Evaluation of 6β-hydroxycortisol, 6β-hydroxycortisone, and a combination of the two as endogenous probes for inhibition of CYP3A4 in vivo

An endogenous probe for CYP3A activity would be useful for early identification of in vivo cytochrome P450 (CYP) 3A4 inhibitors. The aim of this study was to determine whether formation clearance (CL(f)) of the sum of 6β-hydroxycortisol and 6β-hydroxycortisone is a useful probe of CYP3A4 inhibition in vivo. In human liver microsomes (HLMs), the formation of 6β-hydroxycortisol and 6β-hydroxycortisone was catalyzed by CYP3A4, and itraconazole inhibited these reactions with half maximal inhibitory concentration (IC(50))(,u) values of 3.1 nmol/l and 3.4 nmol/l, respectively. The in vivo IC(50,u) value of itraconazole for the combined CL(f) of 6β-hydroxycortisone and 6β-hydroxycortisol was 1.6 nmol/l. The greater inhibitory potency in vivo is probably due to circulating inhibitory itraconazole metabolites. The maximum in vivo inhibition was 59%, suggesting that f(m,CYP3A4) for cortisol and cortisone 6β-hydroxylation is ~60%. Given the significant decrease in CL(f) of 6β-hydroxycortisone and 6β-hydroxycortisol after 200-mg and 400-mg single doses of itraconazole, this endogenous probe can be used to detect moderate and potent CYP3A4 inhibition in vivo.     

Is the combination of remifentanil and propopfol suitable for transsphenoid resection of the hypophysis?

In a multi-center trial, the feasibility of combining remifentanil (RF) and target-controlled infusion of propofol (P) for patients undergoing transsphenoidal resection of the pituitary gland was tested. After IRB approval, 74 patients (29 male/45 female) were included in the study. The concentration of RF and the target concentration of P were recorded as were heart rate (HR) and mean arterial blood pressure (MAP). For intubation the RF dosage was 0.26 +/- 0.06 microgram.kg-1.min-1 and the target concentration of P was 3.16 +/- 0.63 micrograms.ml-1. After induction, HR and MAP decreased significantly. The painful events of the operation were preparation of the nasal mucous membrane and penetration of the sella turcica. By adjusting the RF dose to 0.31 +/- 0.09 microgram.kg-1. min-1 and the target concentration of P to 3.48 +/- 1.49 micrograms.ml-1, an increase of HR and MAP above initial values was avoided at this time. Hypotension and bardycardia were treated in eight patients (10.8%) with a vasopressor, in four patients (5.4%) with atropine and in four more patients (5.4%) with a combination of these drugs. Two patients (2.7%) needed antihypertensive therapy. The average time interval between the end of P-TCI and spontaneous breathing was 6 +/- 3 min (median 6 min) and till patients opened their eyes 9 +/- 4 min (median 9 min). After 13 +/- 4 min (median 13 min) the patients became orientated. The average doses of analgetics were 19.5 +/- 19.9 mg piritramide and 1.8 +/- 1.0 g metamizol during the first 12 hours postoperatively. Eight patients (10.8%) did not need any analgetics. We suggest that the combination of RF and P as a "fast track concept" can supplement the repertoire of anaesthetic managements used for transsphenoidal resection of the pituitary gland.     

What future for combination therapies?

For most patients who require lipid-lowering treatment, statin monotherapy is the appropriate treatment. However, in those patients where statin monotherapy does not produce optimal lipid levels, the combination of a statin with niacin, a bile acid sequestrant, a fibric acid derivative, a cholesterol absorption inhibitor or a fish oil preparation may provide improved control. The choice of combination therapy depends upon the patient's lipid profile and tolerability of the medication. Combination of a statin with niacin, a bile acid sequestrant or ezetimibe, a cholesterol absorption inhibitor, should be considered for patients with very high low-density lipoprotein cholesterol (LDL-C) levels, while combination with either a fibric acid derivative or a fish oil should be considered for patients with high LDL-C and high triglyceride levels. A number of new lipid-lowering agents are currently in development, including cholesteryl ester transfer protein (CETP) inhibitors, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, ileal bile acid transport (IBAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors and dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists. Introduction of these novel therapies will provide opportunities for developing different combination strategies that may help to optimise lipid profiles in patients who are currently difficult to treat. The introduction of new combinations will require careful study to ensure that the risks of drug interactions and adverse events are minimised.     

Correlation of creatinine with TSH levels in overt hypothyroidism — A requirement for monitoring of renal function in hypothyroid patients?

