Research - School of Pharmacy

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Effects of Liver Impairment on the Pharmacokinetics of Brivanib, a Dual Inhibitor of Fibroblast Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Tyrosine Kinases
(StemScientific, 2000) Syed, Shariq
Background: Many patients with hepatocellular carcinoma (HCC) have liver impairment as a result of tumor burden and cirrhosis. Brivanib, which is administered orally as the prodrug brivanib alaninate, is a selective, dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that is currently in phase III studies for HCC. Methods: This phase I study compared the pharmacokinetic profile of brivanib in patients with HCC and varying levels of hepatic impairment with that of patients with advanced solid non-HCC malignancies and normal hepatic function. Patients were assigned to 1 of 4 study groups: Group A, HCC plus Child-Pugh (CP) A status (mild hepatic impairment); Group B, HCC plus CP B (moderate hepatic impairment); Group C, HCC plus CP C (severe hepatic impairment); and Group D, non-HCC malignancy and normal hepatic function. Plasma brivanib concentrations were determined on Days 1 and 28. Brivanib alaninate doses were 400 mg/day in Groups A, B, and D, and 200 mg/day in Group C. Results: Of the 52 enrolled patients, 24 were assigned to 1 of the 4 groups (6 patients/group). After a single brivanib alaninate dose, the brivanib maximum observed plasma concentration and the area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) in patients with HCC and mild or moderate hepatic impairment (Groups A and B) were comparable with those in patients with normal hepatic function (Group D). Brivanib AUCinf was approximately 50% higher in patients with HCC and severe hepatic impairment (Group C) compared with patients with normal hepatic function (Group D). Brivanib alaninate 400 mg/day was tolerated in Groups A, B, and D. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations. Based on modified World Health Organization criteria, stable disease was achieved in 8 of 18 patients (44.4%) with HCC and 1 of 6 patients (17%) with non-HCC tumors. Conclusions: Brivanib exposure in patients with HCC and mild or moderate hepatic impairment was similar to that in patients with non-HCC malignancies and normal hepatic function, suggesting that dose adjustment is not necessary in HCC patients with CP A and B status. Experience in patients with HCC and CP C status is insufficient to recommend brivanib use in this population.
Multiple Dose Pharmacokinetics of Caffeine Administered in Chewing Gum to Normal Healthy Volunteers
(BIOPHARMACEUTICS & DRUG DISPOSITION, 2005) Syed, Shariq
The purpose of this study was to examine the pharmacokinetics of three doses of caffeine administered as Stay Alert1 chewing gum in a multiple dose regimen. Methods: A double-blind, parallel randomized, four-treatment study design was employed. The treatment groups were: 50, 100 and 200mg caffeine and placebo. Subjects were 48 (n ¼ 12 per group), healthy, non-smoking, males and females who had abstained from caffeine ingestion for at least 20 h prior to dosing, who were randomly assigned to the treatment groups. Caffeine was administered at 2400, 0200 and 0400 h depending on the treatment group. Blood samples were collected pre-dose and at 5, 15, 30, 45, 60, 75, 90 and 105 min after each caffeine dose. Samples were also collected at 7.5, 8.5 and 18 h after the last dose of caffeine. Plasma caffeine levels were analysed by a validated UV-HPLC method. Result: The mean Tmax after the third dosing ranged from 0.37 to 1.12 h. Cmax for 50, 100 and 200mg was 2.69, 3.45 and 6.33 mg/l, respectively. AUCinf for 50, 100 and 200mg group was 33.2, 46.94 and 86:94 mg=l h, respectively. AUCinf values suggested a dose proportionate increase. Dose normalized Cmax and AUC0 t values across doses were not significantly different, suggesting linearity was maintained after multiple doses of the Stay Alert1 chewing gum. There were no group related differences in elimination. Conclusions: The results suggest that caffeine administered in the gum formulation (Stay Alert1 chewing gum) via a multiple dosing regimen provides an effective and convenient means of maintaining effective concentrations of caffeine that would in some operational scenarios be desirable for maintaining alertness and performance in sleep deprived individuals. Copyright # 2005 John Wiley & Sons, Ltd. Key words: caffeine chewing gum; caffeine multiple dose; pharmacokinetics; buccal absorption
Transport, Metabolism, and in Vivo Population Pharmacokinetics of the Chloro Benztropine Analogs, a Class of Compounds Extensively Evaluated in Animal Models of Drug Abuse
(THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007) Syed, Shariq
