Burden of disease due to amphetamines, cannabis, cocaine, and opioid use disorders in South America, 1990-2019: a systematic analysis of the Global Burden of Disease Study 2019.

BACKGROUND: South America's substance use profile, poverty, income inequality, and cocaine-supplier role make it a unique place for substance use research. This study investigated the burden of disease attributable to amphetamine use disorder, cannabis use disorder (CAD), cocaine use disorder, and opioid use disorder (OUD) in South America from 1990 to 2019, on the basis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: GBD 2019 estimated the incidence, prevalence, mortality, years of life lost (YLL), years of life lived with disability (YLD), and disability-adjusted life-years (DALYs) due to substance use disorders in each of the 12 South American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay, and Venezuela). Data were modelled using standardised tools (ie, the Cause of Death Ensemble model, spatio-temporal Gaussian process regression, and disease modelling meta-regression) to generate estimates of each quantity of interest by sex, location, and year. The analysis included comparisons by sex and country, and against regional and global estimates. FINDINGS: In 2019, the highest amphetamine use disorder burden per 100 000 population in South America was in Peru (66 DALYs). CAD DALY rates per 100 000 in South America were stable between 1990 and 2019, except in Chile and Colombia, which had the highest rates in 2019 (19 DALYs for Chile and 18 DALYs for Colombia). OUD DALYs per 100 000 increased during the period in Brazil and Peru, which in 2019 had the highest rates in South America (82 DALYs for Brazil and 70 DALYs for Peru). In 2019, Brazil had the highest cocaine use disorder DALYs per 100 000 (45 DALYs), nearly double its rate in 1990. DALY rates were higher in males than females for each substance use disorder, except in Paraguay. The overall burden of substance use disorders was higher in males than in females, mainly because of cocaine use disorder and CAD, whereas for amphetamine use disorder, the difference between sexes was minimal, and for OUD there was no difference. For males and females, the highest rate of substance use disorders DALYs per 100 000 was for OUD except in Argentina (in males, 58 DALYs for cocaine use disorder vs 52 DALYs for OUD) and in Paraguay (in females, 77 for amphetamine use disorder vs 50 for OUD). CAD DALY rates were generally the lowest among the substance use disorders for males and females. Amphetamine use disorder YLD rates were reasonably stable throughout the period and were highest in Peru, Paraguay, and Uruguay (>40 YLD per 100 000). For CAD, YLD rates were stable in all countries except Chile and Colombia. Cocaine use disorder YLD rates per 100 000 for the top four countries (Argentina, Uruguay, Chile, and Brazil) increased from 1990 to 2010 (eg, from 19 to 33 in Brazil), but decreased between 2010 and 2019 (eg, from 36 to 31 in Chile). For OUD, YLD rates showed a slight increase in most countries apart from Brazil, which increased from 52 in 1990 to 80 in 2019 and was top among the countries. Amphetamine use disorder YLL rates per 100 000 were highest in Suriname and Peru during the period, although in Suriname it increased from 2·7 in 2010 to 3·2 in 2019, whereas in Peru it decreased from 2·1 to 1·7. The highest YLL rate for cocaine use disorder was in Brazil, which increased from 3·7 in 1990 to 18·1 in 2019. Between 2000 and 2019, Chile and Uruguay showed the highest OUD YLL rates (11·6 for Chile and 10·9 for Uruguay). A high incidence of CAD was found in Chile, Colombia, Guyana, and Suriname. There were high incidences of amphetamine use disorder in Paraguay, cocaine use disorder in Argentina, and OUD in Ecuador. A decrease in annual prevalence for substance use disorders during the period was observed in Venezuela (amphetamine use disorder, CAD, and OUD), Brazil (CAD and amphetamine use disorder), Colombia (amphetamine use disorder and cocaine use disorder), Peru (amphetamine use disorder and cocaine use disorder), Chile and Suriname (amphetamine use disorder), Uruguay (CAD), and Bolivia (OUD). Overall, the cocaine use disorder burden stabilised then decreased. OUD was less prevalent than other substance use disorders but its burden was the highest. INTERPRETATION: The decrease in the burden of cocaine use disorder probably reflects the success of national standardised treatment programmes. Programmes for amphetamine use disorder, CAD, and OUD management should be improved. We did not find an increase in CAD burden in Uruguay, the country with the highest degree of cannabis decriminalisation in the region. Countries in South America should improve monitoring of substance use disorders, including regular surveys to provide more accurate data on which to base policy decisions. FUNDING: The Bill & Melinda Gates Foundation.

