Metabolic study of trimetazidine using ultra-high performance liquid chromatography-tandem mass spectrometry

Abstract In the present study, the application of ultra-high performance liquid chromatography-tandem mass spectrometry allowed us to study of known-as well as hitherto unknown-trimetazidine (TMZ) metabolites in human urine and to propose their renal excretion profiles. Urine samples from a healthy volunteer were analyzed at baseline and at 0-4 h, 4-8 h, 8-12 h, and 12-24 h after a single dose of TMZ. A dilute-and-shoot procedure was used as sample treatment before separation. Full-scan spectra of possible metabolites were acquired. Additionally, product ion scan spectra of precursor ions of interest were also acquired at two collision energies. Intact TMZ was a major excretion product, with a maximum concentration at 4-8 h after administration. Moreover, five minor metabolites were observed, namely trimetazidine-N-oxide (M1), N-formyl trimetazidine (M2), desmethyl-trimetazidine O-sulfate (M3), desmethyl-trimetazidine O-glucuronide (M4), and desmethyl-trimetazidine-N-oxide-O-glucuronide (M5). Metabolite M5 has not previously been reported. Excretion curves were constructed based on the chromatographic peak areas of specific mass transitions (precursor ion > product ion) related to each of the detected metabolites

Acutely applied melatonin prevents CCl4-induced testicular lesions in rats: the involvement of the oxidative capacity and arginine metabolism

Abstract Carbon tetrachloride (CCl4) represents an organic chemical that causes reactive oxygen species derived organ disturbances including male infertility. Melatonin (MLT) is a neurohormone with strong antioxidant capacity, involved in numerous physiological processes. In this study we evaluated the capability of MLT, administered in a single dose of 50 mg/kg, to preserve the testicular tissue function after an acute administration of CCl4 to rats. The disturbance in testicular tissue and the effects of MLT after CCl4 exposure were estimated using biochemical parameters that enabled us to determine the tissue (anti)oxidant status and the intensity of arginine/nitric oxide metabolism. Also, the serum levels of testosterone and the histopathological analysis of tissue gave us a better insight into the occurring changes. A significant diminution in tissue antioxidant defences, arginase activity and serum testosterone levels, followed by the increased production of nitric oxide and extensive lipid and protein oxidative damage, was observed in the CCl4-treated group. The application of MLT after the CCl4 caused changes, clearly visible at both biochemical and histological level, which could be interpreted mainly as a consequence of general antioxidant system stimulation and a radical scavenger. On the other hand, the application of MLT exerted a limited action on the nitric oxide signalling pathway.

Do avanafil and zaprinast exert positive effects on bone tissue via the nitric oxide/cyclic guanosine monophosphate/protein kinase-G signaling pathway in rats with ovariectomy-induced osteoporosis?

Phosphodiesterase-5 inhibitors (PDE-5Is) exert positive effects on bone healing and mineralization by activation the nitric oxide/cyclic guanosine monophosphate/protein kinase-G (NO/cGMP/PKG) signaling pathway. In this study, the effects of zaprinast and avanafil, two PDE-5Is, on the NO signaling pathway, estrogen levels, selected bone formation and destruction marker levels, whole-body bone mineral density (WB-BMD), right femur trabecular bone thickness (RF-TBT) and epiphyseal bone width, angiogenesis in the bone-marrow, and selected oxidative stress parameter levels were investigated in rats with ovariectomy-induced osteoporosis. Twenty four adult rats (8 months old) were equally divided into four groups. The first group was the sham operated group. Groups 2, 3 and 4 included ovariectomized rats. At six months after ovariectomy, the 3rd and 4th groups were administered 10 mg/kg zaprinast and avanafil daily as a single dose for 60 days, respectively. Increases in the activity of the NO/cGMP/PKG signalling-pathway, C-terminal collagen peptide levels, angiogenesis in the bone marrow, RF-TBT, epiphyseal bone width and WB-BMD were observed compared to the ovariectomized positive control group (OVX), while the pyridinoline and deoxypyridinoline levels were decreased in the OVX+zaprinast and OVX+avanafil groups (p<0.05). The malondialdehyde, ubiquinone10/ubiquinol10 and 8-hydroxy-2-deoxyguanosine/106deoxyguanosine levels were also increased in the ovariectomized groups compared to the sham group (p<0.05). Based on these results, the levels of bone atrophy and some markers of oxidative stress were increased due to acute estrogen deficiency induced by ovariectomy, but zaprinast and avanafil administration significantly prevented these changes