Recently, extensive behavioral research has been conducted on the benztropine (BZT) analogs with the goal of developing successful therapeutics for cocaine abuse. The present study was conducted to characterize the contribution of dispositional factors in mediating the behavioral differences among the chloro BZT analogs and to identify cytochrome P450 enzymes involved in their metabolism. Bidirectional transport and efflux studies of four of the chloro BZT analogs were conducted. Screening with a panel of human and rat Supersomes was performed for 4 ,4 -diCl BZT. In addition, pharmacokinetic and brain distribution studies for 4 -Cl and 4 ,4 -diCl BZT in Sprague-Dawley rats were conducted. The permeability of the chloro analogs ranged from 8.26 to 32.23 and from 1.37 to 21.65 10 6 cm/s, whereas the efflux ratios ranged from 2.1 to 6.9 and from 3.3 to 28.4 across Madin-Darby canine kidneymultidrug resistance 1 (MDCK-MDR1) and Caco-2 monolayers, respectively. The P-glycoprotein (P-gp) inhibitor verapamil reduced the efflux ratios and enhanced the absorptive transport of the chloro BZT analogs. 4 ,4 -diCl BZT was a substrate of human CYP2D6 and 2C19 and rat 2C11 and 3A1. The brain uptake for 4 -Cl and 4 ,4 -diCl BZT was comparable and higher than previously reported for cocaine (brain-to-plasma partition coefficient 4.6–4.7 versus 2.1 for cocaine). The rank order for t1/2 was 4 ,4 -diCl BZT 4 -Cl BZT cocaine and for steadystate volume of distribution was 4 -Cl BZT 4 ,4 -diCl BZT cocaine. In conclusion, the chloro analogs differ significantly in their clearance and duration of action, which correlates to their behavioral profiles and abuse liability. Furthermore, these results suggest that the distinctive behavioral profile of these analogs is not due to limited brain exposure.
Population Pharmacokinetics, Brain Distribution, and Pharmacodynamics of 2nd Generation Dopamine Transporter Selective Benztropine Analogs Developed as Potential Substitute Therapeutics for Treatment of Cocaine Abuse
(JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008, 2008-05) Syed, Shariq
A second generation of N-substituted 3a-[bis(40-fluorophenyl)methoxy]- tropanes (GA 1–69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague–Dawley rats. The BZT analogs displayed a higher distribution (Vd¼8.69–34.3 vs. 0.9 L/kg) along with longer elimination (t1/2: 4.1–5.4 vs. 0.5 h) than previously reported for cocaine. Brain-toplasma partition coefficients were 1.3–2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1–69) to several fold elevation ( 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure–response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1–0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted. 2007 Wiley-Liss, Inc. and the American Pharmacists Keywords: pharmacokinetics; pharmacodynamics; dopamine; benztropine analogs; cocaine.
Lack of Effect of Brivanib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, Administered Intravenously and Orally in Healthy Participants
(Journal of Clinical Phramacology, Online 9 June 2011, 2011) Syed, Shariq
Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/ tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates. Keywords: brivanib; midazolam; pharmacokinetics; VEGF inhibitor; FGF inhibitor
Phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors
(Annals of Oncology, 2011) Syed, Shariq
Background: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. Patients and methods: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. Results: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180–800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly £1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ‡600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. Conclusion: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses £800 mg orally q.d., the recommended phase II study dose. Key words: antiangiogenesis, brivanib, fibroblast growth factor, vascular endothelial growth factor
Lack of food eVect on single-dose pharmacokinetics of brivanib, and safety and eYcacy following multiple doses in subjects with advanced or metastatic solid tumors
(Cancer Chemotherapy and Pharmacology, 2011) Syed, Shariq
Purpose Brivanib alaninate, an orally available prodrug of brivanib, is currently under evaluation for the treatment of several malignancies. This study aimed to (1) investigate eVects of a high-fat meal on single-dose pharmacokinetics of brivanib in subjects with advanced/metastatic solid tumors and (2) assess the safety and preliminary eYcacy of single and multiple doses of brivanib alaninate in this population. Methods A two-part study was conducted consisting of a single-dose phase (Part A) and a multiple-dose phase (Part B). In Part A, subjects received a single dose of brivanib alaninate (800 mg) either in a fasting state or following ingestion of a high-fat meal (approximately 951 kcal [15% protein, 33% carbohydrate, 52% fat]); serial blood samples were collected for pharmacokinetic analysis up to 48 h post-dosing. In Part B, subjects received brivanib alaninate (800 mg) once daily until discontinuation. Throughout both phases, subjects were evaluated for adverse events (AEs) and