Polymorphisms of the Z protein protease inhibitor and risk of venous thromboembolism: a meta-analysis

Two nonsense polymorphisms of Z-dependent protease inhibitor (ZPI; Serpina10) have been identified. To assess the risk of venous thromboembolism (VTE) associated with W303x and R67X Serpina10 mutations, we performed a meta-analysis of studies comparing the prevalence of these two mutations in VTE patients and in controls Odds Ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and pooled using a random-effects model. Five studies involving 5000 patients were included. R67X and W303X mutations of Serpina10 were not associated with increased VTE risk (OR 1.63; 95% CI 0.84, 3.16 and OR 1.21; 95% CI 0.29, 4.98 respectively).     

Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of alpha1-antitrypsin deficiency in Asia.

The current study focuses on updating estimates of the numbers of individuals carrying the two most common deficiency alleles, protease inhibitor (PI)*S and PI*Z, for alpha1-antitrypsin deficiency (AT-D) in 20 Asian countries. A total of 170 cohorts with 31,177 individuals were selected from 20 Asian countries. The total AT-D populations in the countries selected were: 7,264 ZZ; 36,754 SZ; 6,672,479 MZ; 46,492 SS; and 16,881,108 MS. Marked differences among the Asian countries and regions were also found for the prevalence of the deficiency alleles PI*S and PI*Z. These numbers demonstrate that AT-D is not just a genetic disease that affects smaller numbers than various countries, for example, in Europe. There were marked differences between the prevalence of the PI*S and PI*Z deficiency alleles among these 20 Asian countries as well as among the countries within a given geographic region in Asia. The largest numbers of ZZ phenotypes (3,000-14,000) were in Afghanistan, Pakistan, Saudi Arabia and Thailand; with <1,700 in each of the remaining countries.     

Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries.

The current study focuses on developing estimates of the numbers of individuals carrying the two most common deficiency alleles, PI*S and PI*Z, for alpha1-antitrypsin deficiency (AT-D) in Europe. Criteria for selection of epidemiological studies were: 1) AT phenotyping performed by isoelectrofocusing or antigen-antibody crossed electrophoresis; 2) rejection of "screening studies"; 3) statistical precision factor score of > or = 5 for Southwest, Western and Northern Europe, > or = 4 for Central Europe, > or = 3 for Eastern Europe; and 4) samples representative of the general population. A total of 75,390 individuals were selected from 21 European countries (one each from Austria, Belgium, Latvia, Hungary, Serbia-Montenegro, Sweden and Switzerland; two each from Denmark, Estonia and Lithuania; three each from Portugal and the UK; four each from Finland, The Netherlands, Norway and Spain; five each from Russia and Germany; six from Poland; eight from Italy; and nine from France). The total AT-D populations of a particular phenotype in the countries selected were: 124,594 ZZ; 560,515 SZ; 16,323,226 MZ; 630,401 SS; and 36,716,819 MS. The largest number of ZZ (5,000-15,000) were in Italy, Spain, Germany, France, the UK, Latvia, Sweden and Denmark, followed by Belgium, Portugal, Serbia-Montenegro, Russia, The Netherlands, Norway and Austria (1,000-2,000), with < 1,000 in each of the remaining countries. A remarkable lack in number of reliable epidemiological studies and marked differences among these European countries and regions within a given country was also found.     

Global burden of COPD: systematic review and meta-analysis.

The aim of this study was to quantify the global prevalence of chronic obstructive pulmonary disease (COPD) by means of a systematic review and random effects meta-analysis. PubMed was searched for population-based prevalence estimates published during the period 1990-2004. Articles were included if they: 1) provided total population or sex-specific estimates for COPD, chronic bronchitis and/or emphysema; and 2) gave method details sufficiently clearly to establish the sampling strategy, approach to diagnosis and diagnostic criteria. Of 67 accepted articles, 62 unique entries yielded 101 overall prevalence estimates from 28 different counties. The pooled prevalence of COPD was 7.6% from 37 studies, of chronic bronchitis alone (38 studies) was 6.4% and of emphysema alone (eight studies) was 1.8%. The pooled prevalence from 26 spirometric estimates was 8.9%. The most common spirometric definitions used were those of the Global Initiative for Chronic Obstructive Lung Disease (13 estimates). There was significant heterogeneity, which was incompletely explained by subgroup analysis (e.g. age and smoking status). The prevalence of physiologically defined chronic obstructive pulmonary disease in adults aged > or =40 yrs is approximately 9-10%. There are important regional gaps, and methodological differences hinder interpretation of the available data. The efforts of the Global Initiative for Chronic Obstructive Lung Disease and similar groups should help to standardise chronic obstructive pulmonary disease prevalence measurement.     

