Pharmacokinetics and pharmacodynamics comparison between subcutaneous and intravenous butorphanol administration in horses.

The study objective was to compare butorphanol pharmacokinetics and physiologic effects following intravenous and subcutaneous administration in horses. Ten adult horses received 0.1 mg/kg butorphanol by either intravenous or subcutaneous injections, in a randomized crossover design. Plasma concentrations of butorphanol were measured at predetermined time points using highly sensitive liquid chromatography-tandem mass spectrometry assay (LC-MS/MS). Demeanor and physiologic variables were recorded. Data were analyzed with multivariate mixed-effect model on ranks (P ≤ 0.05). For subcutaneous injection, absorption half-life and peak plasma concentration of butorphanol were 0.10 ± 0.07 h and 88 ± 37.4 ng/mL (mean ± SD), respectively. Bioavailability was 87%. After intravenous injection, mean ± SD butorphanol steady-state volume of distribution and clearance was 1.2 ± 0.96 L/kg and 0.65 ± 0.20 L/kg/h, respectively. Terminal half-lives for butorphanol were 2.31 ± 1.74 h and 5.29 ± 1.72 h after intravenous and subcutaneous administrations. Subcutaneous butorphanol reached and maintained target plasma concentrations >10 ng/mL for 2 ± 0.87 h (Mean ± SD), with less marked physiologic and behavioral effects compared to intravenous injection. Subcutaneous butorphanol administration is an acceptable alternative to the intravenous route in adult horses.

Fast neutron activation of ubiquitous materials.

Nuclear explosions expose ubiquitous materials to large numbers of neutrons, producing a variety of radioactive isotopes. To simulate such phenomena from both fission and thermonuclear explosions, we irradiated 29 different targets with approximately 3 and 14 MeV neutrons and measured the beta-delayed gamma rays using germanium detectors. For each neutron energy, the expected radioisotopes, half-lives, and gamma ray energies were deduced. From measurements of the ratios of activities of the radionuclides produced by neutron irradiations, we were able to identify several materials that are particularly sensitive to the neutron energy spectra.

[Do behavioural problems existing at referral become worse in subsequent years? A study of young persons referred to the outpatient unit of the mental health service]. / Wordt het probleemgedrag bij aanmelding in de loop der jaren erger? Een onderzoek bij jeugdigen verwezen naar de ambulante ggz.

BACKGROUND: Although young persons with severe and complex emotional and behavioural problems are often referred to the outpatient unit of the mental health service, little information is available about whether these problems increase over the years. This information is urgently needed in order to ensure that the mental health service provides adequate care. AIM: To obtain more insight into any increase in young persons' emotional and behavioural problems that may occur over a period of six years following referral to an outpatient unit of the mental health service. METHOD: The nature, severity and complexity of the emotional and behavioural problems of 123 young persons (1999) and of 149 young persons (2005) at the time of the referral - as rated by their parents on the basis of the Child Behavior Checklist (CBCL) - were assessed; the young persons' records were also checked for background characteristics. RESULTS: Compared to 1999, the year 2005 saw a slight decrease in the severity of the problems existing at referral; social problems also declined significantly compared to 1999. Problems identified in the 2005 group often seemed less complex than in 1999. The severity of delinquent behaviour as measured on the Delinquent Behaviour Scale seems to have risen in the 12 to 18 age group in 2005, whereas the severity declined in the 4 to 11-year olds. CONCLUSION: Emotional and behavioural problems as reported by the parents at the time their children were referred to the mental health service do not increase.

Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice.

