasterol (3a), and β-sitosterol (3b) mixture with an IC50 value 9.000 nM against AChE demonstrated the best activity.

Key Words: Heptaptera triquetra, Apiaceae, enzyme inhibition, acetylcholinesterase, carbonic anhydrase, isolation

Development and Radiolabeling Evaluation of 177Lutetium- Tedizolid

Merve KARPUZ*°, Emre OZGENC**, Evren GUNDOGDU***, Zeynep BURAK****

* ORCID ID: 0000-0001-6681-2448, Izmir Katip Celebi University Faculty of Pharmacy, Department of Radiopharmacy, Izmir, Turkey.
** ORCID ID: 0000-0002-7586-8520, Ege University Faculty of Pharmacy, Department of Radiopharmacy, Izmir, Turkey.
*** ORCID ID: 0000-0003-2111-101X, Ege University Faculty of Pharmacy, Department of Radiopharmacy, Izmir, Turkey.
**** ORCID ID: 0000-0002-3187-9447, Ege University Faculty of Medicine, Department of Nuclear Medicine, Izmir, Turkey.

° Corresponding Author; Merve KARPUZ,
Tel: +90 232 329 3535, Fax: +90 232 386 08 88, e-mail: merve.karpuz@ikcu.edu.tr, merve-karpuz@hotmail.com

SUMMARY

Infection diseases is still one of the major health problems all around the world. Early diagnosis and differentiation of infection from other pathological conditions such as cancer and inflammation play a critical role in treating the infection in acute stages. Imaging techniques using in the infection diagnosis present some advantages such as, the ability to image the whole body, the detection of focal location and stage, and following up on infection. Although various antibiotics can be used in the treatment, there are some problems including serious side effects of antibiotics or the development of antimicrobial resistance in the clinics. In our study, tedizolid, a second-generation oxazolidinone antibiotic, was radiolabeled with 177Lu radionuclide to develop a theranostic agent against grampositive bacterial infections. The radiolabeling was performed under room conditions, and labeling efficiency and stability were evaluated by paper chromatography and HPLC. The optimum incubation period was found as 60 min to obtain high radiolabeling efficiency. Different mobile and stationary phases in paper chromatography were tested to determine the radiochemical impurities in 177Lu-TDZ solution, and ITLC-SG was found to be proper as the stationary phase. In addition, ammonium hydroxide: methanol: water, and DTPA solutions were chosen as mobile phases. In the HPLC chromatogram, two different peaks were observed depending on the retention times of the free 177Lu and 177Lu-TDZ complex. Unfortunately, over 80% purity values were not obtained in the results of radiolabeling stability analyses; therefore, the addition of a chelating agent in the radiolabeling condition was suggested to increase the stability.

Key Words: lutetium-177, tedizolid, theranostic, infectious diseases

Novel (p-Tolyl)-3(2H)-Pyridazinone Derivatives Containing Substituted-1,2,3-Triazole Moiety as New Anti-Alzheimer Agents: Synthesis, In vitro and In silico Assays

İrem BOZBEY MERDE*°, Gülce TAŞKOR ÖNEL**, Burçin TÜRKMENOĞLU***, Şule GÜRSOY****, Esra DİLEK*****

* ORCID: 0000-0002-9290-938X, Erzincan Binali Yıldırım University, Department of Pharmaceutical Chemistry, Erzincan, Turkey
** ORCID: 0000-0002-9375-2329, Erzincan Binali Yıldırım University, Department of Analytical Chemistry, Erzincan, Turkey
***ORCID: 0000-0002-5770-0847, Erzincan Binali Yıldırım University, Department of Analytical Chemistry, Erzincan, Turkey
**** ORCID: 0000-0001-5236-5974, Erzincan Binali Yıldırım University, Department of Biochemistry, Erzincan, Turkey
*****ORCID: 0000-0002-3629-5168, Erzincan Binali Yıldırım University, Department of Biochemistry, Erzincan, Turkey

° Corresponding Author; İrem BOZBEY MERDE
Phone: +90 446 224 53 44, Fax: +90 446 224 53 43, e.mail: irem.bozbey@erzincan.edu.tr, irembzby@gmail.com

SUMMARY

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is the most common cause of dementia. The risk of developing the disease increases with age. When the histopathology of the disease is examined, senile amyloid plaques, neurofibrillary tangle formation, synapse-neuron loss, and marked atrophy in the brain are detected. The decrease in the level of choline acetyltransferase, which is responsible for the synthesis of acetylcholine in Alzheimer’s disease, is 58-90%. There is a great need for new drugs that target the basis of the cause of the disease, as existing drugs cannot stop the progression of the disease. In this study, triazole-pyridazinone derivative compounds showing acetylcholinesterase inhibition were synthesized and their inhibitions were investigated. Compound 6e exhibited the strongest inhibitory effect with a Ki value of 0.049 ± 0.014 μM (Tacrine Ki=0.226 ± 0.025 μM). In addition, in silico studies were applied for all compounds.

Keywords: 3(2H)-pyridazinone, acetylcholinesterase, molecular docking

Development of Innovative Cosmetic Formulations to Help Fungal Treatment and Testing the Efficiency of Formulations

Fatma Gülgün YENER*°, Caner ACAR**, Berna ÖZBEK ÇELİK***, Emel MATARACI KARA****

* ORCID: 0000-0002-7234-0034, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey
** ORCID: 0000-0002-5063-7515, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey
*** ORCID: 0000-0001-8909-8398, Istanbul University, Department of Pharmaceutical Microbiology, Istanbul, Turkey
**** ORCID: 0000-0003-4541-1893, Istanbul University, Department of Pharmaceutical Microbiology, Istanbul, Turkey

° Corresponding Author; Fatma Gülgün YENER
Tel. +90 212 440 02 91; e.mail: gulgun.yener@istanbul.edu.tr

SUMMARY

In the fungus of hands and toenails, the thickening of the nail and its yellow color is the first signs of attention. The fungus of hands and toenails is mainly caused by Trichophyton rubrum dermatophyte. They have antifungal properties due to the components of lavender oil, geranium oil, and tea tree oil structures. Oral antifungal agents used the treatment of nail fungus can cause serious side effects, especially the liver. Therefore; topical applications have been given importance in recent years. However; in topical applications, antifungal agents have difficulties sending to the target area. Therefore; nanoemulsion technology was preferred in the study. Nanoemulsion formulations of essential oils were prepared using the ultrasonication method. Centrifugal and thermal tests were applied as preliminary stability to the formulations, the pH value, viscosity, droplet size, and polydispersity index of the formulations passing this step were measured, and organoleptic controls were performed. Antifungal efficacy and release studies were performed on the formulations F4P3-I (pelargonium), F4P3-L (lavender), F4P3-C (tea tree), and F4P3-K (mixture), which were successful as a result of all the tests. According to the study, it was concluded that F4P3-I, F4P3-L, F4P3-Ç, and F4P3-K formulations might help in the treatment of fungi.

Key Words: Lavender oil, geranium oil, tea tree oil, nanoemulsion, ultrasonication

Leukotriene D4 Levels In Patients With Breast Cancer

Sevgi AKAYDIN*°, Sümeyye RAMAZANOĞLU**, Ece MİSER SALİHOĞLU***,
Hasan KARANLIK****, Semra DEMOKAN*****

* ORCID: 0000-0002-0927-5188, Department of Biochemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
** ORCID: 0000-0003-3475-6554, Department of Biochemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
*** ORCID: 0000-0003-0681-3566, Department of Biochemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
**** ORCID: 0000-0001-6156-7260, Department of Surgery, Institute of Oncology, University of Istanbul, Istanbul,Turkey.
***** ORCID: 0000-0002-8066-8419, Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey.

° Corresponding Author; Sevgi AKAYDIN,
Phone: +90-312-2023155, e-mail: sevgiy@gazi.edu.tr

SUMMARY

Leukotriene D4 (LTD4) is an inflammatory mediator synthesized from LTC4 via gamma-glutamyltransferase (GGT) enzyme in the arachidonic acid pathway and has been reported to induce cell proliferation and survival in cancer. In recent studies, it has been shown that there is an increase in GGT enzyme activity in breast cancer. In recent studies, it has been shown that there is an increase in GGT enzyme activity in breast cancer. The aim of this study is to determine whether there is a change in serum LTD4 levels in patients with breast cancer and to examine the relationship between LTD4 and GGT. For this purpose, serum samples were taken from 43 patients diagnosed with breast cancer and eight healthy controls. Patients were divided into five subgroups, Luminal A, Luminal B, Luminal B-HER2(+), HER2(+), and triple-negative. LTD4 levels were measured by the ELISA method. Mean levels of LTD4 in the patients were significantly higher than in healthy controls (p < 0.05). Based on the molecular subtypes, serum LTD4 levels were found to be considerably higher in the Luminal A, Luminal B, and Triple (-) subgroups than in the controls (p <0.01, p <0.005, and p <0.005, respectively). Higher levels of LTD4 have been observed in post-menopausal patients than in premenopausal patients (p <0,05). A statistically significant positive correlation was observed between GGT activity and LTD4 levels in the whole study group and post-menopausal patients (R=0.349, p=0.014, and R=0.437, p=0.042, respectively). According to the literature, this study is the first to examine LTD4 levels in breast cancer and supports other studies showing the role of leukotrienes in cancer. Because of LTD4’s ability to induce proliferation and inhibit apoptosis, increased levels of LTD4 in our study may be associated with cancer development, especially in post-menopausal women.

Key Words: Leukotriene D4, Gamma-Glutamyltransferase, Breast Cancer, Post-menopausal Status

Synthesis of 2-Substitutedbenzimidazolium Tetrachloroplatinate(II) Compounds and Their Cytotoxic Activities on Different Cell Lines

Mahmut GÖZELLE*°, Aysun KILIÇ SÜLOĞLU**

* ORCID: 0000-0003-0234-6577, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560, Ankara, Turkey.
** ORCID: 0000-0003-0914-1128, Hacettepe University, Faculty of Science, Department of Biology, 06800, Ankara, Turkey.

° Corresponding Author; Mahmut GÖZELLE
Phone: +903122023223; e-mail: mgozelle@gazi.edu.tr

SUMMARY

The aim of the study was the synthesis of novel platinum compounds having benzimidazole ligands and screening for their in vitro cytotoxic activity on human cervical carcinoma HeLa, human lung carcinoma A549, and human lung epithelial Beas-2B cell lines. 2-Substituted benzimidazole ligands were synthesized by using appropriate aldehydes and o-phenylenediamine. Subsequently, 2-substituted benzimidazole ligands and potassium tetrachloroplatinate(II) (K2PtCl4) were used to synthesize 2-isopropylbenzimidazole tetrachloroplatinate(II) (K1) and 2-(1-methylpropyl)benzimidazole tetrachloroplatinate(II) monohydrate (K2). HRMS, IR, elemental analysis, 1H-NMR, and melting point were used to characterize the synthesized compounds. Cytotoxic activities against HeLa, A549, and Beas-2B cells after 48 h and 72 h incubation of the platinum compounds were investigated via MTT assay. Cisplatin and carboplatin were used as reference drugs. The cytotoxic activity results showed that K2 platinum compound displayed 53.42%±2.21 (at 160 μM) on HeLa, 88.16%±0.22 (at 160 μM) on A549 and 92.09%±0.57 (at 160 μM) on Beas-2B after 48 h incubation, K2 displayed 27.42%±2.03 (at 160 μM) on HeLa, 93.95%±0.53 (at 160 μM) on A549 and 91.99±0.22 (at 160 μM) on Beas-2B after 72 h incubation. Both of the platinum compounds have higher cell inhibitory effects than reference drug carboplatin after 48 h incubation for tested cells.

