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Biomedical subjects

N K Mello

Publications and source records attributed to N K Mello.

At least 91 records · Page 5Linked to original sources
PubMed1993

Effects of intermittent buprenorphine administration on cocaine self-administration by rhesus monkeys.

In previous studies, daily buprenorphine administration significantly reduced cocaine self-administration by rhesus monkeys over 15 to 120 days (Mello et al., 1990, 1992). This report describes the effects of 60 days of intermittent buprenorphine (0.40 mg/kg) treatment once every 48 hr or 72 hr on cocaine and food self-administration by six rhesus monkeys. Cocaine (0.05 or 0.10 mg/kg/injection) and food (1-g banana pellet) self-administration were maintained on a fixed ratio 4, (variable ratio 16:S) reinforcement schedule. Intermittent buprenorphine treatment reduced cocaine self-administration significantly below saline treatment levels (P < .01). On the first day of buprenorphine treatment, cocaine self-administration averaged 53 and 60% below base line (P < .01-.0001). Cocaine self-administration remained significantly below base line on day 2 (P < .02-.0001) but usually returned to base-line levels by day 3. During buprenorphine treatment once every 48 hr, cocaine self-administration gradually increased over time in four monkeys (P < .001-.0005). These data suggest that intermittent buprenorphine treatment is less effective than daily buprenorphine treatment in reducing cocaine self-administration by rhesus monkeys. Food self-administration decreased by 23.6 and 12.7% from the saline base line during buprenorphine treatment every 48 and 72 hr, respectively. On the day of buprenorphine treatment, food self-administration was usually significantly lower than during the saline base line (P < .05-.0001), but usually returned to or exceeded base line levels by days 2 and 3. There were no significant changes in food self-administration over time with intermittent buprenorphine treatment every 48 hr.

Animals↗
PubMed1993

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 drug-free 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 drug-free 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.

Administration, Sublingual↗
PubMed1993

Regional cerebral blood flow improves with treatment in chronic cocaine polydrug users.

Brain perfusion is abnormal in chronic cocaine users. To determine whether these perfusion abnormalities are reversible following treatment, we studied 10 cocaine-dependent polydrug users with 99mTc-HMPAO SPECT 2 to 3 days after admission to an inpatient treatment facility and at 7 to 8 days and 17 to 29 days after abstinence from drugs. The patients also received buprenorphine, an opioid mixed agonist-antagonist, beginning 10 days after admission and continuing to the end of the study. Imaging began 10-15 min after injection of 99mTc-HMPAO (20 mCi) using an annular gamma camera system. MRI was performed during hospitalization using a 1.5 Tesla system. SPECT and MRI were merged and five axial SPECT slices centered at the level of the basal ganglia were selected for analysis. Activity ratios were derived for cortical regions relative to cerebellar activity and were corrected for linearity with respect to regional cerebral blood flow. The cortical regions were classified as abnormal (activity ratio < 0.6), borderline (0.6-0.72) and normal (> 0.72) based on the results of the first SPECT study. In abnormal zones, regional cerebral blood flow (rCBF) increased 11.0% +/- 9.0% at 7 to 8 days and 23.8% +/- 9.4% at 17 to 29 days after initiation of treatment. The increase in rCBF was 4.8% +/- 7.1% (7 to 8 days) and 11.1% +/- 8.0% (17 to 29 days) in borderline cortex and decreased 2.9% +/- 6.3% (7 to 8 days) and increased only 2.7% +/- 13.4% (17 to 29 days) in normal cortex. The increase in rCBF did not vary significantly by location. The perfusion defects observed in chronic cocaine polydrug users are partially reversible with short-term abstinence and buprenorphine treatment.

Adult↗
PubMed1992

Hyperprolactinemia and macrocytosis in women with alcohol and polysubstance dependence.

Chronic alcoholism and drug abuse are often associated in women with derangements of reproductive function such as amenorrhea, anovulation, luteal phase dysfunction and early menopause. Endocrine profiles were studied of the first 18 women (aged 17-58) admitted consecutively to a Massachusetts hospital for treatment of alcohol/polysubstance dependence under civil commitment. Twelve women were diagnosed as alcohol dependent according to criteria established in DSM-III-R. Their daily alcohol consumption ranged from 42-324 grams. Six women were diagnosed as polysubstance dependent. In addition to alcohol (84-831 g/day), cocaine was the most frequently abused drug followed by tranquilizers, marijuana and opiates. Over 60% of alcohol-dependent women of reproductive age had either hyperprolactinemia or macrocytosis (increased mean corpuscular volume, MCV), or both. Over 60% of the polysubstance-dependent women of reproductive age had either hyperprolactinemia or increased MCV. Over 80% of alcohol-dependent women of postmenopausal age had either hyperprolactinemia or increased MCV, or both. We conclude that evaluation of plasma prolactin levels and MCV may be useful as biological state markers for alcoholism and polysubstance abuse in women.

