Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.     

Family of class 1 integrons related to In4 from Tn1696

The class 1 integron In28, found in the multidrug resistance transposon Tn1403, was found to be located in the res site of the backbone transposon and is flanked by a 5-bp direct duplication, indicating that it reached this position by transposition. In28 has a backbone structure related to that of In4, but has lost internal sequences, including the sul1 gene, due to an IS6100-mediated deletion. In28 also lacks the partial copy of IS6100 found in In4 and contains different gene cassettes, blaP1, cmlA1, and aadA1. In1, the class 1 integron found in the multidrug resistance plasmid R46, is also located in a putative res site and belongs to the In4 group. In1 has a shorter internal deletion than In28 and has also lost one end. Additional integrons with structures related to In4 were also found in databases, and most of them had also lost either one end or internal regions or both. Tn610 belongs to this group.     

Effects of nabumetone,celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors

Nonsteroidal anti-inflammatory drugs interfere with certain antihypertensive therapies. In a double-blind study, 385 hypertensive patients stabilized on an angiotensin converting enzyme inhibitor were treated with nabumetone, celecoxib, ibuprofen, or placebo for 4 weeks. Ibuprofen caused significantly greater increases in systolic (P < .001) and diastolic (P < .01) blood pressures (BPs) compared to placebo, but not nabumetone or celecoxib. The proportion of patients with systolic BP increases of clinical concern at end point was significantly higher (P < .001) for the ibuprofen group (16.7%; 15 of 90), but not for the nabumetone group (5.5%; 5 of 91) or the celecoxib group (4.6%; 4 of 87) compared to the placebo group (1.1%; 1 of 91).     

Familial factors in the antihypertensive response to lisinopril

BACKGROUND: Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS: This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS: Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION: Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.     

Arterial inflammation and atherosclerosis

Arterial inflammation is a significant component of atherosclerotic disease and it has been suggested that specific immune responses directed against autoantigens or pathogen-derived antigens presented in the vascular wall could initiate and/or maintain atherosclerotic processes. Atherogenic cofactors such as altered cholesterol metabolism may not only impact locally on inflammatory responses in atherosclerotic lesions, but may also alter general immune-responsiveness. The evidence to date suggests that the mutual chronic perpetuation of immune mediated vascular inflammation and cholesterol-induced atherosclerosis is a key step in atherogenesis.     

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had TSC2 LOH in 33 of 60 (55%) LAM patients. Cells with TSC2 LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.     

Cancer radioimmunotherapy

Targeting of radionuclides with antibodies, or radioimmunotherapy, has been an active field of research spanning nearly 50 years, evolving with advancing technologies in molecular biology and chemistry, and with many important preclinical and clinical studies illustrating the benefits, but also the challenges, which all forms of targeted therapies face. There are currently two radiolabeled antibodies approved for the treatment of non-Hodgkin lymphoma, but radioimmunotherapy of solid tumors remains a challenge. Novel antibody constructs, focusing on treatment of localized and minimal disease, and pretargeting are all promising new approaches that are currently under investigation.     

Midazolam-pain, but one cannot remember it: a survey among Southern German endoscopists

BACKGROUND: Benzodiazepines, especially midazolam, are the most frequently used agents for gastrointestinal endoscopy worldwide. Among other parameters the quality of sedation is determined by patients' satisfaction assessed after endoscopy. This approach is misleading as the potent amnestic effect of midazolam conceals pain actually suffered during the endoscopic procedure involving distraction of the endoscopists from their actual tasks by audible reactions and defense movements. In this study, we eliminated the influence of patients' amnesia on the assessment of the quality of sedation and rather interviewed endoscopists and their assistant personnel about their experience with midazolam sedation. We replaced the mostly vague term 'compliance' by terms which unequivocally describe the reactions of the patient during an unpleasant endoscopy. METHODS: A short survey consisting of 12 questions was developed. The questionnaires were distributed to the participants - 115 endoscopists and their assistants - of a tutorial about sedation for gastrointestinal endoscopy in three major Southern German cities. The questionnaire retrieved the endoscopists' experience regarding patients' discomfort or pain under sedation with midazolam, their wish for better sedative agents, their preferred sedative regimens, their medical specialty and their professional experience. RESULTS: Participants were highly experienced with the majority having more than 10,000 procedures and a median of 18 years of endoscopic experience; 77% of endoscopists utilized midazolam for sedation. Ninety-eight percent of the questioned physicians felt that patients have pain during endoscopy with midazolam+/-opioid, but do not remember later. Ninety-two percent reported that it happens that patients moan aloud because of pain and almost half of the endoscopists (48%) reported of screaming. The majority of the endoscopists (91%) reported fierce defense movements with midazolam or the need to hold the patient down on the examination couch because of fierce movements, respectively (75%). Seventy percent of the endoscopists wished to have the rooms for endoscopy preferably soundproof away from the waiting room and 93% wished for better sedative agents. CONCLUSIONS: Midazolam was rated as insufficient for sedation by both endoscopists and their assistant personnel. A wish for better sedative drugs exists.     

A novel modification of the Thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation

Flow cytometry, singlet platelet counting, and optical aggregation have been used to monitor clopidogrel and glycoprotein IIb/IIIa (GPIIb/IIIa) platelet antagonists. Optical aggregation is considered the gold standard, but neither it nor flow cytometry is convenient in larger-scale clinical studies or point-of-care systems. Singlet platelet counting, a point-of-care assay correlated with optical platelet aggregation, only provides a measurement of platelet function at a single point in time. The Thrombelastograph is used to assay whole blood for thrombin-generated maximal clot-shear elasticity, referred to as the maximal amplitude (MA). Although platelet dysfunction, thrombocytopenia, and the in vitro effect of strong inhibitors such as IIb/IIIa antagonists can be observed, with thrombin generation milder platelet inhibitors cannot be assessed. We modified the Thromboelastograph assay, using reptilase and factor XIIIa, to form a clot, without thrombin generation, in heparinized whole blood. The resulting clot MA is dependent on added platelet agonists such as ADP or arachidonic acid, is sensitive to platelet antagonists, and provides a continuous measure of platelet function more analogous and better correlated with optical aggregation. This novel modification of the Thromboelastograph assay should prove to be a useful point-of-care whole-blood assay with which to monitor the effects of GPIIb/IIIa, ADP, and thromboxane A(2)-receptor-inhibiting drugs in patients.