Conduta terapêutica em pacientes com doença pulmonar obstrutiva crônica: monoterapia ou terapia cominada? / Therapy for chronic obstructive pulmonary disease patients: monotherapy or combination therapy?

Objetivo: Comparar a dupla terapia broncodilatadora com glicopirrônio mais indacaterol à monoterapia com glicopirrônio em pacientes portadores de doença pulmonar obstrutiva crônica. Métodos: Estudo clínico prospectivo, unicêntrico, controlado, cruzado, randomizado e duplo-cego realizado com 14 pacientes com diagnóstico de doença pulmonar obstrutiva crônica grau II. Os participantes receberam cada um dos tratamentos durante 30 dias. Antes de cada terapia, realizou-se período de wash-out por 7 dias, com broncodilador de curta ação. Antes e após cada intervenção, os pacientes passaram por exame de espirometria e responderam ao questionário COPD Assessment Test. Resultados: Observou-se melhora na função pulmonar medida por meio do volume expiratório forçado no primeiro segundo de 19mL (±36) para a monoterapia e 87mL (±33) para a terapia dupla. O ganho foi de 67mL (p=0,042) da associação dos medicamentos em relação ao glicopirrônio isolado. A melhora na qualidade de vida, medida a partir das pontuações do questionário, foi de 4,7 (±8,9) pontos para a monoterapia e 5,2 (±11) pontos para a dupla terapia (p=0,08). Conclusão: Ambos os tratamentos demonstram melhora na função pulmonar dos pacientes.

Objective: To compare dual bronchodilator therapy (Glycopyrronium with Indacaterol) versus Glycopyrronium monotherapy in patients with chronic obstructive pulmonary disease. Methods: This was a prospective, unicentric, controlled, crossover, randomized, and double-blind clinical trial with 14 patients diagnosed with grade II chronic obstructive pulmonary disease. The participants received each treatment during the period of 30 days. Before each therapy, a 7-day wash-out period with a short-acting bronchodilator was instituted. Before and after each intervention, the patients underwent spirometry and answered the COPD Assessment Test questionnaire. Results: An improvement in pulmonary function measured by forced expiratory volume during the first second of 19mL (±36) for monotherapy, and 87mL (±33) for dual therapy was observed. The gain was of 67mL (p=0.042) in the association of the drugs in relation to Glycopyrronium alone. The mean improvement in quality of life measured from the questionnaire scores was 4.7 (±8.9) points for monotherapy and 5.2 (± 11) points for dual therapy (p=0.08). Conclusion: Both treatments show improvement in the patients' pulmonary function.

Effects of indacaterol versus tiotropium on exercise tolerance in patients with moderate COPD: a pilot randomized crossover study / Efeitos do indacaterol versus tiotrópio na tolerância ao exercício em pacientes com DPOC moderada: estudo cruzado randomizado piloto

Abstract Objective: To compare a once-daily long-acting β2 agonist (indacaterol 150 µg) with a once-daily long-acting anticholinergic (tiotropium 5 µg) in terms of their effects on exercise endurance (limit of tolerance, Tlim) in patients with moderate COPD. Secondary endpoints were their effects on lung hyperinflation, exercise-related dyspnea, and daily-life dyspnea. Methods: This was a randomized, single-blind, crossover pilot study involving 20 patients (mean age, 60.9 ± 10.0 years; mean FEV1, 69 ± 7% of predicted). Spirometric parameters, Transition Dyspnea Index scores, Tlim, and exertional dyspnea were compared after three weeks of each treatment (with a one-week washout period between treatments). Results: Nineteen patients completed the study (one having been excluded because of COPD exacerbation). Improvement in Tlim from baseline tended to be greater after treatment with tiotropium than after treatment with indacaterol (96 ± 163 s vs. 8 ± 82 s; p = 0.06). Tlim significantly improved from baseline after treatment with tiotropium (having increased from 396 ± 319 s to 493 ± 347 s; p = 0.010) but not after treatment with indacaterol (having increased from 393 ± 246 to 401 ± 254 s; p = 0.678). There were no differences between the two treatments regarding improvements in Borg dyspnea scores and lung hyperinflation at "isotime" and peak exercise. There were also no significant differences between treatments regarding Transition Dyspnea Index scores (1.5 ± 2.1 vs. 0.9 ± 2.3; p = 0.39). Conclusions: In patients with moderate COPD, tiotropium tends to improve Tlim in comparison with indacaterol. No significant differences were observed between the two treatments regarding their effects on lung hyperinflation, exercise-related dyspnea, and daily-life dyspnea. Future studies, including a larger number of patients, are required in order to confirm our findings and explore mechanistic explanations. (ClinicalTrials.gov identifier: ...

