Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.

CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered. OBJECTIVE: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997. SETTING: Individual hotel rooms; 2 large US university medical schools. PARTICIPANTS: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8). INTERVENTIONS: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days. MAIN OUTCOME MEASURES: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers. RESULTS: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food. CONCLUSIONS: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.     

Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial

CONTEXT: Influenza virus is easily spread among the household contacts of an infected person, and prevention of influenza in household contacts can control spread of influenza in the community. OBJECTIVE: To investigate the efficacy of oseltamivir in preventing spread of influenza to household contacts of influenza-infected index cases (ICs). DESIGN AND SETTING: Randomized, double-blind, placebo-controlled study conducted at 76 centers in North America and Europe during the winter of 1998-1999. PARTICIPANTS: Three hundred seventy-seven ICs, 163 (43%) of whom had laboratory-confirmed influenza infection, and 955 household contacts (aged >/=12 years) of all ICs (415 contacts of influenza-positive ICs). INTERVENTIONS: Household contacts were randomly assigned by household cluster to take 75 mg of oseltamivir (n = 493) or placebo (n = 462) once daily for 7 days within 48 hours of symptom onset in the IC. The ICs did not receive antiviral treatment. MAIN OUTCOME MEASURE: Clinical influenza in contacts of influenza-positive ICs, confirmed in a laboratory by detection of virus shedding in nose and throat swabs or a 4-fold or greater increase in influenza-specific serum antibody titer between baseline and convalescent serum samples. RESULTS: In contacts of an influenza-positive IC, the overall protective efficacy of oseltamivir against clinical influenza was 89% for individuals (95% confidence interval [CI], 67%-97%; P<.001) and 84% for households (95% CI, 49%-95%; P<.001). In contacts of all ICs, oseltamivir also significantly reduced incidence of clinical influenza, with 89% protective efficacy (95% CI, 71%-96%; P<.001). Viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy (95% CI, 57%-95%; P<.001). All virus isolates from oseltamivir recipients retained sensitivity to the active metabolite. Oseltamivir was well tolerated; gastrointestinal tract effects were reported with similar frequency in oseltamivir (9.3%) and placebo (7.2%) recipients. CONCLUSION: In our sample, postexposure prophylaxis with oseltamivir, 75 mg once daily for 7 days, protected close contacts of influenza-infected persons against influenza illness, prevented outbreaks within households, and was well tolerated.     

Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial

Context  Echinacea is a widely used herbal remedy for treatment of upper respiratory tract infections (URIs). However, there are few data on the efficacy and safety of echinacea in treating URIs in children. Objectives  To determine if Echinacea purpurea is effective in reducing the duration and/or severity of URI symptoms in children and to assess its safety in this population. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial of healthy children 2 to 11 years old recruited from a regional practice-based network and an alternative medical center in 4-month periods from 2000 through 2002. Interventions  Study patients were randomized to receive either echinacea or placebo for up to 3 URIs over a 4-month period. Study medication was begun at the onset of symptoms and continued throughout the URI, for a maximum of 10 days. Main Outcome Measures  Primary outcomes were duration and severity of symptoms and adverse events recorded by parents; secondary outcomes included peak severity of symptoms, number of days of peak severity, number of days of fever, and a global assessment of severity of symptoms by parents of study children. Results  Data were analyzed on 707 URIs that occurred in 407 children, including 337 URIs treated with echinacea and 370 with placebo. There were 79 children who completed their study period without having a URI. The median duration of URIs was 9 days (95% confidence interval, 8-10 days); there was no difference in duration between URIs treated with echinacea or placebo (P = .89). There was also no difference in the overall estimate of severity of URI symptoms between the 2 treatment groups (median, 33 in both groups; P = .69). In addition, there were no statistically significant differences between the 2 groups for peak severity of symptoms (P = .68), number of days of peak symptoms (1.60 in the echinacea group and 1.64 in the placebo group; P = .97), number of days of fever (0.81 in the echinacea group vs 0.64 in the placebo group; P = .09), or parental global assessment of severity of the URI (P = .67). Overall, there was no difference in the rate of adverse events reported in the 2 treatment groups; however, rash occurred during 7.1% of the URIs treated with echinacea and 2.7% of those treated with placebo (P = .008). Conclusions  Echinacea purpurea, as dosed in this study, was not effective in treating URI symptoms in patients 2 to 11 years old, and its use was associated with an increased risk of rash.      