Total remission of Tolosa-Hunt Syndrome with single-dose of infliximab / Remissão total da Síndrome de Tolosa-Hunt com dose única de infliximabe

Abstract Tolosa-Hunt syndrome is a painful ophthalmoplegia caused by non-specific granulomatous inflammation, corticoid-sensitive, of the cavernous sinus. The etiology is unknown. Recurrences are common. The diagnosis is made by exclusion, and a variety of other diseases involving the orbital apex, superior orbital fissure and cavernous sinus should be ruled out. This study reports a case of a 29-year-old woman, diagnosed with Tolosa-Hunt Syndrome, who presented ophthalmoparesis and orbital pain. She had poor response to corticotherapy and developed colateral effects, so she was treated with single infliximab dose immunosuppression, evolving total remission of the disease.

Resumo A Síndrome de Tolosa-Hunt é uma oftalmoplegia dolorosa causada por uma inflamação granulomatosa não específica, sensível a corticoides, do seio cavernoso. A etiologia é desconhecida. Recorrências são comuns. O diagnóstico é feito por exclusão, devendo ser descartada uma variedade de outras doenças que envolvem o ápice orbitário, fissura orbitária superior e seio cavernoso. O presente estudo trata-se de um relato de caso de uma paciente de 29 anos, diagnosticada com Síndrome de Tolosa-Hunt, que apresentou paresia e dor em região orbital. Obteve resposta pouco efetiva a corticoterapia e desenvolveu efeitos colaterais, por isso foi tratada com dose única de infliximabe, evoluindo com remissão total da doença.

Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable

Safety and tolerability of a single dose T0001 in Chinese healthy adult volunteers: a first-in-human ascending dose study

T0001 is the first mutant of etanercept with a higher affinity to tumor necrosis factor α (TNF-α) than etanercept. In order to investigate the safety and tolerability of T0001, a study was carried out in healthy Chinese subjects. A first-in-human, dose escalation study was conducted in healthy Chinese subjects. Fifty-six subjects were divided into six dose cohorts (10 mg, 20 mg, 35 mg, 50 mg, 65 mg and 75 mg) to receive a single subcutaneous injection of T0001. Safety and tolerability assessment were based on the records of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms and adverse events (AEs). All subjects were in good compliance and none withdraw due to AEs. No serious AEs occurred. A total of twenty-three AEs in sixteen subjects were recorded, and eighteen of these AEs were believed to be related to T0001. The most frequently reported AEs were injection site reactions and white blood cell count increase. All these AEs were of mild to moderate intensity and most of them recovered spontaneously within 14 days. In this study, no dose-limiting toxicity was observed, and the maximum tolerated dose was identified as 75 mg. T0001 was considered safe and generally well tolerated at doses up to 75 mg in healthy Chinese volunteers

Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects

ABSTRACT Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects.

Eficacia analgésica y seguridad de dosis única de morfina intratecal / Analgesic effectiveness and safety of single-dose intrathecal morphine

