Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial.

Importance: In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. Objective: To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. Interventions: Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. Main Outcome and Measure: Twenty-four-hour urinary excretion of NDMA. Results: Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. Conclusions and Relevance: In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. Trial Registration: ClinicalTrials.gov Identifier: NCT04397445.

Assessing Treatment Effects with Pharmacometric Models: A New Method that Addresses Problems with Standard Assessments.

Longitudinal pharmacometric models offer many advantages in the analysis of clinical trial data, but potentially inflated type I error and biased drug effect estimates, as a consequence of model misspecifications and multiple testing, are main drawbacks. In this work, we used real data to compare these aspects for a standard approach (STD) and a new one using mixture models, called individual model averaging (IMA). Placebo arm data sets were obtained from three clinical studies assessing ADAS-Cog scores, Likert pain scores, and seizure frequency. By randomly (1:1) assigning patients in the above data sets to "treatment" or "placebo," we created data sets where any significant drug effect was known to be a false positive. Repeating the process of random assignment and analysis for significant drug effect many times (N = 1000) for each of the 40 to 66 placebo-drug model combinations, statistics of the type I error and drug effect bias were obtained. Across all models and the three data types, the type I error was (5th, 25th, 50th, 75th, 95th percentiles) 4.1, 11.4, 40.6, 100.0, 100.0 for STD, and 1.6, 3.5, 4.3, 5.0, 6.0 for IMA. IMA showed no bias in the drug effect estimates, whereas in STD bias was frequently present. In conclusion, STD is associated with inflated type I error and risk of biased drug effect estimates. IMA demonstrated controlled type I error and no bias.

A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers.

9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.

Debate 4: ¿Funciona vareniclina a dosis bajas? En contra / Debate 4: Does varenicline work at low doses? Against

No disponible

Efecto placebo y contexto terapéutico: un reto en investigación clínica / Placebo effect and therapeutic context: A challenge in clinical research

Cuando administramos un tratamiento físico o farmacológico, existen muchas variables que pueden explicar la mejoría clínica que experimenta un paciente. El principio activo del fármaco o el agente físico aplicado son importantes, pero también hay que sumarle otros elementos presentes en el contexto de la relación paciente-terapeuta. La evidencia científica ha demostrado que el efecto placebo existe. Se trata de un auténtico fenómeno biopsicosocial producido por el contexto en el cual se lleva a cabo una intervención. Sesgos al margen, las respuestas placebo y nocebo son cambios en los síntomas de los pacientes atribuibles a su participación en el encuentro terapéutico, con sus rituales, símbolos e interacciones. Esta multitud de señales inherentes a toda intervención son percibidas e interpretadas por los pacientes, generando expectativas positivas o negativas (AU)

When we apply a physical or pharmacological treatment, there are many things that may explain the clinical improvement experienced by a patient. The drugs or physical agents applied are important, but we must also add other elements in the context of the patient-therapist relationship. Scientific evidence has proven that the placebo effect exists. This is a true biopsychosocial phenomenon produced by the context in which an intervention is carried out. Biases aside, placebo and nocebo responses are changes in patients’ symptoms, due to their participation at the therapeutic meeting, with its rituals, symbols and interactions. This multitude of signals inherent in any intervention, is perceived and interpreted by patients and can create positive or negative expectations (AU)

Efecto de la terapia adyuvante con memantina en el control de los síntomas positivos, negativos y depresivos de la esquizofrenia: estudio aleatorizado, doble ciego y controlado / The effect of add-on memantine on positive, negative and depressive symptoms of schizophrenia: a double-blind, randomized, controlled trial