best clinical response. Results No clinically signiWcant diVerences in brivanib exposure were observed between fed and fasting subjects in Part A; Cmax was unchanged and AUCINF decreased marginally when administered in a fed versus fasted state. In Part A, the incidence of treatment-emergent AEs was broadly similar in a fed or fasted state. Brivanib alaninate was generally well tolerated throughout the study and showed preliminary evidence of antitumor activity. Conclusions Consumption of a high-fat meal had no signiWcant eVect on brivanib pharmacokinetics. The study further demonstrates the acceptable safety/tolerability proWle and antitumor potential of brivanib in patients with advanced malignancies. Keywords Pharmacokinetics · Exposure · Food · Safety · Brivanib alaninate · Solid tumors
Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy
(British Journal of Cancer, 2011) Syed, Shariq
BACKGROUND: The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies. METHODS: Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mgm–2 loading dose then 250 mgm–2 weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses. RESULTS: Toxicities observed were manageable; the most common treatment-related toxicities (410% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months. CONCLUSIONS: The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer. Keywords: antiangiogenesis; brivanib; cetuximab; gastrointestinal tumours
Evaluation of curculigo orchioides mucilage as suspending agent
(International Journal of PharmTech Research, 2011-04) Gaikar, Nilesh
Plant products served as an alternative to synthetic products because of local accessibility, eco friendly nature and lower prices compared to imported synthetic products. The present study was undertaken to evaluate the mucilage obtained from the roots of Curculigo orchioides Gaertn. as a suspending agent. Characterization studies like solubility, swelling index, loss on drying, ash value, pH, viscosity along with microbial load and acute toxicity studies were carried out on the mucilage. Aluminium hydroxide gel suspension was prepared using different concentration of Curculigo orchioides mucilage and its properties were compared with standard suspending agents like sodium carboxymethylcellulose and Acacia. The evaluation parameters included the sedimentation profile, redispersability, rheology and particle size analysis. The results suggested that the mucilage was found to be a superior suspending agent than acacia indicating that it may be a good source as pharmaceutical adjuvant.
Lack of Effect of Brivanib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, Administered Intravenously and Orally in Healthy Participants
(Sage Pubicaiton, 2011-06) Syed, Shariq
Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/ tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates.
Herbal Drugs for diabetic treatment: an updated review of patents
(Recent Patents on Anti-Infective Drug Discover, 2012) Shaikh, Abusufyan; Shaikh, Ajaz A.
Diabetes mellitus is the most common endocrine disorder, affecting 16 million individuals in the US and 200 million worldwide....
Nanoemulsion as vehicle for transdermal permentation of antihypertensive drug
(International Journal of Pharmacy and Pharmaceutical Sciences, 2012) Shaikh, Abusufyan
Hypertension is a chronic disease which required lifelong therapy. But most of antihypertensive drugs available today, showed extensive first-pass metabolism and low oral bioavailability which can be overcome by preparing its Transdermal Drug Delivery Systems....
Prokinetic effect of Herbomineral unani formulation (Dolabi) in Diabetic rats
(Journal of Research and Education in Indian Medicine, 2012-03) Shaikh, Abusufyan
This study was undertaken to investigate the prokinetic activity of Unani herbomineral formulation (Dolabi) in streptozotocin induced diabetic rats and its in vitro antioxidant activity.
Evaluation of Aegle marmelos fruit mucilage for binding properties
(International Journal of Pharmaceutical Sciences & Research, 2012-04) Gaikar, Nilesh
Plant products served as an alternative to synthetic products because of local accessibility, eco friendly nature and lower prices. Natural gums and mucilages are widely explored as pharmaceutical excipients. The present study was undertaken to separate mucilage from unripe fruits of Aegle marmelos (L) Corr. and explore its use as binder in tablets. The binding properties at different concentrations of mucilage were evaluated using Paracetamol as model drug. Mucilage at 3%w/w was found to be comparable with 10%w/w of starch paste. The drug release studies indicated that Aegle marmelos mucilage could be considered as a potential binding agent.
There are solutions to the predicament faced by Pharmacy graduates - but can they be implementred?
(Pharma Times, 2013-05) Rajani Shettigar
SYNTHESIS AND ANXIOLYTIC ACTIVITY OF 2-METHYL-3-AMINO-4- QUINAZOLINONE ACETAMIDE DERIVATIVES
(Coden HLEEAI, 2014) Patil, Jayshree P.