乌灵胶囊联合黛力新治疗脑卒中后抑郁疗效和安全性的随机对照研究

目的：观察乌灵胶囊联合黛力新治疗脑卒中后抑郁的临床疗效和安全性。 方法：采用平行对照研究方法，将卒中后抑郁病人随机分为乌灵胶囊组（n=39），给予乌灵胶囊，每次3粒，3次/d；黛力新组（n=37），给予黛力新片，每次10．5mg．2次/d，早上、中午各服1次；联合组（n=38）．在黛力新治疗基础上，加服乌灵胶囊。6周为1个疗程，于治疗前，治疗后2、4、6周用汉密顿抑郁量表（Hamilton Depression Scale，HAMD）评估疗效一治疗副反应量表（Treatment Emergent sympton Scale．TESS）评定药物的不良反应，并检测血常规、尿常规、肝肾功能及心电图等。 结果：乌灵胶囊组、黛力新组、联合治疗组总有效率分别为64．1％、64．9％和89．5％，乌灵胶囊组和黛力新组两组疗效差异无统计学意义（P〉0．05），联合组疗效优于另两组（P〈0．05）。单纯应用乌灵胶囊组未见不良反应，应用黛力新的两组不良反应发生率均为9％。 结论：乌灵胶囊联合黛力新治疗脑卒中后抑郁疗效优于单药治疗。     

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial

Context  The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. Objectives  To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. Design and Setting  A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. Patients  The primary efficacy population consisted of 1754 patients (=" BORDER="0">18 years) with severe sepsis and a high INR (=" BORDER="0">1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. Main Outcome Measure  All-cause 28-day mortality. Results  Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P = .88, Pearson ² test; P = .75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P = .006, Pearson ² test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P = .051, Pearson ² test; P = .03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). Conclusions  Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.      

Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial

CONTEXT: Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration. OBJECTIVE: To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy. DESIGN: Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997. SETTING: Thirty-three US HIV treatment centers. PARTICIPANTS: Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 10(9)/L were randomized. INTERVENTION: Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study. MAIN OUTCOME MEASURES: Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir. RESULTS: Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti-HIV effects with adefovir (P< or =.01 vs placebo group). CONCLUSIONS: This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible.     

水蛭素治疗以血尿为主要表现的免疫球蛋白A型肾病的随机对照临床研究

目的：视察以血尿为主要表现的免疫球蛋白A型肾病（immunoglobulin A nephropalhy，IgAN）患者使用水蛭素治疗的近期疗效和副作用。 方法：选择1998～2007年我科经肾组织活检病理证实的以血尿为主要表现的IgAN患者262例，按口服水蛭素（肠溶脉血康胶囊）和潘生丁不同，随机分成水蛭素组和潘生丁组。以尿红细胞形态及计数、24h尿蛋白定量、血肌酐（serum creatinine，Scr）、内生肌酐清除率（creatinine clearance rate，Ccr）、血脂1项、凝血5项和副作用等为疗效评价指标。 结果：两组患者治疗半年后，水蛭素组尿红细胞畸形率与计数和24h尿蛋白定量均较治疗前显著下降（P〈0．01），且显著低于潘生丁组（P〈0．05）；水蛭素组Ccr较治疗前明显升高。并显著高于潘生丁组（P＜0．01）；水蛭素组患者的血脂也有改善，但差异无统计学意义；水蛭素抗凝作用明显强于潘生丁（P〈0．01）。综合判定，水蛭素组的总有效率、完全缓解率和显著缓解率均显著高于潘生丁组（P＜0．01）。两组发生副作用的病例数均较少，水蛭素组胃肠道不良反应的发生率也显著低于潘生丁组（P〈0．05）。 结论：水蛭素在降低IgAN血尿、蛋白尿和肾脏保护方面比潘生丁更具有优势。     

Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial

Context  Despite the high prevalence, chronicity, and associated comorbidity of posttraumatic stress disorder (PTSD) in the community, few placebo-controlled studies have evaluated the efficacy of pharmacotherapy for this disorder. Objective  To determine if treatment with sertraline hydrochloride effectively diminishes symptoms of PTSD of moderate to marked severity. Design  Twelve-week, double-blind, placebo-controlled trial preceded by a 2-week, single-blind placebo lead-in period, conducted between May 1996 and June 1997. Setting  Outpatient psychiatric clinics in 8 academic medical centers and 6 clinical research centers. Patients  A total of 187 outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnosis of PTSD and a Clinician Administered PTSD Scale Part 2 (CAPS-2) minimum total severity score of at least 50 at baseline (mean age, 40 years; mean duration of illness, 12 years; 73% were women; and 61.5% experienced physical or sexual assault). Intervention  Patients were randomized to acute treatment with sertraline hydrochloride in flexible daily dosages of 50 to 200 mg/d, following 1 week at 25 mg/d (n=94); or placebo (n=93). Main Outcome Measures  Baseline-to-end-point changes in CAPS-2 total severity score, Impact of Event Scale total score (IES), and Clinical Global Impression–Severity (CGI-S), and CGI-Improvement (CGI-I) ratings, compared by treatment vs placebo groups. Results  Sertraline treatment yielded significantly greater improvement than placebo on 3 of the 4 primary outcome measures (mean change from baseline to end point for CAPS-2 total score, -33.0 vs -23.2 [P=.02], and for CGI-S, -1.2 vs -0.8 [P=.01]; mean CGI-I score at end point, 2.5 vs 3.0 [P=.02]), with the fourth measure, the IES total score, showing a trend toward significance (mean change from baseline to end point, -16.2 vs -12.1; P=.07). Using a conservative last-observation-carried-forward analysis, treatment with sertraline resulted in a responder rate of 53% at study end point compared with 32% for placebo (P=.008, with responder defined as >30% reduction from baseline in CAPS-2 total severity score and a CGI-I score of 1 [very much improved], or 2 [much improved]). Significant (P<.05) efficacy was evident for sertraline from week 2 on the CAPS-2 total severity score. Sertraline had significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of avoidance/numbing (P=.02) and increased arousal (P=.03) but not on reexperiencing/intrusion (P=.14). Sertraline was well tolerated, with insomnia the only adverse effect reported significantly more often than placebo (16.0% vs 4.3%; P=.01). Conclusions  Our data suggest that sertraline is a safe, well-tolerated, and effective treatment for PTSD.      

Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial

Context  Children with familial hypercholesterolemia have endothelial dysfunction and increased carotid intima-media thickness (IMT), which herald the premature atherosclerotic disease they develop later in life. Although intervention therapy in the causal pathway of this disorder has been available for more than a decade, the long-term efficacy and safety of cholesterol-lowering medication have not been evaluated in children. Objective  To determine the 2-year efficacy and safety of pravastatin therapy in children with familial hypercholesterolemia. Design  Randomized, double-blind, placebo-controlled trial that recruited children between December 7, 1997, and October 4, 1999, and followed them up for 2 years. Setting and Participants  Two hundred fourteen children with familial hypercholesterolemia, aged 8 to 18 years and recruited from an academic medical referral center in the Netherlands. Intervention  After initiation of a fat-restricted diet and encouragement of regular physical activity, children were randomly assigned to receive treatment with pravastatin, 20 to 40 mg/d (n = 106), or a placebo tablet (n = 108). Main Outcome Measures  The primary efficacy outcome was the change from baseline in mean carotid IMT compared between the 2 groups over 2 years; the principal safety outcomes were growth, maturation, and hormone level measurements over 2 years as well as changes in muscle and liver enzyme levels. Results  Compared with baseline, carotid IMT showed a trend toward regression with pravastatin (mean [SD], –0.010 [0.048] mm; P = .049), whereas a trend toward progression was observed in the placebo group (mean [SD], +0.005 [0.044] mm; P = .28). The mean (SD) change in IMT compared between the 2 groups (0.014 [0.046] mm) was significant (P = .02). Also, pravastatin significantly reduced mean low-density lipoprotein cholesterol levels compared with placebo (–24.1% vs +0.3%, respectively; P<.001). No differences were observed for growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume between the 2 groups. Conclusion  Two years of pravastatin therapy induced a significant regression of carotid atherosclerosis in children with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue.      