Antecedentes. Aunque los fármacos antipsicóticos son el pilar básico del tratamiento de la esquizofrenia, no resuelven adecuadamente los síntomas residuales positivos, negativos y depresivos. El objetivo del presente estudio es evaluar el efecto del tratamiento adyuvante con memantina sobre los síntomas positivos, negativos y depresivos de la esquizofrenia. Métodos. Este estudio aleatorizado, controlado con placebo se ha realizado en el hospital Noor en Isfahan, Irán, de 2013 a 2014. En cada grupo se seleccionaron al azar 32 pacientes con tratamiento de mantenimiento. Los pacientes fueron seleccionados como muestreo en bloque. Los criterios de inclusión fueron: edad de 18 a 65 años, con capacidad mental normal, diagnosticados de esquizofrenia durante los últimos dos años y tratados con dosis fijas de antipsicóticos atípicos al menos durante los tres meses previos a la aleatorización. Los criterios de exclusión incluyeron embarazo, lactancia, tratamiento electroconvulsivo en las últimas dos semanas, abuso y dependencia de sustancias, comorbilidad de trastornos psiquiátricos o neurológicos e hipersensibilidad a la memantina. Los pacientes del grupo de intervención recibieron un fármaco antipsicótico atípico más memantina, mientras que el grupo control recibió el antipsicótico atípico más placebo. Los pacientes fueron evaluados por la Escala de Síntomas positivos y negativos (PANSS) y la Escala de Depresión de Calgary para la Esquizofrenia (CDSS) al inicio y luego cada cuatro semanas hasta el final en la duodécima semana. Los datos se analizaron con SPSS-17 utilizando test t, test de ji cuadrado, análisis de varianza (ANOVA) y análisis de covarianza (ANCOVA). Resultados. En el grupo al que se añadió Memantina los síntomas positivos (p=0,028), los síntomas negativos (0,004), la psicopatología general (p<0,001), los síntomas depresivos (p<0,001) y la gravedad general de los síntomas (p<0,001) disminuyeron significativamente. Conclusión. Este estudio muestra que la adición de memantina podría ser útil como tratamiento adyuvante de los síntomas depresivos, positivos, negativos y síntomas generales en pacientes esquizofrénicos (AU)

Background. Although antipsychotics are the mainstay treatment of schizophrenia, they don’t adequately address residual positive, negative and depressive symptoms. The aim of the present study is to assess the effect of adjunctive memantine treatment on positive, negative and depressive symptoms of schizophrenia. Methods. This randomized, placebo-controlled study was conducted in Noor Hospital, Isfahan, Iran, 2013-2014; 32 patients in maintenance treatment were included in each group, using block sampling; inclusion criteria were age 18-65 years, normal intellectual ability, being diagnosed with schizophrenia for the past two years, being treated with fixed doses of atypical antipsychotic for at least three months before randomization. Exclusion criteria were pregnancy, breast-feeding, having received electro-convulsive therapy in the past two weeks, drug or substance abuse and dependence, psychiatric/ neurological comorbidities, and sensitivity to memantine. Patients in the intervention group were treated with memantine plus atypical antipsychotic; while in the control group, patients received placebo and atypical antipsychotic. Patients were assessed by Positive and Negative Symptom Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) initially and every four weeks to the end of the 12th week. Data were analyzed in SPSS 17.0 using t-test, chi square, analysis of variance (ANOVA), and analysis of covariance (ANCOVA). Results. Positive symptoms (p=0.028), negative symptoms (0.004), general psychopathology (p<0.001), depressive symptoms (p<0.001) and total symptom severity (p<0.001) decreased significantly in patients receiving add-on memantine. Conclusion. This study shows that, add-on memantine would be helpful, in the adjunctive treatment of depressive, positive, negative and general symptoms in patients with schizophrenia (AU)

Creatine monohydrate ingestion-related placebo effects on brief anaerobic exercise performance. A laboratory investigation / Efectos placebo de la ingestión de monohidrato de creatina sobre el rendimiento breve del ejercicio anaeróbico. Una investigación de laboratorio / Efeitos de placebo relacionados com a ingestão de monohidrato de creatina no desempenho de exercício anaeróbico breve. Uma investigação laboratorial

People’s thoughts influence their action that led researchers to investigate the placebo effect in exercise performance. In the current study the placebo effects of creatine monohydrate on a one-minute anaerobic step-exercise performance were examined in a double blind laboratory inquiry. University students (n = 79, 64.5% women) were randomly assigned to one of three experimental conditions: 1) intervention (ingestion of 80 mg/kg dissolved creatine monohydrate, n = 26), 2) placebo (ingestion of dissolved corn starch, thought to be creatine, n = 26), and 3) no-intervention control (ingestion of drinking water only, n = 27). After a baseline measurement, participants have consumed their respective drinks and 40 minutes later the 1-minute exercise was repeated. While analysis of variance revealed no group level differences in actual and perceived change in performance, the latter was linked to participants’ expectations regarding performance on the second exercise test in the correlation analysis. Two thirds of the participants in the current study believed that their performance would improve in the actual test-exercise. However, these expectations were not linked to creatine ingestion. These findings suggest that (1) a single dose of creatine monohydrate does not affect anaerobic performance, (2) in low-challenge and low-subjective-importance 'artificial' research conditions sufficient expectations could not be evoked, and probably due to the lack of creatine-related expectations the placebo effects did not emerge (AU)

