One in four die from acute infectious illness in an emergency department in Eastern Cape Province, South Africa.

BACKGROUND: Despite the breadth of data supporting evidence-based practice for sepsis care in high-resource settings, there are relatively few data to guide the management of sepsis in low-resource settings, particularly in areas where HIV and tuberculosis (TB) are prevalent. Furthermore, few studies had broadened sepsis parameters to include all patients with acute infectious illness or followed patients up after hospital discharge. Understanding the epidemiology and outcomes of acute infections in a local context is the critical first step to developing locally informed targeted management strategies. OBJECTIVES: To quantify and describe the incidence of and risk factors for mortality in a cohort of patients with undifferentiated acute infectious illnesses who presented to an emergency department (ED) in the Eastern Cape region of South Africa (SA). METHODS: In this prospective cohort study, patients with suspected acute infectious illness were enrolled at a district casualty ward in Mthatha, SA, between 1 July and 1 September 2017. Demographic data, interventions, diagnostic studies and disposition were prospectively collected during the initial encounter and during the hospital stay. Follow-up was conducted both in hospital and via phone interviews 30 days after the index visit. RESULTS: A total of 301 patients presented to the ED with acute infectious illness during the study period, of whom 54.8% had complete 30-day follow-up. Of the study population, only 5.7% had a complete set of vital signs (heart rate, respiratory rate, blood pressure and temperature) documented. Of the cohort, 51.8% had HIV and 32.9% active or treated TB; 25.2% of patients died within 30 days. Accounting for medical history, diagnosis and ED interventions, risk of mortality was independently associated with age (odds ratio (OR) 1.03; 95% confidence interval (CI) 1.00 - 1.06), HIV-positive status (OR 4.10; 95% CI 1.44 - 11.67) and Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score (OR 1.90; 95% CI 1.14 - 3.19) in an adjusted model. No ED interventions were protective for mortality, with intravenous fluid administration associated with increased 30-day mortality in this cohort (OR 3.65; 95% CI 1.38 - 9.62). CONCLUSIONS: Among adults with suspected acute infectious illness in Mthatha, SA, 30-day mortality was concerningly high. Mortality was highest in patients with concomitant HIV infection. In particular, vital sign assessment to identify possible sepsis in this cohort is crucial, as it affects mortality to a meaningful extent, yet is often unavailable. Future research is needed on the management of sepsis in low-resource settings, particularly in HIV-positive individuals.

The evolution of mammalian brain size.

Relative brain size has long been considered a reflection of cognitive capacities and has played a fundamental role in developing core theories in the life sciences. Yet, the notion that relative brain size validly represents selection on brain size relies on the untested assumptions that brain-body allometry is restrained to a stable scaling relationship across species and that any deviation from this slope is due to selection on brain size. Using the largest fossil and extant dataset yet assembled, we find that shifts in allometric slope underpin major transitions in mammalian evolution and are often primarily characterized by marked changes in body size. Our results reveal that the largest-brained mammals achieved large relative brain sizes by highly divergent paths. These findings prompt a reevaluation of the traditional paradigm of relative brain size and open new opportunities to improve our understanding of the genetic and developmental mechanisms that influence brain size.

Targeted rapid testing for SARS-CoV-2 in the emergency department is associated with large reductions in uninfected patient exposure time.

Opportunity exists to decrease healthcare-related exposure to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), preserve infection control resources, and increase care capacity by reducing the time to diagnosis of coronavirus disease 2019 (COVID-19). A retrospective cohort analysis was undertaken to measure the effect of targeted rapid molecular testing for SARS-CoV-2 on these outcomes. In comparison with standard platform testing, rapid testing was associated with a 65.6% reduction (12.6 h) in the median time to removal from the isolation cohort for patients with negative diagnostic results. This translated to an increase in COVID-19 treatment capacity of 3028 bed-hours and 7500 fewer patient interactions that required the use of personal protective equipment per week.

Venous thromboembolic prophylaxis after simultaneous bilateral total knee arthroplasty: aspirin versus warfarin.

