Hepatoprotective Bile Acid Co-Drug of Isoniazid: Synthesis,Kinetics and Investigation of Antimycobacterial Potential

Pharmaceutical Chemistry Journal - The long-course treatment of tuberculosis with isoniazid (INH) leads to hazardous side effects on liver and poor patient compliance. To overcome these toxic...     

UV and Three Derivative Spectrophotometric Methods for Determination of Ezetimibe in Tablet Formulation

UV, first, second and third derivative spectrophotometric methods have been developed for the determination of ezetimibe in pharmaceutical formulation. The solutions of standard and sample were prepared in methanol. For the first method, UV spectrophotometry, the quantitative determination of the drug was carried at 233 nm and the linearity range was found to be 6-16 μg/ml. For the first, second and third derivative spectrophotometric methods the drug was determined at 259.5 nm, 269 nm and 248 nm with the linearity ranges 4-14 μg/ml, 4-14 μg/ml and 4-16 μg/ml. The calibration graphs constructed at their wavelength of determination were found to be linear for UV and derivative spectrophotometric methods. All the proposed methods have been extensively validated. The described methods can be readily utilized for the analysis of pharmaceutical formulation. There was no significant difference between the performance of the proposed methods regarding the mean values and standard deviations.     

Diacerein mutual prodrug for osteoarthritis: synthesis,in vitro kinetic studies and preliminary pharmacological screening

A gastro-sparing diacerein mutual prodrug was designed and synthesized by linking it to D-glucosamine as a promoiety with an objective of increasing the potential of its anti-inflammatory activity and improving its hydrophilic characteristics so as to make its parenteral administration feasible. Diacerein was linked with D-glucosamine through amide linkage and was subjected to in vitro release studies in aqueous buffers of varied pH range. 97% release of diacerein was achieved in phosphate buffer (pH 7.4) with a half-life of 48 min, following first order kinetics. Preliminary screening was carried in a one-month study in experimental osteoarthritis in rats induced by mono-iodoacetate and therapeutic efficacy of the conjugate was evaluated for changes in knee-diameter, spontaneous locomotor activity, alkaline phosphatase and glucosaminoglycan levels. The prodrug was also tested for anti-inflammatory activity in Freund’s adjuvant arthritis and local irritant effect on rat stomach by Rainsford’s cold stress method. The prodrug exhibited quicker onset of action than diacerein with respect to reduction in knee diameter, improved locomotor activity, better anti-inflammatory and gastro-sparing activity. The preliminary results are promising. In vivo kinetic studies and evaluation in mono-iodoacetate induced osteoarthritis over a period of three months is in progress to establish its effectiveness in the management of osteoarthritis.     

LC–UV and LC–MS evaluation of stress degradation behaviour of tenatoprazole

In the present study, comprehensive stress testing of tenatoprazole was carried out according to ICH guideline Q1A (R2). Tenatoprazole was subjected to stress conditions of hydrolysis, oxidation, photolysis and neutral decomposition. Additionally, the solid drug was subjected to 50 °C for 60 days in dry-bath, and to the combined effect of temperature and humidity at 40 °C/75% RH. Extensive degradation was found to occur in acidic, neutral and oxidative conditions. Mild degradation was observed in basic conditions. The drug is relatively stable in the solid-state. The products formed under different stress conditions were investigated by LC and LC–MS. Successful separation of drug from degradation products formed under stress conditions was achieved on a Chemito ODS-3 column [C₁₈ (5 μm, 250 mm × 4.6 mm, i.d.)] using methanol: 0.01 M acetate buffer pH 4.5 adjusted with glacial acetic acid (55:45) as the mobile phase at flow rate of 1 mL/min and the peak was detected using a UV detector set at 306 nm. The LC–MS m/z values and fragmentation patterns of degradation products formed under different stress conditions were studied and characterized through LC–MS fragmentation. Based on the results, degradation pathway for drug has been proposed.     

Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrug of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease

Mutual azo prodrug of 5-aminosalicylic acid with l-tyrosine was synthesized by coupling l-tyrosine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in rat fecal matter showed 87.18% release of 5-aminosalicylic acid with a half-life of 140.28min, following first order kinetics. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. Myeloperoxidase activity was determined by the method of Krawisz et al. The synthesized prodrug was found to produce comparable mitigating effect as that of sulfasalazine on colitis in rats.     

Transient Leukemia in Down Syndrome: Report of Two Cases with Review of Literature

Transient leukemia (TL) also referred to as transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD) is a unique syndrome that frequently occurs in newborns with Down syndrome (DS). It manifests in the first few days of life and shows leukocytosis with blast cells in the blood and bone marrow. This leukemia resolves spontaneously within first few months of life in the majority of cases. In this report we describe two newborns with a karyotype of 47,XY,+21, presented with marked leukocytosis and many blast cells in the peripheral blood. In both the cases, the blasts disappeared and the total leukocyte count reverted to normal without any specific treatment.     

Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design,synthesis, kinetics and pharmacological evaluation

AIM To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid(INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.METHODS INH was conjugated with N-acetyl cysteine(NAC) and N-(2)-mercaptopropionyl glycine using the SchottenBaumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.RESULTS Prodrugs were found to be stable in acidic(pH 1.2) and basic(pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly(59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially. CONCLUSION The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.     

Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats

AIM To design colon-targeted codrugs of mycophenolic acid(MPA) and aminosugars as a safer option to mycophenolate mofetil(MMF) in the management of inflammatory bowel disease. METHODS Codrugs were synthesized by coupling MPA with aminosugars(D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates(in vitro) and rat blood(in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control.RESULTS The prodrugs resisted activation in HCl buffer(pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer(p H 7.4) and intestinal homogenates. Incubation with colon homogenates(in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine(MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA. CONCLUSION The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid.     

Validated RP-HPLC Method for Simultaneous Quantitation of Losartan Potassium and Metolazone in Bulk Drug and Formulation

A HPLC method has been described for simultaneous determination of Losartan potassium and Metolazone in formulation. This method is based on a HPLC separation of the two drugs on the Thermo Hypersil BDS-C(18) (250 mm × 4.6 mm, 5.0 μm) with isocratic conditions and a simple mobile phase containing acetonitrile:water (60:40) at a flow rate of 0.8 mL/min using UV detection at 237 nm. This method has been applied to a marketed formulation without interference of excipients. The linear regression analysis data for the calibration plots showed a good linear relationship over the concentration range of 2-12 μg/mL for Losartan potassium and 0.2-1.2 μg/mL for Metolazone, respectively. The method was validated for precision, robustness and recovery. Statistical analysis showed that the method is repeatable and selective for the estimation of Losartan potassium and Metolazone.