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABAA receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride can block the formation of ALLO and other GABAergic neurosteroids and also reduce certain effects of EtOH. Treatment with finasteride during chronic EtOH exposure decreased EtOH withdrawal severity and blood EtOH concentrations (BECs), suggesting an additional effect of finasteride on EtOH pharmacokinetics. Thus, the purpose of the present study was to determine the effect of finasteride on acute EtOH withdrawal severity, to minimize the effect of finasteride on EtOH metabolism. Male and female C57BL/6J and DBA/2J mice received a pretreatment of finasteride (50 mg/kg i.p.) or vehicle 24 h prior to an injection of EtOH (4 g/kg i.p.) or saline. Handling-induced convulsions (HICs) were scored at baseline, and then over a 24 h period after EtOH or saline injection. In another experiment, plasma estradiol and corticosterone levels were assessed at selected time points (0, 2, 8, and 24 h). In a final study, retro-orbital blood samples were collected at 30, 60, 120, and 240 min post-EtOH administration to access finasteride's effects on EtOH clearance parameters. Pretreatment with finasteride increased acute EtOH withdrawal severity in female C57BL/6J and DBA/2J mice but decreased withdrawal severity in male mice of both strains. Finasteride did not alter BECs, EtOH clearance, estradiol, or corticosterone concentrations in a manner that appeared to contribute to the sex difference in finasteride's effect on acute EtOH withdrawal severity. These findings suggest that male and female C57BL/6J and DBA/2J mice differ in their sensitivity to changes in ALLO or other GABAergic neurosteroid levels during acute EtOH withdrawal. Sex differences in the modulation of GABAergic 5alpha-reduced steroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.

Determination of continuous atracurium infusion rate in dogs undergoing whole-body hyperthermia.

Infusion rates for atracurium were calculated from multiple bolus injection data for normothermic (38 degrees C; n = 4) and hyperthermic (42 degrees C; n = 14) dogs anesthetized with thiopental and oxymorphone while undergoing whole-body hyperthermia treatment. The calculated infusion rate for atracurium at 38 degrees C was 6.2 +/- 0.3 micrograms/kg/min and the calculated infusion rate at 42 degrees C was 8.5 +/- 0.4 micrograms/kg/min. Infusion of atracurium at the calculated infusion rate of 8.5 micrograms/kg/min produced an estimated 90-100% neuromuscular blockade during heating from 38-42 degrees C and at 42 degrees C. Following discontinuation of the infusion and cooling to 38 degrees C, neuromuscular function returned to normal within 20 min with no evidence of recurarization. Atracurium infusion rates appear to be linear and related to body temperature from 26-42 degrees C. Clinically useful neuromuscular blockade in dogs may be obtained during whole-body hyperthermia by utilizing the 42 degrees C atracurium infusion rate throughout the 38-42 degrees C heating phase.

Temperature measurements in normal and tumor tissue of dogs undergoing whole body hyperthermia.

Temperature was measured in the left ventricle, aorta, liver, brain, lung, bone marrow, kidney, and spontaneous solid tumors in dogs undergoing whole body hyperthermia in a radiant heat device. Rectal temperature was found to be a satisfactory indicator of systemic arterial temperature during plateau temperature conditions but rectal temperature underestimated arterial temperature during heating and overestimated it during cooling. Lung temperature, based on small airway temperature, was the same as rectal temperature during plateau temperature conditions. Liver and brain temperatures were slightly higher (0.1-0.2 degree C) than rectal temperature during the plateau phase. During plateau temperature conditions, kidney temperature measurements were higher than rectal temperature when one site/kidney was measured but were lower than rectal temperature when two sites/kidney were measured suggesting invasive thermometry may have affected measured temperature values. Tibial marrow temperature was greater than rectal temperature during heating but fell below rectal temperature during plateau temperature conditions by as much as 1.3 degree C. Femoral marrow temperature was below rectal during heating but gradually exceeded it during steady state conditions, by 0.1-0.4 degree C. Temperature in solid tumors was variable, sometimes exceeding (0.6 degree C) and sometimes being less (1.8 degree C) than rectal temperature.

Evidence of anhedonia and differential reward processing in prefrontal cortex among post-withdrawal patients with prescription opiate dependence.