Medication Use in the Management of Comorbidities Among Individuals With Autism Spectrum Disorder From a Large Nationwide Insurance Database.

Importance: Although there is no pharmacological treatment for autism spectrum disorder (ASD) itself, behavioral and pharmacological therapies have been used to address its symptoms and common comorbidities. A better understanding of the medications used to manage comorbid conditions in this growing population is critical; however, most previous efforts have been limited in size, duration, and lack of broad representation. Objective: To use a nationally representative database to uncover trends in the prevalence of co-occurring conditions and medication use in the management of symptoms and comorbidities over time among US individuals with ASD. Design, Setting, and Participants: This retrospective, population-based cohort study mined a nationwide, managed health plan claims database containing more than 86 million unique members. Data from January 1, 2014, to December 31, 2019, were used to analyze prescription frequency and diagnoses of comorbidities. A total of 26 722 individuals with ASD who had been prescribed at least 1 of 24 medications most commonly prescribed to treat ASD symptoms or comorbidities during the 6-year study period were included in the analysis. Exposures: Diagnosis codes for ASD based on International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: Quantitative estimates of prescription frequency for the 24 most commonly prescribed medications among the study cohort and the most common comorbidities associated with each medication in this population. Results: Among the 26 722 individuals with ASD included in the analysis (77.7% male; mean [SD] age, 14.45 [9.40] years), polypharmacy was common, ranging from 28.6% to 31.5%. Individuals' prescription regimens changed frequently within medication classes, rather than between classes. The prescription frequency of a specific medication varied considerably, depending on the coexisting diagnosis of a given comorbidity. Of the 24 medications assessed, 15 were associated with at least a 15% prevalence of a mood disorder, and 11 were associated with at least a 15% prevalence of attention-deficit/hyperactivity disorder. For patients taking antipsychotics, the 2 most common comorbidities were combined type attention-deficit/hyperactivity disorder (11.6%-17.8%) and anxiety disorder (13.1%-30.1%). Conclusions and Relevance: This study demonstrated considerable variability and transiency in the use of prescription medications by US clinicians to manage symptoms and comorbidities associated with ASD. These findings support the importance of early and ongoing surveillance of patients with ASD and co-occurring conditions and offer clinicians insight on the targeted therapies most commonly used to manage co-occurring conditions. Future research and policy efforts are critical to assess the extent to which pharmacological management of comorbidities affects quality of life and functioning in patients with ASD while continuing to optimize clinical guidelines, to ensure effective care for this growing population.

Effects of 5-HT2A receptor stimulation on economic demand for fentanyl after intermittent and continuous access self-administration in male rats.

The relative value of and motivation for abused drugs often increases with drug experience and differs based on drug availability. Here, we determined how different intake patterns of fentanyl, a µ-opioid agonist, alter economic demand for fentanyl and how 5-HT2A receptor stimulation affects economic demand for fentanyl. We used a within-session demand threshold procedure to characterize changes in economic demand for fentanyl before and after intermittent or continuous access schedules. We subsequently tested the acute effects of 5-HT2A receptor stimulation with psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on economic demand for fentanyl. Extended fentanyl experience with both intermittent and continuous schedules increased fentanyl consumption at low cost (Q0 ), increased total fentanyl consumption, and decreased demand elasticity (α), indicating both schedules elevated motivation to self-administer fentanyl. Overall, the two schedules produced similar alterations in economic demand for fentanyl, although low-cost consumption (Q0 ) increased more in the continuous access group. Systemic injections of DOI (0.0-0.4 mg/kg, i.p.) dose-dependently produced economic demand changes in the opposite direction produced by fentanyl experience. DOI decreased motivation (increased "α"), decreased Q0 , and decreased total fentanyl consumption. The selective 5-HT2A antagonist, M100907 (0.3 mg/kg, i.p.), blocked the effects of DOI, indicating that DOI is acting through 5-HT2A receptors to alter economic demand for fentanyl. In an economic food demand experiment, DOI (0.4 mg/kg) also increased demand elasticity and reduced food consumption. These results demonstrate that both intermittent and continuous fentanyl experience raise the economic demand for fentanyl, and acute 5-HT2A receptor activation reduces economic demand for fentanyl and food.