La influencia de los pensamientos de las personas sobre sus acciones, llevó a los investigadores a investigar el efecto placebo sobre el rendimiento en el ejercicio. En el presente estudio se analiza el efecto placebo de la creatina monohidrato sobre el rendimiento en un ejercicio anaeróbico de un minuto de duración en laboratorio mediante el método de doble ciego. Los participantes fueron estudiantes universitarios (n = 79, 64,5% mujeres) que se asignaron aleatoriamente a una de las tres condiciones experimentales: 1) intervención (ingestión de creatina monohidrato disuelta, n = 26); 2) placebo (ingestión de almidón de maíz disuelto, creyendo que es creatina , n = 26); y 3) grupo control sin intervención (ingestión de agua potable solamente, n = 27). Después de establecer la línea base, los participantes tomaron sus respectivas bebidas y 40 minutos más tarde se repitió el ejercicio de 1 minuto de duración. Si bien el análisis de varianza no reveló diferencias entre los grupos entre el rendimiento real y el percibido, este último se vinculó, mediante análisis de correlación, a las expectativas de los participantes en relación con el rendimiento en la segunda prueba realizada. Dos tercios de los participantes consideraron que su rendimiento mejoraría en la prueba de ejercicio real, sin embargo, estas expectativas no estuvieron relacionadas con la ingesta de creatina. Los resultados sugieren que: (1) una dosis única de creatina monohidrato no afecta al rendimiento anaeróbico; (2) en la condición de bajo desafío y baja importancia subjetiva, no emergió el efecto placebo debido, probablemente, a la falta de expectativas evocadas sobre los efectos de la creatina (AU)

A influência dos pensamentos das pessoas sobre suas ações, levou os pesquisadores a investigar o placebo efeito sobre o desempenho do exercício. No presente estudo, a creatina mono-hidrato de placebo no desempenho no exercício anaeróbio de um minuto no laboratório pelo método de efeito duplo-cego é analisada. Os participantes eram estudantes universitários (n = 79, 64,5% mulheres) que foram atribuídos aleatoriamente a uma de três condições experimentais atribuída: 1) intervenção (ingestão de creatina monohidratada dissolvida, n = 26); 2) placebo (amido de milho dissolvido ingestão, acreditando que a creatina, n = 26); e 3) grupo de controlo sem intervenção (apenas ingestão de água potável, n = 27). Depois de estabelecer a linha de base, os participantes tomaram suas bebidas e 40 minutos depois do exercício de 1 minuto de duração repetido. Enquanto a análise de variância não revelou diferenças entre os grupos de entre o desempenho real e percebidos, a última foi ligada por análise de correlação, as expectativas dos participantes em relação ao desempenho no segundo teste realizado. Dois terços dos participantes sentiram que seu desempenho iria melhorar no teste de esforço real, no entanto, essas expectativas não foram relacionados com a ingestão de creatina. Os resultados sugerem que: (1) uma única dose de mono-hidrato de creatina não afecta o desempenho anaeróbio; (2) a condição sob desafio e menor importância subjetiva, surgiu o efeito placebo, provavelmente devido à falta de expectativas evocado sobre os efeitos da creatina (AU)

Maintenance of Response After Open-Label Treatment with Atomoxetine Hydrochloride in International European and Non-European Adult Outpatients with Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled, Randomised Withdrawal Study