The role of a protease inhibitor against hepatectomy

BACKGROUND/AIMS: Nafamostat Mesilate (NM) is a synthetic serine protease inhibitor that is capable of inhibiting the various coagulation factors. To determine whether NM may also be useful in attenuating operative invasiveness, we investigated the effects of perioperative administration of NM on postoperative serum levels of proinflammatory cytokine IL-6 and hepatocyte growth factor (HGF). METHODOLOGY: Thirty patients undergoing hepatectomy with hepatocellular carcinoma, biliary carcinoma and metastatic colorectal cancer were enrolled in this study. These patients were separated into two groups; high invasive group (resected liver volume: 1000cm3 <) and less invasive group (resected liver volume: 1000cm3 >). The high invasive group of 11 patients received perioperative administration of NM (Group NM), while the less invasive group of 19 patients did not (Group C). Serum levels of IL-6, HGF and soluble IL-6 receptor (sIL-6R) were simultaneously measured on preoperative and postoperative day ('day 0', 'day 7'). RESULTS: Serum IL-6 levels on day 0 were significantly elevated and returned to preoperative levels on day 7 in both groups, and the serum IL-6 level in Group NM on day 0 was significantly lower than that in Group C on day 0. Serum HGF levels on day 0 and day 7 were significantly higher in Group NM than those in Group C. Compared with healthy control subjects, the higher serum level of HGF on the preoperative day in all patients was attributable to tumor-burden. The sIL-6R levels on day 0 decreased in both groups, and their levels in Group NM were significantly lower than those in Group C, suggesting that increased synthesis of IL-6/sIL-6R complex which could accelerate liver regeneration. CONCLUSIONS: These results suggested that perioperative administration of NM may attenuate surgical stress by decreasing production of proinflammatory cytokine IL-6, and may accelerate liver regeneration through stimulation with the IL-6/sIL-6R complex and possible involvement of increased production of HGF.     

Nutritional support for individuals with COPD: a meta-analysis

RATIONALE: Malnutrition in patients with COPD is associated with an impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rate when compared to adequately nourished individuals with COPD. Nutritional support may therefore be a useful part of their comprehensive care. PURPOSE: To conduct a meta-analysis of randomized controlled trials (RCTs) to clarify whether nutritional supplementation (caloric supplementation for at least 2 weeks) improved anthropometric measures, pulmonary function, respiratory muscle strength, and functional exercise capacity in patients with stable COPD. METHODS: RCTs were identified from several sources, including the Cochrane Airways Group register of RCTs, a hand search of abstracts presented at international meetings, and consultation with experts. Two reviewers independently selected trials for inclusion, assessed quality, and extracted the data. Within each trial and for each outcome, we calculated an effect size. The effect sizes were then pooled by a random-effects model. Homogeneity among the effect sizes was also tested. RESULTS: From 272 references, nine RCTs were ultimately included. Six articles were considered as high quality. Only two studies were double blinded. For each of the outcomes studied, the effect of nutritional support was small: the 95% confidence intervals around the pooled effect sizes all included zero. The effect of nutritional support was homogeneous across studies. CONCLUSION: Nutritional support had no effect on improving anthropometric measures, lung function, or functional exercise capacity among patients with stable COPD.     

Amprenavir: a new protease inhibitor nears approval

The new, second-generation protease inhibitor, amprenavir (Agenerase), discovered by Vertex Pharmaceuticals and clinically developed by Glaxo Wellcome, is awaiting regulatory approval in the U.S. and Europe. Amprenavir has been given "fast track" status by the U.S. Food and Drug Administration (FDA). Amprenavir has shown promising results in human testing, and seems to be a potent inhibitor of HIV replication. Researchers found amprenavir to be successful when used in a three-drug combination with AZT and 3TC. Other data show the drug to be synergistic with abacavir, and to have less cross-resistance than other drugs in the class. Study details, side effects, and drug interactions are described. Contact information for Glaxo Wellcome's expanded access program are also provided.     

JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC(50) values ranging from 13-41 nM (<2-fold changes in IC(50) compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.     

Antithrombin: a new look at the actions of a serine protease inhibitor.

Antithrombin (AT) is a plasma-derived, single-chain glycoprotein with a molecular weight of 58 kDa. It is a serine protease inhibitor (serpin), sharing about 30% homology in amino acid sequence with other serpins. AT is a complex molecule with multiple biologically important properties. It is a potent anticoagulant that has been demonstrated to provide benefit in animal models and small cohorts of patients with coagulation disorders. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Activated coagulation proteases like activated factor X and thrombin contribute to inflammation; for instance, by the release of pro-inflammatory mediators. Inhibition of these proteases by AT prevents their specific interaction with cells and subsequent reactions. Anti-inflammatory properties of AT independent of coagulation involve direct interactions with cells leading to the release of, for instance, prostacyclin. Binding of AT to a recently identified cellular receptor, syndecan-4, leads to the interference with the intracellular signal induced by mediators like lipopolysaccharides and, thereby, to a down-modulation of the inflammatory response. AT has been shown to be effective in prospective and well-controlled small-scale studies of patients with inflammatory conditions, including sepsis. Although AT did not decrease overall patient mortality in a double-blind, placebo-controlled, phase III trial of patients with sepsis, it is important to note that AT improved the survival of individuals in this study not receiving heparin as a prophylactic regimen, which can be explained by the impaired interaction of AT with its cellular receptor in the presence of heparin, resulting in the reduction of the anti-inflammatory properties. Accordingly, the supplementation of AT without concomitant heparin may be beneficial in disorders with inflammatory characteristics, which has to be demonstrated in further clinical studies. Finally, recent results suggest that latent AT can induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Further investigations will have to demonstrate whether latent and/or cleaved AT are physiological means to control angiogenesis. A potential prophylactic or therapeutic use as an anti-angiogenic and antitumor agent merits further exploration, including whether the growth of vessels in tumor tissues or close to tumors can be controlled by latent AT without affecting the formation of blood vessels during wound healing processes.     

Effects of controlled inspiratory muscle training in patients with COPD: a meta-analysis.

The purpose of this meta-analysis is to review studies investigating the efficacy of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients and to find out whether patient characteristics influence the efficacy of IMT. A systematic literature search was performed using the Medline and Embase databases. On the basis of a methodological framework, a critical review was performed and summary effect-sizes were calculated by applying fixed and random effects models. Both IMT alone and IMT as adjunct to general exercise reconditioning significantly increased inspiratory muscle strength and endurance. A significant effect was found for dyspnoea at rest and during exercise. Improved functional exercise capacity tended to be an additional effect of IMT alone and as an adjunct to general exercise reconditioning, but this trend did not reach statistical significance. No significant correlations were found for training effects with patient characteristics. However, subgroup analysis in IMT plus exercise training revealed that patients with inspiratory muscle weakness improved significantly more compared to patients without inspiratory muscle weakness. From this review it is concluded that inspiratory muscle training is an important addition to a pulmonary rehabilitation programme directed at chronic obstructive pulmonary disease patients with inspiratory muscle weakness. The effect on exercise performance is still to be determined.     

Endogenous inhibitor of nonlysosomal high molecular weight protease and calcium-dependent protease.

An endogenous inhibitor of high molecular weight protease was purified from human erythrocytes and partially characterized. The inhibitor was isolated by DEAE-Sephacel ion-exchange chromatography followed by separation on a Bio-Gel A-0.5m column. The inhibitor displayed a native Mr of 240,000 and contained a single subunit of Mr 40,000 after NaDodSO4/polyacrylamide gel electrophoresis. The Mr 240,000 hexamer inhibited high molecular weight protease noncompetitively (Ki = 8.3 X 10(-8) M) and showed marked susceptibility to proteolytic digestion and heat treatment. The purified factor was also a potent inhibitor of calcium-dependent protease (Ki = 2.8 X 10(-8) M), whereas it had no effect on trypsin, chymotrypsin, or papain. Heat treatment (50-70 degrees C X 10 min) caused loss of inhibition against high molecular weight protease; however, inhibition of calcium-dependent protease was stable under the same conditions. This result is consistent with different domains on the inhibitor that interact with high molecular weight protease and calcium-dependent protease. Together with earlier studies in which repression of inhibitor by an ATP-ubiquitin-dependent process was proposed, the present results suggest a general mechanism for regulation of multiple nonlysosomal proteases that are complexed with endogenous inhibitors.     

