Correlation of haemoglobin-acrylamide adducts with airborne exposure: an occupational survey

This paper reports an occupational hygiene survey of exposure to acrylamide comparing acrylamide haemoglobin adduct measurements with personal air monitoring and glove liner analysis. The air monitoring data showed that exposure to acrylamide was well-controlled with all samples below the UK maximum exposure limit (MEL) of 300 microg/m(3) with mean exposure about one tenth of the MEL. Each worker provided two blood samples approximately 3 months apart. These samples were well correlated (r=0.61) with a slope of 0.74, indicating that exposure was reasonably constant. Mean personal airborne acrylamide levels and mean acrylamide haemoglobin adduct levels were well correlated (r=0.72, N=46) and using the calculated linear correlation, exposure at the MEL would be expected to give rise to a haemoglobin adduct level of 1,550 pmol/g globin. Smoking status did not affect the correlation. There was also a correlation between levels of acrylamide detected on gloves and haemoglobin adduct levels. A combined regression model between haemoglobin adducts, airborne acrylamide and acrylamide glove contamination was significant for both airborne acrylamide and gloves with a regression coefficient of 0.89. The study showed that haemoglobin adduct level was a good biomarker of acrylamide exposure which correlated to both inhaled and potentially skin absorbed acrylamide estimates. There was excellent discrimination between well-controlled occupational levels and environmental levels from diet and smoking, allowing haemoglobin adduct measurement to be used to determine even low level exposures. Due to the complexity of the current methodology, new techniques would be useful in making haemoglobin adducts more widely applicable.     

Monitoring multiwalled carbon nanotube exposure in carbon nanotube research facility

With the increased production and widespread use of multiwalled carbon nanotubes (MWCNTs), human and environmental exposure to MWCNTs is inevitably increasing. Therefore, this study monitored the possible exposure to MWCNT release in a carbon nanotube research laboratory. To estimate the potential exposure of researchers and evaluate the improvement of the workplace environment after the implementation of protective control measures, personal and area monitoring were conducted in an MWCNT research facility where the researchers handled unrefined materials. The number, composition, and aspect ratio of MWCNTs were measured using scanning transmission electron microscopy with an energy-dispersive x-ray analyzer. The gravimetric concentrations of total dust before any control measures ranged from 0.21 to 0.43 mg/m(3), then decreased to a nondetectable level after implementing the control measures. The number of MWCNTs in the samples obtained from the MWCNT blending laboratory ranged from 172.9 to 193.6 MWCNTs/cc before the control measures, and decreased to 0.018-0.05 MWCNTs/cc after the protective improvements. The real-time monitoring of aerosol particles provided a signature of the MWCNTs released from the blending equipment in laboratory C. In particular, the number size response of an aerodynamic particle sizer with a relatively high concentration in the range of 2 to 3 microm in aerodynamic diameter revealed the evidence of MWCNT exposure. The black carbon mass concentration also increased significantly during the MWCNT release process. Therefore, the present study suggests that the conventional industrial hygiene measures can significantly reduce exposure to airborne MWCNTs and other particulate materials in a nano research facility.     

Monitoring Multiwalled Carbon Nanotube Exposure in Carbon Nanotube Research Facility

With the increased production and widespread use of multiwalled carbon nanotubes (MWCNTs), human and environmental exposure to MWCNTs is inevitably increasing. Therefore, this study monitored the possible exposure to MWCNT release in a carbon nanotube research laboratory. To estimate the potential exposure of researchers and evaluate the improvement of the workplace environment after the implementation of protective control measures, personal and area monitoring were conducted in an MWCNT research facility where the researchers handled unrefined materials. The number, composition, and aspect ratio of MWCNTs were measured using scanning transmission electron microscopy with an energy-dispersive x-ray analyzer. The gravimetric concentrations of total dust before any control measures ranged from 0.21 to 0.43 mg/m³, then decreased to a nondetectable level after implementing the control measures. The number of MWCNTs in the samples obtained from the MWCNT blending laboratory ranged from 172.9 to 193.6 MWCNTs/cc before the control measures, and decreased to 0.018–0.05 MWCNTs/cc after the protective improvements. The real-time monitoring of aerosol particles provided a signature of the MWCNTs released from the blending equipment in laboratory C. In particular, the number size response of an aerodynamic particle sizer with a relatively high concentration in the range of 2 to 3 μ m in aerodynamic diameter revealed the evidence of MWCNT exposure. The black carbon mass concentration also increased significantly during the MWCNT release process. Therefore, the present study suggests that the conventional industrial hygiene measures can significantly reduce exposure to airborne MWCNTs and other particulate materials in a nano research facility.     