Anhedonia is an important but understudied element of a neuroadaptive model underlying vulnerability to relapse in opioid dependence. Previous research using fMRI has shown reduced activation to pleasant stimuli in rostral prefrontal cortex among heroin-dependent patients in early recovery. This study evaluated the presence of anhedonia among recently withdrawn prescription opiate dependent patients (PODP) in residential treatment compared to control subjects. Anhedonia was assessed using self-report, affect-modulated startle response (AMSR), and a cue reactivity task during which participant's rostral prefrontal cortex (RPFC) and ventrolateral prefrontal cortex (VLPFC) was monitored with functional near infrared spectroscopy (fNIRS). The cue reactivity task included three distinct categories of natural reward stimuli: highly palatable food, positive social situations, and intimate (non-erotic) interactions. PODP reported greater anhedonia on self-report (Snaith-Hamilton Pleasure Scale), and showed reduced hedonic response to positive stimuli in the AMSR task relative to controls. PODP also exhibited reduced neural activation in bilateral RPFC and left VLPFC in response to food images and reduced left VLPFC in response to images depicting positive social situations relative to controls. No differences were found for emotionally intimate stimuli. When patients were divided into groups based on the Snaith-Hamilton criteria for the presence or absence of anhedonia, patients endorsing anhedonia showed reduced neural responses to images depicting positive social stimuli and food relative to patients who did not endorse anhedonia. Activations were in areas of RPFC that support the retrieval of episodic memories. The results suggest the presence of anhedonia in a subsample of PODP.

Immunohistochemical assays in prostatic biopsies processed in Bouin's fixative.

AIMS: To investigate the problems involved in undertaking immunohistochemistry (IHC) and nuclear morphometry using Bouin's fixed prostate biopsies. METHODS: Archival Bouin's fixed and formalin fixed, paraffin wax embedded prostatic biopsies were immunostained for three nuclear biomarkers (minichromosome maintenance protein 2 (MCM-2), p27, and Ki-67), one membrane localised biomarker (C-erb-B2), CD34, and alpha methylacyl-CoA racemase (AMACR). The quality of IHC staining was compared between tissues prepared separately in both fixatives. Feulgen staining was also performed on Bouin's fixed tissues to check its suitability for nuclear morphometry. RESULTS: MCM-2 staining was completely negative in Bouin's fixed tissues, whereas p27 showed more background and excess cytoplasmic staining in Bouin's fixed versus formalin fixed tissues. C-erb-B2 showed non-specific, strong luminal cell staining in the Bouin's fixed tissue. Feulgen staining was also very weak in Bouin's fixed tissue. However, Ki-67, AMACR, and CD34 worked equally well in Bouin's and formalin fixed tissues. CONCLUSIONS: Bouin's fixed tissues may be unsuitable when subsequent IHC and morphometry are contemplated. An awareness of which antibodies are suitable for use in Bouin's fixed biopsies is essential.

Psychopathology in hospitalized alcoholics.

This study utilized the DSM-III criteria and the National Institute of Mental Health Diagnostic Interview Schedule to assess the prevalence of lifetime psychopathology among hospitalized alcoholics. Antisocial personality (ASP) and substance-use disorder were common psychopathologies among male alcoholics and major depression and phobia were common among female alcoholics. The onset of most psychopathologies preceded the abuse of alcohol among women. In men, however, with the exception of ASP and panic disorder, the onset of psychopathology was subsequent to that of alcohol abuse and/or dependence. Diagnoses of ASP and substance abuse were characterized by early onset of regular intoxication and alcohol abuse. Gender and the presence of specific psychopathology appeared to modify the course and symptom picture of alcoholism. In general, alcoholic women showed a later onset of regular intoxication and a more rapid progression to alcohol abuse and dependence than alcoholic men.

Psychopathology and mood during heroin use: acute vs chronic effects.

