Air-sea disequilibrium enhances ocean carbon storage during glacial periods.

The prevailing hypothesis for lower atmospheric carbon dioxide (CO2) concentrations during glacial periods is an increased efficiency of the ocean's biological pump. However, tests of this and other hypotheses have been hampered by the difficulty to accurately quantify ocean carbon components. Here, we use an observationally constrained earth system model to precisely quantify these components and the role that different processes play in simulated glacial-interglacial CO2 variations. We find that air-sea disequilibrium greatly amplifies the effects of cooler temperatures and iron fertilization on glacial ocean carbon storage even as the efficiency of the soft-tissue biological pump decreases. These two processes, which have previously been regarded as minor, explain most of our simulated glacial CO2 drawdown, while ocean circulation and sea ice extent, hitherto considered dominant, emerge as relatively small contributors.

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB(389)IL-2) in patients with severe psoriasis.

BACKGROUND: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. OBJECTIVE: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. METHODS: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. RESULTS: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. CONCLUSIONS: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.

Simplifying modern wound management for nonprofessional caregivers.

Nonprofessional caregivers currently are participating in managing pressure ulcers at home. As this can be a stressful experience, innovative and easy-to-use products are needed to support caregiver confidence. A multicenter, randomized clinical trial was conducted to compare clinical performance and case of instruction of a change indicator dressing (SIG) and a hydrocolloid alginate dressing (HAD) in the management of pressure ulcers in the home and long-term care settings. SIG and HAD were randomized to 17 and 18 partial- or full-thickness pressure ulcers respectively. During five dressing changes, wound area, dressing application, maintenance, appearance, removal, wear time, ease of teaching, and caregiver understanding of each dressing's instructions were measured. Both dressings were rated highly regarding ease of teaching, ease of use, appearance, maintenance, and helpfulness in signaling the need for dressing change by both professional and nonprofessional wound caregivers. Average dressing wear time was 3.2 days for SIG and 2.7 days for HAD. Of these wounds managed in a moist environment, 6 of 17 (35%) subjects whose wounds were dressed with SIG, and 1 of 18 (6%) dressed with HAD healed during the course of the study (alpha < 0.04). Percent wound reduction in area per day of care was also greater for SIG (alpha < 0.01). Innovative dressings may help caregivers provide consistent quality pressure ulcer care and improve wound-healing outcomes.

Skin cancer screening: A growing need.

Skin cancer is the most frequently diagnosed cancer in the United States. Melanoma is the major cause of deaths due to skin cancer, however, squamous cell carcinoma and basal cell carcinoma account for considerable morbidity also. All three types are potentially curable if diagnosed at an early stage. Visual examination of the skin by a trained observer is a simple and effective screening tool which may be utilized in a multitude of settings. Patient education and self-examination augment the impact of office-based screening and mass screening programs.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the fingernail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of fungal infections. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of oral fluconazole 150, 300, and 450 mg administered once weekly compared with placebo in the treatment of distal subungual onychomycosis of the fingernail caused by dermatophytes. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 349 patients with onychomycosis of the fingernails. Clinical and mycologic efficacy as well as measures of safety were assessed monthly for a maximum of 9 months of treatment, with additional safety visits occurring at weeks 2 and 6. For inclusion, patients were required to have clinically and mycologically documented onychomycosis of the fingernail caused by dermatophytes with at least 25% involvement of the target fingernail. After end of therapy, patients with improved or cured fingernails entered a blinded 6-month follow-up without drug treatment during which efficacy was assessed every 2 months. Efficacy was assessed by clinical (visual) and mycologic (microscopic and culture) measures. Clinical measures included assessments of the percentage of target nail involvement, measurement of the distance from the nail fold to the proximal onychomycotic border, and signs and symptoms of onychomycosis. RESULTS: Fluconazole was significantly superior to placebo in eradicating clinical and mycologic symptoms of onychomycosis, both at the end of active treatment and at 6 months after treatment (p=0.0001 for all efficacy measures). At the end of therapy, 91% to 100% of patients in the fluconazole groups were judged clinical successes, defined as reduction of the affected area of the target nail to less than 25% or cure, compared with 8% for placebo. Clinical cure rates at end of therapy were 76%, 85%, and 90% for fluconazole 150, 300, and 450 mg, respectively, compared with 3% for placebo. These clinical success and cure rates were largely maintained or improved during follow-up. Clinical relapse in cured patients during the follow-up period was very low (1.5% to 3.3%). Fluconazole demonstrated mycologic eradication rates of 89% to 100% at the end of treatment and 90% to 99% at the end of follow-up; for placebo the rates were 8% and 12%, respectively. CONCLUSION: Fluconazole administered once weekly is safe and effective in eradicating distal subungual onychomycosis of the fingernail caused by dermatophytes.

Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail.

BACKGROUND: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. OBJECTIVE: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. METHODS: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. RESULTS: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. CONCLUSION: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

Phase 1 clinical trials.

BACKGROUND: In the United States, drug development and approval is a complex process regulated by the Food and Drug Administration under the authority outlined in the Code of Federal Regulation. The goal of this multi-step process is to determine safety and efficacy of new therapeutic entities. Initially, exposure of humans to new therapeutic agents is accomplished in a graded and limited fashion. This approach seeks to minimize risks to study participants from exposure to damaging agents. During early phases, limiting exposure to a few individuals results in the accumulation of preliminary data on pharmacology, short-term toxicity, and efficacy. The inherent limitations of this process necessitate careful critique and caution in extrapolation of phase 1 data. OBJECTIVES: The purpose of this article is to provide a review of the drug approval process focusing on phase 1 trials, which are the earliest human exposure to a new drug. The purpose, variations, and significance of phase 1 trials are described, and a framework is provided to critically evaluate data published from these trials. CONCLUSIONS: Phase 1 trials are primarily designed to accumulate short-term safety (toxicity) and pharmacological data. Although preliminary efficacy may be addressed ("proof of concept" efficacy), it is a secondary endpoint. The numbers of patients are small, the numbers of patients receiving efficacious doses are very small, and controls are absent. Evaluation of efficacy and of long-term toxicity requires longer, larger, and controlled studies.

Anticonvulsant hypersensitivity syndrome.

Anticonvulsant hypersensitivity syndrome is a potentially fatal drug reaction with cutaneous and systemic reactions (incidence, one in 1000 to one in 10,000 exposures) to the arene oxide-producing anticonvulsants--phenytoin, carbamazepine, and phenobarbital sodium. In most cases, the hallmark features of fever, rash, and lymphadenopathy are accompanied by multiorgan-system abnormalities. Fatal outcomes are most often associated with liver failure. Recognition of the syndrome, which may have variable presentations, is the key to prompt discontinuation of the drug, close monitoring, and management. The reaction may be genetically determined, and siblings of patients with anticonvulsive hypersensitivity syndrome may be at increased risk of developing this syndrome. The timely recognition of anticonvulsant hypersensitivity syndrome is important, because accurate diagnosis avoids potentially fatal reexposure and affects subsequent anticonvulsant treatment options.