Medicinal Chemistry plays a vital role in the eradication of fatal diseases in human being. Quinazolin-4-one is versatile lead molecule. The synthesis of its derivatives has been the focus of great interest for the development of newer bioactive agent. The present study involves the synthesis, purification and characterisation of various acetamide derivatives of 3-aminoquinazolinone. Methyl Anthranilate on condensation with acetic anhydride in presence of pyridine and hydrazine hydrate form 2-methyl-3-amino-4-quinazolinone. The purity of synthesized compound was checked by Thin Layer Chromatography. The melting point of synthesized compounds were analysed with an open ended capillary tube method. Structures of synthesized compounds were elucidated by FT-IR, GC-MS, and NMR spectral analysis. The synthesized compounds were evaluated for anxiolytic activity by Elevated plus Maze Test and Light and Dark Test using Diazepam as standard.
Review on Advances in the Synthesis and Bioactivity of Quinazolinone Derivative
(International Journal for Pharmaceutical Research Scholars (IJPRS), 2014) Patil, Jayshree P.
Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. Many of the literature synthetic methods for elaboration of this simple ring structure are, however, time consuming, tedious and often low yielding. This review summarizes the recent advances in the synthesis investigations for the construction of the 4(3H)-quinazolinone and quinazoline skeletons. The synthetic methods were divided into five main classifications, including Aza-reaction, Microwave-assisted reaction, Metal-mediated reaction, Ultrasound-promoted reaction and Phase-transfer catalysis reaction. Literature studies on quinazolinones have shown that these derivatives possess a wide variety of biological activities. This review also focused on the few novel biological activities of quinazolinones but emphasis is specified for synthetic methods.
Formulation and development of mouth dissolving tablets of isolated molecules and evaluation for anti-hyperglycemic activity
(Research Journal of Pharmacy and Technology, 2014-03) Farhana, Nikhat
Fast disintegrating drug delivery system offers a solution for those patients who are having difficulty in swallowing oral dosage forms. The present paper deals with formulation and evaluation of fast dissolving tablets from selected medicinal plants (Syzygium cuminii (L) skeel, Momordica charantia Linn Cassia auriculata Linn,) roots. A Pharmaceutical dosage form was made by using a novel constituent isolated from above mentioned plant constituents (ScReX-6b, McReX-1.CaReX-4) without and with excipients by direct compression. The tablets were evaluated for invivo and in-vitro anti-hyperglycemic activity and in-vitro hardness, friability, weight variation, disintegration time, water absorption ratio, wetting time and in vitro dissolution studies. All the formulations exhibited disintegration time in the range of 12.2 to 27.5 seconds along with rapid in vitro dissolution. It was concluded that the fast dissolving tablets of the poor soluble drug can be formulated by direct compression technique using selective super disintegrants with enhanced dissolution, taste masking and hence ensuring better patient compliance and effective therapy.
Evaluation of Antimicrobial Activity of Coconut Husk Extract
(Annals of Applied Bio-Sciences, 2014-09) Rajani Shettigar
The coconut plant Cocos nucifera (family Arecaceae) is considered as an important fruit crop in tropical countries. It is commonly available plant with wide variety of applications in food, drinks, fibres, building materials and various chemicals finding their way into a huge range of modern day products. Being highly nutritious, young coconuts have also been studied for medicinal qualities. As preliminary investigation of the use of coconut husk, the antimicrobial activity can be evaluated. In present study antimicrobial activity of coconut husk is evaluated. It was observed that the antimicrobial activity of husk extract increased with increasing concentration and was found to be more effective against gram-negative than gram-positive organism. Extract was observed more effective against Pneumonia vulgaris. Presence of tannins and other phenolic compounds may responsible for antimicrobial activity.
A review on polymer drug conjugate - what, why and how?
(International ournal of Pharmaceutical Sciences and Research, 2015-11-01) Patil, Jayshree P.
ABSTRACT: It is well known that polymeric prodrug or polymer-drug conjugate is an effective and fast growing technique for improved use of drugs for therapeutic applications. Polymer conjugated drugs generally exhibit prolonged half-life, higher stability, water solubility, lower immunogenicity and antigenicity and specific targeting to tissues or cells. Polymers are used as carriers in polymeric prodrugs/macromolecular prodrugs for the delivery of drugs, proteins, targeting moieties, and imaging agents. The potential of the polymer-drug conjugates have already been proved by success of many products in the market for the treatment of different diseases. The polymeric pro-drug can be regarded as drug delivery systems that exhibit their therapeutic activities by means of releasing smaller therapeutic drug molecules from a polymer chain molecule for a prolonged period of time which results in enhanced pharmacokinetic behaviour by increasing the t 1/2 , bioavailability, and hence prolonged pharmacological action. This review deals with the Rational for design of polymer-drug conjugates (PDC), requirements for selection of drug candidate for polymeric prodrug, requirements for selecting polymers as candidate drug carriers, classification of polymers, design and synthesis of polymeric prodrugs and strategies to enhance the reactivity of polymer and the drug by incorporation of spacers.

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