Key Words: Benzimidazole, platinum complexes, cytotoxic activity, HeLa, A549, Beas-2B.

Exendin-4 Used in the Treatment of Type 2 Diabetes and Current Approaches for Alternative Administration Routes of Exendin-4

Merve ÇELİK TEKELİ*°, Yeşim AKTAŞ**, Nevin ÇELEBİ***

* ORCID ID: 0000-0002-5234-8434, Erciyes Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji Anabilim Dalı, 38238, Kayseri
** ORCID ID: 0000-0002-3427-6078, Erciyes Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji Anabilim Dalı, 38238, Kayseri
*** ORCID ID: 0000-0002-6402-5042, Başkent Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji Anabilim Dalı, 06790, Ankara

º Corresponding Author: Merve ÇELİK TEKELİ
Tel: +90 352 207 66 66 / 28381, Fax: +90 352 437 91 69,
e-posta: mervecelik@erciyes.edu.tr

SUMMARY

Diabetes is a chronic disease due to impaired glucose metabolism and usually presents with uncontrolled hyperglycemia or persistently high blood sugar levels. According to the tenth edition of the International Diabetes Federation, 10% of global health expenditures ($ 966 billion) are spent on diabetes. In Turkey, the prevalence of diabetes is 15%, showing the fastest increase among European countries. Type 2 diabetes is associated with abnormal insulin secretion or chronic insulin resistance, causing desensitization of the glucose uptake cells to insulin activity. Incretin-based therapies have come to the fore in the treatment of Type 2 diabetes in recent years. Exendin-4, which is widely used in incretin-based therapies, binds to GLP-1 receptors with high affinity, causing glucose-dependent insulin secretion in the body, delaying gastric emptying, suppressing glucagon release and appetite. Also, exendin-4 increases cell proliferation and inhibits apoptotic pathways in β-cells. Commercial products of exendin-4 are Byetta® which is administered twice daily and long-acting Byderuon™ which is administered once weekly via parenteral route. The presence of drawbacks of parenteral administration such as problems in patient compliance and feeling of pain due to injection led researchers to search alternative administration routes such as oral, pulmonary, transdermal, ocular, nasal, vaginal and rectal routes. In this review, exendin-4’s properties, mechanism of action, therapeutic efficacy, new approaches and studies on alternative delivery routes of exendin-4 are mentioned.

Key Words: exendin-4, diabetes, oral route, pulmonary route,transdermal route, nanocarriers

Process Validation in Pharmaceutical Industry and Quality by Design (QbD) Approach

Filiz OZUL*, Kübra Rabia CAN**, Serkan BİLGİÇ***, Sevda ŞENEL****, º

* ORCID: 0000-0002-2791-0616, Turkish Medicines and Medical Devices Agency, Head of Inspectorate , 06520-Ankara, Turkey
** ORCID: 0000-0001-7392-9775, Turkish Medicines and Medical Devices Agency, Head of Inspectorate, 06520-Ankara, Turkey
*** ORCID: 0000-0001-8781-1399, Turkish Medicines and Medical Devices Agency, Head of Inspectorate, 06520-Ankara, Turkey
**** ORCID: 0000-0002-1467-3471, Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100-Ankara, Turkey,

º Corresponding Author: Sevda ŞENEL
Phone: +90 312 310 12 41
E-mail: ssenel@hacettepe.edu.tr

SUMMARY

Process validation, which is defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. In the last decade, continuous process verification has been introduced, which is based on a continuous monitoring of manufacturing performance. This approach is based on the knowledge from product and process development studies and/ or previous manufacturing experiences. Continuous process verification may be applicable to both a traditional and enhanced approach to pharmaceutical development. Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. Many pharmaceutical companies are adopting the principles of Quality by Design (QbD) for pharmaceutical development and manufacturing, which enables enhanced process understanding, and a more systematic and scientific approach to pharmaceutical development, so that better controls can be implemented. QbD is considered in examining validation within a product lifecycle framework. In this review, after reviewing the process validation approaches that are described in the current national and international guidelines, the focus will be on QbD and its significance in process validation.

Key Words: Drug production, Process validation ,Quality by Design (QbD) ,PAT ,Continuous process verification

Fabrication and Evaluation of Cationic Charged Magnetic Nanoparticles for Enhanced Gene Delivery

Hasan AKBABA*°, Gülşah EREL-AKBABA**, Ayşe Gülten KANTARCI***

* ORCID: 0000-0001-9273-6346,Ege University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, İzmir, Turkey
** ORCID: 0000-0003-3287-5277, Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, İzmir, Turkey
*** ORCID: 0000-0001-8813-5353, Ege University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, İzmir, Turkey

° Corresponding Author; Hasan AKBABA
Tel. +90 5354026155, e.mail: hasan.akbaba@ege.edu.tr

SUMMARY

Magnetofection; represents nucleic acid delivery by using magnetic nanoparticles (MNPs) under the influence of a magnetic field; gives promising results for gene delivery. However, pharmaceutical and biomedical studies in this area are very limited. To meet this need, we aimed to develop an effective magnetic gene delivery system in this study. The in-situ surface coating method was handled to develop cationic charged MNPs. Three different MNP formulations were obtained and investigated in terms of characterization, DNA binding, protection, and transfection ability. According to the results, the obtained MNPs have particles under 150 nm with a low PDI (<0.3), and positive zeta potential with a spherical shape. The DNA binding and protecting ability from nucleases were shown by agarose gel studies. No significant cytotoxicity was observed on COS-7 cells in the concentration range of 4-20 µL/well. Moreover, transfection studies revealed that the optimal system (GMS-MNP-1) showed significantly higher transfection efficacy comparing the naked plasmid or non-magnetic version of nanoparticle under a magnetic field (p>0.05). Promising results have been obtained with the use of obtained GMS-MNPs in terms of magnetic gene delivery. This work can be extended to in vivo by using disease-specific therapeutic genetic materials.

Key Words: Gene delivery, magnetofection, cytotoxicity, transfection

Synthesis and Antibacterial Evaluation of Novel Benzimidazole, Benzothiazole, Benzofurane, and Naphtofurane Derivatives of Aminothiazoles

Zafer ŞAHİN*°, Büşra Işıl TOK**, Erol AKGÜN***, Ayşegül ÇAŞKURLU****,
Leyla YURTTAŞ*****, Barkın BERK******, Şeref DEMİRAYAK*******

* ORCID: 0000-0002-5976-676X, Department of Pharmaceutical Chemistry, Istanbul Medipol University, Istanbul, Turkey, 34815
** ORCID: 0000-0002-1619-1732, Department of Pharmaceutical Chemistry, Istanbul Medipol University, Istanbul, Turkey, 34815
*** ORCID: 0000-0001-7391-6157, Department of Pharmaceutical Chemistry, Istanbul Medipol University, Istanbul, Turkey, 34815
**** ORCID: 0000-0001-7277-920X, Department of Pharmacognosy, Istanbul Medipol University, Istanbul, Turkey, 34815
***** ORCID: 0000-0002-0957-6044, Department of Pharmaceutical Chemistry, Anadolu University, Eskisehir, Turkey, 26210
****** ORCID: 0000-0001-6047-2796, Department of Pharmaceutical Chemistry, Istanbul Medipol University, Istanbul, Turkey, 34815
******* ORCID: 0000-0002-0841-1299, Department of Pharmaceutical Chemistry, Istanbul Medipol University, Istanbul, Turkey
° Corresponding Author;Zafer Şahin
Tel. +90 2166815100,
Fax: 2125317555,
e.mail: zsahin@medipol.edu.tr, sahinzfr@gmail.com

SUMMARY

The thiazole ring is the core of bioactive molecules that generate broad activity. These activities include anticonvulsant,
antimicrobial, antituberculosis, antiviral, etc. In this work, starting from seconder/cyclic amines, new compounds containing thiazole and benzimidazole/benzothiazole/benzofurane/naphtofurane rings were synthesized, and their antimicrobial effects were evaluated. 9 compounds were synthesized by converting the seconder and cyclic amines to thiourea, and continued by thiazole ring closure. Ring closure was achieved by methylene-carbonyl condensation except conventional methods. Compound characterization was realized by FT-IR, 1H NMR and 13C NMR and HRMS. Compounds did not show significant activity on bacterial strains. Nine aminothiazole derivatives have been synthesized successfully. Compounds did not show important antibacterial activity and thus were evaluated as inactive.

Key Words: antibacterial, aminothiazole, benzothiazole, benzofurane, naphtofurane

A Cosmetic Nanoemulsion Against Seborrheic Dermatitis: Development, Characterization and Effectiveness

Feda DALO*, Fatma Gülgün YENER**°, Ebru ALTUNTAŞ***, Sibel DÖŞLER****

* ORCID ID: 0000-0002-4113-4596, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey,
** ORCID ID: 0000-0002-7234-0034, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey,
*** ORCID ID: 0000-0003-2902-5554, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey,
**** ORCID ID: 0000-0001-5223-4755, Istanbul University, Department of Pharmaceutical Microbiology, Istanbul, Turkey,
° Corresponding Author; Fatma Gülgün Yener
Tel. +90 212 440 02 91, Fax: +90 212 440 02 52,
e.mail: gulgun.yener@istanbul.edu.tr

SUMMARY

In this study, it was aimed to develop a topically applicable nanoemulsion (NE) that is expected to have an ameliorating effect in seborrheic dermatitis (SD). The main purpose of the formulation is to eliminate the disease factor, to repair the damage caused by the disease on the skin and to smooth the skin appearance by moisturization. For this reason, in vitro antimicrobial effect and in vivo effectiveness of the formulation were tested. For this aim; essential oils from tea tree, sage, cinnamon, oregano; extracts from Aloe vera, colloidal oatmeal, liquorice; vegetable oils from grape seed and sesame, and honey were used in a NE formulation. The NEs were prepared by ultrasonication method. Preliminary stability tests were applied to all formulations and then, pH, conductivity, viscosity, average droplet size, polydispersity index (PDI), and zeta potential measurements were taken on the selected NEs for 3 months. Finally, the antimicrobial effect and in vivo effectiveness of the optimum NE were tested. The average droplet size, PDI, and zeta potential value of the optimum formulation (F6P2) were 108.40 ± 0.90 nm, 0.195 ± 0.07, and -21.40 ± 1.45 mV, respectively. As a result, the moisture content of the skin increased significantly (p < 0.001), the sebum and redness values significantly decreased (p = 0.008 and 0.001, respectively) and there was no significant change in the pH of the volunteers’ skin. Accordingly, it can be concluded that the optimum NE formulation developed in this study may be beneficial as a supplement for patients with SD.