Background and Objectives: We evaluated maintenance of response to atomoxetine during a 25-week, double-blind, placebo-controlled, randomised withdrawal period in adults with attention-deficit/hyperactivity disorder (ADHD) who previously responded to atomoxetine during a 12 week open-label treatment period and maintained that response during a 12-week double-blind maintenance period. Methods: Patients (N = 2017), 18 to 50 years of age, diagnosed with ADHD from 152 outpatient sites in 18 countries received 12 weeks of open-label atomoxetine (40-100 mg/day) followed by 12 weeks of double-blind maintenance (80 or 100 mg/day). Responders were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25-weeks of double-blind treatment. The percentage of patients with a reduction >30% in their baseline Conners' ADHD Rating Scale Investigator-Rated: Screening Version (CAARS-Inv:SV) total score and a score of <3 on the Clinical Global Impression ADHD-Severity (CGI-ADHD-S) after 25 weeks was compared between treatment groups with a Fisher's exact test. Mean changes from baseline in the CAARS-Inv:SV and Adult Attention-Deficit/Hyperactivity Disorder Quality of Life (AAQoL) were analysed. Results: Most patients enrolled (60%) were from Europe. More atomoxetine- than placebo-treated patients maintained a satisfactory response postrandomisation (64.3% vs. 50.0%; p < .001). Time-to-relapse was significantly longer for atomoxetine than placebo (p = .004). Atomoxetine maintained greater improvements in ADHD symptoms compared with placebo (LS mean worsening in the CAARS-Inv:SV total score was 0.9 vs. 4.8 [p < .001] and in the CGI-ADHD-S rating was 0.0 vs. 0.5 [p < .001]). These results were supported by self- or observer-rated measures. Lastly, atomoxetine maintained greater improvements in quality of life compared with placebo (AAQoL total score was 0.4 vs. -4.0; p = .002). Conclusions: This study demonstrated that atomoxetine was superior to placebo in maintaining significantly greater treatment responses for up to 1 year in adults with ADHD (AU)

Tolerance of low-frequency ultrasound sonophoresis: a double-blind randomized study on humans.

BACKGROUND: Sonophoresis [low-frequency ultrasound (US)] has been used in animals and in vitro to investigate enhanced percutaneous absorption of drugs. No study focused on its clinical human tolerance has been published as yet. METHODS: We aimed to assess the bioeffects of low-frequency US in vivo on human skin in a double-blind randomized-controlled study. We applied pulse-mode US at 36 kHz for 5 min in a step procedure of increasing dosage, from 1.57 to 3.50 W/cm(2), and placebo. The primary outcome was toxic effects of the procedure, defined as a pain score >40 on a 0-100 mm visual analogue scale or necrosis. Erythema (scored from 0 to 3 in severity) was also evaluated. The secondary outcomes were measurements of skin thickness by high-resolution skin imaging, of skin capacitance and temperature. RESULTS: We included 34 healthy volunteers. We found no pain score >38 and no skin necrosis with either US or placebo. Erythema was systematically observed immediately after US application, but after 1 day, we observed three cases in the knee group. The most frequent adverse effect was tinnitus. We observed no marked increase in temperature or cutaneous thickness after US or placebo. Cutaneous capacitance increased immediately after both applications. CONCLUSION: Such data demonstrating good tolerance of sonophoresis can be useful before the initiation of a clinical trial of the therapeutic use of low-frequency sonophoresis in humans.

Efficacy and safety of cumaru syrup as complementary therapy in mild persistent asthma: a double-blind, randomized, placebo-controlled study

Amburana cearensis is a medicinal plant known as "cumaru". It is used in Northeast Brazil in the treatment of respiratory diseases. This was a randomized, double-blind, placebo-controlled study, with the aim of evaluating the efficacy and safety of cumaru syrup as complementary therapy in mild persistent asthma. The study consisted of 3 phases, pre-treatment, treatment and post-treatment. The primary efficacy outcome was comparison of the changes reported by patients of the cumaru and placebo groups after treatment, using the "Asthma Quality of Life Questionnaire" (AQLQ). The secondary outcome was the effect of cumaru syrup on lung function based on spirometry. The results showed that in the cumaru group, the proportion of patients who had global improvement in asthma symptoms was significantly greater (61.90%, P=0.0009) than in the placebo group (9.52%). Only the spirometric parameters Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 second (FEV1) showed significant intergroup differences in post-treatment (P<0.05). The hematological and serum chemistry tests performed in the pre-treatment and post-treatment showed no statistically significant differences (P>0.05). Adverse events were reported by 3 patients (14.29%) in the cumaru group and 3 patients (14.29%) in the placebo group. All adverse events were considered non-serious and mild.