Adolescent↗
PubMed1992

Buprenorphine attenuates the effects of cocaine on adrenocorticotropin (ACTH) secretion and mood states in man.

Adrenocorticotropin (ACTH) levels in plasma increased rapidly to 105% above baseline within 5 minutes after intravenous injection of cocaine (30 mg) in cocaine-dependent men. The time course of ACTH stimulation paralleled increases in plasma cocaine levels and self-reports of salient drug effects on mood states and did not occur after placebo administration. An opioid mixed agonist-antagonist, buprenorphine (4 mg/day sublingually), suppressed the acute cocaine-induced stimulation of both ACTH and euphoria. Buprenorphine's suppression of postcocaine ACTH and euphoria were not related to differences in plasma cocaine levels or cocaine-induced alterations of cardiovascular function.

Adrenocorticotropic Hormone↗
PubMed1992

Acute effects of cocaine on plasma adrenocorticotropic hormone, luteinizing hormone and prolactin levels in cocaine-dependent men.

Acute cocaine administration alters secretion of anterior pituitary hormones in experimental animals, and cocaine abuse may compromise neuroendocrine function in humans. The goal of this study was to examine cocaine's acute effects on neuroendocrine hormones in cocaine-dependent men. Plasma adrenocorticotropic hormone (ACTH), luteinizing hormone and prolactin levels were measured in 18 men before and after i.v. administration of cocaine (30 mg) or placebo. Each subject served as his own control during the i.v. placebo and cocaine administration conditions. Plasma cocaine levels peaked at 260 ng/ml within 5 min after the i.v. injection. Plasma ACTH levels increased significantly above base-line levels at 5, 15, 30 (P < .01) and 45 min (P < .05) after i.v. cocaine. Plasma luteinizing hormone levels increased significantly above base-line levels at 5 (P < .05) and at 15 min (P < .01) after i.v. cocaine. No changes in plasma ACTH or luteinizing hormone levels were found after i.v. placebo injection. Plasma prolactin levels decreased significantly at 30, 45, 60, 90 and 120 min (P < .01) after both i.v. cocaine and placebo administration. Cocaine-induced increases in plasma ACTH levels may be due to its effects on dopaminergic systems which modulate corticotropin-releasing factor release in brain.

Adrenocorticotropic Hormone↗
PubMed1992

Effects of alcohol on E2 beta-stimulated luteinizing hormone in ovariectomized rhesus monkeys.

Anovulation is a frequent concomitant of alcohol abuse, but it has been difficult to assess the acute effects of alcohol on ovulation. Estradiol benzoate (E2 beta) can stimulate a luteinizing hormone (LH) surge in ovariectomized monkeys that appears to be associated with increased luteinizing hormone-releasing hormone (LHRH) pulse frequency and amplitude. The acute effects of alcohol (2.5 and 3.5 g/kg) and an isocaloric sucrose control solution on LH and follicle-stimulating hormone (FSH) secretory activity were studied in five ovariectomized monkeys 41 to 51 hours after administration of E2 beta (42 micrograms/kg, IM). Integrated plasma samples were collected at 20-minute intervals over 10 hours. Under sucrose control conditions, LH increased to 445 and 584 ng/ml within 46 to 49.3 hours after E2 beta administration in two monkeys and high-amplitude LH pulses were evident in three monkeys. Alcohol (2.5 and 3.5 g/kg) significantly decreased the number of LH peaks and valleys (p < 0.01). Peak blood alcohol levels averaged 195 and 291 mg/dl. After 2.5 g/kg alcohol, there was no LH surge or LH pulses in four of five monkeys. A delayed LH surge occurred in one monkey 48 to 50.6 hours after E2 beta when blood alcohol levels decreased to 62 mg/dl. After 3.5 g/kg alcohol, no monkey had an LH surge and pulsatile LH release was significantly reduced in comparison to control conditions (p < 0.01). FSH levels remained stable across alcohol and control conditions. These data suggest that alcohol attenuates pituitary release of LH in response to E2 beta stimulation. These findings are consistent with menstrual cycle disruptions observed in alcohol-dependent women, social drinkers, and in a primate model of alcoholism.

Animals↗
PubMed1992

The effects of chronic buprenorphine treatment on cocaine and food self-administration by rhesus monkeys.

