Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, K_I/k_inact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro–in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2-specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2 μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp^®. A modest (2–6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded.     

Lack of benefit of an active pectoral pulse generator on atrial defibrillation thresholds

INTRODUCTION: Atrial defibrillation can be achieved with standard implantable cardioverter defibrillator leads, which has led to the development of combined atrial and ventricular devices. For ventricular defibrillation, use of an active pectoral electrode (active can) in the shocking pathway markedly reduces defibrillation thresholds (DFTs). However, the effect of an active pectoral can on atrial defibrillation is unknown. METHODS AND RESULTS: This study was a prospective, randomized, paired comparison of two shock configurations on atrial DFTs in 33 patients. The lead system evaluated was a dual-coil transvenous defibrillation lead with a left pectoral pulse generator emulator. Shocks were delivered either between the right ventricular coil and proximal atrial coil (lead) or between the right ventricular coil and an active can in common with the atrial coil (active can). Delivered energy at DFT was 4.2 +/- 4.1 J in the lead configuration and 5.0 +/- 3.7 J in the active can configuration (P = NS). Peak current was 32% higher with an active can (P < 0.01), whereas shock impedance was 18% lower (P < 0.001). Moreover, a low threshold (< or = 3 J) was observed in 61% of subjects in the lead configuration but in only 36% in the active can configuration (P < 0.05). There were no clinical predictors of the atrial DFT. CONCLUSION: These results indicate that low atrial DFTs can be achieved using a transvenous ventricular defibrillation lead. Because no benefit was observed with the use of an active pectoral electrode for atrial defibrillation, programmable shock vectors may be useful for dual-chamber implantable cardioverter defibrillators.     

Prostaglandin E1 infusions for vascular insufficiency in progressive systemic sclerosis.

Twelve patients with systemic sclerosis (SS) and severe Raynaud's phenomenon received infusions of prostaglandin E1 (PGE1) at a dose of 6-10 ng/kg/min, with either saline or 5% dextrose, for 72 hours in a single-blind cross-over study. The infusions were administered intravenously by centrally positioned catheters. Infusions were well tolerated with only mild side effects. Following the PGE1 infusion cold tolerance improved and attacks of Raynaud's phenomenon were less frequent, less severe, and shorter in duration. This subjective improvement was maintained for several weeks in most patients, and 2 noted healing of ischaemic ulcers. There was no significant change in objective measurements of hand function after either infusion. However, pain measured on a 10 cm visual analogue scale improved 2.19 cm with PGE1 and only 0.91 cm with normal saline (P less than 0.05). Temperature of the fingers and hands recorded by thermography did not change significantly with saline infusions, but did rise during PGE1 infusions (mean rise 2.0 degrees C at 48 hours, p less than 0.001), and was maintained when measured again 2 weeks later (mean rise 1.56 degrees C, p less 0.001). PGE1 may therefore be suitable treatment for Raynaud's phenomenon and the vascular insufficiency of systemic sclerosis and other connective tissue diseases.     

Consultations with complementary and alternative medicine practitioners amongst wider care options for back pain: a study of a nationally representative sample of 1,310 Australian women aged 60–65 years

Back pain is a significant health service issue in Australia and internationally. Back pain sufferers can draw upon a range of health care providers including complementary and alternative medicine (CAM) practitioners. Women are higher users of health services than men and tend to use CAM frequently for musculoskeletal conditions. However, there remain important gaps in our understanding of women’s consultation patterns with CAM practitioners for back pain. The objective of this study is to examine the prevalence of use and characteristics of women who use CAM practitioners for back pain. The method used was a survey of a nationally representative sample of women aged 60–65 years from the Australian Longitudinal Study on Women’s Health. Women consulted a massage therapist (44.1 %, n?=?578) and a chiropractor (37.3 %, n?=?488) more than other CAM practitioners for their back pain. Consultations with a chiropractor for back pain were lower for women who consulted a General Practitioner (GP) (OR, 0.56; 95 % CI 0.41, 0.76) or a physiotherapist (OR, 0.53; 95 % CI 0.39, 0.72) than for those who did not consult a GP or a physiotherapist. CAM practitioner consultations for back pain were greater for women who visited a pharmacist (OR, 1.99; 95 % CI 1.23, 3.32) than for women who did not visit a pharmacist. There is substantial use of CAM practitioners alongside conventional practitioners amongst women for back pain, and there is a need to provide detailed examination of the communication between patients and their providers as well as across the diverse range of health professionals involved in back pain care.     

Cost‐effectiveness analysis of preoperative transfusion in patients with sickle cell disease using evidence from the TAPS trial

The study's objective was to assess the cost‐effectiveness of preoperative transfusion compared with no preoperative transfusion in patients with sickle cell disease undergoing low‐ or medium‐risk surgery. Seventy patients with sickle cell disease (HbSS/Sß⁰thal genotypes) undergoing elective surgery participated in a multicentre randomised trial, Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS). Here, a cost‐effectiveness analysis based on evidence from that trial is presented. A decision‐analytic model is used to incorporate long‐term consequences of transfusions and acute chest syndrome. Costs and health benefits, expressed as quality‐adjusted life years (QALYs), are reported from the ‘within‐trial’ analysis and for the decision‐analytic model. The probability of cost‐effectiveness for each form of management is calculated taking into account the small sample size and other sources of uncertainty. In the range of scenarios considered in the analysis, preoperative transfusion was more effective, with the mean improvement in QALYs ranging from 0.018 to 0.206 per patient, and also less costly in all but one scenario, with the mean cost difference ranging from ?£813 to £26. All scenarios suggested preoperative transfusion had a probability of cost‐effectiveness >0.79 at a cost‐effectiveness threshold of £20 000 per QALY.