Dissociation between subjective and behavioral responses after cocaine stimuli presentations

This study was designed to explore the relationship between craving and cocaine-seeking behavior with the use of both subjective and behavioral measures. Five males and five females who have used crack at least two times a week for 6 months, and who reported using 0.5 g of crack within 24 h on at least one occasion, participated in an inpatient study. Subjects underwent a total of four experimental sessions, during which they were exposed to either neutral (Neutral Stimuli Condition) or cocaine-related (Cocaine Stimuli Condition) external and internal stimuli. Subjects were exposed to each stimuli condition twice, on separate days, in randomized order. External stimuli comprised neutral or cocaine-related videotapes and paraphernalia, and the internal stimulus was either a 5-mg (`placebo') or 0.4 mg/kg delivery of cocaine. At baseline and after each stimulus exposure, subjects completed a composite cocaine craving questionnaire. Subjects next worked on concurrently-available fixed-ratio tasks either for tokens that could be exchanged for money ($2) or for tokens that were exchangeable for deliveries of cocaine (0.4 mg/kg). The results show that subjects reported significantly greater cocaine craving after exposure to cocaine-related vs. neutral stimuli, indicating that craving for cocaine can be successfully modeled in a laboratory setting. However, this change in subjective response did not predict drug-seeking behavior. The number of cocaine tokens earned following exposure to the cocaine-related vs neutral stimuli was similar. These results suggest that in a laboratory setting, craving may be unrelated to cocaine-seeking behavior in non-treatment-seeking cocaine users.     

Illicit cocaine use patterns in intravenous-naive cocaine users following investigational intravenous cocaine administration

This study evaluated whether cocaine use patterns changed following investigational intravenous cocaine administration to intravenous-naive cocaine users. Subjects were respondents to a follow-up survey who had participated in one to three intravenous double-blind cocaine (0.2 or 0.4 mg/kg) administration studies. The group included healthy men (n = 17) and women (n = 8) with histories of occasional cocaine use (lifetime self-reported use of 12+/-12 (mean +/- S.D.) exposures, primarily via nasal insufflation) who were recontacted an average of 39 weeks (range 7-107 weeks) after study participation. The recontacted group constituted 45% of the total eligible sample of 55 subjects. Baseline demographics for the recontacted and non-recontacted (n = 30) samples were similar, suggesting that the recontacted sample was representative of the group as a whole. Investigational cocaine exposure did not induce adverse health events in any subject. Self-reported cocaine use estimates obtained at follow-up were compared to baseline estimates obtained with identical questionnaires and were highly concordant (Spearman rank correlation p = 0.52 and 0.78, respectively; P < 0.02 and < 0.0002, respectively). This suggests that participants provided stable and reliable reports of cocaine use. No subject reported either illicit intravenous cocaine use or altered frequency of illicit cocaine use by the customary route after investigational intravenous cocaine exposure. These data suggest that illicit cocaine use frequencies and routes of administration are not altered following investigational intravenous cocaine administration to healthy, occasional cocaine users.     

Associations between ambient PM2.5 concentrations and respiratory symptoms in Melbourne, 1998-2005

Particulate matter (PM) has been widely associated with adverse effects on respiratory health, both overseas and in Australia. This study aimed to investigate the impacts of ambient particles of <2.5 microm diameter (PM2.5) in Melbourne on adverse respiratory symptoms. Two cohorts of adults were recruited in 1992-1998, and completed detailed respiratory questionnaires in 1998-1999 and 2004-2005. The mean age at baseline was 37.2 years, 55% were female, and the mean time lapsed between the baseline and follow-up questionnaires was 5.2 years. PM2.5 exposure was assessed from gravimetric data and routine nephelometry at monitoring stations located centrally with respect to the residence of most participants. Daily exposures to PM2.5 were averaged over the previous 12 months and mean daily exposure was 6.8 microg/m3. Logistic regression models were used to examine associations between PM2.5 exposure and adverse respiratory symptoms. Adjustment was made for age, gender, current smoking status, and medication use, but further adjustment for atopy did not alter the results. There was insufficient variability in PM2.5 exposure among participants over the study period to provide convincing evidence for or against associations between PM2.5 and adverse respiratory symptoms.     

