Thrombin binding and response in platelets from patients with dyslipoproteinemias: increased stimulus-response coupling in type II hyperlipoproteinemia

Platelets were obtained from patients with various hyperlipidemias [type II, type V, lecithin-cholesterol acyltransferase (LCAT) deficiency] and hypolipidemias (abetalipoproteinemia, Tangier disease) to ascertain relationships among plasma lipids, platelet lipids, thrombin binding and thrombin-induced platelet aggregation, and to compare these data with those previously obtained on stimulus-response coupling in platelets following in vitro modification of membrane microviscosity. Washed platelets were studied for their ability to bind 125I-thrombin in the range of 10(-10) to 10(-6) mol/L (10 mU/mL to 100 U/mL) and to aggregate with thrombin at concentrations less than 10(-9) mol/L (100 mU/mL). The values for binding and aggregation in eight patients from six kindred with familial hypercholesterolemia, taken as a group, fell in the low normal range. If divided into two groups, patients with overt cardiovascular disease bound normal amounts of thrombin but were more responsive to it, whereas patients without overt cardiovascular disease bound lower amounts of thrombin but gave an aggregation response in the normal range. These results suggest that platelet hyperresponsiveness in familial hypercholesterolemia arises from an alteration in the coupling mechanism between thrombin binding and response such that platelets from patients with familial hypercholesterolemia are able to respond with lower receptor occupancy than is the case with normal platelets. Thrombin binding and aggregation were within normal ranges for platelets from abetalipoproteinemia patients (N = 4) and type V hyperlipoproteinemia (N = 2), although in the latter case the response appeared to be less at very low thrombin concentrations (less than 30 mU/mL). Thrombin binding was elevated in Tangier disease (N = 3) but with lower responsiveness at lower thrombin concentrations. Thrombin binding was also elevated in LCAT deficiency (N = 2), and one patient showed increased and another showed decreased aggregation responses. In general, increased plasma cholesterol levels resulted in increased stimulus-response coupling (type II), whereas increased triglyceride levels resulted in decreased coupling (type V, Tangier), and there was no apparent alteration in the coupling mechanism with overall reduction in plasma lipid levels as in abetalipoproteinemia.     

Pharmacokinetics of Nevirapine: Once-Daily Versus Twice-Daily Dosing in the 2NN Study

Abstract

Objective: As part of the large international, randomized 2NN trial, the pharmacokinetics of nevirapine in once-daily 400 mg and twice-daily 200 mg dosing regimens were investigated. Method: Treatment-naive HIV-1-infected patients were randomized to receive nevirapine 400 mg once daily or 200 mg twice daily, in combination with lamivudine and stavudine. Blood samples were collected at several time-points (day 3, weeks 1, 2, 4, 24, and 48). Differences in pharmacokinetics between once- versus twice-daily dosing were investigated with nonlinear mixed effects modelling (NONMEM). Results: In total, 2,899 nevirapine plasma concentrations were available from 578 patients. Dosage and dosing frequency did not influence clearance or volume of distribution of nevirapine, indicating linear pharmacokinetic behavior of nevirapine whether given as a single daily dose or as divided doses over 24 hours. During steady state, the C_min was lower (3.26 mg/L vs. 4.44 mg/L; p < .001) and the C_max was higher (7.88 mg/L vs. 6.55 mg/L; p < .001) in the once-daily arm. However, compared to total variability in nevirapine levels for both treatments, these differences were minor. During steady state, total exposure, measured as AUC_24h, was comparable for both regimens (133 mg/L*h vs. 133 mg/L*h; p = .084). Conclusion: The daily exposure to nevirapine (AUC_24h) was similar for the 400 mg once-daily and the 200 mg twice-daily dosing regimens. The C_min of nevirapine is lower and the C_max of nevirapine is higher for the once-daily regimen as compared to the twice-daily regimen. As a result, 200 mg nevirapine dosed twice daily may be preferred over 400 mg nevirapine dosed once daily.     

Should prophylactic antibiotics be used routinely in epistaxis patients with nasal packs?

Introduction

The current mainstream practice in otolaryngology departments relating to the use of prophylactic antibiotics in epistaxis patients requiring nasal packing is highly variable. This is due primarily to the lack of any validated guidelines. As such, we introduced a new treatment algorithm resulting in significant reduction of use in the systemic antibiotics, with emphasis instead on the use of topical antibiotics. The results were validated through a complete audit cycle.

Methods

A total of 57 patients undergoing nasal packing for spontaneous epistaxis were studied. Reaudit occurred after the implementation of new guidelines. Telephone surveys were conducted six weeks after hospital discharge, assessing infective nasal symptoms as well as rebleeding and readmission rates.

Results

Systemic antibiotic prescribing in anterior nasal packing fell by 58.2% between audit cycles with no statistically significant associated increase in infective nasal symptoms, rebleeding or readmission rates six weeks following hospital discharge.

Conclusions

Systemic prophylactic antibiotics are unnecessary in the majority of epistaxis patients with nasal packs. The use of topical antibiotics such as Naseptin^® may be more appropriate, cheaper and as effective. Implementation of this treatment algorithm will help standardise systemic antibiotic usage in epistaxis patients with nasal packing and should reduce costs associated with unnecessary use of such medication.     

