Synthesis, characterization and docking studies of amide ligands as anti-leishmanial agents.

Aim of this study was to synthesize new inhibitors on the basis of active site of aspartic protease enzyme and to evaluate their intended biological activity. A3D model of an enzyme was generated via homology modeling and series of novel amide ligands were synthesized by using a short high yield process, subsequently, analyzed in-silico and in-vitro anti-leishmanial activities. Characterization and identification was accomplished via NMR (H1& C13), infrared and mass spectroscopic techniques. Among all compound (4) was found to show significant activity (IC50 58±0.01) against Leishmania major (L. major) species. Furthermore, docking studies confirmed the inhibition of a targeted enzyme that supported the interaction of potent compound (4) with key residues (aspartic protease) via hydrogen bonds. Present study conferred about novel compound (4) as a promising compound to antagonize L. major activities in future.

Review: Therapeutic potential of carbonic anhydrase inhibitors.

Enzymes are biological catalyst involve in different biochemical reactions. But over activation of these biomolecules can cause disease thus different inhibitors and knockout therapies are use in current clinical practice. Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.

Improved in vitro and in vivo performance of carbamazepine enabled by using a succinic acid cocrystal in a stable suspension formulation.

Currently cocrystals are considered as an established approach for making crystalline solids with overall improved physico-chemical properties. However, some otherwise well behaving cocrystals undergo rapid dissociation during dissolution, with ultimate conversion to parent drug and thus apparent loss of improved solubility. The polymeric carriers are long known to manipulate this conversion during dissolution to parent crystalline drug, which may hinder or accelerate the dissolution process if used in a dosage form. The goal of this study was to deliver in vivo a more soluble carbamazepine-succinic acid (CBZ-SUC) cocrystal in suspension formulation utilizing Hydroxypropyl methyl cellulose (HPMC-AS) as a crystallization inhibitor and Polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft copolymer ® as solubilizer. The concentration of these polymers were systemically varied during in vitro dissolution studies, while selected formulations from dissolution studies were tested in vivo. Pharmacokinetic studies (PK) in rabbits demonstrated that formulation F7-X (1% cocrystal, 1% HPMC-AS and 2% Polyvinyl carpolactam-polyvinyl acetatepolyethylene glycol graft co-polymer®) caused almost 6fold improvement in AUC0-72 (***P k 0.05) as well as much higher Cmax of 4.73µ.mL-1 to that of 1.07µ.mL-1 of unformulated 'neat' cocrystal given orally. When reference formulation of CBZ (F5-X) with similar composition to F7-X were given to rabbits, cocrystal formulation gave 1.37fold (***P k 0.05) bioavailability than CBZ reference formulation. Cmax of reference formulation observed was 3.9µmL-1.

Impact of different organic acids on solubility enhancement of cefpodxime proxetil immediate release tablet and its stability studies.

Cefpodoxime proxetil is a third generation cephalosporin antibiotic demonstrates pH dependent solubility and is highly soluble only in acidic pH. The purpose of this investigation was to design and develop immediate release tablets of cefpodoxime proxetil by direct compression method and determine the effect of different solid buffers (organic acids) such as fumaric acid (formulations F1-F4), maleic acid (formulations M1-M4) and citric acid (formulations C1-C4) by using cefpodoxime and acid in the ratios of 4:1, 2:1, 1:1 and 1:2 to achieve pH-independent release of the drug. Physical parameters and assay were found to be within the acceptable range as prescribed in USP 36 / NF 31. In vitro dissolution studies of each formulation were performed in distilled water, USP dissolution medium, HCl buffer solution of pH 1.2, phosphate buffer solutions of pH 4.5 and 6.8 to observe the drug release. The formulations F3, F4, M4 were selected for film coating on the basis of better drug release profile, to protect the drug from chemical degradation through hydrolysis. Film coated formulation F3, F4 and M4 showed a remarkable in vitro release of the drug (72.88±0.43 to 92.67±0.71%) within 30min of observation in all dissolution media and further evaluated by model independent and model dependent approaches. The drug release was found to be best fit to Weibull model as highest r2adjusted (0.924-0.998) and lowest AIC (18.416-54.710) values were obtained in all dissolution media. R Gui® applied for stability studies of F3 and F4 formulations, showing shelf lives of 28 & 27months at ambient and 33 months at accelerated temperatures. Formulation F4 was chosen as best formulation on the basis of physical properties, highest dissolution rate and stability studies.

Formulation and Dissolution enhancement of Meloxicam tablets using Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and Povidone in combination.

Meloxicam is a poor water soluble drug mostly prescribed in various rheumatic diseases. The present research study was design to formulate and increase the solubility of meloxicam in the tablet dosage form. A 32 full factorial design was employed to optimize meloxicam formulations. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG graft copolymer) and Povidone were taken as independent variables while cumulative drug release at 90 minutes was selected as dependent variable. All trial formulations complied with official standards. Multiple regression by Microsoft Excel on cumulative drug release of the selected formulations (F1, F2, F6- F9) showed the positive effect of PVCL-PVA-PEG graft copolymer (α = 0.05) and a negative effect of Povidone (α = 0.05). Formulation six (F6) (PVCL-PVA-PEG graft copolymer 3 mg and Povidone 22.5 mg / tablet) was considered as the optimal formulation based on its cumulative drug release. Dissolution kinetics by model dependent analysis predicted Weibull (R2=0.99) as the best fit model in describing meloxicam dissolution kinetics. The role of PVCL-PVA-PEG graft copolymer should be explored with other solubilizers in future studies.