The goal of this study was to determine if buprenorphine continues to reduce cocaine self-administration over long periods of treatment, or if tolerance develops to this effect. The effects of 30 to 120 days of buprenorphine treatment (0.32 mg/kg/day) on cocaine and food self-administration were examined in six rhesus monkeys. Saline control treatment was studied for 15 days before and after buprenorphine treatment. Intravenous cocaine (0.05 or 0.10 mg/kg) and food (1 g banana pellet) self-administration were maintained on a FR 4 (VR 16:S) schedule of reinforcement. Cocaine self-administration decreased significantly (P less than .0001) and remained 60 to 97% below saline treatment baseline levels (52 +/- 2 injections/day) throughout 120 days of buprenorphine treatment (P less than .01). After substitution of saline for buprenorphine, cocaine self-administration resumed and averaged between 21 (+/- 3.6) and 56 (+/- 6.5) injections per day over 20 days. Buprenorphine plasma levels averaged 18 (+/- 2.84) ng/ml (range 10.9-30 ng/ml) during buprenorphine treatment. Buprenorphine plasma levels usually decreased by 50% or more within 27 hr after the last buprenorphine dose. Low levels of buprenorphine (0.10-0.19 ng/ml) were measured for 30 to 74 days after abrupt termination of daily buprenorphine treatment. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding developed over 30 to 70 days of treatment. Food self-administration returned to and significantly exceeded (P less than .05-.01) saline treatment base-line levels, whereas cocaine self-administration remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Alcohol use and premenstrual symptoms in social drinkers.

The relationship between premenstrual dysphoria and alcohol acquistion and use patterns was studied in 14 women over 35 days on a clinical research ward. A 7-day drug-free baseline was followed by 21 days of alcohol availability and a post-alcohol drug-free period of 7 days. Women could earn alcohol or 50 cents for 30 min of performance on a simple operant task. The Premenstrual Assessment Form (PAF) was administered during baseline and at the premenstruum. Menstrual cycle phase was associated with changes in alcohol use by 8 of the 14 women. Five women drank more during the premenstruum and scored higher on 12 of 18 PAF factors than women whose drinking remained the same (N = 6) or decreased (N = 3). Women who increased drinking had significantly higher PAF scores on impaired social functioning, hostility/anger and hysteroid features (P less than 0.05, 0.01). Women who drank less during the premenstruum reported more pain and physical discomfort, whereas women who drank about the same amount were relatively asymptomatic. PAF profiles reported at the premenstruum and baseline PAF profiles based on recall of the preceding three menstrual cycles were concordant in 13 of the 14 women (P less than 0.001-0.0001). These data suggest that women's perceptions of premenstrual symptomatology are stable through time.

Adult↗
PubMed1990

Desipramine effects on cocaine self-administration by rhesus monkeys.

The effects of desipramine treatment (0.56-10.0 mg/kg per day) on cocaine self-administration were compared to saline treatment in five rhesus monkeys. Cocaine (0.050 or 0.100 mg/kg per inj) and food (1 g banana pellets) self-administration were maintained on an FR 4 (VR 16:S) reinforcement schedule. Desipramine (or an equal volume saline control solution) was infused over 1 h each day through the second lumen of an intravenous catheter. After 5 days of baseline saline treatment, seven doses of desipramine each were administered for 5 days in an ascending order. Cocaine self-administration increased (P less than 0.01) or remained equivalent to base-line levels in 4 of 5 subjects during the first 15 days of desipramine treatment (0.56 to 1.78 mg/kg per day). Three monkeys continued to self-administer cocaine equivalent to or significantly above base-line levels (P less than 0.01) during days 16-30 of desipramine treatment (3.2-7.86 mg/kg per day). The highest desipramine dose (10 mg/kg per day) significantly suppressed cocaine self-administration in only one of these three monkeys (P less than 0.01). Desipramine treatment (3.2-10.0 mg/kg per day) suppressed cocaine self-administration (P less than 0.01) without a concomitant suppression of food-maintained responding in one of five subjects. A generalized suppression of both cocaine and food-maintained responding (P less than 0.01) during desipramine treatment occurred in one monkey that took the highest base-line levels of cocaine (6.3 +/- 1.03 mg/kg per day). Food-maintained responding remained equivalent to or significantly above (P less than 0.01) base-line levels in four of five monkeys during desipramine treatment. A transient decrease in food self-administration at desipramine doses of 1.78-5.62 mg/kg per day occurred in one monkey (P less than 0.01). Thirty days of desipramine treatment at the highest doses (5.62, 7.86 and 10.0 mg/kg per day for 10 days each) also did not suppress cocaine self-administration in a monkey that took an average of 4 mg/kg per day of cocaine during saline base-line treatment. These primate data are concordant with the extant clinical literature on the inconsistent effects of desipramine treatment; i.e., both stimulation of cocaine use and inconsistent or incomplete attenuation of cocaine abuse during desipramine maintenance have been reported.

Animals↗
PubMed1990

Characteristics of women receiving mandated treatment for alcohol or polysubstance dependence in Massachusetts.

Characteristics of the first 20 women consecutively admitted for treatment for alcohol or polysubstance dependence following civil commitment by Massachusetts courts were studied. Women were diagnosed as either alcohol dependent (n = 12) or polysubstance dependent (n = 8). Alcohol dependent women were older at initial alcohol use, onset of regular alcoholic use, first treatment admission, and at this admission. For the group as a whole 75% had completed high school; 50% were divorced and 35% were supported by public assistance. Seventy-five percent had a family history of alcoholism. This sample of women who received court-ordered alcohol and polysubstance dependence treatment had multiple social, psychological, legal and health problems.

Adolescent↗