Caspofungin, a glucan synthesis inhibitor, is being developed as a parenteral antifungal agent. The pharmacokinetics of caspofungin following 1-h intravenous infusions in healthy men was investigated in four phase I studies. In an alternating two-panel (six men each), rising-single-dose study, plasma drug concentrations increased proportionally with the dose following infusions of 5 to 100 mg. The ␤-phase half-life was 9 to 10 h. The plasma drug clearance rate averaged 10 to 12 ml/min. Renal clearance of unchanged drug was a minor pathway of elimination (ϳ2% of the dose). Multiple-dose pharmacokinetics were investigated in a 2-week, serial-panel (5 or 6 men per panel) study of doses of 15, 35, and 70 mg administered daily; a 3-week, single-panel (10 men) study of a dose of 70 mg administered daily; and a parallel panel study (8 men) of a dose of 50 mg administered daily with or without a 70-mg loading dose on day 1. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady state were somewhat dose dependent. Accumulation averaged 24% at 15 mg daily and ϳ50% at 50 and 70 mg daily. Mean plasma drug concentrations were maintained above 1.0 g/ml, a target selected to exceed the MIC at which 90% of the isolates of the most clinically relevant species of Candida were inhibited, throughout therapy with daily treatments of 70 or 50 mg plus the loading dose, while they fell below the target for the first 2 days of a daily treatment of 50 mg without the loading dose. Caspofungin infused intravenously as a single dose or as multiple doses was generally well tolerated. In conclusion, the pharmacokinetics of caspofungin supports the clinical evaluation of once-daily dosing regimens for efficacy against fungal infections.Caspofungin (Cancidas; MK-0991) is an echinocandin that was recently approved by the U.S. Food and Drug Administration for patients with invasive aspergillosis who are refractory to or intolerant of standard therapy. Caspofungin inhibits the synthesis of 1,3-␤-D-glucan, which forms a critical component of many fungal cell walls (3). It has been shown to have potent activity in vitro against many clinically important fungi, including Candida spp. and Aspergillus spp. (2, 7, 9; M. Del Poeta, W. A. Schell, and J. R. Perfect, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F33, 1996). In in vivo studies with healthy and immunocompromised animals, prolonged survival in models of disseminated aspergillosis and candidiasis and clearance of Candida spp. from a target organ have been demonstrated with caspofungin treatment (1,5,6 , abstr. 1103, p. 371, 2000).Caspofungin has been developed as a parenteral agent due to its high molecular weight, unfavorable log P (partition coefficient), and extremely poor oral bioavailability in animals. In all the clinical studies, caspofungin has been administered as a constant-rate, 1-h intravenous (i.v.) infusion. This paper describes the results from four phase I studies conducted with healthy male subjects to ...

Context.-State medical boards discipline several thousand physicians each year. Although certain subgroups, such as those disciplined for malpractice, substance use, or sexual abuse, have been studied, little is known about disciplined physicians as a group. Objective.-To assess the offenses, contributing factors, and type of discipline of a consecutive series of disciplined physicians. Design.-Case-control study on publicly available data matching 375 disciplined physicians with 2 groups of control physicians, one matched solely by locale, and a second matched for sex, type of practice, and locale. Subjects.-All disciplined physicians publicly reported by the Medical Board of California from October 1995 through April 1997. Main Outcome Measures.-Characteristics of disciplined physicians, offenses leading to discipline, and type of discipline. Results.-A total of 375 physicians licensed by the Medical Board of California (approximately 0.24% per year) were disciplined for 465 offenses. The most frequent causes for discipline were negligence or incompetence (34%), abuse of alcohol or other drugs (14%), inappropriate prescribing practices (11%), inappropriate contact with patients (10%), and fraud (9%). Discipline imposed was revocation of medical license (21%), actual suspension of license (13%), stayed suspension of license (45%), and reprimand (21%). Type of offense was significantly associated with severity of discipline (P = .03). In logistic regression models comparing disciplined physicians with controls matched by locale, board discipline was significantly associated with physicians' sex (odds ratio [OR] for women, 0.44; 95% confidence interval [CI], 0.28-0.70) and involvement in direct patient care (OR, 2.56; 95% CI, 1.75-3.75). In the regression model with additional matching criteria, disciplinary action was negatively associated with specialty board certification (OR, 0.42; 95% CI, 0.29-0.60) and positively associated with being in practice more than 20 years (OR, 2.02; 95% CI, 1.39-2.92). Conclusions.-A small but substantial proportion of physicians is disciplined each year for a variety of offenses. Further study of disciplined physicians is necessary to identify physicians at high risk for offenses leading to disciplinary action and to develop effective interventions to prevent these offenses.

Expenditures for specialty drugs account for more than 25 percent of total US drug spending and have been increasing at more than 13 percent annually. We examined insurers' role in maintaining the affordability and accessibility of specialty drugs while maximizing their value. We conducted two analyses: one using an administrative claims database with information on more than ten million commercially insured patients and another using the same database combined with the drug prescription records from a specialty pharmacy. First, we examined the prevalence of specialty drug coupons and the degree to which these reduced patients' out-of-pocket costs, focusing on 264,801 prescriptions. Second, we quantified the association between the magnitude of out-of-pocket costs for specialty drugs and patients' abandonment of their new or restarted therapy, focusing on a group of nearly 16,000 patients. We found that drug coupons accounted for $21.2 million of patients' $35.3 million annual out-of-pocket costs. In the vast majority of cases, coupons reduced monthly cost sharing to less than $250, a point at which patients were far less likely to abandon therapy with biologic anti-inflammatory drugs or with drugs for multiple sclerosis. However, by reducing cost sharing, coupons may also circumvent efforts to encourage patients to use the most cost-effective drugs.

This study tested the hypothesis that low-dose 3,5,3′-triiodothyronine (T3) administration during prolonged bed rest improves the ground-based model of spaceflight. Nine men (36.4 ± 1.3 yr) and five women (34.2 ± 2.1 yr) were studied. After a 5-day inpatient baseline period, subjects were placed at total bed rest with 6° head-down tilt for 28 days followed by 5-day recovery. Fifty micrograms per day of T3( n = 8) or placebo ( n = 6) were given during bed rest. Serum T3 concentrations increased twofold, whereas thyroid-stimulating hormone was suppressed in treated subjects. T3-treated subjects showed significantly greater negative nitrogen balance and lost more weight ( P = 0.02) and lean mass ( P < 0.0001) than placebo subjects. Protein breakdown (whole body [13C]leucine kinetics) increased 31% in the T3 group but only 8% in the placebo group. T3-treated women experienced greater changes in leucine turnover than men, despite equivalent weight loss. Insulin sensitivity fell by 50% during bed rest in all subjects ( P = 0.005), but growth hormone release and insulin release were largely unaffected. In conclusion, addition of low-dose T3 to the bed rest model of muscle unloading improves the ground-based simulation of spaceflight and unmasks several important gender differences.