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

Abstract

AIMTo 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.METHODSINH was conjugated with N-acetyl cysteine (NAC) and N-(2)-mercaptopropionyl glycine using the Schotten-Baumann 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.RESULTSProdrugs 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.CONCLUSIONThe findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.

Advanced Development of Carboxylic Acid Functionalized Multiwall Carbon Nanotubes as Safe Inhalation Drug Carrier

“…Likewise elevated levels of albumin are associated with exposure to toxicants or may be due to dehydration and were observed in MWCNT treated group. [30][31][32] Albumin levels in FMWCNT treated group were however similar to control group suggesting that FMWCNT does not cause any toxic alterations. The kidney function can be measured by estimating concentration of electrolytes sodium, potassium, chloride etc.…”

Double functionalized haemocompatible silver nanoparticles control cell inflammatory homeostasis

“…Isoniazid surface-modified particles can enhance the bioavailability of the drug in treating tuberculosis [23,24]. Conjugation of isoniazid with other molecules, including curcumin, can lower hepatotoxicity, improve stability, and enhance bioavailability [25].…”