In the context of evaluating the effects of a narcotic antagonist on opiate acquisition, 14 detoxified addicts self-administered increasing doses of unblocked heroin intravenously over a ten-day period. Early in the addiction cycle, subjects experienced tension relief and euphoria but this was followed shortly by a shift in the direction of increasing dysphoria and psychopathology. Nonetheless, individual injections of the drug continued to induce brief episodes of positive mood, an effect enhanced by frequent injection. Heroin self-administration was sharply reduced when subjects were blocked with naltrexone, a narcotic antagonist, and the negative effects observed during unblocked drug use were not observed.

Naltrexone and coping skills therapy for alcohol dependence. A controlled study.

Ninety-seven alcohol-dependent patients were treated for 12 weeks in a double-blind, placebo-controlled study evaluating naltrexone and two manual guided psychotherapies in the treatment of alcohol dependence. Patients were randomized to receive either naltrexone or placebo and either coping skills/relapse prevention therapy or a supportive therapy designed to support the patient's own efforts at abstinence without teaching specific coping skills. Naltrexone proved superior to placebo in measures of drinking and alcohol-related problems, including abstention rates, number of drinking days, relapse, and severity of alcohol-related problems. Medication interacted with the type of psychotherapy received. The cumulative rate of abstinence was highest for patients treated with naltrexone and supportive therapy. For those patients who initiated drinking, however, patients who received naltrexone and coping skills therapy were the least likely to relapse.

Psychopathology as a predictor of treatment outcome in alcoholics.

We performed a one-year follow-up study of 266 alcoholics who had received extensive psychiatric assessment, including diagnosis with the National Institute of Mental Health Diagnostic Interview Schedule and DSM-III criteria, during their index treatment episode. The aims were to evaluate the relationship between additional DSM-III diagnoses in alcoholics and outcome at follow-up, assess the relative prognostic power of different ways of measuring psychopathology by comparing categorical DSM-III diagnoses and a global symptom severity measure, and assess whether ratings of psychopathology add to the prognostic power of an alcohol-dependence measure. While coexistent psychiatric diagnoses generally predicted poorer treatment outcome, there were significant interactions in the relationship between diagnoses and treatment outcome for men and women. For men, having an additional diagnosis of major depression, antisocial personality, or drug abuse was associated with poorer outcome. For women, having major depression was associated with a better outcome in drinking-related measures, while antisocial personality and drug abuse were associated with poorer prognosis. The value of determining psychiatric diagnosis was supported by covariance analyses that suggested that prognostic significance of specific disorders was not accounted for by general psychopathology or general dependence dimensions.

Behavioral and social effects of heroin self-administration and withdrawal.

Behavioral and social reactions to intravenously administered heroin were studied during a 33-day experimental addiction cycle. Three groups of four subject volunteers were allowed to self-administer heroin for a ten-day period as part of a longer study of oplate antagonists. Data relevant to sleep patterns, energy expenditure, social interaction, and other observable behaviors were collected during hourly observations. Comparison of behavioral differences before and after drug administration indicated few significant acute reactions. Reactions to long-term heroin self-administration were most pronounced in the areas of sleep behavior and social interaction. Subjects tended to sleep less, especially during the initial period of acquisition, and to withdraw more from social contact. No changes were noted in energy expenditure during waking hours. The results were interpreted in terms of physiological tolerance, central nervous system arousal, and sleep deprivation.

A behavioral paradigm for the evaluation of narcotic antagonists.

We have developed an experimental paradigm for the behavioral evaluation of narcotic antagonists. The study specifically examined the heroin-seeking behavior of hard-core narcotic addicts on a research ward under blocked and unblocked conditions. Each patient served as his own control. A long-term follow-up program in the community, with aftercare services, was utilized to determine the relationship between behavior observed on the research ward and behavior that occurred in the community. While preliminary one-month follow-up data offered some cause for an optimistic view of narcotic antagonist treatment, behavioral data observed on the research ward raised serious doubts about the possibility of extinguishing heroin self-administration with antagonists. The behavioral data were not consistent with laboratory descriptions of extinction. Rather, the data suggested that narcotic antagonist programs should emphasize the development of contingencies for the reinforcement of narcotic antagonist self-administration to ensure an opiate-free state, instead of focusing on an extinction approach.