Efficacy of acupuncture and moxibustion in treating Bell’s palsy: a multicenter randomized controlled trial in China

Background Bell‘s palsy involves acute facial paralysis due to inflammation of the facial nerve. Acupuncture and moxibustion (acu-moxi) is beneficial in treating facial palsy. In order to verify the efficacy of acu-moxi on Bell‘s palsy, a randomized single-blind, multicenter clinical trial was performed.Methods A total of 480 patients from four clinical centers were involved in this trial, of whom 439 completed the trial and 41 did not. All patients were randomly assigned to either the control group or to one of two treatment groups. The control group was treated with prednisone, vitamin B1, vitamin B12,and dibazole; the treatment groups were treated either with acu-moxi alone or in combination with prednisone, Vitamin B1, vitamin B12, and dibazole. Symptoms and signs, the House-Brackmann scale, and facial disability index (FDI) scores were assessed and determined both pre- and post-treatment to evaluate the effectiveness of the treatment methods. Results The characteristics of the control and two treatment groups were comparable without statistically significant differences before treatment. There were significant differences between the control and treatment groups after treatment (X^2=15.265, P=0.018). According to evaluations based on the House-Brackmann scale and FDI scores, the effectiveness of treatment in the two treatment groups was better than in the control group and was most effective in patients receiving acumoxi treatment alone (Z=-2.827, P=0. 005).Conclusion The efficacy of acu-moxi treatment for Bell‘s palsy is verified scientifically.     

Efficacy and safety of Xinglouchengqi decoction for acute ischemic stroke with constipation: study protocol for a randomized controlled trial

Objective

To investigate the efficacy and safety of Xinglouchengqi (XLCQ) decoction in treatment of acute ischemic stroke with constipation.

Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial.

CONTEXT: Tissue plasminogen activator is the only thrombolytic agent approved in the United States for treatment of acute ischemic stroke, and has limitations. Aptiganel hydrochloride is a novel and selective ligand for the ion-channel site of the N-methyl-D-aspartate receptor-channel complex and a promising neuroprotective agent in animal models of focal brain ischemia. OBJECTIVE: To determine whether aptiganel improves the clinical outcome for acute ischemic stroke patients. DESIGN: Nested phase 2/phase 3 randomized controlled trial conducted between July 1996 and September 1997. SETTING: One hundred fifty-six medical centers in the United States, Canada, Australia, South Africa, England, and Scotland. PARTICIPANTS: A total of 628 patients with hemispheric ischemic stroke (50.3% male; mean age, 71.5 years). INTERVENTIONS: Patients were randomly assigned within 6 hours of stroke to receive 1 of 3 treatment regimens: high-dose aptiganel (5-mg bolus followed by 0.75 mg/h for 12 hours; n = 214); low-dose aptiganel (3-mg bolus followed by 0.5 mg/h for 12 hours; n = 200); or placebo (n = 214). MAIN OUTCOME MEASURES: The primary efficacy end point was the Modified Rankin Scale score at 90 days after stroke onset. Secondary end points included mortality and change in National Institutes of Health (NIH) Stroke Scale score at 7 days after stroke. RESULTS: The trial was suspended by the sponsor and the independent data and safety monitoring board because of both a lack of efficacy and a potential imbalance in mortality. There was no improvement in outcome for either aptiganel (low-dose or high-dose) group compared with the placebo group at 90 days (median Modified Rankin Scale score for all 3 treatment groups = 3; P =.31). At 7 days, placebo-treated patients exhibited slightly greater neurological improvement on the NIH Stroke Scale than high-dose aptiganel patients (mean improvement for placebo group, -0.8 points vs for high-dose aptiganel, 0.9 points; P =.04). The mortality rate at 120 days in patients treated with high-dose aptiganel was higher than that in patients who received placebo (26.3% vs 19.2%; P =.06). Mortality in the low-dose aptiganel group was 22.5% (P =.39 vs placebo). CONCLUSIONS: Aptiganel was not efficacious in patients with acute ischemic stroke at either of the tested doses, and m ay be harmful. The larger proportion of patients with favorable outcomes and lower mortality rate in the placebo group suggest that glutamate blockade with aptiganel may have detrimental effects in an undifferentiated population of stroke patients.     

Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group

CONTEXT: Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. OBJECTIVE: To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. SETTING: Eighty-four outpatient centers throughout the United States. PATIENTS: A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. INTERVENTIONS: Patients were randomly assigned to receive either rhNGF, 0.1 microg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. RESULTS: Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P =.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P =.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P =.05 for severity of pain in the legs and P =.003 for 6-month symptoms in the feet and legs). CONCLUSION: Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. JAMA. 2000;284:2215-2221.     

参附注射液治疗缓慢性心律失常的有效性和安全性研究：随机对照试验的系统评价和Meta分析

目的评价参附注射液治疗缓慢性心律失常的有效性及安全性。方法计算机检索中国期刊全文数据库、万方数据库、中文科技期刊数据库、中国生物医学数据库、Medline、EMbase、ClinicalTrials.gov,筛选出参附注射液治疗缓慢性心律失常的随机对照试验;用Cochrane协作网评价偏倚风险工具对纳入研究进行质量评价,Rev Man5.3软件进行Meta分析。结果共收集参附注射液治疗缓慢性心律失常文献99篇,经过初筛和严格评价,纳入13个研究,共978例,纳入文献质量普遍偏低,除一项研究为C级外,其他文献质量级别均为B级。总体疗效(临床症状或心率改善)方面,参附注射液优于阿托品(RR=1.27,95%CI 1.09~1.48,P=0.002),参附注射液联合阿托品较阿托品单用无统计学差异(RR=0.84,95%CI 0.73~0.97,P=0.30),参附注射液与极化液对比,可以更好改善临床症状(RR=0.52,95%CI 0.40~0.67,P=0.01);在心率改善方面无明显差异(RR=0.57,95%CI 0.32~1.20,P=0.06)。有4个研究报道了不良反应的发生,主要表现为口干舌燥等。结论鉴于目前的研究质量较低,尚不能肯定参附注射液在治疗缓慢性心律失常中的疗效,今后需更多高质量的研究以证实其疗效。     

Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial

Context  Acute otitis media (AOM) frequently complicates influenza infection. Previous studies have found influenza vaccine effective in reducing the occurrence of AOM in children mainly older than 2 years. Objective  To evaluate the effectiveness of inactivated influenza vaccine in preventing AOM in children aged 6 to 24 months. Design, Setting, and Patients  Randomized, double-blind, placebo-controlled trial of 786 children aged 6 to 24 months enrolled at Children's Hospital of Pittsburgh before the 1999-2000 (411 children) and 2000-2001 (375 children) respiratory seasons (defined as December 1 through March 31 of the respective following year). Children received influenza vaccine or placebo in a 2:1 ratio. The first cohort was observed for 1 year and the second cohort until the end of the ensuing respiratory season. Intervention  Two doses (0.25 mL each) of inactivated trivalent subvirion influenza vaccine or placebo were administered intramuscularly approximately 4 weeks apart. Main Outcome Measures  Proportion of children who developed AOM, monthly occurrence rate of AOM, estimated proportion of time with middle ear effusion, and utilization of selected health care and related resources. Results  Of the 66 children in the vaccine group from whom serum samples were collected, seroconversion against strains in the vaccine formulations developed in 88.6% to 96.8%, depending on the specific strain. The efficacy of the vaccine against culture-confirmed influenza was 66% (95% confidence interval [CI], 34%-82%) in 1999-2000 and -7% (95% CI, -247% to 67%) in 2000-2001; however, influenza attack rates differed between these 2 periods (in the placebo group, 15.9% and 3.3%, respectively). Compared with placebo, influenza vaccine did not reduce the proportion of children who had at least 1 episode of AOM during the respiratory season (in the first cohort: vaccine, 49.2% vs placebo, 52.2%; P = .56 ]; in the second cohort: vaccine, 55.8% vs placebo, 48.3%; P = .17). The vaccine also did not reduce the monthly rate of AOM; the estimated proportion of time with middle ear effusion; or the utilization of selected health care and related resources. There were also no differences between the vaccine and placebo groups regarding any of these outcomes during peak influenza periods. The vaccines administered to both cohorts of children were well tolerated. Conclusion  Administration of inactivated trivalent influenza vaccine to children aged 6 to 24 months did not reduce their burden of AOM or their utilization of selected health care and related resources.      