Treatment of acute pancreatitis with protease inhibitors: a meta-analysis

OBJECTIVES: Protease inhibitors are used to treat acute pancreatitis, but their effectiveness remains unclear. We performed a meta-analysis to determine whether treatment with protease inhibitors reduces overall mortality or morbidity from acute pancreatitis. METHODS: Articles of randomized controlled trials evaluating effects of protease inhibitors for acute pancreatitis were retrieved by systematically searching Medline, the Cochrane Library and Journal@ovid databases published from January 1966 through December 2003. References of review articles were also searched manually. The main outcome in interest was the overall mortality rate from acute pancreatitis. RESULTS: Ten studies met the inclusion criteria. Treatment with protease inhibitors did not significantly reduce the mortality rate from acute pancreatitis (pooled risk difference, -0.03; 95% confidence interval, -0.07 to 0.01). Subgroup analyses showed that treatment with protease inhibitors significantly reduced the mortality rate in patients with moderate to severe pancreatitis (pooled risk difference, -0.07; 95% confidence interval, -0.13 to -0.01) as defined by mortality rate in the control group (control mortality rate > 0.10). The decrease in mortality rate was not significant in mild pancreatitis (pooled risk difference, 0.00; 95% confidence interval, -0.04 to 0.05). CONCLUSIONS: Treatment with protease inhibitors does not significantly reduce the mortality in patients with acute or mild pancreatitis, but may reduce the mortality in patients with moderate to severe pancreatitis.     

C1-inhibitor: more than a serine protease inhibitor

C1-inhibitor (C1-inh) is a crucial regulator of the activation of plasmatic cascade systems involved in inflammation contributing to the homeostasis in the generation of proinflammatory mediators. The importance of C1-inh is illustrated by patients with hereditary angioedema where decreased levels of C1-inh lead to an uncontrolled generation of vasoactive peptides resulting in potential life-threatening subcutaneous edema. Recent publications, however, suggest that the anti-inflammatory properties of C1-inh do not strictly depend on its capacity to regulate the complement and contact phase system. This review summarizes the biochemical characteristics of C1-inh and its role in the regulation of plasmatic cascade systems as well as the role of the nonserpin domain.     

The pharmacokinetics of HIV protease inhibitor combinations

PURPOSE OF REVIEW: The clinical use of double-boosted protease inhibitor regimens has evolved recently. This strategy offers a number of unique benefits, including pharmacokinetic enhancement of two different protease inhibitors with low dose ritonavir. We review the pharmacologic rationale for the double-boosted protease inhibitor combinations and the complex drug-drug interactions that occur among different protease inhibitors when co-administered. RECENT FINDINGS: The discovery and widespread clinical use of low dose ritonavir as a pharmacoenhancer of other protease inhibitors has significantly improved the management of HIV infection treatment. This has subsequently led to the development of double-boosted protease inhibitor regimens which have been shown to be effective in heavily pre-treated patients, in whom it is crucial to maintain drug concentrations sufficient to suppress viruses with multiple resistance mutations. Interesting pharmacokinetic data have been recently produced showing the complexity of the interactions among three protease inhibitors. As the outcome of these multidrug interactions may be difficult to predict, formal pharmacokinetic studies have been fundamental to determine which protease inhibitors are best to administer in combination. SUMMARY: This review summarizes the current literature regarding the pharmacokinetics of double-boosted protease inhibitor regimens and general considerations regarding their usage in the treatment of HIV-infected patients.     

Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis

BACKGROUND: beta-Adrenergic agonists exert physiologic effects that are the opposite of those of beta-blockers. beta-Blockers are known to reduce morbidity and mortality in patients with cardiac disease. beta(2)-Agonist use in patients with obstructive airway disease has been associated with an increased risk for myocardial infarction, congestive heart failure, cardiac arrest, and acute cardiac death. OBJECTIVES: To assess the cardiovascular safety of beta(2)-agonist use in patients with obstructive airway disease, defined as asthma or COPD. METHODS: A meta-analysis of randomized placebo-controlled trials of beta(2)-agonist treatment in patients with obstructive airway disease was performed, to evaluate the short-term effect on heart rate and potassium concentrations, and the long-term effect on adverse cardiovascular events. Longer duration trials were included in the analysis if they reported at least one adverse event. Adverse events included sinus and ventricular tachycardia, syncope, atrial fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or sudden death. RESULTS: Thirteen single-dose trials and 20 longer duration trials were included in the study. A single dose of beta(2)-agonist increased the heart rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced the potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54), compared to placebo. For trials lasting from 3 days to 1 year, beta(2)-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI, 1.59 to 4.05) compared to placebo. The RR for sinus tachycardia alone was 3.06 (95% CI, 1.70 to 5.50), and for all other events it was 1.66 (95% CI, 0.76 to 3.6). CONCLUSION: beta(2)-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of beta-adrenergic stimulation, that beta(2)-agonists may precipitate ischemia, congestive heart failure, arrhythmias, and sudden death.     

慢性阻塞性肺病TNFA和LTA基因等位基因变异分析

目的中国北方汉族人群中研究TNF超家族基因等位基因变异是否与慢性阻塞性肺病(COPD)相关联.方法 以50例COPD患者为研究对象,应用聚合酶链反应-限制性片段长度多态性方法研究TNF超家族基因(TNFA和LTA)等位基因变异分布.结果 TNFA基因多态性位点-308G/A COPD组和对照组比较AA基因型频率分布差异显著(χ2=7.111,P＜0.01),OR值为10.756(95%CI为9.875～12.640).-308G/A多态性位点A等位基因频率差异显著(χ2=8.219,P＜0.01);LTA基因 252A/G多态性位点AG基因型频率分布COPD组与对照组比较差异显著(χ2=11.974,P＜0.01),OR值为4.373(95%CI为3.301～6.872).LTA基因 252 A/G多态性位点G等位基因频率差异不显著.在COPD患者组中TNFA基因GG正常基因型和LTA基因AG杂合基因型结合个体频率比对照组显著增高(χ2=4.10,P＜0.05).结论 中国北方汉族人群LTA基因等位基因变异、TNFA基因多态性变异组合与COPD相关联.     

Tipranavir: the first nonpeptidic protease inhibitor

Resistance to anti-HIV medications is an ongoing dilemma. A recent study in 16 European countries and Israel found primary drug resistance mutations in 10% of 1,633 people newly diagnosed with HIV disease who had never taken anti-HIV therapy. French clinicians have reported that 78% of viral samples taken between 1997 and 2002 from over 2,000 chronically infected people showed some resistance to at least one antiretroviral drug, and 25% had some resistance to three major drug classes (excluding fusion inhibitors). Similar findings have been reported in the U.S. and Britain. As a significant number of people with HIV find themselves with fewer treatment options, researchers struggle to develop medications that remain effective against genetically varied forms of the virus. Tipranavir, the first in a new category of protease inhibitors (PIs), appears to be such a drug. Studies have shown that tipranavir (formerly known as PNU-140690) durably reduces viral load in some people whose dominant HIV strain is resistant to at least two other PIs. The quality of tipranavir resistance that does develop has also been examined, and the extent of this agent's usefulness in people needing salvage therapy is under investigation.     

慢性丙型肝炎治疗新纪元——口服逆转录酶和蛋白酶抑制剂的临床应用

慢性丙型肝炎患者经过聚乙二醇干扰素（PEG—IFN）联合利巴韦林（RBV）治疗后,多数患者可以获得临床治愈,即停药随访6个月后病毒仍然检测不到,且疾病不再进展。然而,还有相当一部分患者因为不能耐受IFN或RBV而未完成标准治疗,或对治疗完全无应答,或停药后复发,或由于疾病发现较晚而失去了抗病毒治疗的时机。因此,在临床上仍然需要新的抗病毒药物,或者和IFN联合治疗,或者单独治疗。本文将就近年来研发的12服逆转录酶和蛋白酶抑制剂的直接抗病毒药物的临床研究和应用作一综述。