Enantioselective N-Demethylation and Hydroxylation of Sibutramine in Human Liver Microsomes and Recombinant Cytochrome P-450 Isoforms

The enantioselective metabolism of sibutramine was examined using human liver microsomes (HLM) and recombinant cytochrome P-450 (CYP) isoforms. This drug is metabolized to N-mono-desmethyl- (M1) and N,N-di-desmethylsibutramine (M2), and subsequent hydroxylation results in hydroxyl M1 (HM1) and hydroxyl M2 (HM2). No significant difference was noted in formation of M1from sibutramine between R- and S-sibutramine in HLM. However, S-enantiomers of M1 and M2 were preferentially metabolized to M2, HM1, and HM2compared to R-enantiomers in HLM, and intrinsic clearance (Cl_int) ratios of S-enantiomers/R-enantiomers were 1.97, 4.83, and 9.94 for M2, HM1, and HM2, respectively. CYP3A4 and CYP3A5 were only involved in the formation of M1, whereas CYP2B6 and CYP2C19 were responsible for all metabolic reactions of sibutramine. CYP2C19 and CYP3A5 displayed catalytic preference for S-sibutramine to S-M1, whereas CYP2B6 and CYP3A4 showed little or no stereoselectivity in metabolism of sibutramine to M1. In the case of M2 formation, CYP2B6 metabolized S-M1 more rapidly than R-M1 with a Cl_int ratio of 2.14. However, CYP2C19 catalyzed less S-M1 than R-M1 and the Cl_int ratio of S-M1 to R-M1 was 0.65. The most significant enantioselectivity was observed in formation of HM1 from M1, and HM2 from M2. CYP2B6 and CYP2C19 exhibited preferential catalysis of formation of hydroxyl metabolites from S-enantiomers rather than R-enantiomers. These results indicate that S-sibutramine was more rapidly metabolized by CYP isoforms than R-sibutramine, and that enantioselective metabolism needs to be considered in drug interactions involving sibutramine and co-administered drugs.     

Volvulus of ileal S-pouch: A rare complication of ileal pouch anal anastomoses

INTRODUCTION

Ileal pouch anal anastomosis (IPAA) after total proctocolectomy is a frequently performed surgery for medically refractory ulcerative colitis (UC). Volvulus of the ileal pouch as a complication of IPAA is extremely rare. We present a case of volvulus of S-type ileal pouch.

PRESENTATION OF CASE

A 28 year old male, with history of total proctocolectomy with IPAA for severe UC in 2009 presented with signs of bowel obstruction. Emergency laparotomy was done and a volvulus of the S-type ileal pouch was derotated and pouchpexy done.

DISCUSSION

The IPAA has a wide spectrum of complications, with obstruction of proximal small bowel occurring frequently. Volvulus of the ileal pouch is extremely rare with only 3 reported cases. Early diagnosis and intervention is important to salvage the pouch. Computed tomography (CT) may aid the diagnosis in stable patients.

CONCLUSION

The diagnosis of ileal pouch volvulus although rare, should be kept in mind when dealing with patients complaining of recurrent obstruction following IPAA.     

Duplex PCR Assay for Identification of Tissue of Cattle and Buffalo Origin Targeting Mitochondrial Cytochrome b Gene

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - The aim of this study was to develop PCR assay for simultaneous detection of tissues from cattle and buffalo...     

Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: a substudy of the Women's Angiographic Vitamin and Estrogen (WAVE) trial

We measured flow-mediated dilation (FMD) by high-resolution brachial ultrasound in 61 women who participated in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a randomized controlled trial. There were no significant differences in the baseline demographics of women receiving hormone therapy (0.625 mg/day of conjugated equine estrogen plus 2.5mg of medroxyprogesterone acetate for women who had not had a hysterectomy) or placebo; or vitamins (400 IU of Vitamin E and 500 mg of Vitamin C twice daily) or placebo. Baseline FMD was impaired in all subjects (3.3+/-7.6%). Neither hormone therapy (4.1+/-5.2% at baseline, 4.2+/-5.0% at 3 months, and 4.1+/-6.5% at 34 months) nor antioxidant vitamins (3.0+/-8.3% at baseline; 3.5+/-4.6% at 3 months; 3.1+/-7.6% at 34 months) improved FMD (all p-values=NS). Endothelium-independent vasodilation, induced by nitroglycerin (NTG) was similar at baseline and was not affected by either therapy. In univariate and multivariate analysis, neither hormone therapy nor antioxidant vitamins were associated with FMD. Women with established coronary artery disease have impaired flow-mediated vasodilation of the brachial artery that does not improve after 3 months or up to 34 months of treatment with postmenopausal hormone therapy or antioxidant vitamins.     

