Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke.

BACKGROUND AND PURPOSE: Diaspirin cross-linked hemoglobin (DCLHb) is a purified, cell-free human hemoglobin solution. In animal stroke models its use led to a significant reduction in the extent of brain injury. The primary objective of this study was to evaluate the safety of DCLHb in patients with acute ischemic stroke. METHODS: DCLHb or saline was administered to 85 patients with acute ischemic stroke in the anterior circulation, within 18 hours of onset of symptoms, in a multicenter, randomized, single-blind, dose-finding, controlled safety trial, consisting of 3 parts: 12 doses of 25, 50, and 100 mg/kg DCLHb over 72 hours. RESULTS: DCLHb caused a rapid rise in mean arterial blood pressure. The pressor effect was not accompanied by complications or excessive need for antihypertensive treatment. Two patients in the 100 mg/kg group had adverse events that were possibly drug related: one suffered fatal brain and pulmonary edema, the other transient renal and pancreatic insufficiency. Multivariate logistic regression analysis showed that a severe stroke at baseline and treatment with DCLHb (OR, 4.0; CI, 1.4 to 12.0) were independent predictors of a worse outcome (Rankin Scale score of 3 to 6) at 3 months. CONCLUSIONS: Outcome scale scores were worse in the DCLHb group, and more serious adverse events and deaths occurred in DCLHb-treated patients than in control patients. We recommend that additional safety studies be performed, preferably with a second generation, genetically engineered hemoglobin.

Reinforcing and subjective effects of caffeine in normal human volunteers.

The reinforcing and subjective effects of caffeine (100 and 300 mg, PO) were determined in a group of 18 normal, healthy adults. Subjects (eight females, ten males) were light to moderate users of caffeine, and had no history of drug abuse. A discrete-trial choice procedure was used in which subjects were allowed to choose between the self-administration of color-coded capsules containing either placebo or caffeine. The number of times caffeine was chosen over placebo was used as the primary index of reinforcing efficacy. Subjective effects were measured before and several times after capsule ingestion. The low dose of caffeine was chosen on 42.6% of occasions, not significantly different from chance (50%). The high dose of caffeine was chosen on 38.9% of occasions, significantly less than expected by chance, indicating that this dose served as a punisher. Both doses of caffeine produced stimulant-like subjective effects, with aversive effects such as increased anxiety predominating after the high dose. When subjects were divided into groups of caffeine-sensitive choosers and nonchoosers, a consistent relationship emerged between caffeine choice and subjective effects; nonchoosers reported primarily aversive effects after caffeine (increased anxiety and dysphoria), whereas choosers reported stimulant and "positive" mood effects. When compared with previous findings, these results demonstrate that caffeine is less reinforcing than amphetamine and related psychomotor stimulants.

Reinforcing and subjective effects of oral tripelennamine in normal human volunteers.

Tripelennamine is a prescription antihistamine with a history of abuse when combined parenterally with opioids. The present study examined the reinforcing and subjective effects of oral tripelennamine in a group of 18 normal, healthy adults. Self-administration behavior was measured with a discrete-trial choice procedure. Subjects first sampled color-coded capsules containing either placebo or tripelennamine (25 or 50mg). On three subsequent occasions, subjects were allowed to choose which color-coded capsule to self-administer. The number of times subjects chose tripelennamine over placebo was used as the primary index of reinforcing efficacy. Subjective effects questionnaires were used to measure mood before and several times after capsule ingestion. The low dose of tripelennamine produced no significant mood changes relative to placebo, and was chosen on 39% of occasions, not significantly different from chance. The high dose produced mild sedative-like effects, and was chosen on 33% of occasions, significantly less than expected by chance, indicating that this dose was aversive. The results demonstrate that oral therapeutic doses of tripelennamine are not reinforcing and do not produce positive mood changes in subjects without a history of drug abuse.