Amburana cearensis é uma planta medicinal conhecida como "cumaru". No Nordeste do Brasil é usada no tratamento de doenças respiratórias. Este é um estudo randomizado, duplo-cego e controlado por placebo, com o objetivo de avaliar a eficácia e segurança do xarope de cumaru como terapia complementar da asma persistente leve. O estudo consistiu de três fases, pré-tratamento, tratamento e pós-tratamento. A variável primária para determinação da eficácia foi a comparação das mudanças referidas pelos pacientes dos grupos cumaru e placebo após o tratamento, usando o "Questionário sobre Qualidade de Vida na Asma" (QQVA). A variável secundária foi o efeito do xarope de cumaru na função pulmonar baseado na espirometria. Os resultados mostraram que no grupo cumaru, a proporção de pacientes com melhora global dos sintomas da asma foi significativamente maior (61,90%, P=0.0009) que no grupo placebo (9,52%). Somente os parâmetros espirométricos, capacidade vital forçada (CVF) e volume expiratório forçado no primeiro segundo (VEF1), mostraram diferença intergrupo significtivas no pós-tratamento (P<0.05). Os testes hematológicos e do soro realizados no pré-tratamento e pós-tratamento não mostraram diferenças estatisticamente significativas (P>0.05). Eventos adversos foram reportados por 3 pacientes (14,29%) no grupo cumaru e 3 (14,29%) no grupo placebo. Todos os eventos adversos foram não sérios e leves.

Extent of renal effect of cyclo-oxygenase-2-selective inhibitors is pharmacokinetic dependent.

Non-steroidal anti-inflammatory drugs (NSAIDs) cause renal side-effects. In the present study, we tested the hypothesis that the extent of the renal effects of cyclo-oxygenase (COX)-2-selective NSAIDs is linked to their pharmacokinetics. A single oral dose of rofecoxib (10 mg/kg), celecoxib (40 mg/kg), meloxicam (3 mg/kg) or placebo was administered to rats. Urinary excretion of electrolytes, a marker of renal effects, and plasma and kidney concentrations of NSAIDs were measured. Rofecoxib and celecoxib, but not meloxicam, significantly decreased urinary sodium and potassium excretion. There was a significant correlation between the area under the 24 h plasma concentration-time curve (AUC0-24) of rofecoxib and the change in sodium (r = -0.65; P < 0.02) and potassium (r = -0.82; P < 0.0006) excretion. The AUC0-24 of celecoxib was correlated with sodium (r = -0.80; P < 0.05) but not potassium excretion. The ratios of kidney to plasma drug concentrations were 1.72, 3.16 and 0.17 for rofecoxib, celecoxib and meloxicam, respectively. The renal effect of the COX-2-selective NSAIDs examined, marked by their ability to reduce the excretion of electrolytes, is influenced by systemic exposure to the drugs. The relatively higher distribution into the kidneys of rofecoxib and celecoxib compared with meloxicam suggests involvement of direct drug exposure in the kidneys in the adverse renal effect.

Seguridad y utilidad de Zaleplon en operaciones aéreas / Efficacy and safety of zaleplon in aviation operations

Fundamento: El insomnio y su tratamiento farmacológico pueden causar incidentes y accidentes aéreos. La normativa aeronáutica internacional sólo autoriza, de modo excepcional y controlado, el consumo de hipnóticos no benzodiacepínicos tipo zolpidem o zopiclona. Sin embargo, zaleplon, un nuevo hipnótico no benzodiacepínico, posee una seguridad farmacológica superior a las de éstos últimos. Objetivo: Evaluar los posibles efectos adversos de zaleplon sobre la función psicomotora de pilotos de aeronave en situación de vuelo simulado en cámara hipobárica durante su entrenamiento fisiológico. Pacientes y método: Participaron 36 pilotos de aeronave, alumnos varones del Ejército del Aire de España, tomaron una única dosis de zaleplon 10 mg o placebo la noche previa a la sesión de entrenamiento fisiológico en cámara hipobárica. El estudio, aleatorizado y doble ciego, valoró la influencia de zaleplon vs placebo sobre la capacidad de atención en condiciones de prehipoxia, hipoxia hipobárica y posthipoxia, utilizando el test de atención Toulouse-Pieron modificado. Resultados: Los valores medios obtenidos en el grupo zaleplon vs el de placebo fueron, respectivamente: 22,11(5,91 y 22,94(9,21 (prehipoxia); 19,17(8,89 y 15,39(7,90 (hipoxia); 29,33(6.27 y 31,44(7,70 (posthipoxia). No existieron diferencias significativas entre ninguno de los va¬lores encontrados en uno y otro grupo. Conclusiones: Tras descartar efectos adversos sobre la capacidad psicomotora en condiciones de hipoxia hipobárica y revisar las evidencias científicas en la literatura biomédica, se concluye que zaleplon puede convertirse en el hipnótico de primera elección en operaciones aéreas

