Tuberculosis: an overview of current literature on types, diagnosis and drug therapy

Tuberculosis (TB) is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis complex. It is a global problem and increases in case rates are occurring not only in the developing countries of the world but also in several industrialized nations. There has also been an alarming increase in the number and proportion of cases caused by strains of Mycobacterium tuberculosis that are resistant to multiple first-line drugs. The increase in multiple-drug resistant tuberculosis has re-taught physicians about the importance of pursuing and ensuring treatment until cure. In many low-income and middle-income countries, TB continues to be a major cause of morbidity and mortality, and drug-resistant TB is a major concern in many settings. This article offers an overview of types, diagnosis and management of TB

Effect of hesperetin on the pharmacokinetics of metoprolol succinate in rats

Abstract Background Metoprolol is a substrate of CYP3A4, 2B6, CYP2D6, CYP2C9, and p-glycoprotein (p-gp). Hesperetin was reported as an inhibitor of cytochrome P-450 (CYP) enzymes and p-gp. The objective of this study was to investigate the effect of hesperetin on the pharmacokinetics of metoprolol in rats and in vitro models. In in vivo studies, male Wistar rats were treated with metoprolol (30 mg/kg) once a day for 15 consecutive days alone and in combination with hesperetin (25, 50, and 100 mg/kg). Blood samples were withdrawn from the tail vein on the 1st day in the single-dose pharmacokinetic study and on the 15th day in the repeated-dose pharmacokinetic study. In in vitro studies, metoprolol was incubated in the presence or absence of hesperetin and traditional p-gp inhibitors using rat-everted gut sacs. Reverse phase-high-performance liquid chromatography (RP-HPLC) was used to determine the amounts of metoprolol in the plasma and incubated samples (RP-HPLC). Results The C max, AUC, and half-life (t 1/2) of metoprolol significantly increased by twofold compared to the metoprolol group in rats pre-treated with hesperetin. The clearance and volume of distribution both decreased significantly. Metoprolol transport was dramatically increased in the presence of hesperetin and quinidine (standard p-gp inhibitor) in in vitro study. Conclusion The present study results revealed that hesperetin significantly increased the absorption of metoprolol in rats and everted gut sacs in vitro might be due to the inhibition of CYP and p-gp

Chlorzoxazone reduced the paracetamol-induced toxicity via competitive inhibition of CYP2E1-mediated metabolism

Abstract Background Drug metabolism is crucial to attaining the therapeutic index of any drug. The metabolism and elimination of the drugs are governed mainly by P-glycoprotein (P-gp) and Cytochrome P450 (CYP). Paracetamol is mostly used as analgesic and antipyretic agent. The metabolism of paracetamol is primarily via Glucuronidation and sulphation at therapeutic doses. About 5–10% of paracetamol is metabolized via CYP mediated pathway. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for forming a toxic metabolite of paracetamol called N-acetyl-p-benzoquinoneimine (NAPQI). Even at therapeutic doses, long-term usage of paracetamol leads to the hepatic and nephrotoxicity because of NAPQI. Several in-vitro and in-vivo studies conducted by different research groups and reported that chlorzoxazone is a substrate and inhibitor of CYP2E1. However, the effect of chlorzoxazone on the paracetamol (CYP2E1 substrate) metabolism via the CYP2E1 has not yet been reported. This study investigated the effect of chlorzoxazone on the CYP2E1-mediated metabolism of Paracetamol and NAPQI formation in Wistar rats. Results For 15 days, animals were orally administered with Paracetamol (300 mg/kg) with and without Silymarin (100 mg/kg) (standard CYP2E1 inhibitor) and Chlorzoxazone (50 and 100 mg/kg). Analysis was performed using RP-HPLC on the 15th day to determine paracetamol and NAPQI concentration in the plasma. Paracetamol combination with chlorzoxazone (50 and 100 mg/kg) showed a dose-dependent increase in the AUC0–∞ and the peak plasma concentration (Cmax) of Paracetamol and a dose-dependent decrease of AUC0–∞ and Cmax of NAPQI compared to paracetamol control (p < 0.001). Chlorzoxazone significantly decreased the elevated liver and renal markers compared to paracetamol control. Simultaneously, Hepatic and nephrotic tissue studies showed that compared to the paracetamol control group, the combination of chlorzoxazone significantly ameliorated paracetamol-induced hepatotoxicity and nephrotoxicity. Conclusion Finally, this study revealed that paracetamol in combination with chlorzoxazone led to a significant decrease in the plasma levels of NAPQI and enhanced absorption of paracetamol in rats via the inhibition of CYP2E1- mediated metabolism. In addition, chlorzoxazone significantly ameliorated paracetamol-induced hepatotoxicity and nephrotoxicity