Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

Serious Adverse Drug Events Reported to the FDA: Analysis of the FDA Adverse Event Reporting System 2006-2014 Database.

BACKGROUND: Data on adverse drug events (ADEs) observed at the population level provide important evidence regarding the safety of a pharmaceutical product in real-world settings. Recent patterns in serious and fatal ADE reporting have not been documented. OBJECTIVE: To assess recent patterns in serious and fatal ADE reports in the United States. METHODS: We conducted a retrospective analysis of the publicly available 2006-2014 FDA Adverse Event Reporting System database. Non-U.S. reports, reports from clinical trials, and reports with missing outcome data were excluded. The annual numbers of ADEs with reported outcome of death, disability, and other serious outcomes were determined. Types (direct, manufacturer expedited, or manufacturer periodic) and sources (consumer, health professional, or other) of these serious ADE reports were also identified. The distribution of serious ADE reports by patient age groups (< 18, 18-44, 45-64, and ≥ 65 years) was determined. Drugs listed as primary suspects in serious ADEs (death, disability, and other serious outcomes) were identified and ranked. Descriptive statistics were used to characterize the patterns in serious or fatal ADE reporting. RESULTS: From 2006 to 2014, the number of serious ADEs reported to the FDA increased 2-fold. A total of 902,323 serious outcomes were reported over the 9-year study period: 244,408 deaths, 72,141 disabilities, and 585,774 other serious outcomes. The relative percentage of reports of deaths was highest during 2012 (32.4%). The percentage of reports of disability was highest during 2006 (12.1%). Overall, the "other serious outcomes" category accounted for almost 65% of serious ADEs reports. Expedited reports from drug manufacturers were most common (about 72%) of the serious ADEs with available data on report type. Health professionals (47.3%) were the most common source of report followed by consumers (36.1%) and other sources (16.6%). A disproportionately high number of reported ADEs was among patients aged 45-64 years (40%) and ≥ 65 years (32.6%). Antineoplastic drugs were more frequently reported with deaths. Three antidepressant drugs were among the top 10 drugs reported with disability. During 2006-2014, there were 38 drugs with more than 1,000 reports of serious ADEs in a given year: 2 drugs currently withdrawn from the market (rofecoxib and parecoxib), 10 drugs with an FDA risk evaluation and mitigation strategies (REMS) program, 13 biologic or specialty drugs, and 14 others. CONCLUSIONS: An overall increase in the trend of the number of serious ADE reports was observed from 2006 to 2014. Drugs with a REMS program and biologic and specialty drugs were involved in a significant number of reported serious ADEs. Data on reporting patterns can guide surveillance and pharmacoepidemiological studies to understand the public health burden of serious ADEs. DISCLOSURES: No outside funding supported this study. Hansen has received consulting fees from and has provided expert testimony for Daichii Sankyo and Takeda. The other authors have nothing to disclose.

Frequency and correlates of anticholinergic use among patients with schizophrenia in Denmark: A Nation-wide pharmacoepidemiological study.

Anticholinergic medications are used to treat extrapyramidal adverse effects induced by antipsychotics. Anticholinergics are associated with adverse effects: constipation, dry mouth and worsening of cognitive function. Anticholinergics have potential for abuse and are not recommended for long term-treatment. We aimed to investigate the use of anticholinergics in patients with schizophrenia. The national health registers in Denmark were used to examine: The prevalence of anticholinergics in 1996-2012 using a cross-sectional design; geographic variations in the prescription of anticholinergics in 2012; correlates of treatment with anticholinergics. The proportion of patients using anticholinergics decreased significantly from 11.7% in 1996 to 5.7% in 2012. The prescription pattern varied considerably between national regions in 2012, ranging from 4.0% in the Capital Region to 8.1% in the Northern Denmark Region. Long-term use of anticholinergics was predicted by older age, age at debut of schizophrenia, receiving early retirement pension, typical antipsychotic use, antipsychotic polypharmacy, typical + atypical antipsychotics, antidepressant treatment, high doses of antipsychotics measured in defined-daily-dose, physical comorbidity and psychiatrists` greater caseload. Use of anticholinergics declined during the study period, and showed substantial variation across the regions in 2012. Long-term use was linked to typical antipsychotic use and variables that are associated with greater illness severity.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis.

