Use of methadone as an alternative to morphine for chronic pain management: a noninferiority retrospective observational study.

INTRODUCTION: Chronic pain causes disability and is prevalent in the general population. Opioids are a part of a multimodal strategy for pain management. Methadone, a cheap and long-acting synthetic opioid, may represent an option for those who have limited access to the aforementioned class of analgesics. We aimed to provide a real-world evidence for the analgesic use of methadone, compared with morphine. METHODS: We conducted a noninferiority, retrospective observational single center study of patients with chronic pain, managed with either methadone or morphine at an outpatient specialized clinic. We extracted data from the electronic health records of patients who underwent an active treatment between August 2012 and January 2020 and were examined for at least 2 consecutive medical visits, after the administration of one of the aforementioned drugs. Data were analyzed using a generalized additive model with random-effects mixed linear method to account for the individual-related, time-related, and drug-related variations. The numeric verbal scale (0-10) was used to assess the pain severity. RESULTS: From the database of 3373 patients, we included 262 patients (175 methadone and 87 morphine). In an unadjusted analysis, methadone was superior to morphine, and the mean worst pain was 0.86 points lower (95% confidence interval, -1.29 to -0.43). Moreover, methadone was superior to morphine in the adjusted analysis, with the worst pain mean being 1.24 points lower. This provided evidence for the noninferiority of methadone than morphine. CONCLUSION: Methadone was superior to morphine in a 20% noninferiority margin for reducing worst pain.

Workers of São Paulo city, Brazil, exposed to air pollution: Assessment of genotoxicity.

Air pollution affects all major urban centers, particularly megacities with populations greater than 10 million people. Vehicular and industrial emissions are among the most important sources of air pollutants in these cities. Air pollution composition, dose, and time of exposure can cause differential effects on human health. We have evaluated the genotoxic effects of air pollution (PM2.5 and NO2) on São Paulo city workers. Fifty-seven male individuals, 28-66 years old, with occupational exposure to air pollution, participated in this study; all worked daily outdoor shifts in São Paulo. Participants were recruited from three occupations: traffic controllers (n = 18); taxi drivers (n = 21); and workers at the Forestry Institute (n = 18). These workers were classified into two groups based on their workplace locations: Downtown Group (DT): traffic controllers and taxi drivers; Outskirts of Town Group (OT): workers at the Forestry Institute. Individual samplers of air pollution (Harvard air impactor) were used to collect PM2.5 and NO2 pollutants. Genotoxicity analysis (micronucleus test) was performed on buccal mucosa epithelial cells and peripheral blood lymphocytes. PM2.5 concentrations were significantly different between the groups (DT = 32.92 µg m-3, OT = 25.77 µg m-3; p = 0.03); however, no difference was observed in NO2 concentrations. Micronucleus frequencies in both buccal mucosa (DT = 2.78%, OT = 1.16%; p < 0.0001) and in peripheral lymphocytes (DT = 1.51%, OT = 0.73%; p < 0.0001) were significantly different between the groups. We observed a direct correlation between the individual dose of PM2.5 and micronucleus frequency in the buccal mucosa (p = 0.0021). Our results indicate that workers in the most urban areas of São Paulo are exposed to higher concentrations of PM2.5 and showed higher micronucleus frequencies in both buccal mucosa and lymphocytes.

Efficacy and Safety of a Biosimilar Versus Branded Enoxaparin in the Prevention of Venous Thromboembolism Following Major Abdominal Surgery: A Randomized, Prospective, Single-Blinded, Multicenter Clinical Trial.

Several biosimilar versions of enoxaparin are already approved and in use globally. Analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in clinical outcomes between biosimilar and branded enoxaparin. This study evaluated the efficacy and safety of biosimilar Cristália versus branded Sanofi enoxaparin in venous thromboembolism (VTE) prevention in patients undergoing major abdominal surgery at risk for VTE. In this randomized, prospective single-blind study, we compared Cristália enoxaparin (Ce), a biosimilar version, versus branded Sanofi enoxaparin (Se; at a dose of 40 mg subcutaneously per day postoperatively from 7 to 10 days) in 243 patients submitted to major abdominal surgery at risk for VTE for VTE prevention. The primary efficacy outcome was occurrence of VTE or death related to VTE. The principal safety outcomes were a combination of major bleeding and clinically relevant non-major bleeding. Bilateral duplex scanning of the legs was performed from days 10 to 14, and follow-ups were performed up to 60 days after surgery. The incidence of VTE was 4.9% in the Cristália group and 1.1% in the Sanofi group (absolute risk difference = 3.80%, 95% confidence interval [CI]: -1.4%-9.0%) yielding noninferiority since the 95% CI does not reach the prespecified value Δ = 20%. Clinically significant bleeding occurred in 9.9% in the Cristália group and in 5.5% in the Sanofi group (n.s. ). In conclusion, this study suggests that 40 mg once daily of Ce, a biosimilar enoxaparin, is as effective and safe as the branded Sanofi enoxaparin in the prophylaxis of VTE in patients submitted to major abdominal surgery at risk for VTE.