Hospital Variation in Child Protection Reports of Substance Exposed Infants.

OBJECTIVE: To examine whether hospital-level factors contribute to discrepancies in reporting to Child Protective Services (CPS) of infants diagnosed with prenatal substance exposure. STUDY DESIGN: We used a linked dataset of birth, hospital, and CPS records using diagnostic codes (International Classification of Diseases, Ninth Revision) to identify infants diagnosed with prenatal substance exposure. Using multilevel models, we examined hospital-level and individual birth-level factors in relation to a report to CPS among those infants prenatally exposed to substances. RESULTS: Of the 760 863 infants born in Washington State between 2006 and 2013, 12 308 (1.6%) were diagnosed with prenatal substance exposure. Infants born at hospitals that served larger populations of patients with Medicaid (OR, 1.25; 95% CI, 1.07-1.45) and hospitals with higher occupancy rates (OR, 1.43; 95% CI, 1.15-1.77) were more likely to be reported to CPS. Infants exposed to amphetamines (OR, 2.58; 95% CI, 2.31-2.90) and cocaine (OR, 2.33; 95% CI-1.92, 2.83) were more likely to be reported and infants exposed to cannabis (OR, 0.62; 95% CI-0.55, 0.70) were less likely to be reported to CPS than infants exposed to opioids. Infants with Native American mothers were more likely to be reported to CPS than infants with white mothers (OR, 1.47; 95% CI, 1.27-1.70). CONCLUSIONS: Hospital-level and individual birth-level factors impact the likelihood of infants prenatally exposed to substances being reported to CPS, providing additional knowledge about which infants are reported to CPS. Targeted education and improved policies are necessary to ensure more standardized approaches to CPS reporting of prenatal substance exposure.

Crisis under the radar: Illicit amphetamine use is reaching epidemic proportions and contributing to resource overutilization at a Level I trauma center.

INTRODUCTION: Trauma centers reported illicit amphetamine use in approximately 10% of trauma admissions in the previous decade. From experience at a trauma center located in a southwestern metropolis, our perception is that illicit amphetamine use is on the rise and that these patients utilize in-hospital resources beyond what would be expected for their injuries. The purposes of this study were to document the incidence of illicit amphetamine use among our trauma patients and to evaluate its impact on resource utilization. METHODS: We conducted a retrospective cohort study using 7 consecutive years of data (starting July 2010) from our institution's trauma registry. Toxicology screenings were used to categorize patients into one of three groups: illicit amphetamine, other drugs, or drug-free. Adjusted linear and logistic regression models were used to predict hospital cost, length of stay, intensive care unit admission, and ventilation between drug groups. Models were conducted with combined injury severity (Injury Severity Score [ISS]) and then repeated for ISS of less than 9, ISS 9 to 15, and ISS 16 or greater. RESULTS: Eight thousand five hundred eighty-nine patients were categorized into the following three toxicology groups: 1,255 (14.6%) illicit amphetamine, 2,214 (25.8%) other drugs, and 5,120 (59.6%) drug-free. Illicit amphetamine use increased threefold over the course of the study (from 7.85% to 25.0% of annual trauma admissions). Adjusted linear models demonstrated that illicit amphetamine among patients with ISS of less than 9 was associated with 4.6% increase in hospital cost (p = 0.019) and 7.4% increase in length of stay (p = 0.043). Logistic models revealed significantly increased odds of ventilation across all ISS groups and increased odds of intensive care unit admission when all ISS groups were combined (p = 0.001) and within the group with ISS of less than 9 (p = 0.002). CONCLUSIONS: Hospital resource utilization of amphetamine patients with minor injuries is significant. Trauma centers with similar epidemic growth in proportion of amphetamine patients face a potentially significant resource strain relative to other centers. LEVEL OF EVIDENCE: Prognostic/Epidemiological, level II; Therapeutic, level III.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Rapid and simple procedure for the determination of cathinones, amphetamine-like stimulants and other new psychoactive substances in blood and urine by GC-MS.