AIMS: The aims of this study were to compare the efficacy of two agents, aspirin and warfarin, for the prevention of venous thromboembolism (VTE) after simultaneous bilateral total knee arthroplasty (SBTKA), and to elucidate the risk of VTE conferred by this procedure compared with unilateral TKA (UTKA). PATIENTS AND METHODS: A retrospective, multi-institutional study was conducted on 18 951 patients, 3685 who underwent SBTKA and 15 266 who underwent UTKA, using aspirin or warfarin as VTE prophylaxis. Each patient was assigned an individualised baseline VTE risk score based on a system using the Nationwide Inpatient Sample. Symptomatic VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), were identified in the first 90 days post-operatively. Statistical analyses were performed with logistic regression accounting for baseline VTE risk. RESULTS: The adjusted incidence of PE following SBTKA was 1.0% (95% confidence interval (CI) 0.86 to 1.2) with aspirin and 2.2% (95% CI 2.0 to 2.4) with warfarin. Similarly, the adjusted incidence of VTE following SBTKA was 1.6% (95% CI 1.1 to 2.3) with aspirin and 2.5% (95% CI 1.9 to 3.3) with warfarin. The risk of PE and VTE were reduced by 66% (odds ratio (OR) 0.44, 95% CI 0.25 to 0.78) and 38% (OR 0.62, 95% CI 0.38 to 1.0), respectively, using aspirin. In addition, the risk of PE was 204% higher for patients undergoing SBTKA relative to those undergoing UTKA. For each ten-point increase in baseline VTE risk, the risk of PE increased by 25.5% for patients undergoing SBTKA compared with 10.5% for those undergoing UTKA. Patients with a history of myocardial infarction or peripheral vascular disease had the greatest increase in risk from undergoing SBTKA instead of UTKA. CONCLUSION: Aspirin is more effective than warfarin for the prevention of VTE following SBTKA, and serves as the more appropriate agent for VTE prophylaxis for patients in all risk categories. Furthermore, patients undergoing SBTKA are at a substantially increased risk of VTE, even more so for those with significant underlying risk factors. Patients should be informed about the risks associated with undergoing SBTKA. Cite this article: Bone Joint J 2018;100-B(1 Supple A):68-75.

Mobile nucleic acid amplification testing (mobiNAAT) for Chlamydia trachomatis screening in hospital emergency department settings.

Management of curable sexually-transmitted infections (STI) such as Chlamydia can be revolutionized by highly sensitive nucleic acid testing that is deployable at the point-of-care (POC). Here we report the development of a mobile nucleic acid amplification testing (mobiNAAT) platform utilizing a mobile phone and droplet magnetofluidics to deliver NAAT in a portable and accessible format. By using magnetic particles as a mobile substrate for nucleic acid capture and transport, fluid handling is reduced to particle translocation on a simple magnetofluidic cartridge assembled with reagents for nucleic acid purification and amplification. A mobile phone user interface operating in tandem with a portable Bluetooth-enabled cartridge-processing unit facilitates process integration. We tested 30 potentially Chlamydia trachomatis (CT)-infected patients in a hospital emergency department and confirmed that mobiNAAT showed 100% concordance with laboratory-based NAAT. Concurrent evaluation by a nontechnical study coordinator who received brief training via an embedded mobile app module demonstrated ease of use and reproducibility of the platform. This work demonstrates the potential of mobile nucleic acid testing in bridging the diagnostic gap between centralized laboratories and hospital emergency departments.

Food insecurity is associated with diabetes self-care behaviours and glycaemic control.

AIMS: Food insecurity is the 'limited or uncertain availability of nutritionally adequate and safe foods'. Our objective was to examine the association between food insecurity, diabetes self-care and glycaemic control. METHODS: We conducted a cross-sectional analysis of baseline data from adult patients with Type 2 diabetes who were enrolled in a randomized trial evaluating a health literacy-focused diabetes intervention in safety net primary care clinics in middle Tennessee. Food insecurity was assessed with three items from the U.S. Household Food Security Survey. Diabetes self-care behaviours were assessed with the Summary of Diabetes Self-Care Activities Scale, Personal Diabetes Questionnaire and Adherence to Refills and Medication Scale. Glycaemic control was assessed with HbA1c . RESULTS: The sample consisted of 401 participants, 73% of whom reported some level of food insecurity. Food insecurity was significantly associated with self-care behaviours including less adherence to a general diet [Adjusted Odds Ratio (AOR) 0.9, P = 0.02], less physical activity (AOR 0.9, P = 0.04) and with a greater occurrence of medication non-adherence (AOR 1.2, P = 0.002) and calorie restriction (AOR 1.1, P = 0.02). Food insecurity was also associated with worse glycaemic control (adjusted ß = 0.1, P = 0.03). None of the self-care behaviours were significantly associated with HbA1c , limiting the ability to test for self-care as a mechanism linking food insecurity to glycaemic control. CONCLUSIONS: There was a high rate of food insecurity in a sample of patients with Type 2 diabetes who were of low socio-economic status. Food insecurity was associated with less adherence to recommended self-care behaviours and worse glycaemic control.

