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Purpose: To evaluate the RARE (Réseau Action-Recherche sur l'Epilepsie) program, a model of managing and treating people with epilepsy (PWE) at a primary health-care level in rural areas of Mali, we assessed treatment efficacy and compliance of patients who underwent the first year follow-up. Methods: A network of rural general practitioners (GPs) settled in six rural districts of the regions of Koulikoro, Segou and Sikasso, was involved in the diagnosis, evaluation and monitoring of all the identified PWE and in the distribution of phenobarbital (PB). All the participants were included in a prospective database and followed-up by GPs at 4 months intervals during the first year. Seizure frequency, treatment doses and appearance of adverse events (AEs) were systematically recorded. Efficacy was evaluated in terms of reduction of seizures frequency while noncompliance in terms of time to study withdrawal for any cause. Key findings: 596 patients treated with PB were included in the analysis. Of these, 74.0% completed the first year follow-up. At the final visit, 59.6% were seizure-free: 31.0% for 12 months, 10.2% for 8 months and 18.4% for 4 months. Adults and patients with convulsive seizures were the most drug-resistant (p<0.002). Few AEs were recorded. The multivariate analysis showed that being a woman, presenting convulsive seizures, having more than 5 seizures/month and had never be treated were predictors of withdrawal (p≤0.05) at 12 months. Significance: This study showed a good response and compliance to the treatment and allowed the identification of some factors associated with failure of management in a setting very near to clinical practice. Awareness campaigns are needed to assure a broader accessibility to treatment and to improve the compliance and continuity with treatment programs. [ABSTRACT FROM AUTHOR]

Background: To explore the hypothesis that sight restoring cataract surgery provided to impoverished rural communities will improve not only visual acuity and vision-related quality of life (VRQoL) but also poverty and social status. Methods: Participants were recruited at outreach camps in Tamil Nadu, South India, and underwent free routine manual small incision cataract surgery (SICS) with intra-ocular lens (IOL) implantation, and were followed up one year later. Poverty was measured as monthly household income, being engaged in income generating activities and number of working household members. Social status was measured as rates of re-marriage amongst widowed participants. VRQoL was measured using the IND-VFQ-33. Associations were explored using logistic regression (SPSS 19). Results: Of the 294 participants, mean age ± standard deviation (SD) 60±8 years, 54% men, only 11% remained vision impaired at follow up (67% at baseline; p<0.001). At one year, more participants were engaged in income generating activities (44.7% to 77.7%; p<0.001) and the proportion of households with a monthly income ,1000 Rps. decreased from 50.5% to 20.5% (p<0.05). Overall VRQoL improved (p<0.001). Participants who had successful cataract surgery were less likely to remain in the lower categories of monthly household income (OR 0.05-0.22; p<0.02) and more likely to be engaged in income earning activities one year after surgery (OR 3.28; p = 0.006). Participants widowed at baseline who had successful cataract surgery were less likely to remain widowed at one year (OR 0.02; p = 0.008). Conclusion: These findings indicate the broad positive impact of sight restoring cataract surgery on the recipients' as well as their families' lives. Providing free high quality cataract surgery to marginalized rural communities will not only alleviate avoidable blindness but also - to some extent - poverty in the long run. [ABSTRACT FROM AUTHOR]

Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti- cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a "training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final "challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence. [ABSTRACT FROM AUTHOR]