Efficacy and safety of tauroursodeoxycholic acid in the treatment of liver cirrhosis: A double-blind randomized controlled trial

No direct comparison of tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) has yet been carried out in the treatment of liver cirrhosis in China. We designed a double-blind randomized trial to evaluate the potential therapeutic efficacy of TUDCA in liver cirrhosis, using UDCA as parallel control. The enrolled 23 patients with liver cirrhosis were randomly divided into TUDCA group (n=12) and UDCA group (n=11), and given TUDCA and UDCA respectively at the daily dose of 750 mg, in a randomly assigned sequence for a 6-month period. Clinical, biochemical and histological features, and liver ultrasonographic findings were evaluated before and after the study. According to the inclusion criteria, 18 patients were included in the final analysis, including 9 cases in both two groups. Serum ALT, AST and ALP levels in TUDCA group and AST levels in UDCA group were significantly reduced as compared with baseline (P<0.05). Serum albumin levels were significantly increased in both TUDCA and UDCA groups (P<0.05). Serum markers for liver fibrosis were slightly decreased with the difference being not significant in either group. Only one patient in TUDCA group had significantly histological relief. Both treatments were well tolerated and no patient complained of side effects. It is suggested that TUDCA therapy is safe and appears to be more effective than UDCA in the treatment of liver cirrhosis, particularly in the improvement of the biochemical expression. However, both drugs exert no effect on the serum markers for liver fibrosis during 6-month treatment.     

早期胃肠康复治疗机械通气的脓毒症伴急性胃肠损伤患者的有效性和安全性:34例前瞻性、随机对照、先导试验

目的 探讨早期胃肠康复治疗机械通气的脓毒症伴急性胃肠损伤（AGI）患者的疗效和安全性。方法 采用前瞻性、随机、平行对照的研究方法,开放设计,对康复评定人设盲。筛选2017年5月~2018年3月在广州市一家三级甲等教学医院重症监护病房（ICU）住院的脓毒症患者,符合纳入标准则招募入组。以急性生理和慢性健康状况评分Ⅱ（APACHE Ⅱ）等为平衡因素,区组随机化分为干预组和对照组。两组均按脓毒症标准方案治疗,干预组增加早期胃肠康复。主要研究终点为AGI治愈;次要研究终点包括ICU住院病死率、机械通气预后、ICU住院天数等。数据采集时间点定为入组、呼吸机脱机、转出ICU共3个。结果 共招募 60例患者,34例完成研究。干预组 16例,对照组 18例。结果显示,康复治疗后,干预组和对照组 AGI治愈例数的差异无统计学意义（P>0.05）。比较康复治疗前后两组AGI评分的下降值,分别为（-1.9±2.1）分和（0.9±1.6）分,差异有统计学意义（P<0.05）。早期胃肠康复的不良事件发生率为3.33%,无器官损伤或意外死亡等严重不良事件。两组在ICU住院病死率、机械通气预后、ICU住院天数等指标方面,差异均无统计学意义（P>0.05）。结论 早期胃肠康复不能降低AGI患病率,但降低AGI评分,改善胃肠道症状,安全性好,但需在设计更为合理的大样本多中心临床研究中证实。     

Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial

Context  The success of conjugate vaccines in decreasing invasive disease due to Streptococcus pneumoniae and group C Neisseria meningitidis has placed pressure on crowded infant immunization schedules, making development of combination vaccines a priority. Objective  To determine the safety and immunogenicity of a combination 9-valent pneumococcal–group C meningococcal conjugate candidate vaccine (Pnc9-MenC) administered as part of the routine UK infant immunization schedule at ages 2, 3, and 4 months. Design, Setting, and Participants  Phase 2 randomized controlled trial conducted from August 2000 to January 2002 and enrolling 240 healthy infants aged 7 to 11 weeks from 2 UK centers, with home follow-up visits at ages 2, 3, 4, and 5 months. Intervention  Pnc9-MenC (n = 120) or monovalent group C meningococcal conjugate vaccine (MenC) (n = 120) administered in addition to routine immunizations (diphtheria and tetanus toxoids and whole-cell pertussis [DTwP], Haemophilus influenzae type b [Hib] polyribosylribitol phosphate-tetanus toxoid protein conjugate, oral polio vaccine). Main Outcome Measures  Group C meningococcal immunogenicity measured by serum bactericidal titer (SBT) 1 month following the third dose; rates of postimmunization reactions. Results  MenC component immunogenicity was reduced in the Pnc9-MenC vs the MenC group (geometric mean SBT, 179 [95% confidence interval {CI}, 133-243] vs 808 [95% CI, 630-1037], respectively; P<.001). The proportion with group C meningococcal SBT greater than 1:8 was lower in the Pnc9-MenC vs the MenC group (95% vs 100%, P = .05). The geometric mean concentration of antibodies to concomitantly administered Hib vaccine was reduced in the Pnc9-MenC vs the MenC group (2.11 [95% CI, 1.57-2.84] µg/mL vs 3.36 [95% CI, 2.57-4.39] µg/mL; P = .02), as were antibodies against diphtheria (0.74 [95% CI, 0.63-0.87] µg/mL vs 1.47 [95% CI, 1.28-1.69] µg/mL; P<.001). Pnc9-MenC was immunogenic for each of 9 contained pneumococcal serotypes, with responses greater than 0.35 µg/mL observed in more than 88% of infants. Increased irritability and decreased activity were observed after the third dose in the Pnc9-MenC group. Conclusions  Pnc9-MenC combination vaccine administered to infants at ages 2, 3, and 4 months demonstrated reduced group C meningococcal immunogenicity compared with MenC vaccine. The immunogenicity of concomitantly administered Hib and DTwP vaccines was also diminished. The Pnc9-MenC vaccine was safe and immunogenic for all contained pneumococcal serotypes. The reduced MenC immunogenicity may limit the development of the Pnc9-MenC vaccine.      

Continuous emotional support during labor in a US hospital. A randomized controlled trial

The continuous presence of a supportive companion (doula) during labor and delivery in two studies in Guatemala shortened labor and reduced the need for cesarean section and other interventions. In a US hospital with modern obstetric practices, 412 healthy nulliparous women in labor were randomly assigned to a supported group (n = 212) that received the continuous support of a doula or an observed group (n = 200) that was monitored by an inconspicuous observer. Two hundred four women were assigned to a control group after delivery. Continuous labor support significantly reduced the rate of cesarean section deliveries (supported group, 8%; observed group, 13%; and control group, 18%) and forceps deliveries. Epidural anesthesia for spontaneous vaginal deliveries varied across the three groups (supported group, 7.8%; observed group, 22.6%; and control group, 55.3%). Oxytocin use, duration of labor, prolonged infant hospitalization, and maternal fever followed a similar pattern. The beneficial effects of labor support underscore the need for a review of current obstetric practices.     

阿普唑仑联合降压药治疗顽固性高血压的临床疗效和安全性评价

目的观察阿普唑仑联合降压药治疗顽固性高血压的临床疗效和安全性。方法于2008年2月—2010年10月治疗顽固性高血压患者102例,随机分为试验组和对照组各51例,2组在常规治疗基础上分别加用阿普唑仑或安慰剂治疗8周,观察患者的血压情况及不良反应。在治疗结束后随访8周,再次评价临床疗效。结果试验组显效37例(72.6%),有效10例(19.6%),总有效率92.2%,而对照组显效21例(41.2%),有效15例(29.4%),总有效率70.6%;2组间显效率和总有效率比较差异均有统计学意义(P<0.05)。试验组早期不良反应率(31.4%)高于对照组(21.6%),但差异无统计学意义(P>0.05)。随访8周时和试验结束时相比,试验组临床症状改善且血压稳定;而对照组舒张压水平升高(P<0.05)。结论阿普唑仑联合降压药治疗顽固性高血压疗效肯定,且不良反应少而轻微。