Six-month follow-up of naltrexone and psychotherapy for alcohol dependence.

BACKGROUND: The goal of this study was to examine the persistence of naltrexone's effects on drinking outcomes among alcoholics following discontinuation of treatment and to determine whether coping skills therapy improves long-term outcomes compared with supportive therapy. METHODS: Eighty of 97 alcohol-dependent subjects randomized to receive naltrexone or placebo and either coping skills therapy or supportive therapy for 12 weeks were assessed at a 6-month off-treatment follow-up. RESULTS: Subjects who received naltrexone were less likely to drink heavily or to meet criteria for alcohol abuse or dependence than subjects who received placebo. The effect of naltrexone therapy on abstinence rates persisted only through the first month of follow-up. Coping skills therapy was associated with decreased levels of drinking among subjects who received placebo. Psychotherapy condition, however, did not predict alcohol diagnosis at follow-up. CONCLUSIONS: Some but not all of the benefits resulting from short-term naltrexone treatment persist after discontinuation of treatment. The findings suggest that continued treatment with naltrexone may be beneficial for some patients.

Types of alcoholics, I. Evidence for an empirically derived typology based on indicators of vulnerability and severity.

An empirical clustering technique was applied to data obtained from 321 male and female alcoholics to identify homogeneous subtypes having discriminative and predictive validity. The clustering solution identified two "types" of alcoholics who differed consistently across 17 defining characteristics in the male and female samples. One group, designated type A alcoholics, is characterized by later onset, fewer childhood risk factors, less severe dependence, fewer alcohol-related problems, and less psychopathological dysfunction. The other group, termed type B alcoholics, is characterized by childhood risk factors, familial alcoholism, early onset of alcohol-related problems, greater severity of dependence, polydrug use, a more chronic treatment history (despite their younger age), greater psychopathological dysfunction, and more life stress. The two types also differed with respect to treatment outcome assessed prospectively at 12 and 36 months. The results are consistent with historical and contemporary typological theories that have postulated similar subgroups of alcoholics. The findings suggest that an empirically derived, multivariate typology of alcoholism has theoretical implications for explaining the heterogeneity among alcoholics and may provide a useful basis for predicting course and estimating treatment response.

Subjects' rights, freedom of inquiry, and the future of research in the addictions.

Since the recent passage of regulations concerning subjects' rights and freedom on inquiry, opposition by the public and others to some areas of research in the addictions has prevented its implementation or continuation. Research investigators in the biomedical and behavioral sciences have been placed in the position of defending their work in an adversary climate. The author points out the importance of transmitting to the public, the scientific community, and legislators the investigators' concern that "subjects' rights" not be viewed only in a legalistic context, but also in the context of not harming the patient.

Opiate use and sexual function.

Although opiate addicts often equate the drug experience with sexual orgasm, diminished libido and impaired sexual performance are common sequelae of chronic use. Early clinical studies suggested that opiates may interfere with sex hormone secretion. The authors carried out three sequential studies which demonstrated that heroin use in man results in acute suppression of luteinizing hormone (LH) release from the pituitary followed by a secondary drop in plasma testosterone levels. The time course of these neuroendocrine events correlates well with the tension-reducing effects of heroin and suggests that drive reduction is an important component of opiate reinforcement.

The current status of psychiatric education in alcoholism and drug abuse.

The authors conducted a survey of psychiatric education in alcoholism and drug abuse in the United States. Ninety-seven percent of 106 undergraduate training programs and 91% of 169 residency programs offered curriculum units in this field. Most of these programs also provided supervised clinical care. Areas of reported faculty dissatisfaction included problems with attitude and interest of psychiatric faculty and with the amount of curriculum time allotted. The authors conclude that although the amount of curriculum time devoted to training in alcoholism and drug abuse is growing, further investment in developing faculty and fellowships is warranted to increase the quality of teaching commitment.