Siew Koon Teoh

Neuroendocrine consequences of alcohol abuse in women.

Alcohol abuse and alcoholism are associated with a broad spectrum of reproductive system disorders. Amenorrhea, anovulation, luteal phase dysfunction, and ovarian pathology may occur in alcohol-dependent women and alcohol abusers. Luteal phase dysfunction, anovulation and persistent hyperprolactinemia have also been observed in social drinkers studied under clinical research ward conditions. The mechanisms underlying alcohol-related disruptions of the hypothalamic-pituitary-ovarian-adrenal axis are unknown. The reproductive consequences of alcohol abuse and alcoholism range from infertility and increased risk for spontaneous abortion to impaired fetal growth and development. Recent studies of alcohols effects on pituitary gonadotropins and on gonadal, steroid and adrenal hormones in women are reviewed. Research on the acute effects of alcohol on opioid antagonist and synthetic LHRH-stimulated pituitary gonadotropins is summarized. The implications of alcohols effects on reproductive hormones for impairment of fetal growth and development are discussed.

Buprenorphine Treatment of Opiate and Cocaine Abuse: Clinical and Preclinical Studies

&NA; Buprenorphine, an opioid mixed agonist‐antagonist, is a potent analgesic that appears to be effective for the treatment of opiate abuse. Recent preclinical studies have shown that buprenorphine also significantly reduces cocaine self‐administration by rhesus monkeys for periods up to 120 days. This unexpected finding has led to clinical trials to evaluate buprenorphines effectiveness for the treatment of dependence on both cocaine and opiates, as defined by DSM‐III‐R criteria. Buprenorphines safety in combination with cocaine and opiates and its effects on electroencephalographic sleep patterns and regional cerebral blood flow were evaluated during inpatient studies. Buprenorphine (4 or 8 mg/day given sublingually) did not accentuate the cardiovascular and respiratory changes induced by an acute challenge dose of cocaine (30 mg given intravenously) or morphine (10 mg given intravenously) alone. In an outpatient open trial, buprenorphine significantly reduced both opiate and cocaine abuse by patients who had abused these drugs for more than 10 years. Most of these patients had failed in other drug abuse treatment programs. Reports of needle sharing also decreased significantly, and no patient tested positive for human Immunodeficiency virus (HIV). The apparent safety and effectiveness of buprenorphine, combined with a high level of patient acceptance, led the Food and Drug Administration to grant a compassionate extension of the approved period for outpatient buprenorphine treatment from 26 to 52 weeks. Clinical trials of buprenorphine are ongoing. Possible mechanisms underlying buprenorphine‐cocaine interactions are now under investigation.

Buprenorphine Effects on Morphine- and Cocaine-Induced Subjective Responses by Drug-Dependent Men

The effects of daily buprenorphine treatment (4 or 8 mg/day, sublingual) on reports of subjective effects after single intravenous doses of morphine (10 mg), cocaine (30 mg), and saline placebo were studied on an inpatient clinical research ward in 26 men concurrently dependent on opioids and cocaine (DSM-III-R). Latency to detection and certainty of a drug effect, as well as drug quality (intensity, euphoria, and dysphoria), were studied before and after 10 to 12 days of buprenorphine maintenance. Saline was accurately identified by all 26 patients during the drugfree baseline and by 25 patients during buprenorphine maintenance conditions. All patients accurately identified morphine during the drugfree period before treatment with buprenorphine, but 18 (69%) of 26 patients were unable to detect morphine during buprenorphine maintenance and 2 misidentified morphine as cocaine. Six men (23%) accurately identified morphine and reported that the intensity and quality of morphines effects were equivalent to drugfree conditions. Cocaine levels in plasma 5 minutes after intravenous cocaine injection were equivalent before and during buprenorphine treatment and averaged 282.8 +/- 43.6 and 295.2 +/- 28.8 ng/ml during 4 and 8 mg/day of buprenorphine maintenance, respectively. All patients accurately identified cocaine before and during buprenorphine maintenance, and there were no significant changes in latency to detection and certainty of a drug effect or reports of cocaine-induced intensity or euphoria during buprenorphine treatment. The concordance between responses to morphine and cocaine during inpatient buprenorphine maintenance and drug use during the first 4 weeks of outpatient buprenorphine treatment was also examined in 16 men. The effects of buprenorphine on individual responses to an acute intravenous dose of morphine or cocaine during the inpatient study did not reliably predict the frequency of heroin or cocaine self-administration during the first 4 weeks of daily outpatient buprenorphine maintenance.