Introducción: el dolor posoperatorio del hemiabdomen superior es intenso y su control es imprescindible para evitar complicaciones. Objetivos: evaluar la eficacia analgésica y seguridad de dosis única de morfina intratecal en el posoperatorio de la cirugía de hemiabdomen superior de gran envergadura. Método: ensayo clínico aleatorizado a simple ciegas en 40 pacientes, tras intervenciones de hemiabdomen superior. Se emplearon dosis única de morfina intratecal (MIT) de 1 o 2 µg/kg de peso del paciente de acuerdo al grupo de tratamiento. Análisis estadístico con las pruebas Chi cuadrado (x2), exacta de Fisher, análisis de varianza univariado, la prueba de W de Mauchly y la prueba F univariada; nivel de significación de 0,05. Resultados: la administración de opioides durante el acto quirúrgico fue similar en ambos grupos (3,1 ± 2,2 mL vs. 4,1 ± 2,7 mL). En el grupo de dosis de 2 µg/kg de peso de MIT a las 12 y 24 h los pacientes no refirieron dolor; existieron diferencias entre los tratamientos en cuanto al alivio del dolor (p< 0,001) y también entre los momentos en que se midió el mismo (p= 0,001). Se utilizó analgesia de rescate en 25 por ciento de los pacientes. Solo se presentó como complicación la depresión respiratoria. Conclusiones: la dosis única de 2 µg/kg de morfina intratecal es un método eficaz para la analgesia posoperatoria en la cirugía de hemiabdomen superior, la incidencia de complicaciones fue baja y se demostró que ambas dosis son seguras(AU)

Introduction: The superior hemiabdomen postoperative pain is severe and essential to be managed in order to avoid complications. Objectives: To assess the analgesic effectiveness and safety of single-dose intrathecal morphine in the postoperative period of the upper hemiabdomen major surgery. Method: Single-blind randomized clinical trial in 40 patients, after upper hemiabdomen interventions. We used single doses of intrathecal morphine (ITM) of 1 or 2 mg/kg per patient weight according to the treatment group. The statistical analysis used the Chi-square test, Fisher's exact test, univariate analysis of variance, Mauchly's test and Univariate F-test; the significance level was 0.05. Results: Opioids administration during surgery was similar in both groups (3.1 ± 2.2 mL vs. 4.1 ± 2.7 mL). In the 2 mg/kg of ITM dose group, the patients reported no pain after 12 and 14 hours; there were differences between treatments regarding pain relief (p< 0.001) and also between the time when it was measured (p= 0.001). Rescue analgesia was used in 25 percent of the patients. Respiratory depression was the only onset complication. Conclusions: ITM at a single dose of 2 µg/kg is an effective method for postoperative analgesia in upper hemiabdomen surgery, the incidence of complications was low and both doses proved safe(AU)

Antibioticoterapia profiláctica en cirugía bariátrica / Prophylactic antibiotic therapy in bariatric surgery

Describir la experiencia de nuestro grupo con el esquema de antibioticoterapia profiláctica en pacientes sometidos a cirugía bariátrica. Métodos: Trabajo prospectivo y descriptivo, con una población de 164 pacientes sometidos a cirugías bariátricas primarias y revisionales en el lapso enero 2014 ­ diciembre 2015 en el Hospital Dr. Miguel Pérez Carreño y Clínica Santa Sofía, Caracas, Venezuela. Resultados: Se reporta una incidencia de 0 % de infecciones bajo el esquema de antibioticoterapia profiláctica descrito para cirugía bariátrica en las guías internacionales. Conclusión: La antibioticoterapia profiláctica es una práctica segura y efectiva en la prevención de infecciones en pacientes sometidos a cirugía bariátrica. Recomendamos su uso y difusión en nuestra comunidad quirúrgica bajo los esquemas aceptados internacionalmente(AU)

To describe our experience with a standard scheme of prophylactic antibiotic therapy in patients undergo to bariatric surgery. Methods: Prospective and descriptive clinical trial, including 164 patients undergo to primary and review bariatric surgeries between January 2014 and December 2015 at Hospital Dr. Miguel Pérez Carreño and Clínica Santa Sofía. Caracas, Venezuela. Results: We report 0 % incidence of infections with the scheme of prophylactic antibiotic therapy recommended for bariatric surgery in international guides. Conclusion: Prophylactic antibiotic therapy is safe and effective preventing infections in patients undergo to bariatric surgery. We recommend the use and diffusion in our surgical community under schemes accepted internationally(AU)

Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c) (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product) and Levaquin(c) (Janssen-Cilag Farmacêutica Ltda, Brazil, test product) was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c) and Levaquin(c) are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies.

