Small-molecule therapeutics in rheumatoid arthritis: Scientific rationale,efficacy and safety

Rheumatoid arthritis (RA) remains a formidable clinical challenge. This is despite remarkable recent advances in our understanding of pathogenesis and the introduction of a variety of novel agents, particularly biologic therapeutics that are potent inhibitors of extracellular immune pathways. Whereas the latter have brought substantial improvements in efficacy and thus outcomes, there remain significant numbers of non- or partial responders to current standard of care. The discovery of key intracellular pathways, particularly kinases that subserve the function of these pivotal cytokine and immune cell receptors implicated in RA pathogenesis, has facilitated the advent of a new phase of RA drug development. Thus, a range of kinase inhibitors has entered clinical trials and one agent has been licenced for use in some regions. Herein we summarise the chequered history of kinase inhibitor development in RA, describing successes and failures alike, and thereafter examine future trends in this exciting field.     

Antihypertensive efficacy and safety of fixed-dose combination therapy with losartan plus hydrochlorothiazide in Japanese patients with essential hypertension.

A randomized, double-blind, placebo-controlled, parallel-group multicenter study was conducted to evaluate the antihypertensive efficacy and safety of 8-week treatment with one of three fixed-dose combinations-losartan 50 mg plus hydrochlorothiazide 12.5 mg, losartan 50 mg plus hydrochlorothiazide 6.25 mg, or losartan 25 mg plus hydrochlorothiazide 6.25 mg-in comparison with those of hydrochlorothiazide 12.5 mg alone, losartan 50 mg alone, or placebo in Japanese patients with essential hypertension. Significant reductions in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were seen in all three combination groups compared with the placebo group (each p<0.001). The greatest reductions in DBP and SBP were observed in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group (12.7 and 18.0 mmHg, respectively). The reductions in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group were significantly greater (each p<0.001) than those in the placebo group and each of the monotherapy groups. There were no significant differences in the incidences of clinical and laboratory drug-related adverse events between any of the combination groups and the placebo group. All combination groups showed improved hypokalemia and hyperuricemia compared to the hydrochlorothiazide 12.5 mg group. These results demonstrated that once-daily, fixed-dose combination therapy with losartan 50 mg plus hydrochlorothiazide 12.5 mg is well tolerated and more efficacious in lowering DBP and SBP than monotherapy in Japanese hypertensive patients.     

Long-term safety, effectiveness and quality of a generic fixed-dose combination of nevirapine, stavudine and lamivudine

We assessed the long-term safety, effectiveness and quality of a fixed-dose combination of nevirapine, stavudine and lamivudine (triomune). HIV-1-infected adults initially enrolled in a one-year, open-label, single-arm, multicentre trial in Cameroon were followed for 2 years. Our results support the safety and effectiveness of the triomune combination for first-line treatment of HIV infection. Virological effectiveness appeared to wane somewhat during the second year of treatment, however, and plasma nevirapine concentrations were relatively high.     

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity

BackgroundGuidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.MethodsA post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks.ResultsThe analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV₁), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV₁ and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV₁, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV₁, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.ConclusionsIn patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.     

Microbubble contrast agents for echocardiography: rationale, composition, ultrasound interactions, and safety

Imaging the small blood vessels within the myocardium, which contains only a small fraction of the total coronary blood volume, is a significant challenge for ultrasound imaging. Recent advances in microbubble design and ultrasound technology have improved our ability to image the microcirculation. It is essential to understand the fundamentals of microbubble behavior in an ultrasound field and how it impacts technology and safety.     

四联抗结核固定剂量复合剂的临床疗效研究

目的研究四联抗结核固定剂量复合剂的近期疗效及安全性。方法将广东省湛江市6个县区登记的540例初治涂阳肺结核病人分为研究组和对照组,用对照研究方法对2组病例的临床症状、治疗效果和不良反应等进行对比研究。结果(1)研究组治愈率为94.4%,对照组为92.2%,2组的治愈率比较差异无统计学意义(χ2=1.071,P=0.301);(2)2组患者相关临床症状(如咳嗽、胸痛、乏力、盗汗、低热、咯血)逐渐得到改善,2组比较差异无统计学意义(P0.05);(3)2、3个月末研究组痰菌阴转率分别为90.7%、94.1%,对照组分别为89.6%,91.9%,比较差异无统计学意义(P0.05);X线胸片显示空洞愈合方面,研究组的空洞闭合率为78.2%,对照组为61.2%,研究组比对照组高。(4)研究组与对照组的不良反应发生率分别为21.5%和20.0%,比较差异无统计学意义(P0.05);强化期对照组的消化道不良反应发生率明显大于研究组(P0.05);2组血常规、肝功能异常率接近;研究组因不良反应停药率高于对照组(P0.05)。结论四联FDC与板式组合药具有同等的抗结核疗效,不良反应发生率相近,并且在治疗管理方面显示出较大的优势,建议推荐在我国结核病防治规划中应用。     

A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: rationale, design, and baseline patient characteristics

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. Prior research in experimental and human heart failure has shown that CCM signals normalize phosphorylation of key proteins and expression of genes coding for proteins involved in regulation of calcium cycling and contraction. The results of prior clinical studies of CCM have supported its safety and efficacy. A large-scale clinical study, the FIX-HF-5 study, is currently underway to test the safety and efficacy of this treatment. In this article, we provide an overview of the system used to deliver CCM signals, the implant procedure, and the details and rationale of the FIX-HF-5 study design. Baseline characteristics for patients randomized in this trial are also presented.     

Probiotics and irritable bowel syndrome: rationale, putative mechanisms, and evidence of clinical efficacy

The irritable bowel syndrome (IBS) follows an acute, presumably infectious diarrheal illness in approximately 15% of patients. There may be a persistent, mild inflammatory state with changes in mucosal function or structure. Changes in the colonic bacterial flora reported in IBS seem related to predominant bowel. Colonic bacteria normally metabolize nutrients with the formation of gas and short chain fatty acids. The latter may induce propulsive contractions and accelerate colonic transit or they may enhance fluid and sodium absorption in the colon. This review addresses the mechanisms, rationale and current evidence for the efficacy of probiotics, including Lactobacilli, Bifidobacteria, and VSL#3, in the treatment of IBS. The mechanisms influenced by probiotics include immune function, motility, and the intraluminal milieu. Probiotics may suppress the low-grade inflammation associated with IBS or restore normal local immune function. Lactobacilli and Bifidobacteria subspecies are able to deconjugate and absorb bile acids, potentially reducing the colonic mucosal secretion of mucin and fluids that may contribute to functional diarrhea or IBS with diarrhea. Therapeutic trials show the potential benefit of Bifidobacteria or Lactobacilli species alone or in the specific probiotic combination, VSL#3, on symptoms in IBS. Colonic transit was retarded in IBS patients treated with VSL#3 without induction of significant changes in bowel function. In summary, probiotics are promising therapies in IBS.     

Concentrate safety and efficacy

Safety from transmission of infections through plasma-derived clotting factor concentrates is assured by improved donor screening, serological testing of individual donations and direct viral testing of small plasma pools. Modern viral-inactivation techniques are highly effective. Recombinant concentrates stabilized in human albumin are being superaeded by those with other stabilizers. Recently reported discrepancies between estimates of concentrate potency from in vitro assays versus in vivo recovery, depending upon type of assay and reference standard used, are not fully resolved.