Dual-site sampling improved detection rates for MRSA colonization in patients with cutaneous abscesses.

Extranasal sites are common reservoirs of Staphylococcus aureus colonization and may be relevant for methicillin-resistant S. aureus (MRSA) screening and infection control strategies. The objective here was to determine whether inguinal specimens could also be screened using Xpert SA Nasal Complete assay for MRSA. Results were compared to broth enrichment culture. Among 162 consented adults seeking care in the emergency department for cutaneous abscesses, inguinal specimens were found positive for MRSA more often than nares specimens, 24% and 26% by PCR or culture, respectively, compared to 19% each by PCR or culture. Overall, 6% of adults colonized with MRSA would have been missed by nares screening alone. Compared to culture, Xpert SA Nasal Complete assay demonstrated sensitivity and specificity of 89% and 97%, respectively, for detecting nares and/or inguinal MRSA colonization. In conclusion, inguinal specimens were a more common reservoir for MRSA than nares specimens in this population of patients.

Usability characteristics of self-administered computer-assisted interviewing in the emergency department: factors affecting ease of use, efficiency, and entry error.

OBJECTIVE: Self-administered computer-assisted interviewing (SACAI) gathers accurate information from patients and could facilitate Emergency Department (ED) diagnosis. As part of an ongoing research effort whose long-range goal is to develop automated medical interviewing for diagnostic decision support, we explored usability attributes of SACAI in the ED. METHODS: Cross-sectional study at two urban, academic EDs. Convenience sample recruited daily over six weeks. Adult, non-level I trauma patients were eligible. We collected data on ease of use (self-reported difficulty, researcher documented need for help), efficiency (mean time-per-click on a standardized interview segment), and error (self-report age mismatched with age derived from electronic health records) when using SACAI on three different instruments: Elo TouchSystems ESY15A2 (finger touch), Toshiba M200 (with digitizer pen), and Motion C5 (with digitizer pen). We calculated descriptive statistics and used regression analysis to evaluate the impact of patient and computer factors on time-per-click. RESULTS: 841 participants completed all SACAI questions. Few (<1%) thought using the touch computer to ascertain medical information was difficult. Most (86%) required no assistance. Participants needing help were older (54 ± 19 vs. 40 ± 15 years, p<0.001) and more often lacked internet at home (13.4% vs. 7.3%, p = 0.004). On multivariate analysis, female sex (p<0.001), White (p<0.001) and other (p = 0.05) race (vs. Black race), younger age (p<0.001), internet access at home (p<0.001), high school graduation (p = 0.04), and touch screen entry (vs. digitizer pen) (p = 0.01) were independent predictors of decreased time-per-click. Participant misclick errors were infrequent, but, in our sample, occurred only during interviews using a digitizer pen rather than a finger touch-screen interface (1.9% vs. 0%, p = 0.09). DISCUSSION: Our results support the facility of interactions between ED patients and SACAI. Demographic factors associated with need for assistance or slower interviews could serve as important triggers to offering human support for SACAI interviews during implementation. CONCLUSION: Understanding human-computer interactions in real-world clinical settings is essential to implementing automated interviewing as means to a larger long-term goal of enhancing clinical care, diagnostic accuracy, and patient safety.

Emergency department (ED) utilization by HIV-infected ED patients in the United States in 2009 and 2010 - a national estimation.

OBJECTIVES: The aim of the study was to describe the emergency department (ED) resource utilization patterns of ED visits by patients reported to be HIV-infected in the USA in 2009 and 2010 and to compare them with those of the general ED patient population. METHODS: We identified demographics, HIV infection status, and ED utilization patterns in 2009 and 2010 from a weighted sample of US ED visits using the National Hospital Ambulatory Medical Care Survey, a nationally representative survey. Data on visits by patients aged ≥ 13 years were analysed using procedures for multiple-stage survey data. RESULTS: In 2009 and 2010, 1 192 535 visits were documented for HIV-infected patients. The estimated annual ED visit rates were 633 per 1000 known HIV-infected persons and 438 per 1000 non-HIV-infected persons [rate difference 195; 95% confidence interval (CI) 194, 197]. While no difference was recorded in the level of acuity between HIV-infected ED patients and general ED patients, the total number of diagnostic/screening services ordered and medications administered in the ED was significantly higher for visits by HIV-infected patients. HIV-infected patients making ED visits also had a longer duration of stays [mean 5.4 h (95% CI 4.6, 6.2 h) vs. 3.6 h (95% CI 3.5, 3.8 h) for HIV-uninfected patients] and were more likely to be admitted [28% (95% CI 22, 34%) vs. 15% (95% CI 14, 16%), respectively] than their non-HIV-infected counterparts. CONCLUSIONS: ED visits by HIV-infected individuals occur at rates higher than those of visits by the general population, and consume significantly more ED resources than visits by the general population. These national findings represent baseline prior to full implementation of the 2010 Patient Protection and Affordable Care Act.