A bioequivalência média de duas formulações de levofloxacino disponíveis no Brasil, Tavanic(c) (Sanofi-Aventis Farmacêutica Ltda, Brasil, produto referência) e Levaquin(c) (Janssen-Cilag Farmacêutica Ltda, Brasil, produto teste) foi determinada por meio da realização de ensaio aleatório, aberto, cruzado, com dois períodos e duas sequências, em 26 voluntários sadios em condições de jejum. Amostras de sangue dos voluntários foram obtidas ao longo de um período de 48 horas após administração de dose única de 500 mg de levofloxacino. As concentrações plasmáticas do fármaco foram determinadas por método cromatográfico validado. Os parâmetros farmacocinéticos Cmax, Tmax, Kel, T1/2el, AUC0-t e AUC0-inf foram calculados por análise não compartimental. A bioequivalência foi determinada pelo cálculo de intervalos de confiança 90% (IC 90%) para as razões entre os valores de Cmax, AUC0-t e AUC0-inf obtidos para os produtos teste e referência, usando dados transformados logaritmicamente. A tolerabilidade foi avaliada pelo acompanhamento dos sinais vitais e resultados de exames laboratoriais, por consultas e por relato espontâneo dos voluntários. ICs 90% para Cmax, AUC0-t e AUC0-inf foram 92.1% - 108.2%, 90.7% - 98.0%, e 94.8% - 100.0%, respectivamente. Os eventos adversos observados foram náusea e cefaleia. Concluiu-se que os produtos Tavanic(c) e Levaquin(c) são bioequivalentes, uma vez que os ICs 90% estão dentro da faixa de 80%-125% proposta pelas agências reguladoras.

L-arginine, a nitric oxide precursor, reduces dapsone-induced methemoglobinemia in rats

Dapsone use is frequently associated to hematological side effects such as methemoglobinemia and hemolytic anemia, which are related to N-hydroxylation mediated by the P450 enzyme system. The aim of the present study was to evaluate the influence of L-arginine supplementation, a precursor for the synthesis of nitric oxide, as single or multiple dose regimens on dapsone-induced methemoglobinemia. Male Wistar rats were treated with L-arginine at 5, 15, 30, 60 and 180 mg/kg doses (p.o., gavage) in single or multiple dose regimens 2 hours prior to dapsone administration (40 mg/kg, i.p.). The effect of the nitric oxide synthase inhibitor L-NAME was investigated by treatment with multiple doses of 30 mg/kg (p.o., gavage) 2 hours before dapsone administration. Blood samples were collected 2 hours after dapsone administration. Erythrocytic methemoglobin levels were assayed by spectrophotometry. The results showed that multiple dose supplementations with 5 and 15 mg/kg L-arginine reduced dapsone-induced methemoglobin levels. This effect is mediated by nitric oxide formation, since the reduction in methemoglobin levels by L-arginine is blocked by simultaneous administration with L-NAME, a nitric oxide synthase inhibitor.

O uso da dapsona é frequentemente associado a efeitos adversos hematológicos, como a metemoglobinemia e anemia hemolítica, ambos relacionados com a N-hidroxilação mediada pelo sistema P450. O objetivo do estudo foi avaliar a influência da suplementação de L-arginina, um precursor da síntese de óxido nítrico, administrado em regime de dose única ou múltipla na metemoglobinemia induzida pela dapsona. Ratos machos Wistar foram tratados com L-arginina (po, gavagem) em dose única ou múltipla de 5, 15, 30, 60 e 180 mg/kg 2 horas antes da administração de dapsona (40 mg/kg, ip). O efeito do L-NAME, um inibidor de óxido nítrico sintase (NOS), foi avaliado através do tratamento com doses múltiplas de 30 mg/kg. Amostras de sangue foram coletadas duas horas após a administração de dapsona. A concentração de metemoglobina eritrocitária foi analisada por espectrofotometria. Os resultados mostraram que a suplementação em dose múltipla de 5 e 15 mg/kg de L-arginina reduziu os níveis de metemoglobina induzida pela dapsona. Este efeito é mediado pela formação de óxido nítrico, uma vez que a redução nos níveis de metemoglobina pela L-arginina é bloqueada pela administração simultânea de L-NAME, um inibidor da óxido nítrico sintase.