In the last few years an increasing number of new psychoactive substances (NPS), with different chemical structures (of which 37% are stimulants), have been released into the illicit drug market. Their detection and identification in biological samples is hence of great concern. The aim of this work was to develop a high-throughput and rapid method for the determination of different classes of stimulants (amphetamine-type stimulants, cathinones, phenethylamines and ketamine analogues) from blood and urine samples using GC-MS. The proposed method allows the almost simultaneous derivatization and extraction of analytes from biological samples in a very short time, by using hexyl chloroformate as derivatization agent. The extraction of analytes was performed by Dispersive Liquid Liquid Microextraction (DLLME), a very rapid, cheap and efficient extraction technique that employs microliter amounts of organic solvents. The chromatographic method allowed for the separation of 26 stimulants including positional isomers (3-MMC and 4-MMC). The method was validated on urine and blood samples with the ability to detect and quantify all analytes with satisfactory limits of detection (LODs) ranging between 1 and 10ng/mL, limits of quantification (LOQs) between 2 and 50ng/mL, selectivity and linearity (5-1000ng/mL). The method was then applied to real samples from forensic cases, demonstrating its suitability for the screening of a wide number of stimulants in biological specimens.

Purity, adulteration and price of drugs bought on-line versus off-line in the Netherlands.

BACKGROUND AND AIMS: On-line drug markets flourish and consumers have high expectations of on-line quality and drug value. The aim of this study was to (i) describe on-line drug purchases and (ii) compare on-line with off-line purchased drugs regarding purity, adulteration and price. DESIGN: Comparison of laboratory analyses of 32 663 drug consumer samples (stimulants and hallucinogens) purchased between January 2013 and January 2016, 928 of which were bought on-line. SETTING: The Netherlands. MEASUREMENTS: Primary outcome measures were (i) the percentage of samples purchased on-line and (ii) the chemical purity of powders (or dosage per tablet); adulteration; and the price per gram, blotter or tablet of drugs bought on-line compared with drugs bought off-line. FINDINGS: The proportion of drug samples purchased on-line increased from 1.4% in 2013 to 4.1% in 2015. The frequency varied widely, from a maximum of 6% for controlled, traditional substances [ecstasy tablets, 3,4-methylenedioxy-methamphetamine (MDMA) powder, amphetamine powder, cocaine powder, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and lysergic acid diethylamide (LSD)] to more than a third for new psychoactive substances (NPS) [4-fluoroamphetamine (4-FA), 5/6-(2-aminopropyl)benzofuran (5/6-APB) and methoxetamine (MXE)]. There were no large differences in drug purity, yet small but statistically significant differences were found for 4-FA (on-line 59% versus off-line 52% purity for 4-FA on average, P = 0.001), MDMA powders (45 versus 61% purity for MDMA, P = 0.02), 2C-B tablets (21 versus 10 mg 2C-B/tablet dosage, P = 0.49) and ecstasy tablets (131 versus 121 mg MDMA/tablet dosage, P = 0.05). The proportion of adulterated samples purchased on-line and off-line did not differ, except for 4-FA powder, being less adulterated on-line (χ2  = 8.3; P < 0.02). Drug prices were mainly higher on-line, ranging for various drugs from 10 to 23% higher than that of drugs purchased off-line (six of 10 substances: P < 0.05). CONCLUSIONS: Dutch drug users increasingly purchase drugs on-line: new psychoactive substances in particular. Purity and adulteration do not vary considerably between drugs purchased on-line and off-line for most substances, while on-line prices are mostly higher than off-line prices.

Captagon: use and trade in the Middle East.