Key Words: Seborrheic dermatitis, nanoemulsion, herbal cosmetic, efficacy tests, essential oils, plant extracts, vegetable oils, honey

Studying the Protective Effect of Ellagic Acid Against High Glucose-Associated Toxicity in H9C2 Cardiomyocytes

Elham KESHAVARZI*, Azadeh AMINZADEH**,***,°

* Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
** ORCID: 0000-0001-8293-1180 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
*** Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
° Corresponding Author; Azadeh AMINZADEH, Ph.D., Assistant Professor of Pharmacology,
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

Tel: +98-34-31325247, Fax: +98-34-31325003, e-mail: a.aminzadeh@kmu.ac.ir; azadehaminzadeh@yahoo.com

SUMMARY

Diabetes mellitus leads to an increased risk factor for cardiovascular diseases. Accumulating evidence has demonstrated that high glucose (HG) can promote massive apoptosis in cardiomyocytes. Oxidative stress has been known as main factor responsible for HG-induced apoptosis. Ellagic acid, a natural phenolic compound, exhibits anti-inflammatory, anti-atherogenic, and antioxidant effects. This study was carried out to evaluate the effects of ellagic acid on HG-induced oxidative damage in H9C2 cells. The effect of ellagic acid on the viability of cells was evaluated by the MTT method. The oxidative stress parameters, including levels of malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), and superoxide dismutase (SOD) activity were also measured. The results indicated that ellagic acid (10 μM and 20 μM) could remarkably enhance the cell viability of H9C2 cells exposed to HG. In addition, ellagic acid significantly improved the levels of intracellular GSH, TAC, and SOD, whereas the levels of MDA were attenuated. These results revealed a protective effect of ellagic acid on HG-induced cytotoxicity, at least partially, by increasing antioxidant activity and preventing oxidative stress.

Key Words: H9C2 cells, high glucose, ellagic acid, cardiotoxicity, oxidative stress

Evaluation of Anti-Inflammatory Activity of Metronidazole Treatment On Carrageenan Induced Paw Edema in Mice

Inci KAZKAYASI*°, Gokcen TELLI**

*ORCID: 0000-0003-1159-9680, Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
** ORCID: 0000-0003-0028-6769, Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey

° Corresponding Author; Inci KAZKAYASI
e-mail: inci.kazkayasi@hacettepe.edu.tr

SUMMARY

Metronidazole is a nitroimidazole derivative antibiotic that has been used against protozoa and anaerobic organisms for a long time. Furthermore, it has been used in non-infectious inflammatory diseases such as acne, Crohn’s disease, periorificial dermatitis, rosacea and seborrheic dermatitis recently. However, the studies about this issue are very few and its mechanism of action is unknown. The aim of our study is to evaluate the possible anti-inflammatory activity of metronidazole in vivo by using the mice- carrageenan-induced paw edema method. Mice were administered a single dose of 2, 20 or 200 mg/kg metronidazole via oral gavage. One hour later, 2% carrageenan was injected subplantar to the hind paws. The paw thickness of mice was measured just before the carrageenan injection and at 1, 2, 3, 4, 24 and 48 hours after injection by dial thickness gauge. For comparison, another group of mice received indomethacin (10 mg/kg, orally) used as a reference drug. IL-1β and TNF-α levels in the paws of mice were measured by the ELISA method. ANOVA (post-hoc Bonferroni) and Student’s t tests were used for statistical analysis. Metronidazole displayed equi-potent antiinflammatory activity with indomethacin in the carrageenan-induced mouse paw edema model. It is shown that less edema occurred at all doses (2, 20 and 200 mg/kg) compared to the control group and no differences were obtained in effect between the doses. It was observed that in metronidazole treated groups, paw thickness returned to baseline values 48 hours after carrageenan injection, unlike the control group. IL-1β and TNF-α levels, which were increased with carrageenan injection, were significantly decreased with metronidazole treatment. In our study, metronidazole was found to be anti-inflammatory due to its effects on relieving edema and reducing pro-inflammatory cytokines in the paws of carrageenan-induced mice. The effectiveness of metronidazole in treating various non-infectious diseases in recent years may be due to its antiinflammatory activity.

Key Words: Metronidazole, anti-inflammatory activity, mouse, paw-edema test

Design and Characterization of Fluconazole Loaded Elastic Liposome Based Gel for Treatment of Keratomycosis

Ravika NANDA*, Mehak**, Ramandeep Singh NARANG***, Jasjeet Kaur NARANG****°

* ORCID ID: 0000-0003-3676-3221, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, India
** ORCID ID: 0000-0002-1673-6384, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, India
*** ORCID ID: 0000-0002-2036-3883, Department of Oral and Maxillofacial Pathology, Sri Guru Ram Das Institute of Dental Sciences and Research, Amritsar, India.
****° ORCID ID: 0000-0002-2265-7711, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, India

° Corresponding Author; Dr. Jasjeet kaur Narang
Tel. 7837221174, e-mail: jasjeet2975@yahoo.com

SUMMARY

Fungal corneal ulcers, also known as keratomycosis, occur due to a breach in the corneal epithelium. According to WHO, it is the leading cause of blindness. The eye consists of a variety of different structures having different physiological functions that make it highly resistant to external substances, thus resulting in low bioavailability of drugs from most of the conventional dosage forms. To improve drug effectiveness, a series of research groups have tried a variety of strategies. The majority of these modifications provide some benefit over traditional dosage forms, but they have their own set of drawbacks. To overcome the side effects of the formulations mentioned above, Fluconazole-loaded elastic liposome-based gel was prepared. The elastic liposomes were prepared by rotary evaporation method using soya lecithin and sodium deoxycholate. The elastic liposomal suspension was then incorporated into optimised gelling agent (carbopol 934) to have sufficient contact time of the drug in the eye. The elastic liposome-based gel was then characterized for pH, drug content, rheological study, homogeneity and grittiness, in vitro release study, ex vivo permeation study, toxicity study, bio adhesion study and antifungal activity. The optimized formulation had pH 7.0 ± 0.01, drug content 98.5 ± 3.9%, viscosity 7217 ± 340 mPa.s, in vitro release 80.5± 0.32%, ex vivo permeation 72.27±0.65 % and the bio adhesion time of the optimized formulation was found to be significantly higher (p≤ 0.05) as compared to marketed gel. Antifungal activity of the optimized gel was also found to be significantly higher (p≤ 0.05) as compared to the marketed gel. The Fluconazole-loaded elastic liposome gel was prepared successfully and was found to be a good choice over conventional gel formulation for the treatment of keratomycosis.

Key Words: Fungal corneal ulcers, Fluconazole, elastic liposomal gel, antifungal activity.

Potential Use of Breadfruit (Artocarpus altilis) Leaf Extract to Recover Hepatic and Renal Damage in Alloxan-Induced Diabetic Rats

Hesty SETİAWATİ*, Yulia Yusrini DJABİR**o, Hardi HARDİ***, Subehan LALLO****, Muhammad Husni CANGARA*****

**ORCID: 0000-0001-5705-4737, Hasanuddin University, Graduate Program, Faculty of Pharmacy, Makassar, Indonesia
** ORCID:0000-002-5891-7247, Hasanuddin University, Department of Pharmacy, Faculty of Pharmacy, Makassar, Indonesia
*** ORCID: 0000-003-0599-1854, Hasanuddin University, Graduate Program, Faculty of Pharmacy, Makassar, Indonesia
**** ORCID 0000-003-1746-1682, Hasanuddin University, Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Makassar, Indonesia
***** ORCID: 0000-002-5160-8265, Hasanuddin University, Faculty of Medicine, Department of Anatomical Pathology, Makassar, Indonesia

° Corresponding Author; Yulia Yusrini DJABİR
e-mail: yuliayusrini@unhas.ac.id

SUMMARY

The antihyperglycemic effect of breadfruit leaf (Artocarpus altilis) extract has been demonstrated in a preclinical study using an alloxaninduced diabetic model. This study aimed to examine whether breadfruit leaf extract also ameliorated liver and kidney injury in alloxan-induced diabetic rats. Male Wistar rats (n=35) were used in the study. All other animals except control group (group I, n=5) were injected with alloxan (155 mg/kg body weight). After 3 days, the hyperglycemic rats with blood glucose >200 mg/dl were divided into 4 treatment groups: placebo (alloxan group), Breadfruit Leaf (BL) extract 100 mg/kg, BL extract 200 mg/kg, and BL extract 400 mg/kg. Treatments were administered daily for 14 days, and blood samples were drawn at baseline, after alloxan injection, and following treatments to obtain serum glutamic pyruvic transaminase (SGPT) and creatinine levels. Alloxan was found to cause a significant increase in rat blood glucose, SGPT, and creatinine levels three days post alloxan injection (P<0.01). After treatment, rats that received 200 mg/kg and 400 mg/kg BL extracts had significantly lower SGPT
levels compared to those treated with placebo alone (P<0.05). Liver histological damage was also significantly alleviated, especially with the 400 mg/kg dose of BL extract. Although serum creatinine level was restored, alloxan-induced tubular degeneration in renal tissue was still evident. In conclusion, BL extract at a dose of 400 mg/ kg improved alloxan-induced liver dysfunction and tissue damage but was less effective at alleviating kidney damage. This result may support the use of breadfruit leaf extract as herbal drug with a hepatoprotective effect.

Key Words: Breadfruit leaf, Artocarpus altilis, diabetic rats, alloxan, liver damage, kidney damage

Competency of Lyophilization and Spray Drying Techniques to Improve the Solubility of Bosentan Monohydrate: A Comparative Study

Safvan Ali CHEMBAN*, Lakhvir KAUR**o, Gurjeet SINGH***,
Ravi Kumar DHAWAN**** Anureet KAUR***** and Lovepreet SINGH******

* ORCID: 0000-0001-7054-022X, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
** ORCID: 0000-0001-8091-2365, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
*** ORCID: 0000-0003-4399-4693, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
**** ORCID: 0000-0002-8587-6807, Department of Pharmacology, Khalsa College of Pharmacy, Amritsar, Punjab, India
***** ORCID: 0000-0002-2158-9569, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
****** ORCID: 0000-0003-3217-9431, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India

° Corresponding Author; Dr. Lakhvir Kaur
Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar
E-mail: lakhvir86@gmail.com

SUMMARY

The present study focused on comparing the efficacy of two novel techniques, lyophilization and spray drying, which were proposed to overcome the solubility drawbacks of the highly effective antihypertensive drug, bosentan monohydrate. Solid dispersion approach is the most globally acknowledged and successful method for improving solubility. Poloxamer 188 was used as the carrier to prepare the solid dispersions. The results indicated that the particle size, solubility, and dissolution profiles of formulated amorphous systems varied significantly. Lyophilized solid dispersions demonstrated the highest level of solubility in the prepared solid dispersions. The solid dispersion formulations FL10 and FS10 prepared using lyophilization and spray drying techniques were optimized using
a 32 full factorial design approach. The resulting amorphous solid dispersions were characterized using Fourier-transform infrared spectroscopy (FTIR), particle size analysis, differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The optimized solid dispersion (FL10) prepared via lyophilization had an average particle size of 450.9 nm in particle size analysis.
X-ray diffraction analyses of both FL10 and FS10 revealed a decrease in peak intensity compared to the drug and polymer, indicating the transformation of the crystalline form to amorphous. The outcomes of this study allow us to conclude that even though lyophilization and spray drying can be used to enhance solubility, lyophilization showed
superior results.