Uso de ceftriaxona en monodosis para el tratamiento de la otitis media aguda supurada en pacientes de edad pediátrica / Ceftriaxone´s use in monodoses for the treatment of otitis media acute suppurativa in pediatric age patients

La otitis media aguda supurada es muy frecuente en pediatría. El 80 por ciento de los niños en edad preescolar y el 50 por ciento de los lactantes hacen un cuadro de supuración de oídos dos veces al año. Objetivo: evaluar la efectividad de la ceftriaxona en dosis única en pacientes pediátricos con otitis media aguda supurada. Método: se realizó un ensayo clínico, fase IV, durante el segundo semestre del año 2008, a 51 niños ingresados con el diagnóstico de Otitis Media Aguda Supurada, en el Hospital Pediátrico Provincial de Camagüey Eduardo Agramante Piña. Resultados: se encontró un ligero aumento del sexo masculino; con predominio significativo de la raza blanca. Existió una alta incidencia en los pacientes menores de un año. El 58,8 por ciento de los pacientes recibieron tratamiento previamente con antimicrobianos. El tratamiento antimicrobiano utilizado con mayor frecuencia fue la amoxicillina, la penicilina y el Claforan. Más del 66 por ciento presentó una evolución favorable dentro de las 72h siguientes al tratamiento con la monodosis de ceftriaxona. En 48 de los pacientes estudiados se obtuvo una evolución otoscópica favorable, lo que correspondió a un 94,12 por ciento de los casos estudiados. Al estudiar el comportamiento de los pacientes según edad y otras enfermedades asociadas, se pudo observar que sólo dos pacientes no presentaron otras enfermedades asociadas. Conclusiones: se logró una evolución favorable dentro de las 72h siguientes al tratamiento con la monodosis de ceftriaxona en casi la totalidad de los casos.

Otitis media acute suppurativa is very frequent disease in pediatrics. The 80 percent of children in preschool age and 50 percent of infants make ear suppuration twice a year. Objective: to evaluate the efficacy of an only dose of ceftriaxone in pediatric patients with otitis media acute suppurativa. Method: a phase IV clinical trial was performed, during the second semester of 2008 to 51 children admitted with otitis media acute suppurativa as diagnosis, at the provincial pediatric hospital of Camagüey Eduardo Agramonte Piña. Results: a slight increase of the masculine sex was found; with significant prevalence of the white race (44,86 percent). There was a high incidence in patients under one year (29) for 56,9 percent. The 58,8 percent (30) of patients previously received antimicrobial treatment. The most frequent antimicrobial treatment used was amoxicillin (44,1 percent), penicillin (20,5 percent) and claforan (11,7 percent). More than the 66 percent presented a favorable evolution within 72 hours next to the treatment with ceftriaxone monodoses. In 48 of studied patients a favorable otoscopic evolution was obtained, what corresponded to 94,12 percent of studied cases. Conclusions: a favorable evolution was achieved within 72 hours following to the treatment with ceftriaxone monodoses in more than the half of cases.

Debemos prescribir un solo remedio / We prescribe a single remedy

Desde un principio Samuel Hahnemann estableció que el tratamiento homeopático debía realizarse con un solo medicamento, ya que los remedios habían sido experimentados así para la obtención de las patogenesias y porque sólo de esta manera se podría aplicar la Ley de Semejanza de manera cabal, con un riesgo mínimo de error y observando con claridad si la evolución del paciente es exitosa, de acuerdo con las regias de la curación. En contraparte, quien prescribe dos, cinco o más medicamentos para cubrir el mayor número de síntomas que presenta el paciente, en realidad practica alopatia o pseudo-alopatía con remedíos dinamizados. De tal suerte, el médico debe evitar el automatismo en la prescripción y apoyarse en el estudio y uso de la teoría, la Materia Médica y los repertorios, a !in de brindar la atención más honesta y conveniente al enfermo.(AU)

