Objectives
Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum.
Methods
The participants were HIV‐1‐infected ...pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady‐state 12‐h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration–time curve (AUC0–12) was ≥10th percentile NFV AUC0–12 in non‐pregnant historical controls (18.5 μg h/mL).
Results
Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (Cmax), 12‐h post‐dose concentration (C12) and AUC0–12 were significantly lower during the third trimester compared to postpartum (P≤0.03). The metabolite hydroxyl‐tert‐butylamide (M8) AUC0–12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P<0.01). The NFV AUC0–12 exceeded the AUC0–12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (Cmin) was above the suggested minimum trough concentration (0.8 μg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was <400 HIV‐1 RNA copies/mL in 81% of patients at delivery.
Conclusions
These results suggest that higher doses of NFV should be considered during pregnancy.
The rising popularity of the fentanyl transdermal patch and the striking number of deaths attributed to its prescribed use have brought attention to the large variability of fentanyl metabolism and ...the need for predictive models to prevent toxicity.
The purpose of this study was to determine the amount of both intrasubject and intersubject variability in fentanyl metabolism and excretion, using urinary excretion data from patients with chronic pain prescribed the fentanyl transdermal patch.
Liquid chromatography tandem mass spectrometry analytical technique was used to quantitate fentanyl and norfentanyl concentrations in spot urine specimens, after incubation with glucuronidase. Descriptive statistics and graphical analysis were conducted using Microsoft Excel 2007. Analysis was conducted on 206 subjects with > or = 2 visits listing transdermal fentanyl as current medication. Outliers and subjects with no detectable levels of drug were excluded, resulting in subject populations of 200 (all subjects analyzed) and 166 (subjects with drug concentrations above the instrument detection limit for all visits).
The geometric mean metabolic ratio (MR) of norfentanyl to fentanyl was 6.2 x division by 2.4. A wide distribution was observed in total fentanyl load (1,000-fold) and MR (200-fold). The intersubject geometric standard deviation in MR was 2.4 (95% confidence interval CI for MR: 1-37) and the intrasubject geometric standard deviation was 1.8 (95% CI for MR: 2-20).
The level of intrasubject variability over time in the pharmacokinetics of the fentanyl patch is much greater than previously observed and may be due to variability in absorption, interference of metabolism by concomitant medications, and variable metabolism due to genetic polymorphisms. The variation in the MR between subjects and within subjects may explain the unpredictable adverse effects observed with use of transdermal fentanyl.
Background:
In infants and children, treatment of Kawasaki disease (KD) with high-dose intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA aspirin) diminishes inflammatory response and ...reduces the risk for coronary artery abnormalities. However, patients with high serum concentrations of tumor necrosis factor (TNF)-alpha, which is associated with vascular damage, may develop coronary artery lesions even with treatment. The hemorheologic agent pentoxifylline blocks the production of TNF-alpha and may be an appropriate adjunctive therapy to IVIG and ASA.
Objective:
The objective of this study was to assess the pharmacokinetic characteristics and tolerability of a new oral syrup formulation of pentoxifylline as an adjunct to IVIG and ASA in the treatment of KD in children.
Methods:
Hospitalized boys and girls aged 6 months to 5 years and who were diagnosed with KD within the first 10 days of illness were eligible. Patients were assigned to 1 of 4 pentoxifylline treatment groups, by dose level (dose levels 1, 2, 3, and 4: 10, 15, 20, and 25 mg/kg daily, respectively, divided into 3 doses). Six plasma samples collected at the time the first dose was administered, and 4 samples collected after administration of the last dose on study day 6, were assessed by high-performance liquid chromatography using noncompartmental and 1-compartment pharmacokinetic analyses for pentoxifylline and its active metabolite (M-1). TNF-alpha levels on days 1 and 6 were assessed using electroimmunoassay.
Results:
Fourteen boys and 10 girls were enrolled. The mean age, body weight, and illness day at study entry were 34.5 months, 13.8 kg, and 6, respectively. Pentoxifylline exhibited nonlinear kinetic characteristics, with median area under the plasma concentration–time curve from time 0 to infinity(AUC
0–∞) values of 622, 3428, 8416, and 10,347 ng/mL · h for dose levels 1 to 4, respectively, on study day 1. Pentoxifylline noncompartmental oral clearance and volume of distribution were significantly lower, and dose-normalized AUC
0–∞ was significantly higher, for dose level 3 than dose level 1. M-1 parameters were not significantly different between dose levels. No accumulation of pentoxifylline or M-1 was noted. Fifteen of 24 patients (63%) reported mild to moderate adverse events that may or may not have been treatment related. Frequency and severity did not differ significantly between dose levels.