Key Words: Solid dispersion, lyophilization, spray drying, solubility enhancement, hypertension

Conductor of the Astrocyte-Neuron Metabolic Orchestra

Menizibeya O. WELCOME*º

* ORCID: 0000-0001-5737-4626, Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Nile University of Nigeria, Abuja

º Corresponding Author: Menizibeya O. Welcome MD, Ph.D, Chief,
Tel: +2347059151388; e-mail: welcome.menizibeya@nileuniversity.edu.ng

SUMMARY

Disorders such as diabetes mellitus, obesity, Parkinson’s, and Alzheimer’s diseases are characterized by central metabolic dysfunctions and pose an enormous economic burden to public health. Annually, several millions of new cases and deaths are reported worldwide, thus substantiating the need to search for new frontiers in combating the growing prevalence and mortality of these diseases. Over the past few years, scientific evidence has consistently shown that the functional sweet taste receptor, T1R2+T1R3 heterodimer, serves to direct (conduct) peripheral glucose metabolism. Recent data have revealed that this heterodimer can also act as a central glucosensor that conducts cerebral glucose metabolism. Emerging reports have confirmed the central role of this receptor as a driver of glucose metabolism in neurons and astrocytes. In this paper, “metabolic orchestra” is used to depict the organizational complexity of the plasma membrane receptor-network involved in coordinating glucose transport and metabolism in the astrocyte-neuron circuitry. In light of recent works, suggesting that the taste receptor is a crucial central glucosensor and master coordinator of glucose metabolism, here, the T1R2+T1R3 heterodimer is referred to as the metabolic conductor of the astrocyte-neuron circuitry, responsible for a highly coordinated signaling of glucose molecules and multi-directional cross-talk with other plasma membrane receptors. This concept represents a shift on the astrocyte-neuron metabolic machinery from the GLUT- 2 mediated entry of glucose to a more coordinated one, involving multiple players at the plasma membrane. Research focusing on the treatments of brain disorders involving glucose metabolic dysfunctions is also discussed.

Key Words: T1R2+T1R3; cerebral sweet taste receptor antagonists; glucosensors; metabolic conductor; metabolic orchestra; cerebral diseases

Recent Advancements in Antipsoriatic Therapy: An Update

Shaik SHAFIULLA* , Suneela DHANESHWAR **, o

* ORCID: 0000-0002-6620-9558, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Noida, U.P. India
** ORCID: 0000-0001-7646-642X, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Noida, U.P. India

º Corresponding Author: Suneela DHANESHWAR
Phone: +91 9850125430; e-mail: sdhaneshwar1@lko.amity.edu

SUMMARY

Psoriasis is a chronic inflammatory, a multisystem autoimmune disease ith extreme pathological features and unsatisfied pharmacotherapeutic needs. Primarily psoriasis is associated with epidermal cells, keratinocyte hyperproliferation, inflammation, dermal capillary dilation, and proangiogenic mechanisms. Compared with other chronic diseases, patients with psoriasis have severe psychological stress and undergo reduced physical activeness, cognitive dysfunctions, and low-quality life. Pathophysiology is complex with the involvement of various mediators like interleukin- (IL)-17, IL-23, tumor necrosis factor-alpha (TNF-α), interferongamma (IFN-γ), and vascular endothelial growth factor (VEGF) that play a significant role in escalation and localizing the inflammation caused in psoriasis. However, acquiring uninterrupted knowledge of psoriasis pathophysiology allows us to identify the novel therapeutic targets that could be explored to overcome personalized psoriasis treatment challenges. Conventional therapy includes corticosteroids, vitamin-D, methotrexate, and cyclosporine, but with low efficacy and severe side effects and sometimes causing disease comorbidities. New biologics approved by FDA during 2016-2019, such as IL-23 blockers risankizumab-rza, guselkumab, and tildrakizumab-asmn, certolizumab pegol targeting TNF-α, IL-17 blockers brodalumab and ixekizumab have revolutionized the treatment of moderate to severe psoriasis due to targeted approach but are reported to possess many side effects leading to low patient compliance. Biosimilars of adalimumab, etanercept, and infliximab, designed by reverse engineering of biologics, are also becoming popular due to their cost-effectiveness. Drug repurposing focuses mainly on defining new medical uses for old drugs. The main focus of drug repurposing is how the drug molecule interacts with various targets and executes its pharmacological action, revealing the new possibilities of designing effective therapeutic agents with low toxicity.

Key Words: Psoriasis; Drug repurposing, Angiogenesis, Vascular
endothelial growth factor, Keratinocyte proliferation, TNF-α, IFN-γ,
Th-17/Th-23 pathway

Novel Glitazones Reverses Hyperglycemia In STZ Induced Hyperglycaemic Rat Model

Chandan HIRENALLURE MAHESHWARAPPA* , Krishna KAMSAGARA
LINGANNA**° , Prashanth Kumar BOMMENAHALLI REVANAPPA*** , Seema
MEHDI**** , Shreyas AYACHIT***** , Suman SUMAN****** , Nandini HITTANAHALLI
SHIVAKUMAR******* , Sneha DESAI******** , Swerna ESWARAN*********

* ORCID: 0000-0003-2395-2699, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
** ORCID: 0000-0001-7538-0798, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
*** ORCID: 0000-0001-9503-741X, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
**** ORCID: 0000-0002-3212-0774, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
***** ORCID: 0000-0002-7662-4413, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
****** ORCID: 0000-0003-0977-4953, Department of Dravyaguna, Govt. Ayurvedic Medical College & Hospital, New Sayyajiroa Raod, Mysuru-570001, Karnataka, India
******* ORCID: 0000-0003-0750-6373, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
******** ORCID: 0000-0001-7063-4728, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India
********* ORCID: 0000-0003-1185-4442, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru -570015, Karnataka India

° Corresponding Author; Krishna KAMSAGARA
Tel. +91 9886610010, Fax- 0821-2548359, e-Mail: klkrishna@jssuni.edu.in

SUMMARY

Diabetes mellitus is the most common chronic metabolic disorder characterized by reduced secretion of insulin or sensitivity to the insulin. It is also a disease of inadequate control of glucose levels in the blood plasma. The present study was formulated to assess the novel glitazones for hypoglycaemic activity in STZ induced rat model. Before in-vivo studies, thirty-two virtual compounds of novel glitazones were subjected to the molecular docking study. The docking
study showed that, the compounds C5 and C22 showed the better binding activity with the target protein 3CS8. The acute toxicity studies were done on female rats using OECD guideline 425. No mortality observed at 300 mg/kg per kg body weight and based on this result, the dose for in-vivo studies was chosen. The compounds C5 and C22 were evaluated for the hypoglycaemic activity at 10 and 20 mg/kg body weight in STZ induced hyperglycaemic rats. The compound C5 at both the dose (10 mg and 20 mg/kg) showed the better activity than C22, where as C22 exhibited better activity at higher dose when tested. The activity was assessed by behavioural and biochemical parameters, on 0th ,7 th, 14 th and 21st day. The study duration was three weeks, on 21st day, the animals were sacrificed and biochemical estimations were done. The compound C5 showed significant activity when compared with C22. The current findings gives a lead for further research to prove the hypoglycaemic activity of novel glitazones at molecular level by employing some more research models.

Key Words: Molecular docking, PPARγ, glitazones, diabetes, 3CS8, lipid profile.

Development and Characterization of Nano-Sized Emulsion Systems Incorporated Polyphenolic Compound for Application Through the Skin

Bülent SAMANCI*o , Fatma Gülgün YENER** , İsmail Tuncer DEĞİM***

* ORCID: 0000-0002-7198-5375, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey
** ORCID: 0000-0002-7234-0034, Istanbul University, Department of Pharmaceutical Technology, Istanbul, Turkey
*** ORCID: 0000-0002-9329-4698, Biruni University, Department of Pharmaceutical Technology, Istanbul, Turkey

° Corresponding Author; Bülent Samancı
Tel. +90 412 241 10 00 / 7531; e.mail: bulent.samanci@hotmail.com

SUMMARY

In addition to having strong anti-oxidant properties, resveratrol has anti-cancer, anti-angiogenic, cardioprotective, anti-diabetic, antiviral, and neuroprotective activities. Despite its rapid absorption, first-pass effect and intestinal metabolism reduce the bioavailability of resveratrol. Moreover, the lipophilic property of resveratrol reduces its water solubility and metabolized in high incidence reduces its oral bioavailability. Therefore, it was aimed to develop an optimum formulation for the skin application of resveratrol to overcome the negatives after oral administration.Since their easy formulation, thermodynamically stable properties, and facilitating the delivery of both lipophilic and hydrophilic active ingredients, loading resveratrol to microemulsions (MEs) will be a suitable delivery system to overcome the drawback of stability problems and skin bioavailability of resveratrol. A Triangle phase diagram was constructed, and the MEs region was determined by points studies. Subsequently, some formulations were selected within the transparent region by considering characteristics required to achieve optimized transdermal drug delivery. Chosen formulations were exposed to pre-stability tests such as centrifuge and thermal stress tests. Characterization studies such as droplet size, size distribution, zeta potential, viscosity, pH measurement were performed on remained intact formulations after pre-stability tests. In terms of the characterization test results such as pH, viscosity, conductivity, there wasn’t found significant difference observed between formulations. However, polydispersity index and zeta potential values provided to choosing optimal formulation.