Dual depolarization responses generated within the same lateral septal neurons by TRPC4-containing channels

In the central nervous system, canonical transient receptor potential (TRPC) channels have been implicated in mediating neuronal excitation induced by stimulating metabotropic receptors, including group 1 metabotropic glutamate receptors (mGluRs). Lateral septal (LS) neurons express high levels of TRPC4 and group I mGluRs. However, to what extent native TRPC4-containing channels (TRPC4-cc) are activated as well as the impact of different levels of TRPC4-cc activation on neuronal excitability remain elusive. Here, we report that stimulating LS neurons with group I mGluR agonist, (S)-3,5-DHPG, causes either an immediate increase in firing rate or an initial burst followed by a pause of firing, which can be correlated with below-threshold-depolarization (BTD) or above-threshold-plateau-depolarization (ATPD), respectively, in whole-cell recordings. The early phase of BTD and the entire ATPD are completely absent in neurons from TRPC4^?/? mice. Moreover, in the same LS neurons, BTD can be converted to ATPD at more depolarized potentials or with a brief current injection, suggesting that BTD and ATPD may represent partial and full activations of TRPC4-cc, respectively. We show that coincident mGluR stimulation and depolarization is required to evoke strong TRPC4-cc current, and Na⁺ and Ca²⁺ influx, together with dynamic changes of intracellular Ca²⁺, are essential for ATPD induction. Our results suggest that TRPC4-cc integrates metabotropic receptor stimulation with intracellular Ca²⁺ signals to generate two interconvertible depolarization responses to affect excitability of LS neurons in distinct fashions.     

Internal limiting membrane peeling for large macular hole: Tailoring the rhexis to the shape of the hole

Purpose:To report a simple modification of internal limiting membrane (ILM) peeling tailored to the shape of the macular hole to improve the closure rates.Methods:This is a single-center interventional case series. conducted between 2016 and 2020. The minimum follow-up was 4 months. All surgeries were performed by one surgeon. Twenty consecutive patients (21 eyes) with large idiopathic macular holes (horizontal diameter: ≥600 μm) were enrolled; vertical hole diameters were also measured using spectral-domain optical coherence tomography (OCT). Following vitrectomy, ILM peeling was performed over a horizontally oval area (additional 1 disc-diameter temporally); perfluoropropane gas (C3F8, 15%) tamponade was used. Hole closure and change in best-corrected visual acuity (BCVA) were monitored after absorption of the gas. Preoperative and postoperative visual acuities were compared using paired t-test. IBM SPSS (ver. 26) was used for analysis.Results:The macular holes were horizontally oval rather than circular without exception: mean horizontal and vertical diameters were 714 μm (range: 600–1020 μm) and 602 μm (490–844 μm), respectively. Following vitrectomy, macular hole closure was obtained in 20/21 eyes by the last follow-up (mean: 28 months, median: 34 months; range 4–48 months). Mean Snellen BCVA improved from 20/200 to 20/63 (P < 0.0001).Conclusion:All the macular holes in the study were observed to be horizontally oval. A corresponding horizontal enlargement of the ILM rhexis yielded excellent anatomical and satisfactory visual outcomes.     

Refractive prediction by various intraocular lens formulas using optical biometry and effect of ocular parameters on their accuracy

Purpose:To assess the prediction accuracy of intraocular lens (IOL) formulas and study the effect of axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), and lens thickness (LT) on the accuracy of formulas using optic biometry.Methods:This study was performed on 164 eyes of 164 patients who underwent uneventful cataract surgery. Ocular biometry values were measured using Lenstar-900, and intraocular lens (IOL) power was calculated using the SRK/T, SRK II, Hoffer Q, Holladay 2, and Barrett Universal II formulas. We evaluated the extent of bias within each formula for different ocular biometric measurements and explored the relationship between the prediction error and the ocular parameters by using various IOL formulas.Results:The summarization of refractive prediction error and absolute prediction error for each IOL formulation was performed after adjusting the mean refractive error to zero. The deviation in the error values was minimum for SRK/T (0.265) followed by Holladay 2 (0.327) and Barret (0.382). Further, SRK/T had the lowest median (0.15) and mean (0.198) absolute error as compared to other formulations. For the above formulations, 100% of the eyes were in the diopter range of ±1.0. It was observed that the overall distribution of error was closer to zero for SRK/T, followed by Holladay 2 and then Barrett.Conclusion:In summary, we found that accuracy was better in SRK/T formula. We achieved a better understanding of how each variable in the formulas is relatively weighed and the influencing factors in the refraction prediction.