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Study Objective: To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with drotrecogin alfa (activated).Design: Prospective, single-arm, multicenter clinical trial.Setting: Eighty-five study sites in the United States and two in Puerto Rico.Participants: Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for Interventions: Drotrecogin alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN], 24 micro g/kg/h, as a continuous IV infusion for a duration of 96 +/- 1 h.Measurements and Results: The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of drotrecogin alfa (activated). Serious bleeding was monitored to day 28. Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly defined patient populations from the United States. For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with drotrecogin alfa (activated) in the PROWESS US trial (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) [0.35%]. Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa (activated) treatment group.Conclusions: Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS trial. [ABSTRACT FROM AUTHOR]

Study Objectives: The purpose of this 12-week study was to evaluate the efficacy and safety of adjunct modafinil to treat excessive sleepiness in patients with obstructive sleep apnea (OSA) who experience residual sleepiness despite regular nasal continuous positive airway pressure (nCPAP) use.Design: Twelve-week, open-label trial.Setting: Twenty-two centers in the United States.Patients: We studied 125 patients with moderate-to-severe OSA (ie, respiratory disturbance index > or =15) before nCPAP therapy and residual daytime sleepiness (Epworth sleepiness scale [ESS] score > or =10) despite effective and regular nCPAP therapy. Patients were studied after completing a 4-week, double-blind, placebo-controlled trial of nCPAP plus modafinil for the treatment of residual daytime sleepiness.Interventions and Measurements: Patients received individually titrated doses of modafinil (200 to 400 mg qd). Sleepiness was assessed using the ESS, quality of life was evaluated using the Functional Outcomes of Sleep Questionnaire (FOSQ), and the overall clinical effect was indexed using the clinical global impression of change scale. Adverse events, nCPAP use, and vital sign measurements were also recorded.Results: The significant improvements in daytime wakefulness and sleep-related functional status observed with modafinil treatment during the 4-week, double-blind study were maintained throughout 12 weeks of open-label treatment: week 12 ESS, 7.8 (4.7) vs 14.4 (3.1) at double-blind baseline; week 12 FOSQ, 3.3 (0.6) vs 14.4 (2.7) at double-blind baseline (mean [SD]). The percentage of patients rated as clinically improved increased from 83% after 1 week to > or =93% after 2 to 12 weeks of open-label treatment. Mean (SD) nCPAP use decreased from 6.3 (1.3) h/night at baseline to 5.9 (1.4) h/night (p = 0.004) during open-label treatment. The most common adverse events were headache (28%), anxiety (16%), and nervousness (14%).Conclusions: Modafinil remained effective and well tolerated as an adjunct therapy for residual daytime sleepiness even after 12 weeks of daily dosing in patients with OSA receiving nCPAP therapy. [ABSTRACT FROM AUTHOR]

Background: Current treatments for pulmonary arterial hypertension (PAH) have been shown to improve dyspnea, 6-min walk distance (6MWD), and pulmonary hemodynamics, but few studies were designed to compare treatment regimens or assess the impact of treatment on mortality., Methods: We conducted a systematic review to evaluate the comparative effectiveness and safety of monotherapy or combination therapy for PAH using endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids. We searched English-language publications of comparative studies that reported intermediate or long-term outcomes associated with drug therapy for PAH. Two investigators abstracted data and rated study quality and applicability., Results: We identified 28 randomized controlled trials involving 3,613 patients. We found no studies that randomized treatment-naive patients to monotherapy vs combination therapy. There was insufficient statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy. For hospitalization, the OR was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively)., Conclusions: Although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates. Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy.