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.

Triptans use and overuse: A pharmacoepidemiology study from the French health insurance system database covering 4.1 million people.

INTRODUCTION: The objective of this study was to estimate and to characterize the actual patterns of triptan use and overuse in France using a drug reimbursement database. METHODS: We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one dispensed dose of triptans between May 2010 and December 2011. All dispensed doses of triptans, migraine prophylactic treatment and psychotropic medications were extracted from the GHIS database. Triptan overuse was defined as triptan use >20 defined daily doses (DDD) per month on a regular basis for more than three consecutive months. Risk of overuse was assessed using logistic regression adjusted for gender and age. RESULTS: We included 99,540 patients who had at least one prescription of a triptan over the 20 months of the study. Among them, 2243 patients (2.3%) were identified as overusers and received 20.2% of the total DDD prescribed. Twelve percent of overusers and 6.9% of non-overusers were aged more than 65 years (OR: 1.81). Overusers did not have a greater number of prescribers and pharmacists than non-overusers. They were more frequently prescribed a prophylactic medication for migraine treatment (56.8% vs 35.9%, OR: 2.36), benzodiazepines (69.9% vs 54.7%, OR: 1.93) and antidepressants (49.4% vs 30.2%, OR: 2.33). CONCLUSIONS: This work suggests that triptan overuse may be due to insufficient prescriber awareness of appropriate prescribing. The off-label prescription of triptans among the elderly necessitates investigating their cardiovascular risk profile in this sub-group.

Sobre utilización de Inhibidores de la acidez gástrica en pacientes pediátricos / Overuse of acid-suppressive therapy in pediatric patients

Objetivos: Evaluar los patrones de prescripción deranitidina y omeprazol en pacientes pediátricos ingresados enun hospital de niños; la adecuación de dichas prescripcionesy los costos generados por prescripciones incorrectas.Pacientes y Métodos: estudio de utilización demedicamentos para observar pacientes ingresados en elHospital de Niños (Córdoba –Argentina) durante 1 mes.Resultados: Durante el mes de estudio ingresaron 680pacientes, de los cuales 415 (61%) recibieron inhibidoresde la acidez gástrica (IAG). De estos, 330 pacientes (79,5%)no presentaron factores de riesgo para desarrollar úlcerapor estrés, y en 293 pacientes (70,6%) las indicacionesse consideraron incorrectas. Sólo 81 pacientes (19,5%)presentaron indicaciones y dosis correctas de IAG. Seencontró una relación de la prescripción con el ingreso aquirófano y con el uso concomitante de corticoides a dosisbajas. El consumo innecesario de IAG generó un gasto directomensual de US$ 470,42

Objectives: To evaluate prescription patterns of intravenous ranitidine and omeprazolein pediatric patients hospitalized in a children’s hospital, the adequacy of said prescriptionsand the costs originated by incorrect prescriptions.Patients and Methods: A study of medication usage was designed to observe all patientshospitalized at Hospital de Niños (Córdoba- Argentina) during one month.Results: During the month of study 680 patients were hospitalized, 415 (61%) ofthem received acid-suppressive drugs (ASD). From these, 330 patients (79.5%) did notshow risk factors to develop stress ulcer and indications were considered incorrect in 293patients (70.6%). Only 81 patients (19.5%) showed correct indications and doses of ASD.A relationship was found between prescription and access to the operating room alongwith the concomitant use of corticoid in low doses. The unnecessary consumption of ASDgenerated a direct monthly expenditure of USD 470.42

Indicadores do uso racional de medicamentos em ambulatório-escola / Indicators of rational use of drugs in school ambulatory care