Debemos prescribir un solo remedio / We prescribe a single remedy

Desde un principio Samuel Hahnemann estableció que el tratamiento homeopático debía realizarse con un solo medicamento, ya que los remedios habían sido experimentados así para la obtención de las patogenesias y porque sólo de esta manera se podría aplicar la Ley de Semejanza de manera cabal, con un riesgo mínimo de error y observando con claridad si la evolución del paciente es exitosa, de acuerdo con las regias de la curación. En contraparte, quien prescribe dos, cinco o más medicamentos para cubrir el mayor número de síntomas que presenta el paciente, en realidad practica alopatia o pseudo-alopatía con remedíos dinamizados. De tal suerte, el médico debe evitar el automatismo en la prescripción y apoyarse en el estudio y uso de la teoría, la Materia Médica y los repertorios, a !in de brindar la atención más honesta y conveniente al enfermo.

Farmacocinetica de Gentamicina en neonatos de termino: dosis unica versus dosis múltiple diaria / Gentamicin Pharmacokinetics in full term neonates: single daily dosing versus multiple daily dosing

Objetivo: Estimar los parámetros farmacocinéticos poblacionales de gentamicina en recién nacidos a término (RNT)internados en terapia intensiva y comparar regímenes de administración de una versus múltiples dosis diarias. Materiales y Métodos: Se desarrolló un estudio prospectivo y randomizado en 33 RNT (enero de 2003 a junio de 2004), dividiendo en dos grupos según dosificaciones iniciales: A: 2,5 mg/kg/dosis cada 12 horas con menos de 7 días (d) de Edad Postnatal (EP), o cada 8 horas con EP mayor o igual a 7 d; B: 4 mg/kg/dosis cada 24 horas. Criterios de inclusión y exclusión fueron: peso, estados fisiopatológicos que alterasen la disposición de gentamicina y score Apgar. Fueron dosables 88 muestras plásmáticas, incluyendo concentraciones mínimas y máximas (Cmin igual valle y Cmáx igual pico) por inmunofluorescencia polarizada (límite de sensibilidad: 0.27 pg/mL, Variabilidad intra interdía < 5 por ciento). Se cuantificaron creatinina, urea y sodio plásmático. Los valores poblacionales de tiempo de semivida de eliminación plasmática (t1/2) y volumen de distribución (Vd) se calcularon por regresión no lineal bayesiana (valores iniciales de análisis: t1/2 igual 5 horas, Vd igual 0.52 L/kg) y por método estándar en dos etapas (S2S igual estándar two stage). Resultados: En todos los casos se observó buena respuesta clínica. EP media: 11.55 días (d) rango: 0 menos 31 d). Los valores globales de la media de t1/2 y Vd fueron 5.96 horas ( mas menos 3.09) y 0.56 L/kg (mas menos0.17) respectivamente. Los dosajes fuera de franja terapéutica fueron, para el grupo A, del 22.03 por ciento (13 de 59) y para grupo B del 12.00 por ciento (3 de 27), lo que no fue significativamente diferente. Aunque no se observaron efectos nefrotóxicos atribuibles a gentamicina, este punto demandará estudios futuros . La EP modificó significativamente los t1/2. En pacientes con EP < 7 d, la medida del t1/2 fue 7.73 hs. (mas o menos 3.09), mientras que para EP > igual 7 d fue 4.20 hs...

Aminoglucósidos: ¿Cuándo y por qué usar en monodosis? / Aminoglucoside, when and why should they be administered once a day?