The US Food and Drug Administration (FDA) drug approval and over-the-counter drug monograph processes play an essential role in ensuring that all drugs are both safe and effective for their intended uses. Manufacturers of drugs that lack required approval have not provided the FDA with evidence demonstrating that their products are safe and effective. Some of these prescription drugs have been marketed for many years and have remained on the market despite changes to the Federal Food, Drug, and Cosmetic Act, which requires approval for safety and efficacy purposes. Many health-care providers may be unaware that unapproved drugs exist because the product labels of these drugs do not disclose that they lack FDA approval. The FDA recently took action against unapproved prescription oral cough, cold, and allergy drug products because of concerns about the potential risks of these products, particularly some extended-release formulations that have not been reviewed for quality. There is a potential for medication errors because product names and labeling have not been reviewed for potential confusion, with some products inappropriately labeled for use in children aged ≤ 2 years. FDA-approved prescription drugs or drugs appropriately marketed as over the counter remain available for treatment of cough, cold, and allergy symptoms. Such products are of known efficacy, safety, identity, quality, and purity. Removing unapproved drugs from the marketplace and encouraging manufacturers of unapproved products to seek FDA review and approval is a top priority for the FDA. Since the initiation of the Unapproved Drugs Initiative in 2006, the FDA has removed ~1,500 unapproved products from the market and has worked with firms to bring other unapproved drugs into the approval process. The FDA remains committed to its mission of ensuring that safe and effective drugs are available to American consumers.

Study Objectives: Diagnosis and medical intervention for exercise-induced bronchospasm (EIB) are often based on self-reported symptoms, without spirometric confirmation. Inspiratory stridor (IS), a symptom of vocal cord dysfunction (VCD), is frequently mistaken for EIB wheeze. Athletes with exercise IS that spontaneously resolves on activity cessation are suspect for VCD and may not have EIB. This study estimated IS prevalence in elite athletes and determined its relationship to EIB., Subjects/methods: Three hundred seventy athletes (174 female and 196 male subjects) provided a medical history, and underwent spirometry before and after exercise challenge. Exercise challenges were conducted in cold, dry ambient conditions. EIB positive (EIB +) was defined as a > or = 10% postexercise fall in FEV(1). Athletes were monitored for IS during exercise; 78.4% of the athletes in this study (n = 290) were tested on multiple occasions., Results: EIB was identified in 30% of 370 athletes tested (58 female and 53 male subjects). IS was observed in 5.1% (18 female and 1 male subjects) during exercise and spontaneously resolved in these subjects within 5 min after exercise cessation. Ten IS-positive (IS +) athletes (52.6%) were EIB +, and 8 of these athletes had a previous EIB diagnosis; however, beta(2)-agonist treatment resolved IS in only 2 subjects. Eight of nine IS +/EIB-negative (EIB -) athletes had a previous EIB diagnosis; seven subjects received beta(2)-agonist treatment with no IS resolution. Resting spirometric measurements did not distinguish IS, but postexercise mid-flow (FEF(50)/FIF(50)) ratio > 1.5 was more frequent (33%, p < 0.05) among IS + athletes. The FEF(50)/FIF(50) ratio was higher for IS +/EIB + athletes than for IS -/EIB + athletes (1.97 +/- 1.69 vs 0.81 +/- 0.39, p < 0.05). The postexercise fall in FVC was greater (p < 0.05) for IS +/EIB - athletes (9.2 +/- 5.0%) than for IS-negative (IS -) /EIB - athletes (5.3 +/- 4.3%). No difference in postexercise FEV(1) was identified between IS + and IS - athletes (within EIB + or EIB - groups)., Conclusions: Five percent of athletes were IS +, with EIB comorbidity observed in 53% of these subjects. Misdiagnosis of IS as EIB is common. The lack of a beta(2)-agonist response in combination with postexercise serial spirometry can be useful in excluding solitary IS and confirming EIB diagnosis.

Postinfluenza toxic shock syndrome is a recently described entity that results from a respiratory tract infection with toxin-producing Staphylococcus aureus following an episode of influenza or influenzalike illness. This report describes a 19-year-old man who developed an influenza B respiratory infection complicated by staphylococcal pneumonia and toxic shock syndrome. The patient improved rapidly with specific antibiotic therapy, emphasizing the importance of considering this otherwise highly lethal syndrome in any individual who becomes critically ill after an initial influenzalike illness.