RESUMO Objetivo: Comparar um β2-agonista de longa duração administrado uma vez por dia (indacaterol 150 µg) a um anticolinérgico de longa duração administrado uma vez por dia (tiotrópio 5 µg) quanto a seus efeitos na resistência ao exercício (limite de tolerância, Tlim) em pacientes com DPOC moderada. Os desfechos secundários foram seus efeitos na hiperinsuflação pulmonar, na dispneia causada pelo exercício e na dispneia na vida diária. Métodos: Estudo piloto randomizado cruzado e simples cego com 20 pacientes (média de idade: 60,9 ± 10,0 anos; média do VEF1: 69 ± 7% do previsto). Parâmetros espirométricos, pontuação no Transition Dyspnea Index, Tlim e dispneia aos esforços foram comparados após três semanas de cada tratamento (com uma semana de intervalo entre os tratamentos). Resultados: Dezenove pacientes completaram o estudo - um foi excluído por causa de exacerbação da DPOC. A melhora no Tlim tendeu a ser maior com tiotrópio do que com indacaterol (96 ± 163 s vs. 8 ± 82 s; p = 0,06). Em comparação com os valores basais, o Tlim melhorou significativamente com tiotrópio (aumentando de 396 ± 319 s para 493 ± 347 s; p = 0,010), mas não com indacaterol (aumentando de 393 ± 246 para 401 ± 254 s; p = 0,678). Não houve diferença entre os tratamentos quanto à melhora na pontuação na escala de dispneia de Borg e na insuflação pulmonar no "isotempo" e no pico do exercício. Também não houve diferenças significativas entre os tratamentos quanto à pontuação no Transition Dyspnea Index (1,5 ± 2,1 vs. 0,9 ± 2,3; p = 0,39). Conclusões: Em pacientes com DPOC moderada, o tiotrópio tende a melhorar o Tlim em comparação com o indacaterol. Não houve diferenças significativas entre os tratamentos quanto a seus efeitos na insuflação pulmonar, na dispneia durante o exercício e na dispneia na vida diária. São necessários mais estudos, com um número maior de pacientes, para confirmar nossos achados e explorar explicações mecanicistas. (ClinicalTrials.gov ...

Novedosos agentes dopaminérgicos centrales derivados del 2-aminoindano-4,7 disustituido atípico. Síntesis y perfil farmacológico central / Novel central dopaminergic agents derived from atypical di-substituted 2-aminoindane-4, 7. Synthesis and central pharmacological profile

En las últimas décadas son muchos los compuestos con actividad dopaminérgica central que se han diseñado, sintetizado y evaluado farmacológicamente. A pesar de ello, no se ha logrado obtener un fármaco capaz de mejorar o curar las patologías que involucran la regulación dopaminérgica en el sistema nervioso central tales como la Enfermedad de Parkinson y la esquizofrenia, entre otras. Tomando en consideración el término de “farmacóforo atípico” y a partir del compuesto 5, se incorporó el fragmento aralquil y se sintetizaron los compuestos 10, 11, 13a-h y 14a-h. Tanto los compuestos 10 y 13a-h bajo su forma metoxilada como los compuestos 11 y 14a-h bajo su forma fenólica, fueron evaluados farmacológicamente para determinar su actividad agonística y antagonística sobre el sistema dopaminérgico central. Para ello se determinó el efecto de la inyección intracerebroventricular de dichos compuestos sobre el balance hidromineral y la conducta estereotipada en ratas. Los resultados de la evaluación farmacológica preliminar muestran una acción central a través de mecanismos dopaminérgicos, siendo que los compuestos 10, 11, 13d-h y 14a mostraron respuestas como agonistas, mientras que los compuestos 14b-h, tuvieron respuestas como antagonistas.

