Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double-blind, single-dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half-life prolonged at the 500-mg compared to the 250-mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500-mg dose exceeded those of the 250-mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high-dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration-dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11 Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent. While favorable subjective and performance-enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

Objective To explore reasons for increased risk of hospital admission among south Asian patients with asthma.

Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m2 retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon’s two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33–72) enrolled with a median of six prior chemotherapeutic regimens (range 2–20). On study, patients received a median of three treatment cycles (range 1–12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1–8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/m² weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing.

Objectives Evaluation of clinical activity and safety of IPI-504 (retaspimycin hydrochloride) in patients with castration-resistant prostate cancer (CRPC). Methods A single arm trial was conducted in two cohorts: Group A (chemotherapy-naïve), Group B (docetaxel-treated). IPI-504 was administered intravenously at 400 mg/m2 on Days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if at least one prostate specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected following the first dose; safety was assessed throughout. Results Nineteen patients were enrolled (4 in Group A; 15 in Group B), with a median age of 66 years (range 49-78). Group B had received a median of 2 prior chemotherapy regimens. All Group B patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One Group A patient remained on trial for 9 cycles; PSA declined 48% from baseline. No PSA responses were observed in other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in Group B died on study, involving study drug-related events of hepatic failure and ketoacidosis, respectively. Conclusions In this study, Hsp90 inhibition with IPI-504 administered as a single agent had a minimal effect on PSA or tumor burden and was associated with unacceptable toxicity in several patients; therefore, further evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less intensive doses and schedules in other tumor types.

The pharmacokinetics and pharmacodynamics of the benzodiazepine anxiolytic alprazolam (1 mg orally) were compared between young and elderly healthy volunteers. Eight young subjects (mean age 29.8 years) and eight elderly volunteers (mean age 68.4 years) received oral placebo and alprazolam (1.0 mg) in a randomized, double-blind, single-dose crossover study. In the elderly subjects, plasma concentrations were higher, although not significantly so, than in young volunteers 0.25, 0.5, and 0.75 hours after dosage. Apparent elimination half-life, time of maximum concentration, maximum concentration, volume of distribution, and apparent clearance were similar for the two groups. In both groups, alprazolam treatment (versus placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and fatigue, reduced excitement, increased feelings of spaciness, and perception of thinking slowed. For some measures, the alprazolam-placebo difference was greater in young than in elderly subjects. In both groups, alprazolam significantly impaired performance on the digit-symbol substitution test (DSST). EEG studies indicated significant increases in relative beta amplitude (13-30 Hz range) after alprazolam compared to placebo. Percent DSST decrement and percent EEG change were highly correlated with plasma alprazolam concentrations for both groups. There were modest increases in alprazolam plasma concentration in the elderly compared to the younger group shortly after drug administration, but there was no evidence of increased sensitivity to the pharmacodynamic effects of alprazolam in the elderly.