Effects of cocaine on luteinizing hormone in women during the follicular and luteal phases of the menstrual cycle and in men.

Cocaine stimulates luteinizing hormone (LH) release in rhesus monkeys and in men, but its effects on LH in women are unknown. Cocaine (0.2 and 0.4 mg/kg i.v.) was administered to groups of follicular and luteal phase women (N = 22) and to men (N = 12) to examine the influence of gender and menstrual cycle phase on cocaine and LH interactions. All subjects met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for cocaine abuse, and menstrual cycle phase was verified by estradiol and progesterone measures. Baseline LH levels were equivalent between groups. Peak cocaine levels did not differ significantly between men and women and averaged between 87 +/- 21 and 124 +/- 18 ng/ml after 0.2 mg/kg cocaine and between 227 +/- 22 and 287 +/- 21 ng/ml after 0.4 mg/kg cocaine. The lower dose of cocaine (0.2 mg/kg) significantly increased LH levels in men (P < 0.001) but not in women at either phase of the menstrual cycle. The higher dose of cocaine (0.4 mg/kg) stimulated significant increases in LH in men (P < 0.001) and in women at both phases of the menstrual cycle (P < 0.004-0.001). Although cocaine's effects on LH in women were dose-dependent, there were no significant differences as a function of menstrual cycle phase. LH remained significantly elevated longer in men (32 min) than in women (8 and 12 min). This gender difference in cocaine's potency in stimulating LH was unexpected.

Cocaine-induced erythrocytosis and increase in von Willebrand factor: evidence for drug-related blood doping and prothrombotic effects.

BACKGROUND: Mechanisms that mediate cocaine-induced cardiovascular events following vasoconstriction are incompletely understood. OBJECTIVE: To examine the effects of cocaine in moderate doses on hematologic and hemostatic parameters that influence blood viscosity and thrombotic potential. METHODS: Changes in hemoglobin concentration, hematocrit, and red blood cell counts were measured in human subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for long-term cocaine abuse, before and sequentially after moderate intranasal and intravenous doses of cocaine. Hemostatic parameters, including von Willebrand factor, fibrinolytic activity, fibrinogen, plasminogen activator inhibitor antigen, and tissue-type plasminogen activator antigen, were sequentially measured after intravenous cocaine or saline placebo with cardiac troponin subunits T and I. RESULTS: Hemoglobin level (P= .002), hematocrit (P =.01), and red blood cell counts (P = .04) significantly increased from 4% to 6% over baseline from 10 to 30 minutes after intranasal (n = 14) and intravenous (n = 7) cocaine administration in doses of 0.9 mg/kg and 0.4 mg/kg, respectively, with no change in white blood cell or platelet counts. There was a significant increase (P =.03) in von Willebrand factor from 30 to 240 minutes, peaking at 40% over baseline following intravenous cocaine administration in a dose of 0.4 mg/kg (n = 12), with no change after 0.2 mg/kg (n = 3) or placebo (n = 6). Other hemostatic factors, creatinine, blood urea nitrogen, and cardiac troponin subunits T and I showed no changes. CONCLUSIONS: Cocaine induced a transient erythrocytosis that may increase blood viscosity while maintaining tissue oxygenation during vasoconstriction. An increase in von Willebrand factor without a compensatory change in endogenous fibrinolysis may trigger platelet adhesion, aggregation, and intravascular thrombosis.

Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle.

Preclinical and clinical studies suggest that females may be less vulnerable to cocaine's toxic effects than males. The pharmacokinetics of intravenous cocaine (0.2 and 0.4 mg/kg) were measured in 12 men and 22 women with a history of cocaine abuse, matched with respect to age and body mass index (BMI). Women were studied during the follicular and the luteal phases of the menstrual cycle. There were no differences between men and women in pharmacokinetic measures [peak plasma cocaine levels (Cmax), elimination half-life (T 1/2 min), area under the curve (AUC)] or cardiovascular or subjective effects "high" measures. Heart rate increases were cocaine dose-related (p < .01-.02) and also did not differ between men and women. Cocaine's pharmacokinetic and pharmacodynamic effects were similar in men and women, and in women during the follicular and mid-luteal phases of the menstrual cycle.

Cocaine administration induces human splenic constriction and altered hematologic parameters.

Cocaine is a potent vasoconstrictor that has been shown to alter hemoglobin, hematocrit, and red blood cell counts in both animals and humans. The present study evaluated whether cocaine administration induces splenic constriction in men and whether spleen-volume changes temporally correlate with altered hematologic parameters. Spleen volume was assessed at baseline and after cocaine administration (0.4 mg/kg) by using magnetic resonance imaging. A group of five healthy men, aged 31 +/- 2 (SE) yr and reporting occasional cocaine use (13 +/- 5 lifetime exposures), participated. Cocaine reduced spleen volume by 20 +/- 4% (P < 0.03) 10 min after drug administration. Spleen volume returned to normal (101 +/- 3% baseline) within 35 min after cocaine administration, indicating that the reduction is a transient phenomenon. In subjects administered cocaine from whom blood samples were obtained (n = 3), cocaine increased hemoglobin levels, hematocrit, and red blood cell count to 104.5 +/- 0.9, 105.6 +/- 1.2, and 106.5 +/- 1.0% of baseline levels, respectively (P < 0.03), but it did not alter white blood cell and platelet counts. Placebo administration (n = 5) did not alter hematologic parameters. These results suggest that cocaine induces splenic constriction in humans, and this may contribute to temporally concordant hematologic parameter changes. These events may help to preserve or increase tissue oxygenation in periods of high oxygen demand and/or increased vascular resistance.

Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men.

The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 +/- 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r2 = 0.44). Pharmacokinetic analysis showed that the t(max) (observed time to maximum concentration) values for cocaine (6.0 +/- 1.4 min) and ACTH (7.3 +/- 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 +/- 1070 ng/min x mL, and the area under the curve for ACTH was 1873 +/- 188 pmol/min x L. The mean half-life for plasma cocaine was 46.7 +/- 4.0 min, and that for ACTH was 35.8 +/- 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.

An electromyographic marker for neuroleptic-induced akathisia: preliminary measures of sensitivity and specificity.

Previous polysomnographic (PSG) investigations have reported a rhythmic electromyographic (EMG) pattern (0.5-3.0 cps) of leg movement activity in a subset of patients with neuroleptic-induced akathisia (NIA). It has been suggested that this EMG pattern may represent a pathophysiological correlate of NIA and thus have clinical utility as an objective marker for this condition. We present preliminary measures of sensitivity and specificity for this EMG pattern as a diagnostic marker for NIA for 26 neuroleptic-treated patients. The EMG marker yielded a diagnostic sensitivity of 68.9% and a specificity of 70.0%, falling just short of statistical significance (Fisher's exact test p = 0.06). Quantitative analysis of the EMG pattern revealed a significant positive correlation between the percentage of time the NIA marker occurred during wakefulness and corresponding chlorpromazine equivalent levels. Clinical demographic findings for true-positive, false-positive, true-negative, and false-negative groups are discussed. Overall findings suggest that this particular pattern of EMG marker activity observed in neuroleptic-treated patients during PSG and EMG studies is valuable in facilitating the diagnosis and monitoring treatment.