BACKGROUND: Fenetheylline, a psychostimulant drug, often branded as Captagon, is a combination of amphetamine and theophylline. Since the cessation of its legal production in 1986, counterfeited products have been produced illicitly in south-east Europe and far-east Asia. Its profitable trade has been linked to terrorist organizations, including Islamic State of Iraq and the Levant. This study aims to reach up-to-date data, concerning the Captagon e-commerce and use in the Middle East. METHODS: A multi-staged and multi-lingual literature search was carried out. A list of prespecified keywords was applied across medical and paramedical databases, web and Dark web, search engines, social communication media, electronic commerce websites, media networks, and the Global Public Health Intelligence Network database. RESULTS: The use of Captagon as a stimulant in terrorist settings has been marginally covered in the literature. Data can widely be retrieved from Google and AOL search engines, YouTube, and Amazon e-commerce websites, and to a lesser extent from Alibaba and eBay. On the contrary, Middle Eastern e-commerce websites yielded almost no results. Interestingly, the Dark web generated original data for Captagon e-commerce in the Middle East. CONCLUSION: Further investigations are needed on the role that psychoactive drugs play in terrorist attacks and civil war zones. Unless a comprehensive methodological strategy, inclusive of unconventional methods of research, is implemented, it will not be feasible to face such a threat to humanity.

Self-administration and behavioral economics of second-generation synthetic cathinones in male rats.

RATIONALE: Synthetic cathinones have become increasingly available as drugs of abuse. Distribution of these drugs is made possible by altering the chemical structures of prohibited cathinones and marketing them under misleading labels. Very little is known about the relative reinforcing effectiveness of new synthetic cathinones relative to known drugs of abuse. OBJECTIVE: We examined self-administration of three second-generation synthetic cathinones: alpha-pyrrolidinopentiophenone (alpha-PVP), 4-methyl-N-ethylcathinone (4-MEC), and 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP) relative to methamphetamine. METHOD: Male, Sprague-Dawley rats, implanted with intravenous catheters, were trained to self-administer methamphetamine (0.05 mg/kg/injection) under a fixed-ratio schedule. Following training, various doses of methamphetamine (0.006-0.1 mg/kg/injection), alpha-PVP (0.0015-0.1 mg/kg/injection), 4-MEC (0.1-3.2 mg/kg/injection), or 4-MePPP (0.1-0.8 mg/kg/injection) were available for self-administration in separate groups, followed by a behavioral-economics evaluation of the reinforcing effectiveness of each drug. RESULTS: For all drugs, at least one dose functioned as a reinforcer. Alpha-PVP and 4-MePPP maintained the highest numbers of infusions per session and both were more effective reinforcers relative to methamphetamine. 4-MEC and methamphetamine were not significantly different in terms of infusions per session or reinforcing effectiveness. CONCLUSION: Emerging synthetic cathinones whose primary pharmacological mechanism is to block dopamine uptake but with little effects on monoamine release or serotonin uptake may have a greater degree of abuse potential compared with known abused stimulants.

Predictive Value of Positive Drug Screening Results in an Urban Outpatient Population.

Urine drug testing (UDT) has become an essential component in the management of patients prescribed opioid analgesics for the treatment of chronic non-malignant pain. Several laboratory methods are available to monitor adherence with the pharmacological regimen and abstinence from illicit or unauthorized medications. Immunochemical screening methods are rapid and economical, but they have limitations, including lack of specificity, and confirmatory methods are often necessary to verify presumptive positive results. We analyzed the results of confirmatory assays in an outpatient setting to determine the predictive value of presumptive positive urine drug screen results using an automated immunoassay for eight common drugs or drug classes. Positive predictive values (PPVs), in descending order, were as follows: cannabinoids (100%), cocaine (100%), opiates (86.8%), benzodiazepines (74.6%), oxycodone (67.6%), methadone (44.1%) and amphetamines (9.3%). The number of positive barbiturate results was too small to be included in the statistical analysis.

History full circle: 'Novel' sympathomimetics in supplements.

Since the banning of ephedrine in over-the-counter nutritional supplements a decade ago, a plethora of untested and/or unsafe sympathomimetic stimulants have taken its place. This paper argues that these 'novel' stimulants in supplements recapitulate the work of synthetic chemists at commercial pharmaceutical firms during the 1930s and 1940s, all seeking substitutes for recently successful products based on ephedrine and amphetamine. Copyright © 2015 John Wiley & Sons, Ltd.