US national estimation of emergency department utilization by patients given 'HIV/AIDS-related illness' as their primary diagnosis.

BACKGROUND: The emergency department (ED) is one of the most frequent sources of medical care for many HIV-infected individuals. However, the characteristics and ED utilization patterns of patients with HIV/AIDS-related illness as the primary ED diagnosis (HRIPD) are unknown. METHODS: We identified the ED utilization patterns of HRIPD visits from a weighted sample of US ED visits (1993-2005) using the National Hospital Ambulatory Medical Care Survey, a nationally representative survey. Data on visits by patients≥18 years old were analysed using procedures for multiple-stage survey data. We compared the utilization patterns of HRIPD vs. non-HRIPD visits, and patterns across three periods (1993-1996, 1997-2000 and 2001-2005) to take into account changes in HIV epidemiology. RESULTS: Overall, 492 000 HRIPD visits were estimated to have occurred from 1993 to 2005, corresponding to 5-in-10 000 ED visits. HRIPD visits experienced longer durations of stay (5.2 h vs. 3.4 h; P=0.001), received more diagnostic tests (5.1 vs. 3.3; P<0.001), were prescribed more medications (2.5 vs. 1.8; P<0.001) and were more frequently seen by physicians (99.5%vs. 93.8%; P<0.001) compared with non-HRIPD visits. HRIPD visits were more likely to result in admission [adjusted odds ratio (OR) 7.67; 95% confidence interval (CI) 5.14-11.44]. The proportion of HRIPD visits that required emergent/urgent care or were seen by attending physicians, and the number of diagnostic tests ordered, significantly increased over time (P<0.05), while the wait time (P=0.003) significantly decreased between the second and third study periods (P<0.05). CONCLUSIONS: Although HRIPD visits were infrequent relative to all ED visits, HRIPD visits utilized significantly more resources than non-HRIPD visits and the utilization also increased over time.

Preventing glycaemic relapse in recently controlled type 2 diabetes patients: a randomised controlled trial.

AIMS/HYPOTHESIS: After achieving glycaemic control, many type 2 diabetic patients relapse to clinically significant levels of hyperglycaemia. We sought to determine the optimal frequency of telephone contact by nurse practitioners that was necessary to prevent glycaemic relapse. METHODS: This parallel, randomised controlled trial ran from June 2002 to February 2006 at an academic medical centre, studying 164 type 2 diabetic patients who had recently achieved glycaemic control. Participants were randomly assigned by sequential, concealed, computer-generated allocation to a 2 year maintenance strategy consisting of: (1) routine follow-up (n = 54); (2) routine follow-up and quarterly telephone contact (n = 55); or (3) routine follow-up and monthly telephone contact (n = 55). Blinding was not possible. The primary outcome was cumulative incidence of glycaemic relapse, defined as an increase in HbA(1c) of > or =1%; all participants were analysed. Cumulative incidence and prevalent proportions were compared. Weight change and hypoglycaemia were also assessed. RESULTS: All participants randomised were included in the analyses. The study was completed by 90% of participants and intervention fidelity was high. At 24 months, the cumulative incidence of relapse was 41%. At 12 months, prevalent proportions of relapse were 20%, 14% and 15% for control, quarterly contact and monthly contact, respectively. At 24 months, they were 25%, 21% and 29%, respectively. There was no statistically significant difference in cumulative incidence or prevalent proportions of relapse among the study arms. Adverse events did not differ between study arms. CONCLUSIONS/INTERPRETATION: This first randomised controlled trial to test an intervention to prevent glycaemic relapse found that regularly scheduled telephone contact by a nurse practitioner was no more effective than routine follow-up care in preventing glycaemic relapse.

Selective suppression of cocaine- versus food-maintained responding by monoamine releasers in rhesus monkeys: benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine.

Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032-0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.

Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges.