Key Words: Microemulsion, Penetration enhancers, Resveratrol, Transdermal Drug delivery, Triangle phase diagrams

Effect of Solvent Polarity on Extraction Yield of Total Flavonoids with Special Emphasis to Glabridin from Glycyrrhiza glabra Roots

Sadanand YEWALE* , Zeba FARASH** , Shrikant KULKARNI*** , Shital PALGHADMAL**** , Neelam ATHAWALE***** , Laxman SAWANT****** , Shrinivas BHOPE******* , Sriram PADMANABHAN********°

* ORCID: 0000-0003-4613-3012, Herbal Division, Sava Healthcare Limited, Research Center, MIDC, Chinchwad, Pune, India.
** ORCID: 0000-0002-0225-910X, Analytical Development Laboratory, Sava Healthcare Limited, Research Center, MIDC, Chinchwad, Pune, India.
*** ORCID: 0000-0002-1981-5651, Analytical Development Laboratory, Sava Healthcare Limited, Research Center, MIDC, Chinchwad, Pune, India.
**** ORCID: 0000-0002-8998-3044, Herbal Division, Sava Healthcare Limited, Research Center, MIDC, Chinchwad, Pune, India.
***** ORCID: 0000-0003-1664-0443, Ayush Center of Excellence, Interdisciplinary School of Health Sciences, Center of Complementary and Integrative Health,
Savitribai Phule Pune University, Pune, India.
****** ORCID: 0000-0002-3037-9168, Dabur Research and Development Center, Ghaziabad, India,
******* ORCID: 0000-0002-1723-8002, Analytical Development Laboratory, Sava Healthcare Limited, Research Center, MIDC, Chinchwad, Pune, India.
******** ORCID: 0000-0001-8049-3703, Sava Healthcare Limited, Research Center, Block D1, Plot No. 17/6, MIDC, Chinchwad, Pune-411019, India

° Corresponding Author; Dr. Sriram Padmanabhan
Phone: +91-20-68181222; e-mail: sriram.p@savaglobal.com

SUMMARY
Different organic solvents (ethanol, dichloromethane, ethyl acetate and acetone) were studied for their effects on the extraction efficiency of glabridin and total flavonoids (TF) from Glycyrrhiza glabra roots. The extract yield of Glycyrrhiza glabra roots was in the range of 3% to 6% following the extraction efficiency in the order ethanol>acetone>ethyl acetate>dichloromethane. A higher extraction yield of TF and glabridin was obtained with dichloromethane, followed by ethyl acetate, acetone and ethanol, indicating that the non-polar solvents help in optimal extraction of TF and glabridin. We also demonstrate for the first time, that the extraction efficiency of the flavonoids is not significantly affected by the use of the recovered solvents except in case of ethanol which reflects that the moistureabsorbing capacity of the solvent dictates the extraction efficiency of such compounds. The glycyrrhizin content in all the extract types was rather low (0.1 % to 1%) except for extract prepared with water, where the glycyrrhizin content was ~10% as expected since glycyrrhizin is a polar compound. Interestingly, we observed that ethyl acetate selectively isolated only glabridin with no traces of glycyrrhizin, which is a finding reported for the first time.

Key Words: Licorice, Glabridin, Flavonoids, Glycyrrhizin, Extraction, Solvent polarity

COVID-19: Mutated Strain, Treatment Options and Vaccine Development

Ayushi MAHAJAN* , Lakhvir KAUR**º , Gurjeet SINGH*** , RK DHAWAN**** , Anureet KAUR*****

* ORCID: 0000-0002-8666-4523, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
** ORCID: 0000-0001-8091-2365, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
*** ORCID: 0000-0003-4399-4693, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
**** ORCID: 0000-0002-8587-6807, Department of Pharmacology, Khalsa College of Pharmacy, Amritsar, Punjab, India
***** ORCID: 0000-0002-2158-9569, Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India

º Corresponding Author: Dr. Lakhvir Kaur
e-mail: lakhvir86@gmail.com

SUMMARY

The ongoing outbreak of the COVID-19 is a significant threat to global health and the economy. This disease is a highly contagious pathogenic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has a high reproduction rate, due to that it is highly transmittable and has turned into a catastrophe. Scientists and researchers worldwide are exaggerating every possible approach to limit the spread of this malicious disease. An abrupt rise has been reported in the number of cases due to newly mutated strains like SARS-CoV-2 VUI 2020/12/01. To date, no specific drug is effective in the complete eradication of this dangerous disease but, some broad-spectrum antivirals such as Remdesivir and Lopinavir are being used in the management of this ailment. Also, every possible effort has been made in the development of vaccines for preventing the outbreak of this deadly virus. The BNT162b2 by Pfizer and m-RNA-1273 by Moderna have been recently launched into the market, which have shown undesirable effects in geriatrics leading to mortality. In this review, we have tried to highlight important aspects of the COVID-19 that will aid in global awareness and will help the researchers to investigate possible ways to eradicate this menace and design new moieties for its effectual management.

Key Words: COVID-19, SARS-CoV-2, Mutations, Spike protein, Pandemic, Vaccine.

Neuroprotective Therapy with Citicoline and Piracetam at Acute Cerebrovascular Disease: Clinical and Psychosomatic Effects

Iryna SOKOLOVA*° , Serafima TAZINA** , Oksana ZAKHAROVA***

* Orcid ID: 0000-0002-3102-2910, Department of Practical Psychology, Ukrainian Engineering and Pedagogical Academy, Kharkiv, Ukraine;
** Orcid ID: 0000-0003-3676-3467, Department of Therapy, Sechenov First Moscow State Medical University, Moscow, Russian Federation;
*** Orcid ID: 0000-0003-0249-5257,Department of Organization and Economics of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation

° Corresponding Author; Iryna SOKOLOVA
Phone: +380503642304; E-mail: sokolovairr@ukr.net

SUMMARY

Contemporary pharmacological market is well developed, suggesting a wide choice of medical preparations for treating various disorders. Particular attention is paid to the group of diseases related to cerebrovascular accidents as the complications and consequences are often unfavorable. A study was conducted in the post-Soviet countries and aimed to determine the effect and efficacy of using neuroprotective drugs in the treatment of cerebrovascular disease,
taking into account the psychosomatic effect in patients. Two preparations were chosen for the study, namely, Citicolin and Piracetam. The main purpose was to compare the effectiveness and necessity of these drugs in improving the patients` condition and reducing the effects and mortality. The results of this study and works of other scientists proved a higher efficacy of using Citicolin compared to Piracetam. Among 680 patients (100%) receiving Citicolin as a neuroprotective therapy, 625 (91.9%) patients noted improvement in general condition already after three days. Of 405 patients (100%) receiving Piracetam, the regression of neurological symptoms occurred on the 4th or 5th day of treatment. The improvement of visual functions was noted in 26 patients from Citicolin group and only in 3 patients who received Piracetam as neuroprotective therapy.

Key Words: Ischemic stroke, citicoline, piracetam, neuroprotective therapy, psychosomatic effect

Molecular Investigation of Carbapenem and Colistin Resistance Mechanisms in Klebsiella pneumoniae Bloodstream Isolates

Neslihan GENİŞEL*° , Nida ÖZCAN** , Kadri GÜL*** , Nezahat AKPOLAT**** , Selahattin ATMACA***** , Levent KENAR****** , Nurten ALTANLAR******* , Tuba DAL********

* ORCID: 0000-0002-2579-1932, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Dicle University, Diyarbakir, Turkey
** ORCID: 0000-0001-6898-7516, Department of Medical Microbiology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
*** ORCID: 0000-0002-4642-0276, Department of Medical Microbiology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
**** ORCID: 0000-0002-8653-6046, Department of Medical Microbiology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
***** ORCID: 0000-0002-2730-5790, Department of Medical Microbiology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
****** ORCID: 0000-0002-6613-1308, Department of Medical CBRN Defense, University of Health Sciences, Ankara, Turkey
******* ORCID: 0000-0003-2977-2269, Department of Pharmaceutical Microbiology, University of Ankara, Ankara, Turkey
******** ORCID: 0000-0002-4245-1534, Department of Clinical Microbiology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara,

° Corresponding Author; ; Neslihan GENİŞEL
Tel: +90 412 2411000 - 7545; e-mail : ngenisel@gmail.com

SUMMARY

Carbapenem-Resistant Klebsiella pneumoniae (CRKp) infections are worrying health problems due to decreasing treatment options. This study investigates the carbapenemase (OXA-23,24, 48, 51, 55, 58, KPC, NDM-1, VIM, IMP) and mcr-1 genes of the CRKps isolates A total of 33 CRKp isolates isolated from patient blood samples from the Dicle University Medical Faculty Hospital, intensive care units (ICUs) between February 2020 and June 2020, were included in the study. The presence of carbapenemase encoding genes -including all CRKp isolates, bla OXA-23, 24, 48, 58, bla KPC, blaNDM-1, bla VIM, bla IMP- were investigated by multiplex Polymerase Chain Reaction (PCR). CRKp isolates were
tested for mcr-1 gene and bla OXA-51, bla OXA-55 genes by monoplex PCR. All CRKp isolates studied with Kirby Bauer Disc Diffusion Method (DDM) (100%) were resistant to ertapenem, 9 (27.27%) resistant to imipenem, and 23 (69.70%) were resistant to meropenem. 20 (60.61%) of the isolates were found resistant to colistin. bla OXA-48, bla NDM-1 and bla OXA-24 genes were found in 75.76% (n = 25), 6.06% (n = 2) and 3.03% (n = 1) isolates, respectively. Both bla OXA-48 and bla NDM-1 genes were detected in two (6.06%) isolates and mcr-1 gene in 16 (48.48%) isolates. While the mean hospitalization was 20.3 days in 13 patients with a colistin minimum inhibitory concentration (MIC) of 2
μg/ml, it was 33.9 days in 20 patients with a colistin MIC of > 2 μg/ml. The average length of stay in the hospital was 21.8 days in mcr-1 negative patients and 35.7 days in mcr-1 positive patients. Carbapenemase and mcr-1 positivities were found at dramatically high rates in Diyarbakır, Turkey. It was indicated that plasmid-mediated antimicrobial resistance in Kp isolates was problematic. Each hospital should monitor the colistin and carbapenem resistance mechanisms by molecular methods. Colistin resistance should be confirmed by the broth microdilution method (BMD).

Key Words: Klebsiella pneumoniae, carbapenemase, bla OXA-48, mcr-1, multiplex PCR, broth microdilution.

Association Between TP53 Gene Polymorphism and Obesity

Mehmethan CİHAN* , Hakan BULUŞ** ° , Onur DİRİCAN*** , Serpil OĞUZTÜZÜN**** , Doğan ÖZTÜRK***** , Abdulkadir ÜNSAL****** , Ahmet Oğuz ADA******* , Mümtaz İŞCAN********

* ORCID: 0000-0001-8701-754X, University of Health Sciences; Keçiören Training and Research Hospital, General Surgery Department; Ankara/Turkey
** ORCID: 0000-0001-7439-8099, University of Health Sciences; Keçiören Training and Research Hospital, General Surgery Department; Ankara/Turkey
*** ORCID: 0000-0003-0511-6611, Kırıkkale University Faculty of Science; Department of Biology, Kırıkkale/Turkey
**** ORCID: 0000-0002-5892-3735, Kırıkkale University Faculty of Science; Department of Biology, Kırıkkale/Turkey
***** ORCID: 0000-0003-1754-9246, University of Health Sciences; Keçiören Training and Research Hospital, General Surgery Department; Ankara/Turkey
****** ORCID: 0000-0002-7989-4232, University of Health Sciences; Keçiören Training and Research Hospital, General Surgery Department; Ankara/Turkey
******* ORCID: 0000-0001-9987-0572, Ankara University Faculty of Pharmacy Department of Toxicology; Ankara/Turkey.
******** ORCID: 0000-0001-5839-4987, Cyprus International University, Faculty of Pharmacy, Lefkoşe, Turkish Republic of Northern Cyprus.