Recent Trends in Stimulant Usage.

OBJECTIVE: In the last decade, dramatic changes have occurred in stimulant medication prevalence and in patterns of stimulant treatment. The resultant trends merit analysis. METHOD: Usage patterns of stimulant medication, specifically amphetamine and methylphenidate, were analyzed for trends. The data were obtained from datasets including pharmacy claims, aggregate production quotas, bulk distribution to counties, pharmacy prescription sales, parent surveys, and physician visit surveys. Stimulant medication trends were organized by drug subclass, year, age group, gender, country, prescriber specialty, diagnosis, and expenditures. RESULTS: Major recent trends are as follows: amphetamine medication usage has prominently surpassed methylphenidate, total stimulant prescription sales to adults have surpassed those for youth, and more adult women are prescribed stimulants than adult men. CONCLUSION: Stimulant medication treatment-particularly of amphetamines-is rapidly expanding in the United States. Off-label use is reported to be at least 40% of total use and appears to be more common in adults. (J. of Att. Dis. 2016; 20(6) 471-477).

Stimulant use following the publicity of cardiovascular safety and the introduction of patient medication guides.

PURPOSE: To explore changes in stimulant utilization and pre-treatment electrocardiography (ECG) screening in response to cardiovascular (CV) safety concerns. METHODS: Two source populations were established from Florida Medicaid Fee-for-service beneficiaries between 2001 and 2008: approximately 44 571 newly diagnosed attention deficit/hyperactivity disorder patients and 33 000 new stimulant users. Time-series design and Joinpoint analysis were used to describe monthly trend changes in stimulant initiation, persistence, dosing, and pre-treatment ECG screening. RESULTS: Initial and maintenance daily dose declined 6 mg (95% confidence interval [CI] -14 to -1.9) methylphenidate (MPH) equivalent dose from a steady 27 mg after Canada withdrew Adderall XR in February 2005; the trend rebounded to a daily dose of 23 mg, after the remarketing of Adderall XR and a debate in the US over issuing a boxed warning on stimulant CV safety in early 2006. Monthly initiation increased 3.9% (CI -1.0 to 9.1) after the boxed warning debate to 54 per 100 patients per month (CI 44 to 68), but declined 2.4% (CI -3.6 to -1.2) after requirement of medication guides in February 2007. Monthly ECG screening increased 3.2% (CI 2.3 to 4.2) after Adderall XR withdrawal and further increased 13% (CI 4 to 23) after the American Heart Association recommended pre-treatment ECG screening to 40 per 100 patients per month (CI 17 to 48). CONCLUSIONS: The first signal of stimulant CV safety concerns was followed by varying responses depending on the outcome measure used, suggesting that patients and physicians responded at different times after the publicity of safety concerns. Clinical consequences of the changes are uncertain. Copyright © 2015 John Wiley & Sons, Ltd.