Introdução: O uso inadequado de medicamentos é um problema de Saúde Pública prevalente em todo o mundo e pode causar danos à saúde da população. A OMS estabeleceu indicadores do uso racional de medicamentos com o objetivo de minimizar os erros relativos ao ato da prescrição. Metodologia: Foi realizado um estudo transversal prospectivo no Ambulatório Central da Faculdade de Medicina de Passo Fundo/RS, entre agosto e novembro de 2006. Foram avaliados os indicadores do uso racional de medicamentos: número médio de medicamentos por receita; porcentagem de medicamentos receitados por seu nome genérico; porcentagem de prescrições contendo antimicrobiano; porcentagem de prescrições com medicamentos injetáveis e porcentagem de medicamentos receitados que constam na lista de medicamentos essenciais (RENAME e REMUME). Resultados: Foram prescritos 1.430 medicamentos e em média 2,62 ±1,80 medicamentos por prescrição. Dos medicamentos, 18,1% eram antimicrobianos e 9,2% eram injetáveis. Dos medicamentos prescritos, 84,8% pertenciam à RENAME e 77,3% à REMUME. Foram prescritos 86,2% dos medicamentos pela denominação genérica. Conclusões: Em relação aos indicadores do uso racional de medicamentos, pode-se observar que a maioria das receitas continha medicamentos da REMUME, que foram prescritos pela denominação genérica e que o número de antimicrobianos e medicamentos injetáveis foi abaixo daqueles indicados por outros estudos. O número médio de medicamentos por prescrição foi maior que o recomendado pela OMS. Entretanto, as outras variáveis foram consideradas adequadas.

Introduction: The inadequate use of medication is a public health issue that is prevalent all over the world and is a threat to the health of the population. The WHO has established indicators of the rational use of medical drugs in order to minimize errors concerning drug prescription. Methods: A prospective transversal study was performed in the Outpatient Center of the Medical School of Passo Fundo-RS from Aug to November 2006. The following indicators of the rational use of medication were assessed: mean number of drugs per prescription; percentage of drugs prescribed by their generic name; percentage of prescriptions containing antimicrobials; percentage of prescriptions of injectable drugs, and percentage of prescribed drugs that are present in the essential medicines lists (RENAME and REMUME). Results: A total of 1,430 drugs were prescribed, with a mean 2.62 ±1.80 drugs per prescription. Of these,18.1% were antimicrobials and 9.2 % were injectable. Of the prescribed drugs, 84.8% were in the RENAME and 77.3% were in the REMUME. 86.2% of the drugs were prescribed by their generic name. Conclusions: Concerning the indicators of the rational use of medication, most of the prescriptions hadREMUME drugs, were prescribed by their generic name, and the number of antimicrobials and injectable substances was below the one reported in other studies. The mean number of drugs by prescription was greater than that recommended by the WHO. However, the other variables were considered appropriate.

Implementação de um programa para evitar possíveis interações fármaco-alimento em pacientes adultos internados em unidades clínicas e cirúrgicas de um hospital universitário / Implementation of a program to prevent possible drug-food interactions in adult patients hospitalized in the clinical and surgical units of a university hospital

Introdução: As interações fármaco-alimento (IFA) são definidas como alterações produzidas nos efeitos terapêuticos de um medicamento em razão da ingestão concomitante de alimento. Objetivo: Identificar prescrições médicas com possíveis IFA dos pacientes internados no Hospital de Clínicas de Porto Alegre (HCPA) e orientar o corpo clínico quanto aos horários adequados de administração dos medicamentos. Métodos: O estudo analisou, entre fevereiro e julho de 2006, 2.645 prescrições de pacientes adultos internados nas unidades clínicas e cirúrgicas do HCPA e que recebiam dieta oral. Resultados: Observou-se que 54,5% (1.442) das prescrições apresentavam potenciais IFA. Nesses casos, as equipes assistenciais recebiam, através de notificação em prontuário médico, informações sobre os medicamentos que necessitavam de intervalo de jejum para garantir sua máxima biodisponibilidade. Conclusão: A alta incidência de prescrições contendo medicamentos possíveis de interagir com os alimentos demonstra a necessidade de um sistema que disponibilize, sistematicamente, as orientações relacionadas à correta administração dos medicamentos.