° Corresponding Author; Hakan BULUŞ
Tel.: +90-312 356 90 00 / 1158; e-mail: hakan_bulus6@hotmail.com

SUMMARY

Obesity is a chronic disorder with increasing prevalence worldwide and occurs when energy intake is greater than energy expenditure. Obesity is one of the factors that cause oxidative stress and arises from an imbalance between the reactive oxygen species (ROS) and the cell’s antioxidant defense system. Increasing ROS in obesity, influencing the hypothalamic neurons, affects hunger and satiety control, so correspondingly on body weight control. When ROS amount
increases, through DNA, protein and lipid oxidation, cell damage, necrosis, and apoptosis take place. Tumor protein p53, the guardian of the genome, is responsible for the regulation of genes involved in apoptosis as well as energy generating metabolic pathways. In our study, we investigated the TP53 (Arg72Pro) polymorphism in 151 patients diagnosed with obesity. TP53 mutation (rs1042522) was determined by real-time PCR. In 8 patients, the TP53 mutation was
identified as carrying heterozygous (Arg72Pro) and in 143 patients carrying homozygous (wild type) (Arg72Arg). No individual with a homozygous mutant (Pro72Pro) genotype was found in the studied group. Associations between TP53 genotypes and clinical obesity parameters such as body mass index, thyroid stimulating hormon, glucose, postprandial blood sugar, triglyceride and cholesterol levels were compared statistically. According to the results of statistical
analysis, it was observed that TP53 polymorphism was associated with insulin level. Genotype frequencies were also compared with previous studies performed in control populations and found to be different. This study shows that there may be a relationship between TP53(Arg72Pro) polymorphism and obesity.

Key Words: Obesity, Oxidative stress, TP53, Polymorphism.

Synthesis, Characterization and In Vitro Evaluation for Antimicrobial and Anthelmintic Activity of Novel Benzimidazole Substituted 1,3,4-Thiadiazole Schiff ’s Bases

Saravanan KALIYAPERUMAL* , Priyabrata PATTANAYAK**,°

* ORCID: 0000-0002-8859-8099, Department of Pharmacy, Bhagwant University, Sikar Road, Ajmer, Rajasthan, India, 305004.
** ORCID: 0000-0003-4035-1182, Department of Pharmacy, Bhagwant University, Sikar Road, Ajmer, Rajasthan, India, 305004.

° Corresponding Author; Priyabrata Pattanayak
Phone: +91 9438269361, e-mail: Priyabrata2005@gmail.com

SUMMARY

Benzimidazoles, 1,3,4-Thiadiazoles, and Schiff bases have shown many properties against different types of diseases, including bacterial infection and helminthiasis. Because of the need for new antimicrobial and anthelmintic agents, novel benzimidazole substituted 1,3,4-thiadiazole Schiff’s bases were designed and synthesized. The synergy arising from the successful incorporation of benzimidazole ring, thiadiazole ring, and Schiff’s base in one pharmacophore was exploited in this work. Eleven such derivatives were synthesized and investigated for their in vitro antimicrobial and anthelmintic properties.1H-benzo[d]imidazole-2-carboxylic acid was first prepared by the oxidation of 2-methyl-1H-benzo[d]
imidazole with alkaline potassium permanganate. 1H-benzo[d] imidazole-2-carboxylic acid was then converted to N-arylidene-5- (1H-benzo[d]imidazol-2-yl)-1,3,4-thiadiazol-2-amine by reacting with an aqueous solution of thiosemicarbazide in the presence of few drops of concentrated sulphuric acid. Finally, different benzimidazole substituted 1,3,4-thiadiazole Schiff’s bases were prepared by reacting thiadiazole substituted benzimidazole with
suitable aryl aldehyde. Compound PP-4 was found to be more potent than the standard drug in causing the death of nematodes, which took an average time of 13.22 and 19.00 min against Perionyx excavatus and Pheretima posthuma, respectively. Compounds PP-4, PP-6, and PP-8 containing electron-withdrawing groups (4-nitro, 2-bromo, 4-chloro) exhibited antimicrobial activity with the zone of inhibition ranging from 8-27 mm comparable to Ampicillin with
the value ranging from 22-27 mm for all the tested strains.

Key Words: Schiff base, Benzimidazole, 1,3,4-Thiadiazole, Anthelmintic activity, Helminthiasis, Antibacterial

Effect of Spathodea campanulata Ethanol Leaf Extract on Hematology and Liver Function of Salmonella-infected and Paracetamol-induced Swiss Albino Mice

Fred. Coolborn AKHARAIYI*° , Arthur Chinedu OKAFOR**

* ORCID: 0000-0001-5605-5543, Microbiology Department, Edo State University Uzairue, KM 7 Auchi-Abuja Road, Iyamho, Edo State, Nigeria
** ORCID: 0000-0002-6819-4724, Microbiology Department, Edo State University Uzairue, KM 7 Auchi-Abuja Road, Iyamho, Edo State, Nigeria

° Corresponding Author; Fred. Coolborn AKHARAIYI

Phone: +234 8066982772, e-mail: akharaiyi.fred@edouniversity.edu.ng

Herbal remedies for healing is basically on the existing traditional methods, which is different from one tradition to the other. Liver performs useful functions that maintain health in humans but it can be affected to become malfunction if not guided or protected against some chemical substances contained in some foods, hard drugs and drinks. Effect on hematology and hepatoprotective activity of Spathodea campanulata ethanol leaf extract was studied using an animal model. Group I mice served as the positive control, group II mice as negative control, and groups III – XII mice as satellite groups which were treated with 200, 400, 800, 1000, and 2000 mg/kg of extract after respective Salmonella typhi infection and paracetamol inducement. Overdose of mice with paracetamol caused changes in the mice’s physiology status. In hematology parameters of mice, red blood cell mean count was higher in the negative control (7.6±70.92 million/mm3) than the positive control (4.36±0.12 million/ mm3) and lower white blood cells mean count of 3.50±0.18 thousand/mm3 in the negative control than positive control with a value of 9.62±0.39 thousand/mm3. However, in biochemical evaluation, albumin (2.21±0.60 mg/dL) and bilirubin (2.11±0.63 mg/dL) were higher in the positive control than negative control with values of 4.90±0.11 and 1.08±0.10 mg/dL, respectively. These abnormalities in the mice’s physiological status were reversed on treatment with extract concentrations of 200 to 2000 mg/mL for five days. S. campanulata ethanol leaf extract can be used as traditional medicine for the treatment of liver diseases.

Key Words: Liver function, Spathodea campanulata, paracetamol, Salmonella typhi.

Interactions between Warfarin and Herbal Products: Case reports, Preclinical and Clinical Studies

İçim GÖKKAYA* , Tuğba SUBAŞ** , Gülin RENDA***° , Ufuk ÖZGEN****

* ORCID: 0000-0003-0803-2886, Karadeniz Teknik Üniversitesi Eczacılık Fakültesi, Farmakognozi ABD, Trabzon, TÜRKİYE
** ORCID: 0000-0002-0956-6567, Karadeniz Teknik Üniversitesi Eczacılık Fakültesi, Farmakognozi ABD, Trabzon, TÜRKİYE
*** ORCID: 0000-0001-6323-0338, Karadeniz Teknik Üniversitesi Eczacılık Fakültesi, Farmakognozi ABD, Trabzon, TÜRKİYE
**** ORCID: 0000-0001-9839-6717, Karadeniz Teknik Üniversitesi Eczacılık Fakültesi, Farmakognozi ABD, Trabzon, TÜRKİYE

º Corresponding Author: Gülin RENDA
Phone: 04623778830 – 05323331133; e-mail: gulingurhan@yahoo.com

SUMMARY

Plants have been used in the prevention and treatment of diseases since ancient times. Due to the popularity and unconscious use of herbal products, the risk of health problems is increasing day by day. Simultaneous use of herbal products especially with drugs having narrow therapeutic index can lead to very serious toxic effects. Warfarin, which is used to treat or prevent atrial fibrillation, venous thromboembolism, deep vein thrombosis, pulmonary embolism, artificial heart valve and myocardial infarction, acts as an anticoagulant by blocking the epoxide reductase enzyme and inhibiting the conversion of vitamin K and vitamin K epoxide. Warfarin is rapidly absorbed from the gastrointestinal tract, has high bioavailability and reaches the maximum concentration in blood plasma after 90 minutes orally and is therefore widely used in the clinic. Warfarin has the potential to interact with many drugs, herbal products and foods, and it has been reported that it is the drug that causes the most frequent plant-drug interactions. In this study, case reports of warfarin-herb interaction in the literature were examined and the herb/herbal product used by the patient, drugs used by the patient other than warfarin, and the clinical symptoms related to the interaction were compiled. In addition, in vivo, in vitro, and clinical studies conducted on plants reported to be interacting in case reports were investigated, and the results obtained regarding the herbal products, dose, duration of use, study type, warfarin dose, and interaction mechanism were presented. Herbal products cause an interaction by inducing or inhibiting CPY2C9, CYP3A4, and CYP1A2 enzyme activities as well as P-glycoprotein, which play a role in warfarin metabolism. The responsibility of healthcare professionals and the importance of selling herbal products under the consultancy of healthcare personnel is emerging in preventing possible adverse drug reactions and toxic effects and ensuring rational drug use.

Key Words: Warfarin, drug-herb interactions, drug-food interactions, P-glycoprotein, rational drug use, herbal product.

Design of Tyrosine Kinase Inhibitory Compounds and Anticancer Mechanisms of Action

Süreyya ÖLGENº* , Ahmet Mesut ŞENTÜRK**

* ORCID: 0000-0002-0725-8413, Biruni Üniversitesi Eczacılık Fakültesi, Farmasötik Kimya Anabilim Dalı, 10. Yıl Cad. No:45 Topkapı/ İSTANBUL
** ORCID: 0000-0001-6818-6161, Biruni Üniversitesi Eczacılık Fakültesi, Farmasötik Kimya Anabilim Dalı, 10. Yıl Cad. No:45 Topkapı/ İSTANBUL

º Corresponding Author: Süreyya Ölgen
Tel: 444 8 276, Fax: 90 212 416 46 46, e-mail: solgen@biruni.edu.tr

SUMMARY

Cancer is a complex disease that is caused by uncontrolled division and proliferation of cells and under the influence of genetic and conditions. There are more than 100 types of cancers known and standardized therapies to certain types of cancers as much as possible have been developed. The DNA of any human on Earth is not alike. Therefore, patients provide different responses to similar treatments. Tyrosine kinases (TKs) are a family of enzymes involve the signal transduction in human cell. TKs are essential needs for normal human physiology. Destruction of normal functions cause abnormal cell activities, immunological, neurological, metabolic and infectious diseases, especially cancer. Among the kinases, Abelson Leukemia (Abl), sarcoma (Src), epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are primary molecular targets for selective inhibition and are considered the most successful targeted therapy for tyrosine kinase inhibitors (TKIs). Today, there are many Food and Drug Administration approved TKIs, which are frequently used in cancer treatment. In this review, the design strategies of the compounds as TKIs, the structure-protein interaction relationships, the functional role of the kinases targeted in the inhibitor design, the structural analysis of the binding modes of the kinase inhibitors, and the current developments in the therapeutic interventions of tyrosine kinase inhibitors have been discussed.