Se realizó una revisión bibliográfica para unificar criterios sobre el uso de aminoglucósidos en intervalo extendido o monodosis. Se hizo una intensa búsqueda para encontrar las referencias de los estudios calificados y de los artículos de revisión sobre este tema. Los criterios de selección exigían que fueran estudios clínicos controlados y aleatorios en pacientes adultos, que compararan dosis única versus dosis múltiples, y que la administración de los medicamentos fuera por vía parenteral

Terapia hormonal de liberación transdérmica para el tratamiento de mujeres menopáusicas / Transdermal release hormone therapy for the treatment of menopausal women

The recent publication of the initial outcomes from the Women's Health Initiative (WHI) study of menopausal management have cast concern on the safety of oral hormone therapy, despite the lack of new or increased risks associated with the use of hormone therapy. As with any study there are biases that limit our ability to use the clinical outcomes and apply them to all menopausal women. In particular, the WHI studies recruited asymptomatic women and evaluated only a single dose of a daily oral regimen of conjugated equine estrogen (0.625 mg) and medroxyprogesterone acetate (2.5 mg). The failure to evaluate symptomatic women and non-oral regimens precluded the evaluation of hormone delivery systems that have been shown to provide similar symptom relief to oral regimens but with a considerably different physiological impact. A recent evaluation of the clinical efficacy and safety of a transdermal combination hormone therapy for the menopause will be reviewed in this article.

La reciente publicación de los resultados iniciales del estudio Women's Health Initiative (WHI) respecto del tratamiento de la menopausia causó preocupación acerca de la seguridad de la terapia hormonal oral, pese a que su uso no conlleva aumento de riesgos o riesgos nuevos. Como en cualquier otro estudio, existen sesgos que limitan nuestra capacidad para utilizar los resultados clínicos y aplicarlos a todas las mujeres menopáusicas. En particular, los estudios WHI reclutaron mujeres asintomáticas y evaluaron sólo una dosis única de un régimen diario oral de estrógenos equinos conjugados (0.625 mg) y acetato de medroxiprogesterona (2.5 mg). La falta de evaluación de mujeres sintomáticas y de regímenes no orales impidió la valoración de otros sistemas de liberación hormonal que proveen alivio sintomático similar al de los regímenes orales, pero con un impacto fisiológico considerablemente diferente. En este trabajo se revisa una reciente evaluación de la eficacia clínica y seguridad de una terapia hormonal combinada transdérmica en la menopausia.

Efecto del parathion sobre el índice de apoptosis en hepatocitos de ratones CF1 / Effect of parathion on the apoptosis of CF1 mouse hepatocytes

El las últimas décadas el uso masivo de agropesticidas órganofosforados, como Parathion y Malathion, ha permitido el control de plagas en la producción hortofrutícola, mejorando la productividad e incrementando la oferta de alimentos de mayor calidad. Sin embargo, pese a su efectividad, estos compuestos químicos son potenciales causantes de daños morfológicos y genéticos, de alto riesgo para la Salud Humana y animal (Draper, 1985; Rodríguez y Bustos-Obregón, 2000). El parathion© (PT), inhibidor de la aceltilcolinesterasa, se metaboliza en hígado, pulmón y cerebro. El efecto tóxico se debe a un proceso de desulfuración oxidativa hepática, que transforma el PT en paraoxon (PO), siendo éste su metabolito activo (Chambers y Chambers, 1990; Siller et al., 1997). El objetivo del presente trabajo es evaluar los efectos de una dosis única de PT sobre los índices de apoptosis en hepatocitos de ratón CFI. Se usaron ratones macho CFI de 8 a 10 semanas, con un peso promedio de 30 g, a los cuales se les aplicó una dosis intraperitoneal única de PT de 20 mg/Kg de peso (Sobarzo y Bustos-Obregón, 2000). Posteriormente fueron sacrificados a 1, 8, 16, 28 y 50 días postratamiento. El análisis histológico del hígado se realizó mediante microscopía óptica sobre cortes teñidos con hematoxilina/eosina en que se analizó la presencia y frecuencia de hepatocitos apoptóticos. Los resultados obtenidos permiten demostrar el efecto del PT sobre el hepatocito con un aumento estadísticamente significativo de apoptosis. Se postula que el PT es carcinogénico, que bloquea o modifica la capacidad de replicación de los hepatocitos, alterando la susceptibilidad del tejido hepático (Fausto, 2000; Metcalfe y Streuli, 1997). Se concluye que el PT tiene un efecto tóxico, aún en dosis consideradas bajas, aumentando significativamente los índices de eventos apoptóticos, alterando el ciclo celular y afectando la histofisiología del tejido hepático