Amantadine: evaluation of reinforcing properties and effect on cocaine self-injection in baboons

The ability of amantadine to maintain self-injection behavior and to alter self-administration of cocaine was examined in baboons using a standard intravenous cocaine self-injection procedure. Responding was maintained under a FR 80- or 160-response schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections/day. Vehicle or amantadine doses were substituted for cocaine for a period of 15 or more days. Evaluation of a wide range of amantadine doses (0.32-32 mg/kg per injection) showed that this compound did not maintain self-administration behavior above vehicle control levels. In another experiment using the cocaine self-injection baseline, amantadine (10 or 32 mg/kg per day) was administered via a chronic intravenous infusion. Cocaine self-injection behavior was maintained and re-initiated during chronic amantadine exposure, suggesting that the reinforcing efficacy of cocaine was not modified by chronic amantadine administration.     

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

Background:

Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown.

Methods:

This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.

Results:

In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine.

Conclusions:

Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.     

Biological monitoring of low benzene exposure in Italian traffic policemen

A comparative evaluation of urinary biomarkers was carried out to characterize benzene exposure in a group of 100 traffic policemen of the city of Parma (Italy). All subjects were monitored once, in two consecutive days characterized by similar climatic conditions but preceded by two windy days. Benzene ambient concentration measured by municipal air monitoring stations was 1 microg/m(3) (Day 1) and 2 microg/m3 (Day 2). Personal exposure to ambient concentrations of benzene, toluene, ethylbenzene and xylene (BTEX) was assessed by using Radiello((R)) passive-diffusive samplers in a subgroup of 24 workers. Benzene metabolites, t,t-muconic acid (t,t-MA) and S-phenylmercapturic acid (S-PMA) were determined by isotopic dilution liquid chromatography-tandem mass spectrometry on spot urine samples collected at the end of the shift. Urinary benzene (U-B) was determined by solid-phase microextraction gas chromatography-mass spectrometry. Airborne benzene concentration expressed as median [and interquartile range] was 6.07 [0.28-9.53] microg/m(3), as assessed by personal sampling. Urinary concentrations of biomarkers in the whole group were 41.8 [34.1-89.8] microg/g creatinine for t,t-MA, 0.67 [0.23-1.32] microg/g creatinine for S-PMA, and 0.16 [0.13-0.26] microg/l for U-B. Smokers eliminated significantly higher concentrations of unchanged BTEX and benzene metabolites than non-smokers (p < 0.05). When traffic policemen were distinguished into indoor (n=31) and outdoor workers, no significant differences were observed for either airborne benzene or urinary biomarkers. Significantly lower concentrations of S-PMA and U-B were determined in samples collected at Day 1 as compared to Day 2 (p < 0.0001 and p = 0.003, respectively) suggesting that these biomarkers are enough sensitive and specific to detect changes in airborne benzene concentration even at few microg/m(3).     

Asbestos Exposure of Building Maintenance Personnel

The exposures of building maintenance personnel and occupants to airborne asbestos fibers, and the effects of operations and maintenance programs on those exposures, continue to be an important public health issue. The subject of this investigation was a large metropolitan county with numerous public buildings which routinely conducted air sampling for asbestos. A total of 302 personal air samples in nine task categories collected during maintenance worker activities in proximity to asbestos-containing materials were analyzed; 102 environmental air samples in four task categories were also analyzed. The arithmetic means of the 8-hr time weighted average exposures for personal sampling for each task category were all below the Occupational Safety and Health Administration permissible exposure level of 0.1 fibers (f)/cc > 5 μm. The highest mean 8-hr time weighted average exposure was 0.030 f/cc > 5 μm for ceiling tile replacement. The maximum asbestos concentration during sample collection for environmental samples was 0.027 f/cc > 5 μm. All asbestos-related maintenance work was done within the framework of an Operations and Maintenance Program (OMP) which utilized both personal protective equipment and controls against fiber release/dispersion. Results are presented in association with specific OMP procedures or controls. These results support the effectiveness of using Operations and Maintenance Programs to manage asbestos in buildings without incurring unacceptable risk to maintenance workers performing maintenance tasks.     

Reactivity to laboratory stress provocation predicts relapse to cocaine

Background

Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood.

Methods

The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1 μg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocortico-trophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants’ cocaine use was monitored for approximately 1 month following testing.

Results

The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use.

Conclusions

The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention.     

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers

OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.     

