Research - School of Pharmacy

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Application of Box–Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity
(International Journal of Biological Macromolecules, 2015-12-29) Mirza, Salman Baig
The aim ofthe present study was to develop and optimize levofloxacin loaded solid lipid nanoparticles for the treatment of conjunctivitis. Box–Behnken experimental design was applied for optimization of solid lipid nanoparticles. The independent variables were stearic acid as lipid (X1), Tween 80 as surfactant (X2) and sodium deoxycholate as co-surfactant (X3) while particle size (Y1) and entrapment efficiency (Y2) were the dependent variables. Further in vitro release and antibacterial activity in vitro were also per- formed. The optimized formulation oflevofloxacin provides particle size of 237.82 nm and showed 78.71% entrapment efficiency and achieved flux 0.2493 g/cm2/h across excised goat cornea. In vitro release study showed prolonged drug release from the optimized formulation following Korsmeyer–Peppas model. Antimicrobial study revealed that the developed formulation possesses antibacterial activity against Staphylococcus aureus, and Escherichia coli equivalent to marketed eye drops. HET-CAM test demonstrated that optimized formulation was found to be non-irritant and safe for topical ophthalmic use. Our results concluded that solid lipid nanoparticles are an efficient carrier for ocular delivery of levofloxacin and other drugs.
Comparative in vitro antidiabetic and antioxidant activity of various extracts of Ficus specie
(Pharmacogn J., 2018) Shaikh, Abusufyan
ABSTRACT Introduction: Ficus religiosa, Ficus benghalensis and Ficus glomerata are plants from Ficus species used traditionally for the treatment of various ailments. This study aimed to investigate in vitro antidiabetic and antioxidant activity of three plants from Ficus species and effect of extracting solvents, total flavonoids and phenolics content on its in vitro activity. Methods: Dried leaf powder was extracted successively by using solvents with increasing order of polarity index (PI). In vitro antioxidant (RP: reducing power assay, DPPH: 2,2-diphenyl-1-picrylhydrazyl assay and HP: Hydrogen peroxide assay) and antidiabetic (αA: α-amylase assay and αG: α-glucosidase assay) activities as well as total flavonoid (TF) and total phenolic (TP) contents of extracts were evaluated. The correlation between in vitro activities and solvent polarity index, total flavonoid and phenolic content were established by using pearson’s correlation coefficient (R). Results: Strong positive correlation was observed with PI of extracting solvents and TP content of Ficus religiosa (PI/ TP, R=0.8159) and Ficus glomerata (PI/ TP, R=0.9172). Comparatively benzene and water extracts of Ficus glomerata were found to have significantly (P<0.05) highest in vitro antidiabetic and antioxidant activity respectively. Strong positive correlation was observed between TF and αG inhibitory (TF/ αG, R=0.793) effects of Ficus benghalensis. In addition, strong positive correlation observed between TP and antioxidant activity (TP/DPPH, R=0.9744; TP/RP, R=0.9514 and TP/HP, R=0.8108) of Ficus glomerata. Conclusions: Finding of our research will help in selection of solvents for extracting antidiabetic and antioxidant rich phytoconstituents from Ficus species.
Comparative study of anti-inflammatory activity of aqueous and methanolic extracts of hibiscus cannabinus leaf (Malvaceae)
(International Journal of Pharmacy and Pharmaceutical Sciences, 2016-04) Shaikh, Saba
Objective: The present study was undertaken to investigate and compare the anti-inflammatory activity of an aqueous and methanolic extract of Hibiscus cannabinus (Malvaceae) using carrageenan-induced rat paw edema. Methods: Aqueous and methanolic extracts of Hibiscus cannabinus was prepared and tested for anti-inflammatory activity in female spargue dawley rat weighing 150-180 g. The animals were randomly divided into 6 groups of 6 each. First group served as vehicle control, second group served as standard, third and fourth group served as high (400 mg/kg) and low (200 mg/kg) dose of methanolic extract of Hibiscus cannabinus leaves (MHCL) respectively and fifth and sixth group as high (400 mg/kg) and low (200 mg/kg) dose of aqueous extract of Hibiscus cannabinus leaves (AHCL) respectively. The In vivo anti-inflammatory activity was studied using carrageenan induce rat paw edema animal model. The estimation of liver and blood parameters consist of serum glutamic oxalate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), lipid peroxidation (LPO), reduced glutathione (GSH) and superoxide dismutase (SOD). Results: Both MHCL and AHCL extracts showed significant (*p<0.05) inhibition of rat paw edema in dose-dependent manner. The maximum percent inhibition in paw edema was found in MHCL at dose of 400 mg/kg was 52.00% and AHCL at dose of 400 mg/kg was 49.93%. Both MHCL and AHCL at dose of 400 mg/kg reduce LPO level as 31.10 nmol/g and 35.23 nmol/g respectively when compared with standard indomethacin. Conclusion: An anti-inflammatory activity was found in both MHCL and AHCL extracts. But the MHCL showed more significant anti-inflammatory activity.