Background: Bisphenol A is widely used in food and drinks packaging. There is evidence of associations between raised urinary bisphenol A (uBPA) and increased incidence of reported cardiovascular diagnoses. Methodology/Principal Findings: To estimate associations between BPA exposure and angiographically graded coronary atherosclerosis. 591 patients participating in The Metabonomics and Genomics in Coronary Artery Disease (MaGiCAD) study in Cambridgeshire UK, comparing urinary BPA (uBPA) with grades of severity of coronary artery disease (CAD) on angiography. Linear models were adjusted for BMI, occupational social class and diabetes status. Severe (one to three vessel) CAD was present in 385 patients, 86 had intermediate disease (n = 86) and 120 had normal coronary arteries. The (unadjusted) median uBPA concentration was 1.28 ng/mL with normal coronary arteries, and 1.53 ng/mL with severe CAD. Compared to those with normal coronary arteries, uBPA concentration was significantly higher in those with severe CAD (OR per uBPA SD = 5.96 ng/ml OR = 1.43, CI 1.03 to 1.98, p = 0.033), and near significant for intermediate disease (OR = 1.69, CI 0.98 to 2.94, p = 0.061). There was no significant uBPA difference between patients with severe CAD (needing surgery) and the remaining groups combined. Conclusions/Significance: BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease. Larger studies are needed to estimate true dose response relationships. The mechanisms underlying the association remain to be established. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) analysis is an important tool in the diagnostic work- up of many neurological disorders, but reference ranges for CSF glucose, CSF/plasma glucose ratio and CSF lactate based on studies with large numbers of CSF samples are not available. Our aim was to define age-specific reference values. In 1993 The Nijmegen Observational CSF Study was started. Results of all CSF samples that were analyzed between 1993 and 2008 at our laboratory were systematically collected and stored in our computerized database. After exclusion of CSF samples with an unknown or elevated erythrocyte count, an elevated leucocyte count, elevated concentrations of bilirubin, free hemoglobin, or total protein 9,036 CSF samples were further studied for CSF glucose (n = 8,871), CSF/plasma glucose ratio (n = 4,516) and CSF lactate values (n = 7,614). CSF glucose, CSF/plasma glucose ratio and CSF lactate were age-, but not sex dependent. Age-specific reference ranges were defined as 5-95th percentile ranges. CSF glucose 5th percentile values ranged from 1.8 to 2.9 mmol/L and 95th percentile values from 3.8 to 5.6 mmol/L CSF/plasma glucose ratio 5th percentile values ranged from 0.41 to 0.53 and 95th percentile values from 0.82 to 1.19. CSF lactate 5th percentile values ranged from 0.88 to 1.41 mmol/L and 95th percentile values from 2.00 to 2.71 mmol/L. Reference ranges for all three parameters were widest in neonates and narrowest in toddlers, with lower and upper limits increasing with age. These reference values allow a reliable interpretation of CSF results in everyday clinical practice. Furthermore, hypoglycemia was associated with an increased CSF/plasma glucose ratio, whereas hyperglycemia did not affect the CSF/plasma glucose ratio. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Methamphetamine (MA) is a chiral compound. • The S-(+) enantiomer is more commonly abused and is more potent in producing central nervous system and cardiovascular effects than the R-(−) enantiomer. • Studies describing the metabolism of MA have mainly been done with the S-(+)-isomer; pharmacokinetic data for R-(−)-MA or racemic MA are very limited. WHAT THIS STUDY ADDS • Stereoselectivity exists in the metabolism of MA. • Urinary excretion of para hydroxymethamphetamine (pOH-MA) was found to be least affected by stereoselectivity. • It is suggested that pOH-MA may be a more stable biomarker of MA abuse. AIM To characterize the formation and urinary elimination of metabolites of S-(+) and R-(−) methamphetamine (MA) in humans. METHODS In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg−1, R-(−)-MA 0.25 and 0.5 mg kg−1, racemic MA 0.5 mg kg−1, or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(−)-AMP ( P < 0.001). Furthermore, less R-(−)-pOH-MA was excreted in the urine compared with S-(+)-pOH-MA (8% vs. 11%, P= 0.02). Correspondingly, S-(+)-MA excretion was less than R-(−)-MA (42% vs. 52%; P= 0.005). CONCLUSIONS The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH-MA (8–11%) than AMP (2–7%). The formation of pOH-MA was less affected by the MA enantiomer administered, suggesting that urine pOH-MA may be a more stable biomarker of MA metabolism. [ABSTRACT FROM AUTHOR]

Background: We studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant. Methods: 12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 µg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured. Results: Plasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 ± 56.1, 124.7 ± 106.6, and 268.1 ± 220.5 &microc;g for ascending exposures (mean 4.2 ± 3.3 µg/inhalation). Physiological changes were minimal and not dosedependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen. Conclusion: Inhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant. [ABSTRACT FROM AUTHOR]

Objective: To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers.Methods: In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration–time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for “intoxication,” “good drug effect,” and “drug liking”) were obtained.Results: Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3-15.0 hours) than for d-methamphetamine (10.2-10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 ± 23.4 beats/min, 13.5 ± 18.5 beats/min, and 10.7 ± 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 ± 17.8 beats/min and 34.5 ± 18.9 beats/min, respectively, versus 19.5 ± 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 ± 35.3 versus 30.3 ± 24.9) and drug liking (47.7 ± 35.1 versus 28.6 ± 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures.Conclusion: The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities.Clinical Pharmacology & Therapeutics (2006) 80, 403–420; doi: 10.1016/j.clpt.2006.06.013 [ABSTRACT FROM AUTHOR]

Offers letters to the editor in response to previous medical-related articles. Cost-effectiveness of colorectal cancer screening; Drug dependence as a chronic medical illness; Dextromethorphan and ecstasy pills; Other issues.

Patients treated for methamphetamine (MA) dependence have a high rate of relapse, and stress is thought to play a key role. We sought to develop a computerized procedure for experimentally inducing stress in MA users. In a within-subjects design, we compared a computerized subtraction stress task (SST) to personalized stress-imagery scripts and a control condition (neutral imagery) in 9 former MA users, recruited in San Francisco in 2006-2007. We assessed blood hormone levels, anxiety and craving for MA on visual analog scales, and the Positive and Negative Affect Schedule and made linear mixed-effects models to analyze the results. Both the SST and stress scripts were effective in inducing self-report markers of stress in MA users. Because the SST is easily reproducible and requires less time of staff and participants, it may be a useful alternative for measuring stress reactivity in drug users.

BACKGROUND: Predictors of relapse to methamphetamine use are poorly understood. State variables may play an important role in relapse, but they have been difficult to measure at frequent intervals in outpatients. METHODS: We conducted a feasibility study of the use of cellular telephones to collect state variable data from outpatients. Six subjects in treatment for methamphetamine dependence were called three times per weekday for approximately seven weeks. Seven questionnaires were administered that assessed craving, stress, affect, and current type of location and social environment. RESULTS: 395/606 (65%) of calls attempted were completed. The mean time to complete each call was 4.9 (s.d. 1.8) minutes and the mean time to complete each item was 8.4 (s.d. 4.8) seconds. Subjects rated the acceptability of the procedures as good. All six cellular phones and battery chargers were returned undamaged. CONCLUSION: Cellular telephones are a feasible method for collecting state data from methamphetamine dependent outpatients.