Comparative pharmacokinetic and pharmacodynamic evaluation between a new biosimilar and reference recombinant human growth hormone.

OBJECTIVE: To extend available dosing options in the treatment of growth hormone deficiency, a comparative pharmacokinetic and pharmacodynamic phase-1 clinical study involving subcutaneous administration of growth hormone was conducted. DESIGN: The test formulation (biosimilar recombinant human growth hormone; r-hGH; Somatotropin) and reference formulation (Genotropin®) were tested in 38 adult healthy subjects after their subcutaneous administration of 12.8IU in an open label, single dose, randomized, two period cross over study separated with a washout period of 11days. Endogenous growth hormone release was suppressed by a continuous Octreotide infusion up to 24h after r-hGH administration. All the subjects were evaluated for local tolerance using Wong-Baker Faces pain rating scale and an injection site reaction (ISR) score. Detection of serum levels of r-hGH, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) was done by suitable validated bio-analytical methods. Assessment of bioequivalence for pharmacokinetic parameters was done using log-transformed area under the curve (AUC) and maximum concentration (Cmax) for r-hGH. The pharmacodynamic assessment was done by comparing the area under the effect-time curve (AUEClast) and maximum measured effect concentration (Emax) of IGF-1 and IGFBP-3. RESULTS: The biosimilar formulation of recombinant human growth hormone fulfilled the predefined bioequivalence criteria for pharmacokinetic and pharmacodynamic parameters. CONCLUSION: The new biosimilar recombinant human growth hormone bears the potential to become an alternative option for the treatment of growth hormone deficiency.

[Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5 / Repercusión cardiovascular, con y sin alcohol, del carbonato de lodenafila, un nuevo inhibidor de la PDE5 / Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption

FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, assim como as alterações na farmacocinética que esta associação possa determinar. MÉTODOS: Estudo realizado com 15 voluntários sadios que receberam em momentos diferentes o carbonato de lodenafila (CL) na dose de 160 mg em jejum, CL (160 mg) com álcool, ou somente placebo. Esses pacientes foram monitorados por 24 horas, sendo avaliado o quadro clínico, a pressão arterial (PA), a frequência cardíaca (FC), o intervalo QT e também os dados de farmacocinética. RESULTADOS: O carbonato de lodenafila, isoladamente ou associado com álcool, não determinou alterações clínicas significativas na PA ou FC, embora tenha ocorrido diminuição da PA estatisticamente significativa após 4 horas, nos voluntários que receberam medicamento e álcool, assim como um aumento da FC após 6 horas nos pacientes que receberam o CL. A análise do intervalo QT corrigido não mostrou alteração significativa. O álcool aumentou a biodisponibilidade do medicamento em 74 por cento. Houve somente 2 queixas de cefaleia leve, possivelmente associada ao medicamento. CONCLUSÃO: O carbonato de lodenafila, mesmo associado ao álcool, não determinou repercussões clínicas importantes na PA, FC, ou alterações no intervalo QTc; a ingestão com álcool, por sua vez, aumentou significativamente sua biodisponibilidade.

BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74 percent when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

FUNDAMENTO: La disfunción eréctil afecta a un gran número de hombres en el mundo y los inhibidores de PDE5 (iPDE5) están entre los principales métodos de tratamiento de estos pacientes. El consumo social de alcohol y el acto sexual presentan una relación considerable. Por lo tanto, puede ocurrir una asociación entre alcohol e iPDE5. El carbonato de lodenafila es un nuevo iPDE5 desarrollado por una empresa brasileña. OBJETIVO: Evaluar la repercusión cardiovascular del carbonato de lodenafila, asociado o no al alcohol, así como las alteraciones en la farmacocinética que esta asociación pueda determinar. MÉTODOS: Estudio realizado con 15 voluntarios sanos que recibieron en momentos diferentes el carbonato de lodenafila (CL) en la dosis de 160mg en ayunas, CL (160 mg) con alcohol, o solamente placebo. Estos pacientes fueron monitoreados por 24 horas, siendo evaluado el cuadro clínico, la presión arterial (PA), la frecuencia cardíaca (FC), el intervalo QT y también los datos de farmacocinética. RESULTADOS: El carbonato de lodenafila, aisladamente o asociado con alcohol, no determinó alteraciones clínicas significativas en la PA o FC, aunque se haya registrado una disminución de la PA estadísticamente significativa después de 4 horas en los voluntarios que recibieron medicamento y alcohol, así como un aumento de la FC después de 6 horas en los pacientes que recibieron el CL. El análisis del intervalo QT corregido no mostró alteración significativa. El alcohol aumentó la biodisponibilidad del medicamento en un 74 por ciento. Se registraron sólo 2 quejas de cefalea leve, posiblemente asociada al medicamento. CONCLUSIÓN: El carbonato de lodenafila, aun asociado al alcohol, no determinó repercusiones clínicas importantes en la PA, FC, o alteraciones en el intervalo QTc; la ingestión con alcohol, a su vez, aumentó significativamente su biodisponibilidad.

Farmacocinética da associação de glucosamina e sulfato de condroitina em humanos sadios do sexo masculino / Pharmacokinetic profile of glucosamine and chondroitin sulfate association in healthy male individuals

A osteoartrose é uma doença crônica das articulações que, uma vez instalada, leva seus portadores a uma incapacidade funcional progressiva. Como os proteocondroitins sulfato são os maiores constituintes das cartilagens, espera-se que com a ingestão de glucosamina e condroitina haja uma melhora das condições biológicas desse tecido. Uma vez que não temos conhecimento de estudo da farmacocinética da administração oral dessa associação em seres humanos, o objetivo deste trabalho foi avaliá-la utilizando a associação entre o sulfato de glucosamina (SG) e o sulfato de condroitina (SC) administrada a dois grupos de doze voluntários sadios do sexo masculino (grupo I uma cápsula de (500 mg SG; 400 mg SC) e grupo II quatro cápsulas). Amostras de sangue foram retiradas a intervalos de tempo pré-definidos até 48 horas pós-dose. O SG e o SC foram dosados no plasma pelo método de DMMB (azul de 1,9,dimetildimetileno). A concentração máxima foi atingida em 2 horas (média ±SE; 0,893±0,093 'g/mL, grupo I e 2,222±0,313 'g/mL, grupo II). As áreas sob a curva até 48 horas foram de 10,803±0,965 'g-hr/mL e 38,776±2,981 'g-hr/mL, respectivamente para os grupos I e II. Os dois grupos apresentaram um segundo pico após 18 horas, indicando circulação êntero-hepática. Os nossos resultados indicam que essa associação é absorvida por via oral por mecanismo saturável, o que pode facilitar o seu uso em tratamentos clínicos.

Gene expression of extracellular matrix proteoglycans in human cyclosporin-induced gingival overgrowth.

BACKGROUND: Gingival overgrowth is one of the side effects associated with the systemic use of cyclosporin A (CsA). In vitro studies on the extracellular matrix of gingival tissues have demonstrated an altered composition, particularly an accumulation of proteoglycans and collagen. We investigated the gene expression of extracellular matrix proteoglycans in CsA-induced gingival tissue alterations. METHODS: mRNA expression of the proteoglycans perlecan, decorin, biglycan, and versican was analyzed by reverse transcription polymerase chain reaction (RT-PCR) in gingival samples obtained from 12 individuals, six with CsA-induced gingival overgrowth (CsA group) and six with a normal gingiva (control group). The RT-PCR products were subjected to 1% agarose gel electrophoresis containing ethidium bromide and analyzed qualitatively and semiquantitatively by densitometry. Density values were normalized by determining the expression of the housekeeping gene beta-actin in the same sample. Groups were compared by the Student's t test. RESULTS: Perlecan expression showed a marked increase (54%) in the CsA group compared to the control group (P < 0.01), while no significant differences were observed for the other proteoglycans. CONCLUSION: CsA-induced gingival overgrowth seems to be associated with increased expression of perlecan, a typical basement membrane proteoglycan, but not decorin, biglycan, or versican.