ObjectiveRenal function is influenced by thyroid status. Therefore, this study was done to determine the relationship between renal function and different degrees of thyroid dysfunction.Design and methodsThyroid and kidney function tests were analyzed in 47 patients with overt (TSH ≥ 10.0 μIU/L) and 77 patients with subclinical hypothyroidism (TSH 6.0–9.9 μIU/L) in a cross-sectional study. These were compared with 120 age- and sex-matched euthyroid controls.ResultsOvert hypothyroid subjects showed significantly raised serum urea, creatinine and uric acid levels as compared to controls whereas subclinical hypothyroid patients showed significant increased levels of serum urea and creatinine levels. TSH showed significant positive correlation with creatinine and uric acid values and, fT4 had a negative correlation with uric acid in overt hypothyroidism.ConclusionHypothyroid state is associated with significant derangement in biochemical parameters of renal function. Hence the renal function should be regularly monitored in hypothyroid patients.     

200例甲亢T3,T4,FT3,FT4,TSH检测临床分析

1.资料和方法1.1资料 ①病例组:系1994年12月～1996年5月来,我院就诊的200例甲亢患者,其中男79例,女121例,年龄在14岁～65岁,平均29岁.②对照组:为企事业单位健康体检,排除甲状腺、肝、肾疾病及妊娠者,共50例,其中男27例,女23例,年龄18岁～60岁.1.2方法 ①T_3、T_4、FT_3、FT_4、TSH试剂药盒由北京     

Myocardial T1 and T2 mapping at 3?T: reference values,influencing factors and implications

Background

Myocardial T₁ and T₂ mapping using cardiovascular magnetic resonance (CMR) are promising to improve tissue characterization and early disease detection. This study aimed at analyzing the feasibility of T₁ and T₂ mapping at 3 T and providing reference values.

Methods

Sixty healthy volunteers (30 males/females, each 20 from 20–39 years, 40–59 years, 60–80 years) underwent left-ventricular T₁ and T₂ mapping in 3 short-axis slices at 3 T. For T₂ mapping, 3 single-shot steady-state free precession (SSFP) images with different T₂ preparation times were acquired. For T₁ mapping, modified Look-Locker inversion recovery technique with 11 single shot SSFP images was used before and after injection of gadolinium contrast. T₁ and T₂ relaxation times were quantified for each slice and each myocardial segment.

Results

Mean T₂ and T₁ (pre-/post-contrast) times were: 44.1 ms/1157.1 ms/427.3 ms (base), 45.1 ms/1158.7 ms/411.2 ms (middle), 46.9 ms/1180.6 ms/399.7 ms (apex). T₂ and pre-contrast T₁ increased from base to apex, post-contrast T₁ decreased. Relevant inter-subject variability was apparent (scatter factor 1.08/1.05/1.11 for T₂/pre-contrast T₁/post-contrast T₁). T₂ and post-contrast T₁ were influenced by heart rate (p < 0.0001, p = 0.0020), pre-contrast T₁ by age (p < 0.0001). Inter- and intra-observer agreement of T₂ (r = 0.95; r = 0.95) and T₁ (r = 0.91; r = 0.93) were high. T₂ maps: 97.7% of all segments were diagnostic and 2.3% were excluded (susceptibility artifact). T₁ maps (pre-/post-contrast): 91.6%/93.9% were diagnostic, 8.4%/6.1% were excluded (predominantly susceptibility artifact 7.7%/3.2%).

Conclusions

Myocardial T₂ and T₁ reference values for the specific CMR setting are provided. The diagnostic impact of the high inter-subject variability of T₂ and T₁ relaxation times requires further investigation.     

急性脑梗塞T3,T4的临床变化

近年来对非甲状腺疾病的甲状腺功能状态研究日益为人们所关注.一些危重病症病人的病情严重性及病死率与患者三碘甲状腺原氨酸T_3、甲状腺素T_4水平有明显相关性.脑血管病患者可出现丘脑一垂体一肾上腺皮质轴的功能紊乱.为探讨急性脑梗塞患者血清甲状腺功能变化,本文对35例急性脑梗塞患者血清T_3、T_4进行了观察,现报告如下:     

T3,T4自身抗体引起甲状腺激素误测

甲状腺疾病患者血清抗球蛋白抗体ＴＧ和抗微粒体ＴＭ（ＴＰＯ）是常见的抗体。但抗自身激素Ｔ_３或Ｔ_４的抗体确十分罕见。国内汪美娟［１］等曾报道２例Ｔ_３自身抗体病例；戴为信［２］等报道１例Ｔ_４自身抗体病例。我们最近发现了１例同时存在Ｔ_３、Ｔ_４自身抗体，并因此引起激素误测的病例，现报道如下。１病例报告患者王某，女，７５岁，住院号９９０４０。入院前１年，逐渐出现畏寒、乏力、寡言少动，颜面及四肢浮肿，体重增加３．５ｋｇ。查体：神清，反应迟钝，毛发稀少，呼吸平缓，心率６０次／分，双侧甲状腺肿大，质地中等硬…     