Prolactin and cortisol levels following acute alcohol challenges in women with and without a family history of alcoholism.

In a pilot study 5 matched pairs of female social drinkers received both 0.56 g/kg alcohol and placebo in a double-blind crossover design. Family history positive (FHP) women had biological fathers who met criteria for alcohol dependence, and FHN women had no relatives who met these criteria. FHP and FHN women had BALs about 70 mg/dl 60 min after alcohol. FHP subjects had significantly lower prolactin levels 40, 60 and 80 min following alcohol, but higher cortisol levels 130 and 150 min following alcohol. No significant differences in hormone levels occurred after placebo.

Divided attention task performance and subjective effects following alcohol and placebo: differences between women with and without a family history of alcoholism

Women with (FHP) and without (FHN) family histories of alcoholism received either 0.56 g/kg alcohol or an isocaloric placebo in a repeated measures group design. Subjects performed a divided attention task and gave subjective ratings of 12 alcohol effects over a 3-h interval. After comparable doses of alcohol, 7 FHP and 10 FHN women had comparable ascending (blood alcohol levels) BALs. BALs peaked earlier for FHP women and then steadily declined. FHP women had a concomitant increase in visual search response times 30 min after alcohol. In contrast, scores on a simultaneously presented compensatory tracking task were virtually identical for the 7 FHP and 10 FHN women after alcohol and for the 8 FHP and 10 FHN women after placebo. After alcohol the FHP and FHN women had 7 out of 12 significantly different subjective ratings of alcohol responses. FHP women had lower subjective responses to alcohol and lower BALs, but their subjective responses were more strongly correlated with BALs. Our findings for women studied in a group design confirm the lower magnitude of subjective responses reported for pair-matched FHP men following comparable doses of alcohol in within-subjects and between-subjects designs in other laboratories.

Acute interactions of buprenorphine with intravenous cocaine and morphine : an investigational new drug phase I safety evaluation

Recent preclinical and clinical studies suggest that buprenorphine, an opioid mixed agonist-antagonist, may be useful for the treatment of dual dependence on cocaine and opiates. This report describes an inpatient clinical evaluation of the safety of buprenorphine alone and in combination with single doses of cocaine and morphine. Twenty subjects with a DSM-III-R diagnosis of concurrent cocaine and opioid dependence were randomly assigned to maintenance treatment with single daily doses of 4 or 8 mg of sublingual buprenorphine for 21 days. Side effects and vital signs were evaluated every day once every 8 hours and for 2 hours after daily buprenorphine administration. The physiologic effects of a single-blind challenge dose of cocaine (30 mg intravenously), morphine (10 mg intravenously), and intravenous saline placebo were measured before and during buprenorphine maintenance. Before buprenorphine maintenance, subjects underwent methadone detoxification followed by a 9-day drugfree period. Three baseline single-blind challenge dose studies were conducted on study days 7, 8, and 9 during the drug-free period. Cardiovascular responses to cocaine and to morphine were equivalent under drugfree and buprenorphine maintenance conditions. Respiration and temperature changes in response to cocaine were also equivalent before and during buprenorphine maintenance. Respiratory rates were slightly lower after morphine administration during maintenance on 8 mg of buprenorphine, but this was not statistically significant. Mild opioid agonist-like side effects were reported during buprenorphine induction and maintenance. These included headache, sedation, nasal discharge, abdominal discomfort, and anxiety. Most opioid agonist side effects decreased within 12 to 14 days. An electrocardiogram and blood chemistry measures were normal before and during buprenorphine maintenance. These data suggest that daily maintenance on buprenorphine is not associated with adverse side effects or toxic interactions with a single acute dose of intravenous cocaine or morphine.

An inpatient study of the effects of buprenorphine on cigarette smoking in men concurrently dependent on cocaine and opioids