Key Words: Cancer, inhibitor design, TKIs, structural analysis, selectivity, specifity.

Hydroxychloroquine: Similarity Search and Structure- Based Virtual Screening for Identification of Potential Hits for Chemoprophylaxis Against SARS-CoV-2

Shravan Kumar PASWAN°*† , Virendra NATH***† , Pritt VERMA** , Arun Pratap SIKARWAR**** , Sudhir K. VERMA*****

* ORCID: 0000-0002-2729-6257, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India
** ORCID: 0000-0003-1433-2623, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India
*** ORCID: 0000-0003-1367-7144, Central University of Rajasthan, Ajmer, India
**** ORCID: 0000-0001-5322-3951, Department of Zoology, Dayalbagh Educational Institute, Agra, Uttar Pradesh, India
***** ORCID: 0000-0002-7713-2250, Department of Chemistry, Dayalbagh Educational Institute, Agra, Uttar Pradesh, India
† Equally contributed authors

° Corresponding Author; Shravan Kumar PASWAN
e-mail: paswanshravan@gmail.com

SUMMARY

The current eruption of the novel severe acute respiratory syndrom causing coronavirus 2 (SARS-CoV-2) is an atrocious health tragedy. In this virulent disease, the computational approach appears to be the most hopeful choice to make out an efficient remedial medicinal agent for the treatment of an infected population. This current exploration inclined to analyze the similar druggable compounds as hydroxychloroquine to combat unworn coronavirus (COVID-19), using a pharmacoinformatics study. Docking-based virtual screening was carried-out using Glide, followed by Absorption Distribution Metabolism Excretion (ADME) anticipation. Hydroxychloroquine is being used as the criterion for comparison as it showed potential effect for symptomatic relief. Target-based virtual screening study divulged 28 top-ranked compounds based on their binding energy and dock score from 10695 PubChem compounds. In the additional weed-out process, 07 compounds were selected based on their similar interactions as hydroxychloroquine, comparable binding energy, and shape complementarity of the binding pocket of 6LU7. The
three-dimensional binding pose of screened 07 hits and their chemoessential features were successfully matched with reference compound. These candidates showed potential interactions with the amino acid residues of the active site of SARS-CoV-2 (PDB ID 6LU7). Therefore, they may have the capability as lead compound(s) against COVID-19.

Key Words: Binding energy, COVID-19, Docking,Hydroxychloroquine, SARS-CoV-2, Virtual Screening

Investigation of GSTM1 and GSTT1 Polymorphisms in Obesity Patients Under Bariatric Surgery

Abdulkadir Ünsal* , Hakan Buluş** , Onur Dirican*** , Serpil Oğuztüzün**** , Doğan Öztürk***** , Mehmethan Cihan****** , Ahmet Oğuz Ada******* , Mümtaz İşcan********

* ORC ID: 0000-0002-7989-4232, University of Health Sciences; Keçiören Training and Research Hospital; General Surgery Department; Ankara/Turkey
** ORC ID: 0000-0001-7439-8099, University of Health Sciences; Keçiören Training and Research Hospital; General Surgery Department; Ankara/Turkey
*** ORC ID: 0000-0003-0511-6611, Kırıkkale University Faculty of Science; Department of Biology; Kırıkkale/Turkey
**** ORC ID: 0000-0002-5892-3735, Kırıkkale University Faculty of Science; Department of Biology; Kırıkkale/Turkey
***** ORC ID: 0000-0003-1754-9246, University of Health Sciences; Keçiören Training and Research Hospital; General Surgery Department; Ankara/Turkey
****** ORC ID: 0000-0001-8701-754X, University of Health Sciences; Keçiören Training and Research Hospital; General Surgery Department; Ankara/Turkey
******* ORC ID: 0000-0001-9987-0572, Ankara University Faculty of Pharmacy Department of Toxicology; Ankara/Turkey.
******** ORC ID: 0000-0001-5839-4987, Cyprus International University, Faculty of Pharmacy, Lefkoşe, Turkish Republic of Northern Cyprus.

° Corresponding Author; Hakan BULUŞ
Tel.: +90-312 356 90 00 / 1158, e-mail : hakan_bulus6@hotmail.com

SUMMARY

Obesity is a chronic disorder with increasing prevalence worldwide and occurs when energy intake is more than energy expenditure. Obesity is one of the factors that cause oxidative stress and arises from an imbalance between the reactive oxygen species ROS and the cell’s antioxidant defense system. Increasing ROS in obesity, influencing the hypothalamic neurons, affect hunger and satiety control, so correspondingly on body weight control. When ROS amount increases, through DNA, protein, and lipid oxidation, cell damage, necrosis, and apoptosis take place. Oxidative stress increment in adipose tissue causes the development of metabolic syndrome in obese people. Also, weight loss due to calorie restriction or exercise reduces oxidative stress. Mitochondria is the essential source for ROS formation. In the electron transfer system, reactive oxygen species forming due to oxidative phosphorylation reactions are involved in various physiological processes such as cell proliferation and differentiation. Glutathione S-transferase M1 and T1 genes encode enzymes that have oxidant-scavenging activities. Deletion polymorphisms in these genes cause the absence of their corresponding enzymes. In this study, we investigated the parameters associated with obesity such as body mass index (BMI), TSH, glucose, satiety blood glucose, triglyceride,
and cholesterol levels, and deletion polymorphisms of GSTM1 and GSTT1 genes in 152 patients diagnosed with obesity in a Turkish population. No statistically significant relationship was found
between the parameters studied in obese patients and GSTM1 and GSTT1 polymorphisms. More studies are needed to elucidate the relationship of GSTM1 and GSTT1 polymorphisms with obesity.

Key Words: Obesity, GSTM1, GSTT1, Oxidative stress, Polymorphism, Multiplex PCR.

Rice Bran Supplement Enhances GSH Levels in Testis and Liver of Carbon Tetrachloride-induced Rats

Dwirini Retno Gunarti* , Dewi Sukmawati** ° , Mochammad Kamal Nasser*** , Teuku Abdi Zil Ikram**** , Rizqi Nanda Pribawa***** , Dwi Anita Suryandari******

* ORCID ID: 0000-0002-1990-0098, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
** ORCID ID: 0000-0003-3777-8118, Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
*** ORCID ID: 0000-0002-9895-8019, Undergraduate student, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
**** ORCID ID: 0000-0003-1109-4893, Undergraduate student, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
***** ORCID ID: 0000-0002-0984-925X, Undergraduate student, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
****** ORCID ID: 0000-0003-2711-8335,Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

° Corresponding Author; Dewi Sukmawati, MD., Ph.D.
Phone: +62 21 3146129, e-mail: ds_histoui@outlook.com; dewi.sukmawati@ui.ac.id

SUMMARY

In the present study, the potency of rice bran as an antioxidant was examined. Rice bran is a by-product of the rice milling process, despite being a rich nutrient, it has limitations in food application. In this study, we used carbon tetrachloride-induced rats (CCl4) as a model of oxidative stress and examined the effect of extract IPB 3S rice bran supplement (RBS) on testis and liver endogenous antioxidant. The testis and liver were used as the representative organs which prone to exposure to reactive oxygen species (ROS). We used 150 and 300 mg.kg-1 Body weight (BW) of RBS. The Concentration of glutathione (GSH) in both organs was measured. All groups administered by RBS had significantly higher GSH levels compared to the CCl4 group, both in testis and liver. The dose of 300 mg.kg-1 BW RBS had a significantly higher GSH level in testis, while 150 mg.kg-1 VA RBS had a significantly higher GSH level in the liver tissue compared to the control group accordingly. Thus, the rice bran supplement enhances GSH levels in rat’s liver and testis which potentially has protective effects.

Key Words: Rice bran, IPB 3S, antioxidants, glutathione, CCl4, liver, testis.

Protective Effects of Ferulic Acid Against Isoniazid-Induced Hepatotoxicity in Rats

Ahmad AHMADIPOUR* , Fariba SHARIFIFAR** , Hussein ANANI*** , Somayyeh KARAMI-MOHAJERI****°

* ORCID: 0000-0001-7987-3872 Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran,
** ORCID: 0000-0003-1792-3760 Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran,
*** ORCID: 0000-0002-4770-3008 Faculty of Allied Medical Sciences, Kerman University of Medical Sciences, Kerman, Iran,
**** ORCID: 0000-0001-6256-6550 Department of Pharmacology and Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran,

° Corresponding Author; Somayyeh KARAMI-MOHAJERI,
Tel: +98 34 31325239, Fax: +98 34 31325003, e-mail: s_karami@kmu.ac.ir

SUMMARY

Isoniazid (INH) is an antibiotic that is used for the prevention and treatment of tuberculosis. The most common side effect of INH is seemingly hepatotoxicity through the induction of oxidative damage. Ferulic acid (FA) is an organic compound with antioxidant properties that is found abundantly in plant cell walls. The aim of this study was to evaluate the hepatoprotective effects of FA against hepatotoxicity induced by INH in Wistar rats. The rats were injected with INH (100 mg/kg/d for 21 days) with and without co-administration of FA (10 and 20 mg/kg/d) or silymarin (100 mg/kg/d) from day 11 to day 21. Then, the animals were sacrificed to evaluate the serum levelof aminotransferases and total bilirubin, and liver histopathology and oxidative stress parameters. Co-administration of FA prevented the hepatotoxicity of INH according to the biochemical and histology findings. FA dose-dependently decreased level of lipid peroxidation in liver tissue. The activities of catalase, superoxide dismutase, and glutathione peroxidase in liver tissues of rats treated with FA were higher than those in non-treated INH-exposed rats. Taken together,
the results demonstrated that FA could be used as a hepatoprotective supplement to prevent INH-induced hepatotoxicity.

Key Words: Isoniazid, ferulic acid, hepatotoxicity, antioxidant, oxidative stress, histopathology.