3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) stimulates the transporter-mediated release of monoamines, including 5-HT. High-dose exposure to MDMA causes persistent 5-HT deficits (e.g. depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of three i.p. injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kgx3, low dose) or at a fivefold higher amount (7.5 mg/kgx3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute i.v. challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by i.v. MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting approximately 50% loss of forebrain 5-HT 2 weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of i.v. MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with i.v. MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation.

Concordance of chlamydia trachomatis infections within sexual partnerships.

OBJECTIVES: The enhanced sensitivity of nucleic acid amplification tests (NAAT) provides an opportunity for estimating the prevalence of untreated Chlamydia trachomatis infections. The transmissibility and public health significance of some NAAT-identified infections are, however, not known. METHODS: Adults attending an urban emergency department provided specimens for C trachomatis screening using NAAT. Participants testing positive were offered follow-up including re-testing for C trachomatis using NAAT and traditional methods, eg culture and direct fluorescent antibody, and were treated. Partners were offered identical evaluation and treatment. Overall, 90 C trachomatis-positive participants had one or more sexual partners enrolled. RESULTS: Evidence of transmission, as defined by infection concordance between partnerships, was observed among 75% of partners of index cases testing positive by both NAAT and traditional assay but only 45% of partners of index cases testing positive by NAAT only (prevalence ratio 1.7, 95% CI 1.1 to 2.5). Among index participants returning for follow-up, 17% had no evidence of C trachomatis infection by NAAT or traditional assay (median follow-up three weeks). CONCLUSIONS: A substantial proportion of positive NAAT results for chlamydial infection may be of lower transmissibility and may not persist after a short follow-up. The long-term health effects of some positive NAAT are uncertain.

Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) causes persistent decreases in brain 5-HT content and 5-HT transporter (SERT) binding, with no detectable changes in SERT protein. Such data suggest that MDMA impairs 5-HT transmission but leaves 5-HT nerve terminals intact. To further test this hypothesis, we carried out two types of experiments in rats exposed to high-dose MDMA. First, we examined the effects of MDMA on SERT binding and function using different in vitro assay conditions. Next, we treated rats with the 5-HT precursor, l-5-hydroxytryptophan (5-HTP), in an attempt to restore MDMA-induced depletions of 5-HT. METHODS: Rats received three i.p. injections of saline or MDMA (7.5 mg/kg), one injection every 2 h. Rats in one group were decapitated, and brain tissue was assayed for SERT binding and [(3)H]5-HT uptake under conditions of normal (100 or 126 mM) and low (20 mM) NaCl concentration. Rats from another group received saline or 5-hydroxytryptophan/benserazide (5-HTP-B), each drug at 50 mg/kg i.p., and were killed 2 h later. RESULTS: MDMA reduced SERT binding to 10% of control when assayed in 100 mM NaCl, but this reduction was only 55% of control in 20 mM NaCl. MDMA decreased immunoreactive 5-HT in caudate and hippocampus to about 35% of control. Administration of 5-HTP-B to MDMA-pretreated rats significantly increased the 5-HT signal toward normal levels in caudate (85% of control) and hippocampus (66% of control). CONCLUSION: 1) Following high-dose MDMA treatment sufficient to reduce SERT binding by 90%, a significant number of functionally intact 5-HT nerve terminals survive. 2) The degree of MDMA-induced decreases in SERT binding depends on the in vitro assay conditions. 3) 5-HTP-B restores brain 5-HT depleted by MDMA, suggesting that this approach might be clinically useful in abstinent MDMA users.

Impact of weight loss on the metabolic syndrome.

OBJECTIVE: To evaluate the effects of weight loss on the risk of having metabolic syndrome after 1 year of treatment with lifestyle modification alone, pharmacotherapy alone (sibutramine) or the combination of the two. DESIGN: Randomized, controlled, 1-year clinical trial. PATIENTS: One hundred and eighty women and 44 men, 18-65 years of age, with a body mass index of 30-45 kg/m(2), free of uncontrolled hypertension or type 1 or 2 diabetes. INTERVENTION: Fifteen milligrams of sibutramine per day alone, lifestyle modification counseling alone, sibutramine plus lifestyle modification counseling or sibutramine plus brief lifestyle modification counseling. MEASUREMENTS: The metabolic syndrome, as defined by the Adult Treatment Panel III. RESULTS: Before treatment, 34.8% of the participants had the metabolic syndrome. Metabolic syndrome was more prevalent in Caucasians than African Americans (42.5 vs 20.3%; P<0.03), in males than females (65.1 vs 34.9%; P<0.002) and in older (>44 years) than younger (

Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.

Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.