Cocaine treatment in neonatal rats affects the adult behavioral response to amphetamine

This study investigated whether exposure to cocaine during critical periods of brain development alters the motor stimulating effects of amphetamine given in adulthood. Female rats received 50 mg/kg/day cocaine HCl SC or vehicle during either postnatal days 1-10 or 11-20. At 60-65 days of age, activity counts were collected over a 15-min baseline period. Subjects then received one of 3 doses (0, 0.1, 0.25 mg/kg) of d-amphetamine sulfate SC followed by a 90-min period of activity monitoring. Adult activity in 1-10-day cocaine-treated rats was different from vehicle-treated rats in response to 0.1 mg/kg amphetamine only. Adult activity in 11-20-day cocaine-treated rats was different from vehicle-treated rats in response to 0.25 mg/kg only. The observed differences represented an increase and decrease in activity, respectively. These alterations in amphetamine response may be related to the observed alterations in D-1 receptor concentrations as well as the altered rates of brain glucose metabolism we have observed in adult rats neonatally exposed to cocaine.     

An examination of the intravenous self-administration of phenylpropanolamine using a cocaine substitution procedure in the baboon

Intravenous self-administration of phenylpropanolamine HCl (0.10 to 10.0 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-hr time-out allowing a maximum of eight injections per day. Phenylpropanolamine or phenylpropanolamine vehicle (saline) was substituted for cocaine for a period of 15 days followed by a return to the cocaine baseline. Response rates after phenylpropanolamine substitution were similar to those maintained by saline substitution, and lower than those maintained under cocaine baseline conditions. At the two highest doses of phenylpropanolamine tested (3.2 and 10.0 mg/kg/injection) concurrent food maintained behavior was suppressed.     

Inhaled formaldehyde: exposure estimation,hazard characterization,and exposure-response analysis

Formaldehyde has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Probabilistic estimates of exposure of the general population in Canada to formaldehyde in ambient and indoor air are presented. Critical health effects include sensory irritation and the potential to induce tumors in the upper respiratory tract (the nasal region in rodents and potentially the lungs of humans). The majority of the general population is exposed to airborne concentrations of formaldehyde less than those typically associated with sensory irritation (i.e., 0.1 mg/m3). Based primarily upon data derived from laboratory studies, the inhalation of formaldehyde under conditions that induce cytotoxicity and sustained regenerative proliferation within the respiratory tract is considered to present a carcinogenic hazard to humans. At airborne levels for which the prevalence of sensory irritation is minimal (i.e., 0.1 mg/m3), risks of respiratory-tract cancers for the general population estimated on the basis of a biologically motivated case-specific model are exceedingly low. This biologically motivated case-specific model incorporates two-stage clonal expansion and is supported by dosimetry calculations from computational fluid dynamics analyses of formaldehyde flux in various regions of the nose and single-path modeling for the lower respiratory tract. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.     

Inhaled Formaldehyde: Exposure Estimation,Hazard Characterization,and Exposure-Response Analysis

Formaldehyde has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Probabilistic estimates of exposure of the general population in Canada to formaldehyde in ambient and indoor air are presented. Critical health effects include sensory irritation and the potential to induce tumors in the upper respiratory tract (the nasal region in rodents and potentially the lungs of humans). The majority of the general population is exposed to airborne concentrations of formaldehyde less than those typically associated with sensory irritation (i.e., 0.1 mg/m 3 ). Based primarily upon data derived from laboratory studies, the inhalation of formaldehyde under conditions that induce cytotoxicity and sustained regenerative proliferation within the respiratory tract is considered to present a carcinogenic hazard to humans. At airborne levels for which the prevalence of sensory irritation is minimal (i.e., 0.1 mg/m 3 ), risks of respiratory-tract cancers for the general population estimated on the basis of a biologically motivated case-specific model are exceedingly low. This biologically motivated case-specific model incorporates two-stage clonal expansion and is supported by dosimetry calculations from computational fluid dynamics analyses of formaldehyde flux in various regions of the nose and single-path modeling for the lower respiratory tract. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.     

Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period

 We have shown previously, using an animal model of relapse, that acute exposure to intermittent footshock stress induces reinstatement of heroin-taking behavior in rats. Here we report that in rats trained to self-administer cocaine, exposure to acute intermittent footshock stress induces reinstatement of cocaine-taking behavior after prolonged extinction sessions and after a 4- to 6-week drug-free period; an effect comparable to that induced by a priming injection of cocaine. Animals were initially allowed to self-administer cocaine HCl (1.0 mg/kg per infusion, IV) during one 3-h session/day for 12 days. Subsequently, extinction conditions were introduced by substituting saline for cocaine so that lever-pressing resulted in IV infusions of saline rather than of drug. Extinction conditions were maintained until animals made 15 responses or less in the 3 h, after which animals were given saline infusions at the start of each daily session to establish baseline responding of ten responses or less. Subsequently, animals were tested for reinstatement of responding for saline infusions following a non-contingent injection of cocaine (2.0 mg/kg, IV) and exposure to intermittent footshock (10 min, 0.5 mA, 0.5 s on, mean off period of 40 sec). After an additional 4- to 6-week drug-free period, tests for reinstatement were repeated. Reinstatement of cocaine-taking behavior was observed in both sets of tests in response to footshock and cocaine. These results extend previous reports from this laboratory that footshock stress is an effective stimulus for reinstatement of drug-taking behavior in the rat. Received: 21 March 1996 / Final version: 13 July 1996     

Metabolic and sympatho-adrenal abnormalities in the obese zucker rat: Effect of chronic phenoxybenzamine treatment

The obese Zucker rat manifests a number of physiologic and metabolic abnormalities which are controlled or modulated by the sympatho-adrenal system. The interrelationship of these was examined by subjecting 3–4 month old male, homozygous lean and obese Zucker rats to various stresses which are known to activate the sympatho-adrenal system, and by chronic (16–19 days) phenoxybenzamine (PBZ) treatment to block α-adrenergic receptors. Both obese and lean PBZ treated rats gained only 1% and 10% of the body weight of their respective control rats during the treatment period, while only the lean rats had a significant reduction (20%) in food intake. Control obese rats failed to maintain rectal temperature after 4 hr at 7°C and their relative output of plasma catecholamines (CA) to cold stress, as measured from indwelling atrial cannulae, was decreased. PBZ treatment did not alter this rectal temperature response although it was associated with increased baseline norepinephrine levels (at ambient temperature 21–22°C) and relative output of CA in the obese rats, suggesting that sympathetic neural activity was increased under these circumstances. No abnormalities of sympatho-adrenal function, as reflected in plasma CA levels, were found in treated or control obese rats after immobilization for 1 hr followed by decapitation. Simultaneously obtained baseline plasma glucose levels were similar in untreated lean and obese rats, but insulin and glycerol levels in the obese rat were 1350% and 213% of lean values, respectively. During sequential stresses, the obese rats became markedly hyperglycemic and hyperglycerolemic compared to the lean rats, while insulin levels were depressed more in the obese than lean rats (12–15% versus 34–35% of controls, respectively). PBZ affected insulin levels only in the obese rats, reducing their baseline levels by 4-fold and stress induced levels to those seen in the lean control rats. These results suggest that some of the metabolic and physiologic abnormalities of the obese Zucker rat which are modulated by the sympatho-adrenal system can be normalized by procedures which increase sympatho-adrenal activity.     

A double-blind, placebo-controlled trial of modafinil for cocaine dependence

This is a randomized, double-blind, placebo-controlled study of modafinil treatment for cocaine dependence. Patients (N = 210) who were actively using cocaine at baseline were randomized to 8 weeks of modafinil (0 mg/day, 200 mg/day, or 400 mg/day) combined with once-weekly cognitive-behavioral therapy. Our primary efficacy measure was cocaine abstinence, based on urine benzoylecgonine (BE) levels, with secondary measures of craving, cocaine withdrawal, retention, and tolerability. We found no significant differences between modafinil and placebo patients on any of these measures. However, there was a significant gender difference in that male patients treated with 400 mg/day tended to be more abstinent than their placebo-treated counterparts (p = .06). Our negative findings might be explained by gender differences and/or inadequate psychosocial treatment intensity in patients with severe cocaine dependence.     

Intravenous cocaine challenges during desipramine maintenance.

Intravenous challenges with placebo and cocaine doses ranging from 0.125 to 0.5 mg/kg were administered to five subjects using a within subjects design during placebo and active desipramine (DMI) maintenance at a fixed dose of 150 mg daily for at least 10 days. The "high" reported after cocaine infusion was not altered by DMI, but "desire for cocaine" after a single dose was attenuated. Together with the results of clinical trials of DMI for cocaine abuse, these laboratory results suggest that DMI may reduce cocaine craving both during and between cocaine binges. Physiologically, baseline heart rate was higher on DMI, but the incremental heart rate response to cocaine was attenuated.