The effect of sublingual buprenorphine on cigarette smoking was examined in 23 adult men with DSM III-R diagnosis of concurrent opiate and cocaine dependence. After admission to a clinical research ward, subjects were detoxified with methadone (10-50 mg/day), then were drug-free for 6 days before random assignment to either 4 or 8 mg/day of buprenorphine. Gradually increasing daily sublingual doses of buprenorphine were administered for 5 days, then subjects were maintained on 4 or 8 mg/day of buprenorphine for 12 days. Each subjects preferred brand of cigarettes was available ad libitum throughout the study. Five responses (FR 5) on a key were required to earn each cigarette. The time and number of cigarettes were recorded by an automated cigarette dispenser. Subjects acquired significantly more cigarettes during the buprenorphine induction and maintenance phases (25.5+/-2.0) than during the drug-free phase (18.5+/-1.8; p<0.0002). During buprenorphine induction, the number of cigarettes acquired was positively correlated with increasing doses of buprenorphine (p<0.001) and the inter-cigarette interval was significantly shorter during buprenorphine maintenance than during drug-free conditions (p<0.001). These data showed that daily administration of the partial mu opioid agonist buprenorphine was associated with increased smoking in men concurrently dependent on opiates and cocaine. These findings are consistent with previous reports of opioid-cigarette interactions.

Quantitative magnetic resonance imaging in heroin- and cocaine-dependent men: A preliminary study

Quantitative magnetic resonance imaging (MRI) of the brain was performed in nine drug-dependent men with a primary diagnosis of opioid and/or cocaine dependence, and 10 age-matched, non-drug-dependent controls. Individuals were screened for the presence of gross cerebral abnormalities before T1 and T2 analyses. Regional T1 and T2 times were calculated on a single 5-mm thick axial slice positioned just below the caudal margin of the lateral ventricles, passing through the caudate and putamen. A voxel of interest (VOI) cursor was placed bilaterally within the putamen, caudate, frontal gray matter, frontal white matter, or posterior white matter. T1 and T2 values were determined for each VOI using an iterative chi 2 minimization program. T1 and T2 relaxation times did not differ significantly between the subject groups in any brain region studied. These results suggest that T1 and T2 relaxation times may not identify microstructural central nervous system changes resulting from chronic opiate and cocaine abuse.

In vivo proton magnetic resonance spectroscopy of alcohol in human brain

The covariance between blood and brain alcohol levels and subjective reports of mood were examined in 6 healthy adult men after consumption of 0.7 g/kg of beverage alcohol. There was significant (p less than 0.01) temporal concordance between ascending and peak blood alcohol levels and regional brain alcohol levels as measured by in vivo proton Magnetic Resonance Spectroscopy (MRS) when N-acetyl aspartate (N-AA) concentration was used as an internal standard. The frequency of reports of both euphoria and dysphoria also paralleled the ascending limb of the blood and brain alcohol curve. However, peak blood alcohol levels were higher (125.67 +/- 10.91 mg/dl) and earlier (35 min postdrinking) than peak brain alcohol levels (26.25 +/- 6.38 mg/dl) detected 50 min after alcohol intake. This difference in brain and blood alcohol levels appears to be associated with the echo time (TE) parameters of the MRS. A decrease in TE from 270 msec to 50 msec resulted in a marked increase in brain alcohol detectability. MRS measures will permit analysis of regional differences in brain alcohol concentrations and covariance with behavioral, neurophysiologic and neuroendocrine concomitants of acute alcohol intoxication in man.

Platelet Adenylate Cyclase and Monoamine Oxidase in Women with Alcoholism or a Family History of Alcoholism

&NA; Purpose. Characteristic changes of platelet membrane monoamine oxidase and adenylate cyclase activities have been described in men with alcoholism. We studied the occurrence of these changes in abstinent alcoholic women and in nonalcoholic female control subjects with and without family histories of alcoholism. Methods. Blood samples were collected from 23 female alcoholics and 39 nonalcoholic female social drinkers. Platelet membrane assays were performed for monoamine oxidase and adenylate cyclase activities. Results. Alcoholic women had lower basal adenylate cyclase (p < 0.01) and adenylate cyclase activities stimulated by cesium fluoride (p < 0.001), by the guanine nucleotide analog 5‐guanylylimidodiphosphate (p < 0.02), and by prostaglandin E1 (p < 0.01). Female control subjects with family histories of alcoholism also had lower basal adenylate cyclase (p < 0.01) and adenylate cyclase activities enhanced by incubation with cesium fluoride (p < 0.005) and 5′‐guanylylimidodiphosphate (p < 0.001). Monoamine oxidase activity levels measured with (p < 0.001) and without ethanol (p < 0.01) were higher for alcoholic women. No significant differences were found between female control subjects with and without family histories of alcoholism for monoamine oxidase in the absence or presence of ethanol. Discussion. In vitro platelet adenylate cyclase activity may facilitate a diagnosis of alcoholism in women and may be a biologic indicator of vulnerability in the offspring of alcoholics.