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...     

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.     

Efficacy of less Invasive modified O-arm navigated delta fixation in osteoporotic high-grade spondylolisthesis: “a LIMO delta technique”

Purpose

In 1994, the technique of transdiscal screws fixation in spondylolisthesis was introduced but did not gained popularity as it failed to address problems with spinal sagittal imbalance, retroverted pelvis, pseudoarthrosis, implant failure and neural injury. Majority of problems were due to lack of clear indications; hence, in this study, with modification of traditional technique and use of O-arm navigation for selected group of patients, we have addressed the above problems and given good to excellent functional outcomes.

Methods

We did prospective study on 15 patients with osteoporotic high-grade spondylolisthesis Meyerding grade 3 & 4 admitted in period 2020–2021. Intraoperative assessment was done in form of blood loss, incision length, operative time and complications. The preoperative & postoperative assessment was done in the form of clinical and radiological parameters.

Results

The average follow-up was of 21.2 months (18–24 months). There was no significant difference between pre- & postoperative spinopelvic parameters. Intraoperative average blood loss was 100 ml (90–120 ml) with mean surgical time of 138 min (120–150 min). Incision length was about 5–6-cms-posterior midline with two paraspinal 1-cm incisions for transdiscal screws. Patients were mobilized on postoperative day-2. There was statistically significant improvement in mean ODI, COMI and VAS for LBP and radicular pain with no intra- or postoperative complication observed till latest follow-up with all patients showing solid monoblock fusion on 1-year follow-up CT scan.

Conclusions

LIMO delta technique is a newly modified version of conventional transdiscal screw technique. Minimal incision, decreased blood loss & operative time with in situ 3-column rigid fixation and solid fusion minimizing risk of complications makes this novel technique safer, simpler & effective in osteoporotic HGS.