Effects of the NMDA antagonist memantine on human methamphetamine discrimination

Abstract Rationale. The discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. Objective. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Methods. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Results. Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. Conclusion. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects. Electronic Publication     

Treatment of psoriasis with alefacept: correlation of clinical improvement with reductions of memory T-cell counts

OBJECTIVE: To examine the relationship between the pharmacodynamic and antipsoriatic effects of alefacept, a biologic agent that targets CD4+ and CD8+ memory T cells. DESIGN: Randomized, double-blind, placebo-controlled study of 3 parallel groups. SETTING: Fifty-one study centers. PATIENTS: Five hundred fifty-three patients with chronic plaque psoriasis. INTERVENTIONS: Patients were randomized (1:1:1) to 1 of the following 3 cohorts: alefacept, 7.5 mg, in both courses (cohort 1); alefacept, 7.5 mg, in the first course and placebo in the second course (cohort 2); or placebo in the first course and alefacept, 7.5 mg, in the second course (cohort 3). In each course, alefacept or placebo was administered by intravenous bolus once weekly for 12 weeks, followed by 12 weeks of observation. MAIN OUTCOME MEASURES: Circulating lymphocyte levels and the Psoriasis Area Severity Index. RESULTS: One or 2 courses of alefacept reduced CD4+ and CD8+ memory T-cell counts, while sparing the naive population. At 12 weeks after the last dose of alefacept in courses 1 and 2, 88% and 83% of patients, respectively, had CD4+ cell counts greater than the lower limit of normal. In course 1, alefacept-treated patients with the largest decreases in memory T-cell counts experienced the greatest reductions in disease activity (P<.001). The duration of clinical benefit seemed to be longer among patients who had the greatest reduction in CD4+ and CD8+ memory T-cell counts. CONCLUSIONS: One or 2 courses of intravenous alefacept reduced circulating memory T-cell counts while sparing the na?ve T-cell population. The reductions in memory T-cell counts were related to all measures of disease activity evaluated and the duration of response to therapy, suggesting that prolonged remissions of psoriasis can be attained with reduction of the pathogenic T-cell count.     

Mapping therapeutic response in a patient with malignant glioma

Short-interval scanning of patients offers a detailed understanding of the natural progression of tumor tissue, as revealed through imaging markers such as contrast enhancement and edema, prior to therapy. Following treatment, short-interval scanning can also provide evidence of attenuation of growth rates. We present a longitudinal imaging study of a patient with glioblastoma multiforme (GBM) scanned 15 times in 104 days on a 3 T MR scanner. Images were analyzed independently by two automated algorithms capable of creating detailed maps of tumor changes as well as volumetric analysis. The algorithms, a nearest-neighbor-based tissue segmentation and a surface-modeling algorithm, tracked the patient's response to temozolomide, showing an attenuation of growth. The need for surrogate imaging end-points, of which growth rates are an example, is discussed. Further, the strengths of these algorithms, the insight gained by short-interval scanning, and the need for a better understanding of imaging markers are also described.     

Alternative reinforcers differentially modify cocaine self-administration by humans

Six experienced cocaine smokers (two men, four women) participated in an inpatient study to compare self-administration of smoked cocaine when either a $5 money or merchandise voucher was available as an alternative reinforcer. A six-trial choice procedure was used, with sessions consisting of (1) one sample trial, where participants received the cocaine dose and the alternative reinforcer available that day, and (2) five choice trials, where participants chose between the available cocaine dose and the alternative reinforcer. There were eight sessions: in separate sessions, each dose of cocaine (0, 12, 25, 50 mg) was paired with a money voucher and with a merchandise voucher. The choice to self-administer cocaine significantly increased with escalating cocaine doses, and significantly less cocaine was self-administered when money vouchers were available as compared to merchandise vouchers. These data demonstrate that money vouchers are a more effective alternative reinforcer than merchandise vouchers in cocaine abusers.     

A model for forecasting intermittent skilled home nursing needs

The problem of forecasting the need and the cost for post-discharge skilled home nursing services is addressed by a simple statistical model. The model, assumptions, and simple calculations are described. Use of the model is illustrated with 7598 cancer patients and 2337 myocardial infarction patients. Simulation of the impact of changes in the health care delivery system toward greater and lesser severity of hospitalized patients is carried out. Two key projections illustrating the model's output are the number of patients with these diseases who will need care and the cost of that care.     

Diastolic heart failure: a review and primary care perspective

Previously the subject of much debate, there is now consensus that diastolic heart failure (DHF) represents a distinct form of heart failure. Epidemiologic data indicate that DHF is common. Indeed, there is evidence that, among elderly persons, DHF is more common than systolic heart failure (SHF). Like SHF, DHF is associated with significant morbidity, mortality, and cost; however, few clinical trials focusing on isolated DHF have been completed. Much of the treatment of DHF is based on current concepts of the pathophysiology of DHF, small clinical studies, and experience gained from treating patients with SHF. The diagnosis of DHF is clinical; data supporting the establishment of a diagnosis of DHF are limited. Differences exist in prognosis and treatment between diastolic and systolic heart failure. This article reviews diastolic heart failure with emphasis on evidence-based management, aimed at primary care physicians who routinely provide care to patients with DHF.