Volume 59 (2009): Issue 1 (March 2009)

The current study involves development of oral bioadhesive hydrophilic matrices of hydralazine hydrochloride, and optimization of their in vitro drug release profile and ex vivo bioadhesion against porcine gastric mucosa. A 3² central composite design was employed to systematically optimize the drug delivery formulations containing two polymers, viz., carbomer and hydroxypropyl methyl cellulose. Response surface plots were drawn and optimum formulations were selected by brute force searches. Validation of the formulation optimization study indicated a very high degree of prognostic ability. The study successfully undertook the development of an optimized once-a-day formulation of hydralazine with excellent bioadhesive and controlled release characteristics.

Extended release formulation of tramadol hydrochloride (TRH) based on osmotic technology was developed and evaluated. Target release profile was selected and different variables were optimized to achieve it. Formulation variables such as the level of swellable polymer, plasticizer and the coat thickness of semipermeable membrane (SPM) were found to markedly affect drug release. TRH release was directly proportional to the levels of plasticizer but inversely proportional to the levels of swellable polymer and coat thickness of SPM. Drug release from developed formulations was independent of pH and agitation intensity but dependent on osmotic pressure of the release media. In vivo study was also performed on six healthy human volunteers and various pharmacokinetic parameters (c_max, t_max, AUC_0-24, MRT) and relative bioavailability were calculated. The in vitro and in vivo results were compared with the performance of two commercial TRH tablets. The developed formulation provided more prolonged and controlled TRH release compared to the marketed formulation. In vitro-in vivo correlation (IVIVC) was analyzed according to the Wagner-Nelson method. The optimized formulation (batch IVB) exhibited good IVIV correlation (R = 0.9750). The manufacturing procedure was found to be reproducible and formulations were stable over 6 months of accelerated stability testing.

HIV integrase has emerged as a promising target for discovery of agents against the acquired immunodeficiency syndrome (AIDS) pandemic. With the purpose of designing new chemotypes with enhanced potencies against the HIV integrase enzyme, the QSAR study carried out on 37 novel phthalimide derivatives is presented. The developed QSAR model was validated by standard statistical parameters and through a detailed structural study of how it reproduces and explains the quantitative differences seen in experimentally known pharmacological data. The model showed a good correlative and predictive ability having a cross-validated correlation coefficient (r²_cv) of 0.709 and a conventional correlation coefficient (r²) of 0.949. The predictive correlation coefficient (r²_pred) was found to be 0.512. The study revealed that the antiretroviral activity is predominantly explained by the substituent size, shape and polarity and provided insights into how modulation of the steric bulkiness and polarities of the substituents could be made to optimize the integrase-inhibitor interaction chemistry. A detailed investigation was made of the structural basis for the antiretroviral activity and the findings from the study could be usefully employed to design antagonists with a much more enhanced potency and selectivity.

[⁶¹Cu]diacetyl-bis(N⁴-methylthiosemicarbazone) ([⁶¹Cu] ATSM) was prepared using in house-made diacetyl-bis(N⁴-methylthiosemicarbazone) (ATSM) ligand and [⁶¹Cu]CuCl₂ produced via the ^natZn(p, x)⁶¹Cu (180 μA proton irradiation, 22 MeV, 3.2 h) and purified by a ion chromatography method. [⁶¹Cu]ATSM radiochemical purity was >98 %, as shown by HPLC and RTLC methods. [⁶¹Cu]ATSM was administered into normal and tumor bearing rodents for up to 210 minutes, followed by biodistribution and co-incidence imaging studies. Significant tumor/non-tumor accumulation was observed either by animal sacrification or imaging. [⁶¹Cu]ATSM is a positron emission tomography (PET) radiotracer for tumor hypoxia imaging.

This study sought to determine the potential prophylactic and antioxidant effects of aminoguanidine in experimentally induced diabetes. Four groups of Wistar rats, each composed of ten rats, were used. Two groups served as control. In group 3, diabetes was induced by a single intraperitoneal injection of streptozotocin (65 mg kg^-1). In group 4, diabetes was induced and treated with aminoguanidine (100 mg kg^-1 daily) orally for 3 months. Levels of serum glucose, glutathione peroxidase, glutathione reductase and erythrocytes catalase were analyzed on day 90 of the experiment. Retinal and kidney specimens were examined histopathologically after sacrifice of the animals. A significant antioxidant effect of aminoguanidine and its prophylactic role in diabetic retinopathy and nephropathy were observed in experimental animals.

A series of novel 3-cyclohexyl-2-substituted hydrazino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 3-cyclohexyl-2-hydrazino quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material, 3-cyclohexyl-2-hydrazino quinazolin-4(3H)-one, was synthesized from cyclohexyl amine. Title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic behavior. The compound 3-cyclohexyl-2-(1-methylbutylidene-hydrazino)-3H-quinazolin-4-one (4c) emerged as the most active compound of the series and is moderately more potent in its analgesic and anti-inflammatory activities compared to the reference standard diclofenac sodium. Interestingly, test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid.

Ethanolic extract (50 %) of stems of Calotropis gigantea R. Br. (Asclepiadaceae) at doses of 250 and 500 mg kg^-1 were studied for hepatoprotective activity in male Wistar rats with liver damage induced using carbon tetrachloride, 2 mL kg^-1 twice a week. The protective effect of C. gigantea extract was compared with the standard drug silymarin. Various biochemical parameters such as aspartate amino transferase (AST), alanine amino transferase (ALT), glutathione (GSH), lipid peroxide (LPO), superoxidedismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were evaluated. The results revealed that the C. gigantea extract significantly decreased AST, ALT (p < 0.001) and lipid peroxide (p < 0.01) levels. The antioxidant parameters GSH, GPx, SOD and catalase levels were increased considerably compared to their levels in groups not treated with C. gigantea extract.

A series of novel 4-(3-ethylphenyl)-1-substituted-4H-[1,2,4] triazolo[4,3-a]quinazolin-5-ones (4a-j) were synthesized by the cyclization of 3-(3-ethylphenyl)-2-hydrazino-3H-quinazolin-4-one (3) with various one-carbon donors. The starting material, compound 3, was synthesized from 3-ethyl aniline by a new innovative route with improved yield. When tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs, all test compounds protected the animals from histamine induced bronchospasm significantly. Compound 4-(3-ethylphenyl)-1-methyl-4H - [1,2,4]triazolo[4,3-a]quinazolin-5-one (4b) emerged as the most active compound of the series and it is more potent (74.6 % protection) compared to the reference standard chlorpheniramine maleate (71 % protection). Compound 4b shows negligible sedation (10 %) compared to chlorpheniramine maleate (30 %). Therefore compound 4b can serve as the leading compound for further development of a new class of H₁-antihistamines.

New primaquine conjugates 5-7 with glucosamine and two polymers of polyaspartamide type, poly[α,β-(N-2-hydroxyethyl-DL-aspartamide)] (PHEA) and poly[α,β-(N-3-hydroxypropyl-DL-aspartamide)] (PHPA), were synthesized, characterized and screened for their antimalarial activity. The conjugates differed in the type of covalent bonding, length of the spacer between the polymeric carrier and drug, molecular mass and drug-loading. Blood-schizontocidal activity of the prepared conjugates was tested against Plasmodium berghei infection in Swiss mice. Polymeric conjugates showed better antimalarial activity than the glucosamine conjugate.