In recent decades, many compounds with central dopaminergic activity have been designed, synthesized and evaluated pharmacologically. However, it has not been possible to obtain a drug able to improve or cure diseases involving dopaminergic regulation in the central nervous system, such as Parkinson’s disease and schizophrenia, among others. Taking into consideration the term “atypical pharmacophore” and from the compound 5, the aralkyl fragment was incorporated, and the compounds 10, 11, 13a-h and 14a-h were synthesized. Both the compounds 10 and 13a-h under its methoxylated form and the compounds 11 and 14a-h under the phenolic form, were evaluated to determine their pharmacologically agonistic and antagonistic effects on central dopaminergic activity. For this, the effect of intracerebroventricular injection of said compounds on the hydromineral balance and stereotyped behavior in rats, was determined. The results of the preliminary pharmacological evaluation show a centrally acting action through dopamine mechanisms, in which the compounds 10, 11, 13d-h and 14a showed responses as agonists, whereas compounds 14b-h, had responses as antagonists.

Medicamentos utilizados para trastornos cognitivos: Análisis de un millón y medio de prescripciones en la Argentina / Drugs used for cognitive impairment: Analysis of 1.5 million prescriptions in Argentina

Los costos originados por trastornos cognitivos y demencias son significativos para los sistemas de salud. Según guías nacionales e internacionales, los fármacos recomendados para su tratamiento son inhibidores de colinesterasa (donepecilo, galantamina y rivastigmina) y memantina. En la Argentina también son utilizados otros nootrópicos, galantamina, rivastigmina, vasodilatadores, vitaminas y antioxidantes. El objetivo del presente estudio es describir y comparar el patrón de prescripción de drogas para el tratamiento de trastornos cognitivos y demencias en las distintas regiones del país. Se realizó un estudio observacional retrospectivo a partir de las prescripciones (1 814 108 envases) realizadas en la práctica clínica habitual durante el segundo semestre del 2008 y el primer y segundo semestre del 2009. El trabajo fue realizado sobre la población total del Instituto Nacional de Servicios Sociales para Jubilados y Pensionados. Se analizaron variables demográficas, cantidad y tasa de prescripciones, presentaciones y dosis utilizadas por regiones. Considerando todo el país, memantina fue la droga más prescripta en esos períodos, con un total de 570 893 envases. Memantina, donepecilo, rivastigmina e idebenona presentaron un incremento en las tasas de prescripción 2008-2009. Analizando los cambios regionales en tasas de prescripción, la memantina aumentó en el Noroeste y Noreste argentino, la idebenona en el Noroeste y la Patagonia y el donepecilo en el Noreste. Grupos de fármacos no recomendados fueron altamente prescriptos en todas las regiones del país. Algunos fueron indicados en adultos jóvenes o de mediana edad.

Cognitive impairment and dementia treatment costs are significant for health systems. According to national and international guidelines, recommended drugs for treatment of dementias are cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Despite these guidelines recommendations, other nootropics, vasodilators and antioxidants are often used in Argentina. The purpose of this study was to describe and compare the prescription pattern of commonly used drugs for the treatment of cognitive disorders and dementia in different regions of Argentina. An observational, retrospective study of 1 814 108 recipes prescribed to National Institute of Social Services for Retired and Pensioners outpatients during the during the second half of 2008 and the first and second half of 2009 was performed, taking in count the whole country and also different Argentina´s regions. Demographic variables, quantity and rate of prescriptions, dosage forms and strengths were analyzed. Considering the entire country, memantine was the most prescribed drug in these periods (570 893 packages). An increase in the memantine, donepezil, rivastigmine and idebenone rates of prescription was observed. Prescription rate of memantine increased in the North-West and North-East regions, that of idebenone in the North-East region and Patagonia and donepezil in the North-East region. Non recommended drugs were highly prescribed in all the analyzed regions. Some of them were indicated to young and middle-aged patients.

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Índex of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 ± 4.8 percent, 92.3 percent ± 22.8 percent of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C0(2). In the other experiment, apneic threshold PaC0(2) was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.