Formulation and stability evaluation of immediate release antioxidant tablet.

Oxidative stress plays an important part in the development of human diseases. Pharmaceutical strategies are required to be work out in order to fight against such oxidative damages. Designing of new formulations that can protect human beings from the undesirable effects, consequence of oxidative stress, the crucial cellular and molecular processes, along with recurring oxidative damage and diseases is to be expedited. The main objective of present work was to design a rapidly releasing synthetic antioxidant tablet dosage form comprising of vitamin A, vitamin C, vitamin E and zinc in combination with lecithin (a phospho-lipid) that can fulfill human health and nutritional requirement and to perform stability studies. Beside active ingredients, the excipients used in present formulation were; Avicel pH 102, starch pregelatinized, silicon dioxide colloidal and polyethylene glycol 8000 milled magnesium stearate, acid stearic fine powder and aq.opa dry coating material. The immediate release formulation of antioxidant was prepared by wet granulation method. Three different trials were developed. Vitamin C was selected as tracer for detection and evaluation of tablet dosage form. When the resulting formulation was evaluated by USP 24 / NF 19, 2000 guidelines and later by stability studies, it was found that their quality can be maintained over a storage period of 24 months.

Antihyperglycemic and hypolipidemic effects of Hibiscus schizopetalus (Mast) Hook in alloxan-induced diabetic rats.

The antihyperglycemic and hypolipidemic activities of Hibiscus schizopetalus (Mast) Hook (Malvaceae) flower and leaves extracts were investigated in alloxan-induced diabetic rats. The hypoglycemic activity of both the extracts (100mg/kg, body weight) was tested in fasting normal rat, glucose loaded rats. Observation on body weight was also recorded. The extracts showed a significant (p<0.001) reduction in blood glucose level in normal fasting rats. In glucose tolerance test, significant (p<0.01) decreased observed in all glucose loaded animals. While in alloxan induced diabetic rats, the percent blood glucose reduction was 59.94% and 45.14% in extracts treated groups. The results obtained were compared with the reference standard drug Tolbutamide (100mg/kg, body weight). The diabetic rats showed sign of decreased in their body weight during the treatment period. Cholesterol and triglycerides levels were significantly decreased (p<0.001) by HFE. The results obtained demonstrated the potential hypoglycemic activity of methanolic extracts of H. schizopetalus. There is need of bioassay-directed assay of the active principles responsible for the anti-diabetic activity. The methanolic extracts showed the presence of carbohydrates, alkaloids, steroids, terpenes, saponins and glycosides.

Formulation development and evaluation of Diltiazem HCl sustained release matrix tablets using HPMC K4M and K100M.

The aim of this study was to develop a sustained release hydrophilic matrix tablet of Diltiazem HCl and evaluates the effect of formulation variables (e.g. lubricant, binder, polymer content and viscosity grades of HPMC) on drug release. Twelve different formulations (F1-F12) were prepared by direct compression. The results of the physical parameters and assay were found to be within the acceptable range. Rate of drug release was found to be slow as the fraction of the polymer was increased from 20-50%. The drug release rate from tablets containing K4M was effectively controlled by increasing the talc concentration, whereas the burst effect was reduced by increasing binder content. The drug release was higher with K4M as compare to K100M. Model-dependent and independent methods were used for data analysis and the best results were observed for K4M in Higuchi (R(2)=0.9903-0.9962) and K100M in Baker and Lonsdale (R(2)=0.9779-0.9941). The release mechanism of all formulations was non-Fickian. F7 (50% K4M, 2% talc, 10% Avicel PH101) and F11 (40% K100M) were very close to targeted release profile. F12 (50% K100M) exhibited highest degree of swelling and lowest erosion. The f1 and f2 test were performed taking F11 as a reference formulation.

Report: Studies on antibacterial activity of some traditional medicinal plants used in folk medicine.

Ethanolic extracts of eight medicinal plants commonly used in folk medicine were tested for their antibacterial activity against four Gram positive strains (Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis and, Streptococcus pneumoniae) and six Gram negative strains (Escherichia coli, Proteus vulgaris, Proteus mirabilis. Salmonella typhi para A, Salmonella typhi para B and Shigella dysenteriae) that were obtained from different pathological laboratories located in Karachi, Pakistan. Disc diffusion method was used to analyze antibacterial activity. Out of eight, five medicinal plants showed antibacterial activity against two or more than two microbial species. The most effective antimicrobial plant found to be Punica granatum followed by Curcuma zedoaria Rosc, Grewia asiatica L and Carissa carandas L, Curcuma caesia Roxb respectively. From these results, it is evident that medicinal plants could be used as a potential source of new antibacterial agents.

Pharmacokinetics of diclofenac sodium in normal man.

Diclofenac sodium was administered as 50 mg tablets to four healthy male volunteers in a two-way randomized crossover study in which volunteers were either fasted or were given a standard breakfast immediately prior to dosing. Blood samples were obtained upto 9 hours period and drug concentration were determined by HPLC method. Besides a significantly delayed (at p > 0.1) peak in fed state; an increase in absorption rate constant was observed as the only significant (at p > 0.05) effect of food on biopharmaceutic characteristic of diclofenac sodium. However, the intrinsic absorption of diclofenac sodium is also fast and it is not being the rate limiting factor in the bioavailability of diclofenac sodium, its decrease upto about 18 minutes (0.31 +/- 0.05 hr) from 11 minutes (0.19 +/- 0.02 hr) produces a null difference as the net effect on bioavailability, particularly when the drug is to be used in multiple dosage regimen.