Conclusions:
In the children in this study, pentoxifylline was well tolerated at the doses studied. No notable differences in clinical outcomes were observed between dose levels, and dose levels 3 and 4 (20 and 25 mg/kg daily, respectively) resulted in similar exposure to both pentoxifylline and M-1. Future efficacy and tolerability studies should use a daily dose of 20 mg/kg of pentoxifylline in acute KD.
Summary Background Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We ...aimed to quantify these associations for a wide range of circumstances. Methods We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. Findings Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8·49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2·00 (95% CI 1·83–2·19) for coronary heart disease; 2·27 (1·95–2·65) for ischaemic stroke; 1·56 (1·19–2·05) for haemorrhagic stroke; 1·84 (1·59–2·13) for unclassified stroke; and 1·73 (1·51–1·98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40–59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10–12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3·90 mmol/L and 5·59 mmol/L. Compared with fasting blood glucose concentrations of 3·90–5·59 mmol/L, HRs for coronary heart disease were: 1·07 (0·97–1·18) for lower than 3·90 mmol/L; 1·11 (1·04–1·18) for 5·60–6·09 mmol/L; and 1·17 (1·08–1·26) for 6·10–6·99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. Interpretation Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. Funding British Heart Foundation, UK Medical Research Council, and Pfizer.
Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help ...judge likelihood of causality. Methods We assessed the −1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 ( APOA5 ) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2·79 million person-years at risk). We analysed −1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of −1131T>C was 8% (95% CI 7–9). −1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3·5% 95% CI 2·6–4·6; 0·053 mmol/L 0·039–0·068), lower apolipoprotein AI (1·3% 0·3–2·3; 0·023 g/L 0·005–0·041), and higher apolipoprotein B (3·2% 1·3–5·1; 0·027 g/L 0·011–0·043). By contrast, for every C allele inherited, mean triglyceride concentration was 16·0% (95% CI 12·9–18·7), or 0·25 mmol/L (0·20–0·29), higher (p=4·4×10−24 ). The odds ratio for coronary heart disease was 1·18 (95% CI 1·11–1·26; p=2·6×10−7 ) per C allele, which was concordant with the hazard ratio of 1·10 (95% CI 1·08–1·12) per 16% higher triglyceride concentration recorded in prospective studies. −1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12·2 nmol/L 95% CI 7·7–16·7; p=9·3×10−8 ) and smaller HDL particle size (0·14 nm 0·08–0·20; p=7·0×10−5 ), factors that could mediate the effects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.
Recent large randomized, controlled trials (BEST β-blocker Evaluation of Survival Trial, CIBIS-II Cardiac Insufficiency Bisoprolol Trial II, COPERNICUS Carvedilol Prospective Randomized Cumulative ...Survival Study, and MERIT-HF Metoprolol Randomized Intervention Trial in Congestive Heart Failure) have addressed the usefulness of β-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that β-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to β-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to β-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure.
To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of β-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed.
In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR)=0.77 95% CI=0.65, 0.92), cardiovascular death (HR=0.71 0.58, 0.86), sudden death (HR=0.77 0.59, 0.999), and pump failure death (HR=0.64 0.45, 0.91).
Although not excluding the possibility of differences resulting from chance alone or to different properties among β-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to β-blocker therapy.