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.
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.
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.
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.
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.
Formulation and evaluation of transfersomal cream of Acriflavin
(International Research Journal Of Pharmacy, 2016-09) Gaikwad, Madhuri
A burn can be major medical problems or life threatening emergencies admitted to any hospital. Conventional topical burn formulations are required to be applied 3 to 4 times a day and previous application is needed to be removed prior to application of each new dose which is very painful to burn patients. In this research an attempt was made to increase the patient compliance by reducing the dosing frequency through sustained released vesicular drug delivery system like transfersomes. Transfersomes were formulated using by thin film hydration method and evaluated for entrapment efficiency, photo microscopy, scanning electron microscopy, vesicle size, poly dispersity and zeta potential. optimized transfersomal batch was incorporated in cream base and evaluated for pH, spread ability, viscosity, grud contyent and in-vitro diffusion. Transfersomes prepared by using 1:3 ratio of Sodium cholate with cholesterol and 200 mg drug showed highest entrapment(91.65%) and sustained release(65.18% in was 24 hrs.)was obtained with transfersomal cream in comparison with conventional formulation(97.54%) in 8 hrs.
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....
In vitro and in vivo screening of anti-inflammatory activity of methalonic and aqueous extracts of anogeissus latifolia leaves
(Innovare Publications, 2022) Shaikh, Saba (PHF009); Badruddeen; Khan, Mohammad Irfan; Ajaz Ahmad, (PHF002)
Objective: To evaluate and compare anti-oxidant and anti-inflammatory activity of methanolic and aqueous extract of Anogeissus latifolia leaves Methods: The in vitro antioxidant activity was investigated using nitric oxide radical inhibition activity assay, hydroxyl radical scavenging activity assay, DPPH free radical scavenging assay, and reducing power assay. The in vitro anti-inflammatory activity was investigated using erythrocyte membrane stabilization, inhibition of protein denaturation, and proteinase inhibitory activity the in vivo anti-inflammatory activity was investigated using carrageenan-induced rat paw edema. The biochemical parameters were evaluated in the blood, which included the determination of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase values and in the liver, which includes the estimation of lipid peroxidation, reduced glutathione, and superoxide dismutase. Results: The methanolic extract caused a significant dose depended on the reduction of inflammation when compared with the aqueous extract of Anogeissus latifolia. The anti-inflammatory activity of all groups was found to be comparable to the standard indomethacin group. The maximum percent inhibition in paw edema was found in methanolic extract of Anogeisuss latifolia at a dose of 500 mg/kg was 53.33%, with significant anti-inflammatory activity p<0.001. Conclusion: The leaf extract of Anogeissus latifolia possesses anti-oxidant and anti-inflammatory activity. The therapeutic effect of Anogeisuss latifolia extracts will encourage its use in the treatment of inflammation.
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.
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
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
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
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....
Nebumetone in binary solvent: solubility analysis
(International Research Journal Of Pharmacy, 2017) Kharwade, Meena
The solubility prediction of nabumetone was studied in different solvent system (hexane- ethyl acetate- ethanol- water). The theories such as ideal, Hildebrand-Scatchard and extended Hildebrand solubility approaches were used for finalizing the solubility behavior of nabumetone. Entropy of fusion expression was used to calculate the ideal solubility. The experimental mole fraction solubility deviated from the ideal mole fraction solubility, indicating the self association of solute or solvent or both in solution. The extended Hildebrand equation was used to reproduce solubilities of nabumetone in selected solvent blend. The solubilities of nabumetone were back calculated with an interaction energy term ‘W’ and rational activity coefficient term ‘(log10 2)/A’. These parameters were regressed against a polynomial of δ1, solubility parameter of solvent blend. Solubility parameter of the nabumetone δ2 was determined and found to be ˜ 20 MPa 1/2
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
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
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.

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