心血管疾病血T3,T4测定的临床意义

近年来甲状腺激素与心血管疾病的联系不断被认识。我们自1987年12月至1988年7月测定了52例心血管疾病的甲状腺素水平,其中27例观察了治疗前后T_3、T_4变化,并分析了心功能与T_3、T_4的关系。现报道如下。     

Team nursing and ITU--a good combination?

Deficits in 'measurable care', in an 11-bedded intensive care unit, prompted a pilot study of team nursing. Team nursing was introduced for three beds out of the total 11 for a period of six months. In order to evaluate the effects, aspects of care and job satisfaction were measured and compared between the team nursing beds and the rest of the unit. The study revealed that job satisfaction and the levels of 'measurable care' did not improve whilst team nursing was practised. Based on this evidence, the authors question the relevance of team nursing in this particular intensive therapy unit (ITU) and maintain that the best method of delivering nursing care in ITU remains unclear.     

A randomized pragmatic trial of telephone-delivered cognitive behavioral-therapy,modafinil, and combination therapy of both for fatigue in multiple sclerosis: The design of the “COMBO-MS” trial

BackgroundFatigue is one of the most common and disabling chronic symptoms in multiple sclerosis (MS). Optimization of available treatments for MS-related fatigue has been stymied by lack of comparative effectiveness research that focuses on real-world treatment delivery methods and potential modification of treatment effect by other chronic MS symptoms or disability level. This report describes the design of a patient centered, comparative effectiveness trial of cognitive behavioral-therapy (CBT), modafinil, and combination therapy of both for fatigue in MS (“COMBO-MS”).MethodsWe describe the methods of this pragmatic comparative effectiveness trial that is guided by a team of patient, family, provider, community, and payer stakeholders. Eligible participants with MS and significant fatigue severity are randomly assigned (1:1:1) to received either CBT, modafinil, or a combination of CBT and modafinil for 12 weeks. The primary outcome is change in fatigue impact as measured by the Modified Fatigue Impact Scale (MFIS) at 12 weeks. Secondary outcome measures include ecological momentary assessment (EMA) measures of fatigue intensity, fatigue interference, and fatigability (measured over 7 days' time at baseline and at 12 weeks), and change in MFIS score at 24 weeks.Projected outcomesWe hypothesize that combination therapy will more effectively ameliorate fatigue severity than either monotherapy, and that heterogeneity of treatment effects will be found based on depression status, presence of known or suspected sleep disorder, and disease severity. Study findings will assist patients, providers, payers, and policy makers to provide more effective care for managing fatigue in MS.     

Phentermine,topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic disease

Positive caloric balance often causes pathologic adipocyte and adipose tissue anatomical and functional changes (termed adiposopathy or ‘sick fat’), which may lead to pathogenic adipocyte and adipose tissue responses and metabolic disease. Fat weight loss may improve adiposopathy, and thus improve metabolic disease in overweight patients. Unfortunately, the efficacy of non-surgical weight loss therapies is often limited due to redundant physiological systems that help ‘protect’ against starvation and/or negative caloric balance. One strategy to overcome these limitations is to combine weight loss drug therapies having complementary mechanisms of action, thereby affecting more than one physiologic process influencing body fat accumulation. Phentermine is a noradrenergic sympathomimetic amine approved for short-term treatment of obesity. Topiramate is a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide D-fructose approved as a treatment for migraine headaches and seizure disorders. Although known to facilitate weight loss since its approval, topiramate monotherapy does not have a regulatory indication as an anti-obesity agent. Phentermine HCl/topiramate controlled-release (PHEN/TPM CR) is a combination agent containing immediate-release phentermine and controlled-release topiramate. Clinical trials involving thousands of patients demonstrate PHEN/TPM CR to be effective in improving the weight of patients, and also effective in improving adiposopathy-associated metabolic diseases. This review examines the pathophysiology of adiposopathy as a contributor to metabolic disease, the data supporting phentermine monotherapy, topiramate monotherapy and their combination as anti-obesity and anti-adiposopathy agents, and the preliminary evidence supporting PHEN/TPM CR as a generally well-tolerated and effective agent to improve metabolic disease.