Estudo da circulaçäo retrobulbar e do campo visual após dose única oral de citrato de sildenafil (Viagra) / Study of retrobulbar circulation and visual field after oral single dose of sildenafil citrate (Viagra)

Objetivo: Estudar os efeitos na circulaçäo retrobulbar e no campo visual de uma dose oral única de 100 mg de citrato de sildenafil (Viagra). Métodos: Um estudo duplo-mascarado e controlado por placebo foi realizado em 10 voluntários do sexo masculino, com idade média de 27,7 ñ 5,68 anos. O olho direito de cada voluntário foi submetido aos exames de Doppler colorido de órbita e análise de campo visual por meio de perimetria computadorizada (Humphrey, programa 30-2, estratégia "Full Threshold") em 3 ocasiöes: "baseline",1 hora após placebo e 1 hora após 100 mg de sildenafil via oral. No campo visual, analisaram-se o limiar foveal e o "mean deviation" (MD) nas 3 ocasiöes. No Doppler colorido, medimos a velocidade sistólica máxima (VSM), a velocidade diastólica final (VDF) e o índice de resistência (IR) da artéria central da retina (ACR) e da artéria oftálmica (AO) nas 3 ocasiöes. Resultados: A administraçäo do sildenafil näo alterou significativamente o limiar foveal e o "mean deviation" em relaçäo ao "baseline" e ao placebo. Houve um aumento significativo da velocidade sistólica máxima e velocidade diastólica final na artéria oftálmica após a administraçäo do citrato de sildenafil (p<0,001). Näo houve alteraçäo significativa dos parâmetros hemodinâmicos na artéria central da retina e no índice de resistência da artéria oftálmica. Conclusöes: A administraçäo de 100 mg de citrato de sildenafil promoveu um aumento da velocidade de fluxo sanguíneo na artéria oftálmica de indivíduos normais e näo promoveu alteraçäo significativa no limiar foveal e "mean deviation" da campimetria computadorizada.

Tratamento clínico da gravidez ectópica com metotrexato / Medical treatment of ectopic pregnancy with methotrexate

A gravidez ectópica é uma importante causa de morbimortalidde materna no primeiro trimestre gestacional. As dosagens hormonais seriadas e a ultrassonografia endovaginal, realizadas atualmente, facilitaram o diagnóstico e tratamento da gravidez ectópica, antes que ocorresse a ruptura tubária. O tratamento clínico medicamentoso com o metotrexato, um antagonista do ácido fólico altamente tóxico a tecidos em rápida replicação, é bastante utilizado em gestações ectópicas íntegras, adequadamente selecionadas. Muitos estudos vêm sendo realizados a fim de tentar definir quais grupos de pacientes se beneficiariam desse tratamento e, qual seria o melhor esquema de administração dessa droga, com redução dos efeitos colaterais e melhores taxas de sucesso. Esta revisão expõe as opções de tratamento medicamentoso mais estudadas para tratamento da gravidez ectópica íntegra, com ênfase nas taxas de sucesso de tratamento (cura, persistência de tecido trofoblástico e permeabilidade tubária) e no prognóstico a longo prazo.

Ectopic pregnancy is a significant cause of morbity and mortality in the first trimester of pregnancy. Serial hormone assays and transvaginal ultrasonography facilitate the diagnosis and treatment of ectopic pregnancy before rupture occurs. Early nonsurgical diagnosis and appropiate treatment have resulted in diversity of management options and decline in mortality, due to this pathology. Treatment with methotrexate, a folic acid antagonist, highly toxic to rapidly replicating tissues, can be applied on selected patients with non-ruptured ectopic pregnancy. Many studies have been developed intending to define which patients would be benefited by this treatment and how to administer this drug, with low side effects and good successful rates. This review refers to the best practice on non-ruptured ectopic pregnancy, with emphasis on treatment success rates (cure rate, incidence of persistent trophoblast and tubal patency) and long-term prognosis.