We study how the proportion of star-forming galaxies evolves between z = 0.8 and 0 as a function of galaxy environment, using the OII line in emission as a signature of ongoing star formation. Our ...high-z data set comprises 16 clusters, 10 groups, and another 250 galaxies in poorer groups and the field at z = 0.4-0.8 from the ESO Distant Cluster Survey, plus another 9 massive clusters at similar redshifts. As a local comparison, we use galaxy systems selected from the Sloan Digital Sky Survey (SDSS) at 0.04 < z < 0.08. At high z most systems follow a broad anticorrelation between the fraction of star-forming galaxies and the system velocity dispersion. At face value, this suggests that at z = 0.4-0.8 the mass of the system largely determines the proportion of galaxies with ongoing star formation. At these redshifts the strength of star formation (as measured by the O II equivalent width) in star-forming galaxies is also found to vary systematically with environment. SDSS clusters have much lower fractions of star-forming galaxies than clusters at z = 0.4-0.8 and, in contrast with the distant clusters, show a plateau for velocity dispersions .550 km s super(-1), where the fraction of galaxies with O II emission does not vary systematically with velocity dispersion. We quantify the evolution of the proportion of star-forming galaxies as a function of the system velocity dispersion and find that it is strongest in intermediate-mass systems (s 6 500-600 km s super(-1) at z = 0). To understand the origin of the observed trends, we use the Press-Schechter formalism and the Millennium Simulation and show that galaxy star formation histories may be closely related to the growth history of clusters and groups. If the scenario we propose is roughly correct, the link between galaxy properties and environment is extremely simple to predict purely from a knowledge of the growth of dark matter structures.
Type 1 diabetes is associated with chronic hyperglycemia and exposure to intermittent severe hypoglycemia. The long-term cerebral effects of these consequences of diabetes are ill defined. In this ...study, the history of preceding severe hypoglycemia and the presence of background retinopathy were examined in relation to cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging) in a cross-sectional evaluation of 74 young people with type 1 diabetes. Participants differed by their severe hypoglycemia exposure and degree of diabetic retinopathy and none had previous neuropsychological pathology. Severe hypoglycemia did not influence cognitive ability or brain structure. Background diabetic retinopathy was associated with small focal white-matter hyperintensities in the basal ganglia (33.3 vs. 4.7%, after correction for age, P = 0.005) and significant cognitive disadvantage, affecting fluid intelligence (P = 0.008, Eta(2) = 0.14), information processing (P = 0.001, Eta(2) = 0.22), and attention and concentration ability (P = 0.03, Eta(2) = 0.09). In conclusion, recurrent exposure to severe hypoglycemia alone in young people with type 1 diabetes had no detrimental impact on brain structure or function over the duration of diabetes examined. Chronic hyperglycemia (inferred by the presence of background diabetic retinopathy) may affect brain structure and function.
Introduction Venous thromboembolism (VTE) remains a major public health issue around the world. Ethnicity is known to alter the incidence of VTE. To our knowledge, there are no reports in the ...literature investigating the incidence of VTE in British Indians. The aim of this study was to investigate the rates of symptomatic VTE in British Indian patients in the UK. Methods Patients referred to our institution between January 2011 and August 2013 with clinically suspected VTE were eligible for inclusion in the study. Those not of British Indian or Caucasian ethnicity were excluded. A retrospective review of these two cohorts was conducted. Results Overall, 15,529 cases were referred to our institution for suspected VTE. This included 1,498 individuals of British Indian ethnicity. Of these, 182 (12%) had confirmed VTE episodes. A further 13,159 of the patients with suspected VTE were coded as Caucasian, including 2,412 (16%) who had confirmed VTE events. VTE rates were a third lower in British Indians with clinically suspected VTE than in the equivalent Caucasian group. The British Indian cohort presented with VTE at a much earlier age than Caucasians (mean 57.0 vs 68.0 years). Conclusions This study suggests that British Indian patients have a lower incidence of VTE and are more likely to present at an earlier age than Caucasians. There was no significant difference in VTE type (deep vein thrombosis vs pulmonary embolism) among the ethnic groups. Clinicians should be aware of variations within ethnicities but should continue to adhere to existing VTE prevention guidance.
Abstract Client functioning and treatment engagement were examined in relation to staff attributes and organizational climate across a diverse sample of drug treatment and outreach programs in ...England. Self-rating assessments were obtained from 1,539 clients and 439 counselors representing 44 programs, and results were interpreted using comparable data from studies of treatment programs in the United States. Client scores on treatment participation and counseling rapport in England were directly related to their higher levels of motivation and psychosocial functioning, as well as to staff ratings of professional attributes and program atmosphere. By linking records from English clients with their counselors in each program, findings also indicate these relationships are rooted in the personal interactions between clients and their counselor. Standardized assessments of treatment structure, process, and performance used across therapeutic settings and national boundaries show there is generalizability in the pattern of clinical dynamics, including the relationships between organizational functioning and quality of services.
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