Background: Insomnia and its pharmacological treatment can cause aviation incidents and accidents. International aviation regulations only exceptionally and under controlled conditions authorize the use of non-benzodiazepine hypnotics such as zolpidem or zopiclone. However, zaleplon, a new non-benzodiazepine hypnotic, affords greater pharmacological safety than these latter drugs. Objective: To evaluate the potential adverse events of zaleplon on psychomotor function among aviation pilots under simulated flight conditions in a hypobaric chamber in the course of physiological training. Patients and method: Thirty-six male pilots in training and belonging to the Spanish Air Force were administered a single dose of zaleplon 10 mg or placebo the night before a physiological training session in a hypobaric chamber. The randomized, double-blind study assessed the influence of zaleplon versus placebo on sustained alertness and fatigue resistance under conditions of prehypoxia, hypobaric hypoxia and posthypoxia, based on the modified Toulouse-Pieron alertness test. Results: The mean values obtained in the zaleplon versus the placebo group were respectively: 22.11(5.91 and 22.94(9.21 (prehypoxia); 19.17(8.89 and 15.39(7.90 (hypoxia); 29.33(6.27 and 31.44(7.70 (posthypoxia). There were no significant differences between any of the recorded values in either group. Conclusions: After discarding potential adverse effects on psychomotor capacity under conditions of hypobaric hypoxia and reviewing the sciéntific evidence in the biomedicalliterature, it is concluded that zaleplon may become the first-choice hypnotic in aviation operations

The trigonometric responder approach: a new method for detecting responders to pharmacological or experimental challenges.

The paper presents a newly developed response measure that is particularly suitable for the evaluation of pharmacokinetic data. This method is based on trigonometric considerations, defining a hormone response as the difference between the angle of the slope of the curve before and after drug intake. In addition, the size of this difference is compared to the difference obtained in placebo conditions. In this way, the trigonometric response measure overcomes one of the most problematic shortcomings of the 'area under the curve' (AUC) approach, the problem of the initial value. We will present the mathematical background of the trigonometric method and demonstrate its usefulness by evaluating empirical data (a pharmacological challenge test using the dopamine agonist lisuride) and comparing it to classical AUC measures. This has been achieved by contrasting both approaches with responder definitions according to binary time series analysis and the peak value of the curve.

Evaluación clínica, hormonal y bioquímica de la administración de estrógenos conjugados naturales y sintéticos en pacientes perimenopáusicas / Clinical, hormonal and biochemical evaluation of natural and synthetic conjugated estrogen administration in perimenopausic patients

Determinar el efecto sobre la sintomatología clínica, perfil lipídico y niveles plasmáticos de estradiol y estrona frente a la administración de estrógenos conjugados equinos y estrógenos conjugados genéricos formulados localmente. Estudio prospectivo, controlado y randomizado, comparando cuatro grupos de 20 pacientes cada uno con formulaciones diferentes de estrógenos conjugados (EC) contra placebo por un período de 6 meses. No hubo diferencias significativas en la respuesta clínica ni en los niveles plasmático de estradiol y estrona entre los grupos con EC. Todos los grupos mostraron mejorías en el perfil lipídico al compararse contra placebo, se encontró significación sólo en dos de ellos. La respuesta a la sintomatología clínica así como los niveles plasmáticos de estradiol son comparables entre los grupos de EC. Las diferencias significativas entre estrógenos conjugados equinos y los genéricos sobre algunas fracciones de perfil lipídico deber ser precisadas con estudios complementarios para precisar su real significado