Eficacia y seguridad del mazindol / Efficacy and safety of mazindol

ANTECEDENTES Y CONTEXTO: El mazindol es un estimulante central imidazólico, de efecto similar a las anfetaminas, utilizado fundamentalmente como anorexígeno y también para el tratamiento de otras patologías. Produce excitabilidad, irritabilidad y aumenta el riesgo cardiovascular; también genera rápida tolerancia, dependencia y un alto potencial de abuso. En la actualidad el uso de mazindol es controvertido y ha sido retirado del mercado en la mayoría de los países. OBJETIVO: Evaluar la seguridad y la eficacia del mazindol en la práctica clínica. MÉTODO: Revisión sistemática de la bibliografía obtenida en las bases de datos de estudios publicados desde 1975 a 2016, sin restricción de lenguaje y que evaluaran la eficacia y/o seguridad de mazindol en seres humanos. RESULTADOS: Cumplieron las condiciones de inclusión 20 estudios de un total de 338 encontrados: cuatro revisiones sistemáticas, un metaanálisis, siete ICCAs, tres guías de práctica clínica, dos series de casos, una revisión narrativa, un estudio observacional de corte transversal y un estudio descriptivo. Los estudios incluidos carecen de potencia suficiente para evaluar la eficacia y seguridad del mazindol para los puntos finales evaluados con excepción del tratamiento de la narcolepsia o narcolepsia/cataplexia. En síntesis: -Obesidad Refractaria: Los estudios presentan un limitado número de pacientes y del tiempo de seguimiento. Son de baja calidad metodológica y reportan severos eventos adversos; -Diabéticos con sobrepeso: hay fuerte evidencia para desaconsejar su uso; -Sindrome de Prader Willi: no demostró eficacia; -Distrofia muscular de Aran-Duchenne: no demostró eficacia a los nueve meses de seguimiento; -Narcolepsia y Narcolepsia/Cataplexia: es efectivo, redujo a la mitad o menos la frecuencia de la parálisis del sueño, constituyendo una segunda opción terapéutica luego del modafilino, metilfenidato, oxibato sódica; -Prevención de la recaída en el consumo de cocaína: no hay evidencia de eficacia; -Efectos adversos: los más frecuentes se circunscriben a los sistemas cardiovascular, gastrointestinal y nervioso. Son moderados a severos. El 84% de las notificaciones al Sistema Nacional de Farmacovigilancia están vinculadas a preparaciones magistrales con mazindol. CONCLUSIONES: Las evidencias disponibles, en términos de eficacia, efectividad y riesgo/beneficio, no justifican el uso del mazindol en el tratamiento de la obesidad y de las demás condiciones analizadas a lo largo de esta revisión, excepto para su empleo en el tratamiento de la narcolepsia o narcolepsia/cataplexia como droga de segunda línea cuando los pacientes no responden a modafinilo, metilfenidato u oxibato sódico.(AU)

Impact of a restrictive drug access program on the risk of cardiovascular encounters in children exposed to ADHD medications.

BACKGROUND: ADHD medications increase clinical encounters for cardiovascular symptoms. Uncertain are the roles of differences in ADHD medications and restrictive practices by drug programs. METHODS: We conducted two nested case-control studies. The first was nested within a cohort of children de novo users of methylphenidate, amphetamines or atomoxetine and the second case-control study was nested within a subcohort of de novo amphetamine or atomoxetine users with no cardiovascular events prior to the first dispensing of either drug. The outcome for both studies was the composite of physician visits, emergency room visits or hospitalizations for cardiovascular reasons. Cases were matched on sex, age and date of entry within the cohorts, with up to 10 controls. Patients with an active dispensation of ADHD medications at the index date (and up to 90 days previously) were considered exposed. Conditional logistic regression was used to calculate odd ratios (OR). RESULTS: The full cohort comprised 38,495 patients. Among these patients, 3595 (9.3%) had no prior cardiovascular events (the subcohort). In the full cohort, an association was demonstrated with exposure to amphetamine and atomoxetine (but not methylphenidate) and the cardiovascular encounter outcomes. When the sub-cohort was analyzed the associations with amphetamine or atomoxetine were no longer evident. CONCLUSION: Reimbursement policies need to be considered when conducting observational studies. Had the analysis been conducted without consideration of these policies the results would have incorrectly identified amphetamine and atomoxetine as important risk factors for cardiovascular encounters.

Quantitative assessment of rest and acetazolamide CBF using quantitative SPECT reconstruction and sequential administration of (123)I-iodoamphetamine: comparison among data acquired at three institutions.

