Isoniazid Mediates the CYP2B6*6 Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6

Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [K_i] = 368 μM) and pyrazinamide (K_i = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [K_I] = 30 μM; maximal rate constant of inactivation [k_inact] = 0.023 min⁻¹) and recombinant CYP2A6 (K_I = 15 μM; k_inact = 0.024 min⁻¹) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.     

Tamilnadia uliginosa (Retz) Tirveng and Sastre: Potential Application from Traditional Remedies to Modern Therapeutics

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Tamilnadia uliginosa (Retz) Tirveng and Sastre (Rubiaceae) is a small edible medicinal plant utilized in...     

Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart.

To define the mechanism(s) responsible for the negative inotropic effects of tumor necrosis factor-alpha (TNF alpha) in the adult heart, we examined the functional effects of TNF alpha in the intact left ventricle and the isolated adult cardiac myocyte. Studies in both the ventricle and the isolated adult cardiac myocyte showed that TNF alpha exerted a concentration- and time-dependent negative inotropic effect that was fully reversible upon removal of this cytokine. Further, treatment with a neutralizing anti-TNF alpha antibody prevented the negative inotropic effects of TNF alpha in isolated myocytes. A cellular basis for the above findings was provided by studies which showed that treatment with TNF alpha resulted in decreased levels of peak intracellular calcium during the systolic contraction sequence; moreover, these findings did not appear to be secondary to alterations in the electrophysiological properties of the cardiac myocyte. Further studies showed that increased levels of nitric oxide, de novo protein synthesis, and metabolites of the arachidonic acid pathway were unlikely to be responsible for the TNF alpha-induced abnormalities in contractile function. Thus, these studies constitute the initial demonstration that the negative inotropic effects of TNF alpha are the direct result of alterations in intracellular calcium homeostasis in the adult cardiac myocyte.     

Breast carcinoma with metastasis to the gallbladder:an unusual case report with a short review of literature

Gallbladder metastases are very rare and usually arise from malignant melanoma, renal cell carcinoma and cervical carcinoma. Breast carcinoma tnetastatic to the gallbladder is extremely rare and only 4 cases have been reported in the English literature. We hereby report a 54-year-old lady who was diagnosed as having breast carcinoma and underwent modified radical mastectomy. One month after the operation, she developed acute abdomenal pain and underwent cholecystectomy after clinical investigation. Histopathological examination revealed metastasis to the gallbladder. Being considered a patient with tnetastatic breast carcinoma she was subjected to taxane and anthracycline-based palliative chemotherapy. Later she had CNS involvement and died of the progressive disease soon after few months.     

Knowledge,attitude, beliefs and practices in HIV/AIDS in India: identifying the gender and rural–urban differences

ObjectiveTo promote the use of preventive measures and raise awareness regarding HIV/AIDS in India.MethodsData from the population-based NFHS-3 survey 2005-06 was used. In this study, information collected on 87 961 women aged 15-49 years and 44 717 men aged 15-54 years was used in the final analysis. The data collected was stratified by gender and place of residence. Analyses of the variables related to the outcomes i.e. knowledge, attitude, belief and practices, was conducted using Chi-square test to calculate significant differences among proportions of categorical variables.ResultsWe found that knowledge of HIV transmission and prevention was low among women and rural residents. Most of the respondents had a non-discriminatory attitude towards HIV positives and majority agreed that children should be educated on HIV/AIDS. The use of condoms and proportion of respondents who had undergone HIV testing was found to be significantly low. We found a significant gap in the beliefs regarding ways to avoid HIV.ConclusionsThere are significant gender and urban-rural differentials in India in terms of knowledge, attitude, beliefs and practices in HIV/AIDS. Information dissemination in India should be designed in a way that not only raises the level of awareness but also result in behavioral change.     

Factors that Determine the Use of Skilled Care During Delivery in India: Implications for Achievement of MDG-5 Targets

The objective of this study is to identify individual level factors that determine the use of skilled birth attendants in India. Data from the cross-sectional, population-based NFHS 3 Survey 2005–06 was used. A sample of 31,797 women, aged 15–49 years, who gave births in the 3 months preceding the survey and for whom information was available on most variables, were included in the analysis. Both bivariate and multivariate techniques were used to determine factors associated with the use of skilled attendants at birth. In the study we found that wealth is one of the strongest determinants of skilled birth attendant use, with the poor being at a disadvantage. There are significant differences in the use of skilled delivery care among the urban and rural populations in India. Women in urban areas are more likely to use skilled attendants. Muslim women and women with lower levels of education are also less likely to avail skilled delivery services. The use of skilled care depended significantly on the place of delivery. Women who gave history of antenatal visits were more likely to have skilled attendants at birth. Our analysis demonstrates that there are several financial, social, regional and cultural barriers to skilled birth attendant use in India. Effective strategies need to be planned to generate demand for skilled birth attendants and reduce barriers to care seeking, especially among rural poor.     

A Comparison of Microdebrider Assisted Endoscopic Sinus Surgery and Conventional Endoscopic Sinus Surgery for Nasal Polypi

Nasal polyposis is often encountered in rhinology practice. Those who fail conservative management, a definitive surgery is essential to achieve sufficient ventilation and drainage of the affected sinuses by using either microdebrider or conventional instruments for functional endoscopic sinus surgery (FESS). A prospective study was conducted on 40 cases of nasal polypi in a tertiary care hospital. 20 cases were operated by conventional endoscopic instruments and 20 using the microdebrider. The study aimed at comparing the intra operative (blood loss, duration of surgery) and post operative results (crusting, scarring, discharge, symptoms, recurrence) between the two groups using Lund–Mackay scoring system and the data was statistically analysed. There was no statistically significant difference in surgical outcome for patients when either conventional endoscopic instruments or microdebrider was used. However, there was a significant symptomatic improvement in cases undergoing microdebrider FESS. Microdebrider assisted polypectomy is precise, relatively bloodless surgery though the precision depends on the surgeon’s anatomical knowledge and operative skills. Study substantiates that these instruments are helpful but not a prerequisite for successful outcomes in FESS. The study re-emphasises the utility of the microdebrider to young learning FESS surgeons.     

Recurrent metastasi zing neuroendocrine tumor of paranasal sinuses

Neuroendocrine tumours- their rare occurrence and propensity for recurrences can undoubtedly pose as a diagnostic and therapeutic dilemma. A case report of one such case with recurrence and bony metastasis is presented.