Background: Drug-food interactions (DFI) are defined as alterations produced in the therapeutic effects of a drug due to concomitant food ingestion. Objective: To identify medical prescriptions with possible DFI in patients hospitalized at Hospital de Clínicas de Porto Alegre (HCPA) and to provide guidance to the clinical staff about the appropriate time for drug administration. Methods: Between February and July 2006, we analyzed 2,645 prescriptions of adult inpatients receiving oral diet. Results: We found that 54.5% (1,442) of the prescriptions had potential DFI. In such cases, the medical staff was receiving information about the drugs that needed a fasting interval to ensure maximum bioavailability by means of notifications in medical records. Conclusions: The high incidence of prescriptions with possible DFI shows the need for a system that provides systematic guidance regarding the adequate administration of drugs.

[Pharmacoepidemiology. Analysis of drug prescription data]. / Pharmakoepidemiologie. Nutzung der Arzneimittelverordnungsdaten.

Due to an increase in pharmaceutical expenditure and growing demands on the observation and analysis of the pharmaceutical use in the overall population, pharmacoepidemiology has increasingly gained importance. In the foreground of this scientific discipline is the analysis of drug use in every day treatment; pharmaceutical prescription data are a suitable data source as they are part of the health care routine. In Germany prescription data are collected as process data of the Statutory Health Insurance (GKV) under naturalistic conditions and are for this reason not distorted by study designs nor artificial survey conditions. The contribution at hand states the most common data sources und gives an overview on the character of pharmaceutical prescription data, their information content and how they can be used for scientific research. The prevailing study designs which are applied in pharmacoepidemiologic surveys and the prevalent methodological approaches of the pharmaceutical appliance research on the basis of secondary GKV data are presented. Furthermore, an outlook is given on Pharmacoepidemiological Databases (PDb) that are already well-established in other countries and possibilities will be shown for monitoring drug utilization and turnover.

Determinants of medicine use in a Swedish primary health care practice population.

BACKGROUND: Pharmaceuticals represent an increasing share of private and public health care expenditures. The aim of this study was to characterise users and to determine the pattern of uses of prescribed medicines and to identify determinants of medicine use in a multi-ethnic Swedish general practice population. METHODS: The study was performed in 1055 of 1442 consecutive adult patients visiting the Jordbro Health Centre (JHC) in Stockholm, Sweden. RESULTS: In a regression analysis adjusted for the influence of confounders, subjects reporting 10-30 complaint symptoms, subjects with chronic disease and subjects that had a cost limitation card all reported a higher number of used medicines than subjects with a few (0-10) symptoms and those without chronic disease and a cost limitation card. In a Poisson's regression analysis, high age, female gender, not working, more than 10 symptoms, chronic disease and having a cost limitation card were related to use of prescribed medicines. All included variables predicted 19% of the explanation. Marital status, multi-symptomatology, chronic disease and having a cost limitation card were related to polypharmacy in a logistic regression analysis. CONCLUSION: A high number of complaint symptoms, chronic disease and having a cost limitation card were all significantly and independently related to use of medicines and polypharmacy.

The use of CDK inhibitors in oncology: a pharmaceutical perspective.

To date dozens of pharmacophores with CDK-inhibitory properties have been discovered and the first compounds possessing such activity are now under clinical evaluation. Because the real therapeutic utility of these agents should be able to be assessed in the foreseeable future, it is unfortunate that CDK biology remains a moving target. Until recently is has been held that inhibiting CDK2, presumed master of the 10 known CDK isoforms, should be most beneficial in terms of achieving potent and selective antiproliferative effects in transformed cells. Recent findings, however, suggest that CDK2 may not be the key cell cycle player previously assumed, after all. It has also now become clear that CDKs have functions in physiological processes other than coordination of cell cycle progression, particularly regulation of DNA transcription. The implications of these new biological insights for the discovery and development of CDK inhibitors in oncology are discussed.