PURPOSE: A recently developed technique which reconstructs quantitative images from original projection data acquired using existing single-photon emission computed tomography (SPECT) devices enabled quantitative assessment of cerebral blood flow (CBF) at rest and after acetazolamide challenge. This study was intended to generate a normal database and to investigate its inter-institutional consistency. METHODS: The three institutions carried out a series of SPECT scanning on 32 healthy volunteers, following a recently proposed method that involved dual administration of (123)I-iodoamphetamine during a single SPECT scan. Intra-institute and inter-institutional variations of regional CBF values were evaluated both at rest and after acetazolamide challenge. Functional images were pooled for both rest and acetazolamide CBF, and inter-institutional difference was evaluated among these images using two independent software programs. RESULTS: Quantitative assessment of CBF images at rest and after acetazolamide was successfully achieved with the given protocol in all institutions. Intra-institutional variation of CBF values at rest and after acetazolamide was consistent with previously reported values. Quantitative CBF values showed no significant difference among institutions in all regions, except for a posterior cerebral artery region after acetazolamide challenge in one institution which employed SPECT device with lowest spatial resolution. Pooled CBF images at rest and after acetazolamide generated using two software programs showed no institutional differences after equalization of the spatial resolution. CONCLUSIONS: SPECT can provide reproducible images from projection data acquired using different SPECT devices. A common database acquired at different institutions may be shared among institutions, if images are reconstructed using a quantitative reconstruction program, and acquired by following a standardized protocol.

Designing a tool allowing for a standardized assessment of resistance to drug diversion.

OBJECTIVES: Drug diversion is a growing problem in numerous countries. Some laboratories have developed tamper-resistant formulations. The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion for administration by another mode and intended mode. It would be helpful to have a pertinent panel of in vitro tests allowing assessment of how a formulation may be altered, both for healthcare authorities and for laboratories, so as to implement adequate sanitary measures. We designed a methodology/tool allowing assessment, in a standardized manner, of the formulation's resistance to drug diversion. We present the various steps leading to the construction of the scale and to its first use. METHODS: Creating a Steering Committee - Choosing assays or parameters - standardized by a monograph of the European Pharmacopoeia and pragmatic assays related to users' behaviors - for the assessment of formulation resistance to drug diversion. Designing a scale: i) applying all these tests to a panel of formulations; ii) applying a score by drug and by test; and iii) attribution of weighting per test and calculating the total score for a drug. RESULTS: Eight tests or parameters and 14 drugs (diverted drugs and controls) were chosen. Buprenorphine Subutex® had the lowest score and flunitrazepam Rohypnol® the highest. CONCLUSIONS: Our tool allowed classification of the various drugs selected. This classification correlated with results of postmarketing authorization assessment. Rohypnol®, which was the object of many measures, including formulation changes, obtained the highest score in our study.

Treatment persistence in attention deficit/hyperactivity disorder: a retrospective analysis of patients initiated on lisdexamfetamine vs other medications.

OBJECTIVE: To compare treatment persistence in attention-deficit/hyperactivity disorder (ADHD) of patients initiated on lisdexamfetamine (LDX) vs other ADHD medications. METHODS: A large US administrative claims database was used to select ADHD patients who initiated an ADHD medication (index treatment) during/after 2007. Patients were classified, based on age and previous treatment status, as treatment-naïve or previously treated children and adolescents (6-17 years) and treatment-naïve or previously treated adults (18 years and older). Furthermore, patients were classified into seven mutually exclusive treatment groups, based on their index treatment: LDX, atomoxetine (ATX), osmotic-release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate short-acting (MPH SA) and long-acting (MPH LA), and amphetamine/dextroamphetamine short acting (AMPH SA) and long-acting (AMPH LA). Treatment persistence, analyzed through discontinuation (interruption of the index treatment for ≥30 consecutive days), was compared between treatment groups using multivariate Cox proportional hazards. Patients were followed until first treatment discontinuation or up to 12 months after the initiation of the index treatment, whichever occurred first. RESULTS: Among children and adolescents, LDX patients had a significantly lower discontinuation rate compared to other treatment groups (range hazard ratios [HRs]; 1.04-2.26; all p < 0.05), except when compared to treatment-naïve patients on ATX and OROS MPH, where no statistically significant differences were found and where LDX had a higher risk of discontinuation, respectively. Among adults, LDX patients had a significantly lower discontinuation rate compared to patients in other treatment groups (range HR; 1.14-1.86; all p < 0.05), except for the comparison with AMPH LA patients, where differences were not statistically significant. LIMITATIONS: This study did not control for ADHD severity. CONCLUSION: LDX-treated patients were associated with higher persistence compared to patients initiated on other ADHD medications, except for the comparisons with OROS MPH and ATX treated patients in treatment-naïve children and adolescents and AMPH LA-treated patients in adults.