EGF促进RPE细胞β_2肾上腺能受体诱导的cAMP形成：受体间交互作用分析

研究证实表皮生长因子（ＥＧＦ）不影响培养人眼视网膜色素上皮（ＲＰＥ）细胞ｃＡＭＰ的基础水平，但促进异丙肾上腺素激活β＿２受体后诱导ｃＡＭＰ水平升高的效应，并呈量效依赖关系。ＥＧＦ对腺嘌呤核苷Ａ＿２受体激动剂ＮＥＣＡ诱导ｃＡＭＰ水平升高的效应没有明显影响。细胞增殖分析表明，ＥＧＦ刺激人眼ＲＰＥ细胞增殖，而ＤｉｂｕｔｙｒｙｌｃＡＭＰ和异丙肾上腺素抑制ＥＧＦ刺激增殖的效应。结果提示，在人眼ＲＰＥ细胞ＥＧＦ和β２受体之间存在受体间交互作用。     

Evaluating a computer system used as a microswitch for word utterances of persons with multiple disabilities

Purpose: To assess the effectiveness of a computer system used as a microswitch for word utterances of two adults with multiple disabilities. The system combined a new control software programme with a commercially available speech recognition programme. Method: Nine word utterances were targeted for each participant. The participant's emission of those utterances triggered the occurrence of related (favourite) stimuli during the intervention and the post-intervention check. Results: Intervention data showed that (1) the participants increased the frequencies of the target utterances and (2) the computer system recognized about 80% of those utterances correctly, providing the participants with high levels of favourite stimulation. The post-intervention check showed comparable data with both participants. Conclusions: The computer system proved an adequate microswitch for word utterances. Based on this evidence, microswitch programmes could be extended beyond the use of conventional motor responses.     

Are adverse events of nevirapine and efavirenz related to plasma concentrations?

OBJECTIVE: The relationships between adverse events (AEs) and plasma concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part of the large, international, randomized 2NN study. METHODS: Treatment-naive, HIV-1-infected patients received NVP (once or twice daily), EFV or their combination, each in combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian estimates of the area under the plasma concentration-time curve over 24 h (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as measures for drug exposure of NVP and EFV, were generated using a previously developed population pharmacokinetic model. Pharmacokinetic parameters were compared for patients with and without central nervous system (CNS) and psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic parameter could be identified above which the incidence of AEs was clearly increased. AEs were also related to demographic parameters and baseline characteristics. RESULTS: In total, from 1077 patients, NVP (3024 samples) and EFV (1694 samples) plasma concentrations and AE data (825 observations) were available. For all patients Cmin, Cmax and AUC24h were determined. When corrected for known covariates of gender, CD4 cell count at baseline, region, hepatitis coinfection and possible interactions between these factors, no significant associations between AEs and any tested exposure parameter of NVP was observed. Also, no target Cmin value, above which patients were at increased risk for AEs, could be established. On the other hand, geographical region, hepatitis coinfection, CD4 cell count and gender were found to be significantly related with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash during the treatment with NVP. The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk for elevated liver enzymes. No other correlations between AEs and EFV pharmacokinetics or patient characteristics could be identified. CONCLUSIONS: Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN trial when corrected for known covariates. The value of periodical drug monitoring of NVP as a way to prevent toxicity is therefore limited. Treating physicians should instead focus on factors that are more predictive of AEs (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in elevated liver enzyme values during the first 6 weeks of treatment. Regular measurement of EFV levels and liver enzymes at the start of therapy may therefore be advised.     

Serum hepatitis B surface antigen correlates with fibrosis and necroinflammation: A multicentre perspective in China

The kinetics of serum hepatitis B surface antigen (HBsAg) during the natural history of hepatitis B virus (HBV) infection has been studied, but the factors affecting them remain unclear. We aimed to investigate the factors affecting HBsAg titres, using data from multicentre, large‐sized clinical trials in China. The baseline data of 1795 patients in 3 multicentre trials were studied, and the patients were classified into 3 groups: hepatitis B early antigen (HBeAg)‐positive chronic HBV infection (n = 588), HBeAg‐positive chronic hepatitis B (n = 596), and HBeAg‐negative chronic hepatitis B (n = 611). HBsAg titres in the different phases were compared, and multiple linear progression analyses were performed to investigate the implicated factors. HBsAg titres varied significantly in different phases (P = .000), with the highest (4.60 log10 IU/mL [10%‐90% confidence interval: 3.52 log10 IU/mL‐4.99 log10 IU/mL]) in patients with HBeAg‐positive chronic HBV infection. In all phases, age and HBV DNA were correlated with serum HBsAg level. In HBeAg‐positive chronic hepatitis B patients, a negative correlation between HBsAg titres and fibrosis stage was observed. Alanine amonitransferase or necroinflammatory activity was also correlated with HBsAg titres in HBeAg‐negative chronic hepatitis B patients. In conclusion, decreased HBsAg titres may be associated with advancing fibrosis in HBeAg‐positive chronic hepatitis B patients or increased necroinflammation in those with HBeAg‐negative chronic hepatitis B. Our findings may help clinicians better understand the kinetics of HBsAg and provide useful insights into the management of this disease.