Perfil de consumo de antibióticos en un hospital pediátrico de la ciudad de México / Antibiotics consumption in pediatric hospital in Mexico City

Antecedentes. El uso de antibióticos (ATB) representa una de las actividades más comunes que se llevan acabo en la práctica diaria. Objetivo. Determinar como se efectúa la distribución y consumo de los ATB en el Instituto Nacional de Pediatría (INP) por ser el grupo de fármacos de mayor interés terapéutico. Método. El análisis sobre la distribución y consumo de medicamentos se realizó directamente en la farmacia del hospital, en un período de 15 meses (de enero-1994 a marzo-95). Resultados. Se entregaron 406,773 medicamentos, encontrándose una mayor distribución hacia el servicio de infectología con 120,731 (29.6 por ciento), Medicina Interna 92,206 (22.6 por ciento). Del total de medicamentos distribuidos entre los servicios 130,627 (32.1 por ciento) correspondió al grupo de los ATB, llamando la atención el "consumo" de ATB en Cirugía con 63.0 por ciento, cantidad que superó significativamente el consumo de anestésicos en dicho servicio (p<0.05). Conclusiones. El perfil de consumo de medicamentos en el INP mostró tendencias al consumo excesivo de ATB. Además, una de las fallas detectadas para el uso adecuado de ATB en el Instituto fue que, no existe colaboración entre las Comisiones de Control de medicamentos con el Servicio de Farmacoología para que se norme y vigile el uso de los mismos, como una contribución del manejo racional de los ATB, y con ello evitar o disminuir sus consecuencias

Changing patterns of psychotropic medications prescribed by child psychiatrists in the 1990s.

The active (1994) and closed (1988 to 1992) outpatient records of youths seen in four separate community mental health centers (CMHC) in Baltimore County, Maryland were reviewed in mid-1994 to document recent changes in the medication-prescribing practices of local child psychiatrists. Inpatient summaries of previously hospitalized CMHC youths were also reviewed to supplement the outpatient medication assessment with hospital data. This regional survey of medication treatments in child psychiatry revealed that, during the half decade before 1994, there was an increase in overall psychotropic medication treatment, multiple concurrent medication treatments (polypharmacy), and antidepressant treatment with serotonin reuptake inhibitors (SRIs). Inpatient youths were consistently prescribed more psychotropic medications and diagnosed more frequently with major depressive disorder than outpatients. Medications typically used to first treat mood disorders became the predominant medication prescribed for both outpatients and inpatients by child psychiatrists in 1994, leading to a proportional decline in prescribed stimulant treatment. The shift from tricyclic antidepressants to SRI antidepressants in the 1990s by child psychiatrists matches the same recent practice shift by adult psychiatrists. Likewise, the increased prescription of drugs to treat mood disorders and the increased rate of polypharmacy notable of late among child psychiatrists now also mirrors adult psychiatry practice. Wide geographic variations in neuroleptic and antidepressant medication patterns were noted, even among facilities in the same metropolitan region. After psychiatric hospitalization, most youths who continued treatment at a CMHC outpatient clinic discontinued their inpatient medications within 3 months; the sole exception were children who had been placed on psychostimulants.

The evolution of clinical practice and time trends in drug effects.

Evidence from contemporary studies suggests that the quantification of adverse drug effects through state-of-the-art non-experimental methods may be confounded by some aspects of clinical practice. Support for this hypothesis is manifest in the finding that drug effects sometimes show within-study time trends when clinical practice with regard to drug use is evolving. Three studies which show simultaneous trends in prescription frequency and drug effects are discussed as examples. These include a study of benzodiazepines in the etiology of hip fracture, postmenopausal estrogens as a preventive for major coronary disease and human insulin as a risk factor for severe hypoglycemia. For instance, during a period when clinical perceptions regarding the safety of benzodiazepine use in the elderly underwent gradual change, the relative risk for hip fracture among long half-life benzodiazepine users declined progressively from 2.0 (95% CI, 1.6-2.5) in 1977-79 to 1.3 (95% CI, 0.9-1.8) in 1984-85. The implications of these observations are set against the scientific objectives which guide etiologic research.