CYP3A-dependent drug metabolism is reduced in bacterial inflammation in mice.

BACKGROUND AND PURPOSE: Gene expression of Cyp3a11 is reduced by activation of Toll-like receptors (TLRs) by Gram-negative or Gram-positive bacterial components, LPS or lipoteichoic acid (LTA) respectively. The primary adaptor protein in the TLR signalling pathway, TIRAP, plays differential roles in LPS- and LTA-mediated down-regulations of Cyp3a11 mRNA. Here, we have determined the functional relevance of these findings by pharmacokinetic/pharmacodynamic (PK/PD) analysis of the Cyp3a substrate midazolam in mice. Midazolam is also metabolized by Cyp2c in mice. EXPERIMENTAL APPROACH: Adult male C57BL/6, TIRAP+/+ and TIRAP-/- mice were pretreated with saline, LPS (2 mg·kg⁻¹) or LTA (6 mg·kg⁻¹). Cyp3a11 protein expression, activity and PK/PD studies using midazolam were performed. KEY RESULTS: Cyp3a11 protein expression in LPS- or LTA-treated mice was reduced by 95% and 60% compared with saline-treated mice. Cyp3a11 activity was reduced by 70% in LPS- or LTA-treated mice. Plasma AUC of midazolam was increased two- to threefold in LPS- and LTA-treated mice. Plasma levels of 1'-OHMDZ decreased significantly only in LTA-treated mice. Both LPS and LTA decreased AUC of 1'-OHMDZ-glucuronide. In the PD study, sleep time was increased by ∼2-fold in LPS- and LTA-treated mice. LTA-mediated decrease in Cyp3a11 protein expression and activity was dependent on TIRAP. In PK/PD correlation, AUC of midazolam was increased only in LPS-treated mice compared with saline-treated mice. CONCLUSIONS AND IMPLICATIONS: LPS or LTA altered PK/PD of midazolam. This is the first study to demonstrate mechanistic differences in regulation of metabolite formation of a clinically relevant drug by Gram-negative or Gram-positive bacterial endotoxins.

Simultaneous determination of lignocaine hydrochloride and phenylephrine hydrochloride by HPTLC.

A high performance thin layer chromatographic (HPTLC) method for the simultaneous quantification of lignocaine hydrochloride (LIG) and phenylephrine hydrochloride (PHE) is described. The mobile phase consisted of ethyl acetate-methanol ammonia (4:1:0.4 v/v/v). The densitometric determination of LIG and PHE was carried out at 262 nm and 291 nm, respectively. The calibration curves of LIG and PHE were linear in the range of 8-18 microg and 4-9 microg, respectively. The method was validated with respect to system precision, method precision, recoveries, intra-day and inter-day variation. The system was applied for the simultaneous determination of LIG and PHE from a new drug delivery system. The results indicate that the method is simple, specific, selective and reliable for simultaneous quantitative determination of LIG and PHE as bulk drug and from formulations.

Safety of copper T as contraceptive after caesarean section.

Copper T was inserted in 45 cases following caesarean section. Motivation was easier, acceptance was higher and follow-up was good in this group of patients. With proper selection and careful follow-up complications could be reduced to the minimum.

PIP: To assess the safety of insertion of the Copper T IUD after cesarean section, 45 women who underwent this process were followed for a period of 1-3 years. The majority of study participants were 26-30 years of age. 27 were para 1, 17 were para 2, and 1 was para 3. In 37 women, the IUD was inserted in tube postmenstrual phase. Complications occurring in this series were bleeding, pain, leukorrhea, perforation, and infection. The 1 case of perforation was diagnoses 1 1/2 years after IUD insertion when the patient requested removal to achieve pregnancy. The uterus was found to be hyperinvoluted. The case of pelvic infection also was revealed 1 1/2 years after insertion. This patient was treated with antibiotics and conceived 6 months after IUD removal. IUD expulsion occurred in 4 cases--2 within 5 days of insertion and 2 at 3 and 5 months after insertion. During the study period, 5 women had the device removed for reasons that included bleeding, formation of an adnexal lump, and desire for pregnancy. Notable in this series was an excessive bleeding rate of 6.6% compared to rates as high as 15% obtained in studies of IUD insertion after vaginal delivery. There were no ectopic pregnancies or contraception failures among women in this study. In general, it appears that the Copper T IUD is a safe contraceptive choice after cesarean section. However, given the risk of perforation or expulsion, the device is not recommended for women with a hyperinvoluted small uterus.