Morphological Investigations on the Diagnostic Features of Six Hypericum Species of the Ukrainian Flora

Valentyna MINARCHENKO* , Oksana FUTORNA** , Vitalii PIDCHENKO***° , Iryna TYMCHENKO**** , Tetyana DVIRNA***** , Larysa MAKHYNIA******

* ORCID: 0000-0002-5049-7620, M.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine 2 Tereshchenkivska Str., Kyiv 01004, Ukraine;
O.O. Bogomolets National Medical University. 22 Pushkinska Str., Kyiv 01004, Ukraine
** ORCID: 0000-0002-3713-6644, M.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine 2 Tereshchenkivska Str., Kyiv 01004, Ukraine
*** ORCID: 0000-0003-0850-6666, O.O. Bogomolets National Medical University. 22 Pushkinska Str., Kyiv 01004, Ukraine
**** ORCID: 0000-0001-7505-3164, M.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine 2 Tereshchenkivska Str., Kyiv 01004, Ukraine
***** ORCID: 0000-0002-9279-9766, M.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine 2 Tereshchenkivska Str., Kyiv 01004,
Ukraine; O.O. Bogomolets National Medical University. 22 Pushkinska Str., Kyiv 01004, Ukraine
****** ORCID: 0000-0002-8095-4255, O.O. Bogomolets National Medical University. 22 Pushkinska Str., Kyiv 01004, Ukraine

° Corresponding Author: Vitalii Pidchenko
Phone: +380937670224; e-mail: pidchenkovitalii@gmail.com

SUMMARY

The results of comparative analysis of the main diagnostic features of the medicinal raw material of six species of the genus Hypericum of Ukraine are presented. The most important diagnostic features of H. alpigenum Kit, H. elegans Steph. ex Willd., H. hirsutum L., H. maculatum Crantz, H. montanum L., and H. perforatum L. are the localization, form, and color of secretory structures. Characteristics of the basic morphological features of leaves, sepals, petals, and stems of the studied species are provided. It is emphasized that a comprehensive analysis of the species-specific peculiarities of the main raw organs of species of the genus Hypericum allows us to determine their species affiliation clearly. The use of these features makes it impossible to intentionally falsify or incorrectly identify the raw material of a particular species of St. John’s worth during merchandising analysis.

Key Words:

Diagnostic features, Hypericum, medicinal raw materials, leaves, sepals, petals, stems, secretory structures, Ukraine

Enhancing Skin Penetration: The Role of Microneedles

Bülent SAMANCI*º , Fatma Gülgün YENER** , İsmail Tuncer DEĞİM***

* ORCID: 0000-0002-7198-5375, Pharmaceutical Technology Department, Faculty of Pharmacy, Dicle University, Diyarbakir, Turkey,
** ORCID: 0000-0002-7234-0034, Proffesor, Pharmaceutical Technology Department, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
*** ORCID: 0000-0002-9329-4698, Proffesor, Pharmaceutical Technology Department, Faculty of Pharmacy, Biruni University, Istanbul, Turkey

º Corresponding Author: Bülent SAMANCI
Phone: +904122411000-7531; e-mail: bulent.samanci@dicle.edu.tr

SUMMARY

Since transdermal delivery systems provide some important advantages over oral delivery systems and parenteral delivery systems, they have attracted the attention of researchers. Degradation of the drug in the gastrointestinal (GI) system, irritation of the GI system tract, and the first-pass effect of the drug are some of the disadvantages of oral administration, while the need for medical staff to administer it and creating phobia in the patient are among the disadvantages of parenteral administration. To overcome these drawbacks, researchers have developed formulations for the transdermal delivery of drugs. The most important handicap of transdermal drug administration is the Stratum Corneum layer (St. Corneum), which forms the enormous barrier layer of the skin. Some techniques have been developed to overcome this serious barrier problem of the skin. Microneedles are one of the physical methods to increase the penetration of therapeutic agents through the skin. Microneedles consist of needle arrays long enough to deliver the drug to the dermis layer and micron-sized enough to not reach the nerve cells and not cause pain. Microneedles can
be classified into five different types as solid microneedles, dissolving microneedles, hollow microneedles, coated microneedles, and hydrogel microneedles according to the properties of the materials used in the fabrication and the mechanisms of release of the therapeutic agent. Microneedles can be used in the application of vaccines, proteins, nucleotides, drug delivery systems, cosmetic, and for diagnostic purposes. Although important technological developments have been experienced for microneedle in many areas such as drug delivery systems, disease diagnosis, and cosmetics in the last two decades, there are many working areas that need to be developed. Especially in longterm treatments, studies should be done to develop them as smart devices.

Key Words:

Drug Delivery, Intradermal, Microfabricated device, Microneedle, Skin Penetration, Transdermal.

Bioactivities of A Major Compound from Arthrinium rasikravindrae An Endophytic Fungus of Coleus amboinicus Lour.

Puji ASTUTI°* , Dwi Koko PRATOKO** , Rollando ROLLANDO*** , Giri Wisnu NUGROHO**** , Subagus WAHYUONO***** , Triana HERTIANI****** , Arief NURROCHMAD*******

* ORCID: 0000-0003-3316-6149, Pharmaceutical Biology Department, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia 55281
** ORCID: 0000-0001-7262-4515, Faculty of Pharmacy, Universitas Jember, Jember, Indonesia
*** ORCID: 0000-0001-6210-6247, Program of Pharmacy, Faculty of Science and Technology, Ma Chung University, Malang, Indonesia
**** ORCID: 0000-0001-9086-3181, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia 55281
***** ORCID: 0000-0002-1374-4506, Pharmaceutical Biology Department, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia 55281
****** ORCID: 0000-0002-1756-2478, Pharmaceutical Biology Department, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia 55281
******* ORCID: 0000-0001-7597-2574, Pharmacology and Clinical Pharmacy Department, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia

°Corresponding author: Puji Astuti
Phone/Fax: +62-274-543120; e-mail: puji_astuti@ugm.ac.id

SUMMARY

Many studies reported the ability of endophytic fungi to produce various bioactive compounds having therapeutic values. An endophytic fungus identified as Arthrinium rasikravindrae was isolated from the stem of Coleus amboinicus Lour. This study examined cytotoxic and antimicrobial activities of a major compound isolated from ethyl acetate extract of the fungus fermentation broth. Cytotoxic activities were conducted using MTT assay against T47D, MCF-7, WiDr, 3T3, and Vero cells. IC50 values against Staphylococcus aureus and Escherichia coli were used as the parameters for determining antimicrobial activities. The isolated compound appeared as a single peak in HPLC chromatogram (98.55 %), displayed the highest cytotoxic activity on WiDr cells (IC50 35.03 ± 2.08 μg/mL) and antimicrobial activities against S. aureus (IC50 232.10 ± 1.20 μg/mL) and E. coli (243.59 ± 1.32 μg/mL). Analysis of the UV spectrum and TLC data generated by various detection reagents revealed that the compound was predicted as an N-containing substance having conjugated double bonds.

Key Words:

Coleus amboinicus Lour., cytotoxicity, antimicrobial, Arthrinium rasikravindrae, endophyte, fungus.

Effects of Pycnogenol and Its Combinations with Cisplatin on Hepatocellular Carcinoma Cell Viability

Merve BECİT*,° , Sevtap AYDIN DİLSİZ** , and Nurşen BAŞARAN***

* ORCİD: 0000-0002-8084-4419, Department of Pharmacology, Faculty of Pharmacy, Ataturk University, Erzurum, 25240, TURKEY
** ORCİD: 0000-0002-6368-2745, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, 06100, TURKEY
*** ORCİD: 0000-0001-8581-8933, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, 06100, TURKEY

° Corresponding Author: Merve BECİT
Phone: +904422315241; Fax: +904422315201; e-mail: mervebecit@hotmail.com

SUMMARY

Many challenges of hepatocellular carcinoma treatment, such as side effects and drug resistance, still remain. Therefore, new improvements with high pharmaceutical function and low toxicity
are needed. Recently, the efficacy of the combination therapy of antineoplastic drugs with natural products like pycnogenol has garnered attention. Pycnogenol® is a standardized extract from the bark of Pinus pinaster and consists of phenolic compounds. Pycnogenol is considered complementary in the treatments of some cancer besides its good tolerability and high safety. This study aims to reveal the synergistic effects of pycnogenol combination with cisplatin and its relation to human hepatocellular carcinoma (HepG2) cell viability. Effects of single and combined treatment on cell viability were evaluated in Chinese hamster lung fibroblasts (V79) and HepG2 cells using MTT assay. In HepG2 cells, this combined treatment showed a more cytotoxic effect than singledose
groups. Pycnogenol increased the cytotoxicity of cisplatin at 500 μM for 24 h; at 250-500 μM for 48 h in V79 cells; and also, at 125-500 μM for 24 h; at 62.5-500 μM for 48 h in HepG2 cells (p<0.05). Our study is the first study to show that pycnogenol treatment with cisplatin has been combined in the HepG2 cell line. As a result, pycnogenol induced cisplatin cytotoxicity via combined treatment on HepG2 cells and exhibited a synergistic effect with cisplatin. In conclusion, pycnogenol may play a role in the chemotherapy of hepatocellular carcinoma; however, further
studies are required to confirm their interactions with cisplatin.

Key Words:

Pycnogenol, cisplatin, MTT, cancer, hepatocellular carcinoma, HepG2 cells.

Improvement in Aqueous Solubility of Cilnidipine by Amorphous Solid Dispersion, Its Formulation into Interpenetrating Polymer Network Microparticles and Optimization by Box-Behnken Design

Amit KUHIKAR* , Shagufta KHAN**° , Komal KHARABE*** ,
Dilesh SINGHAVI**** , Girish DAHIKAR*****

* ORCID: 0000-0001-7353-9814, Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha, Maharashtra, India.
** ORCID:0000-0002-2827-7939, Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha, Maharashtra, India.
*** ORCID: 0000-0002-5237-6929, Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha, Maharashtra, India.
**** ORCID: 0000-0002-2544-7226, Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha, Maharashtra, India.
***** ORCID: 0000-0002-2284-535X, Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha, Maharashtra, India.

°Corresponding Author: Shagufta Khan, Professor,
Phone: (+91)7152-240284, Fax (+91)7152-241684; e-mail: shaguftakhan17@rediffmail.com

SUMMARY

Cilnidipine(CPN), a Biopharmaceutics Classification System class II drug, has dissolution rate-limited bioavailability and a very short half-life (20.4 min). Thus, there is a need to improve the solubility and prolong the drug release so that the therapeutic concentration of CPN could be maintained for a prolonged time. Therefore, the present investigation was aimed to improve the solubility of CPN by preparing amorphous solid dispersion (ASD) and sustain its release by incorporating CPN loaded ASD (CPNASD) in interpenetrating polymer network (IPN) microparticles. ASD was prepared using Solutol HS 15 and Gelucire®50/13. Solutol HS 15 provided a better effect by increasing 84.09 folds solubility of CPNASD in water as compared to the free CPN, therefore it was used in the formulation of IPN microparticles. Characterization of ASD by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed a decrease in the crystallinity
of CPN. IPN microparticles loaded with CPNASD were prepared by varying chitosan concentrations, polyvinyl alcohol (PVA), and massratio of chitosan:TPP and optimized by Box-Behnken Design. The constraints on the responses were maximum drug entrapment efficiency and sustained drug release with more than 80% drug release in 12 h. IPN microparticles with composition, chitosan 50mg, PVA 74.99mg (Volume of aqueous phase; 10 ml, Volume of organic phase; 50 ml) and chitosan:TPP 2.52 was the predicted optimized condition by the software and IPN with this composition provided high % entrapment efficiency (83.87±0.85) and sustained release (83.29±0.55) for 12 h. Solutol HS 15 was successful in providing a massive increase in solubility of CPN, and a uniform sustained release was achieved by loading CPNASD in IPN microparticles.

Key Words:

Cilnidipine, Solid dispersion, Solutol HS 15, Interpenetrating polymer network microparticles, Chitosan, Polyvinyl alcohol.

2007 – Volume 32, Issue 3

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