Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action.

BACKGROUND: the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H2O)2]·H2O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD. METHODS: ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl2 were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91phox and p47phox) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis. RESULTS: The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment. CONCLUSION: Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

Drug-related problems in hypertension and gestational diabetes mellitus: A hospital cohort.

OBJECTIVE: To characterize the drug-related problems (DRPs) in high-risk pregnant women with hypertension and gestational diabetes mellitus according to frequency, type, cause, and factors associated with their occurrence in the hospital setting. METHODOLOGY: This is an observational, longitudinal, prospective study that included 571 hospitalized pregnant women with hypertension and gestational diabetes mellitus using at least one medication. DRPs were classified according to the Classification for Drug-Related Problems (PCNE V9.00). In addition to descriptive statistics, a univariate and multivariate logistic regression model was employed to determine the factors associated with the DRPs. RESULTS: A total of 873 DRPs were identified. The most frequent DRPs were related to therapeutic ineffectiveness (72.2%) and occurrence of adverse events (27.0%) and the main drugs involved were insulins and methyldopa. These were followed in the first five days of treatment by: the ineffectiveness of insulin (24.6%), associated with underdosage (12.9%) or insufficient frequency of administration (9.5%) and methyldopa associated with the occurrence of adverse reactions (40.2%) in the first 48h. Lower maternal age (OR 0.966, 95% CI 0.938-0.995, p = 0.022), lower gestational age (OR 0.966, 95% CI 0.938-0.996, p = 0.026), report of drug hypersensitivity (OR 2.295, 95% CI 1.220-4.317, p = 0.010), longer treatment time (OR 1.237, 95% CI: 1.147-1.333, p = 0.001) and number of prescribed medications (OR 1.211, 95% CI: 0.240-5.476, p = 0.001) were risk factors for occurrence of DRPs. CONCLUSION: DRPs are frequent in pregnant women with hypertension and gestational diabetes mellitus, and they are mainly related to therapeutic ineffectiveness and the occurrence of adverse events.

Hypertensive Disorders of Pregnancy and Medication Use in the 2015 Pelotas (Brazil) Birth Cohort Study.

Hypertensive disorders of pregnancy account for approximately 22% of all maternal deaths in Latin America and the Caribbean. Pharmacotherapies play an important role in preventing and reducing the occurrence of adverse outcomes. However, the patterns of medications used for treating women with hypertensive disorders of pregnancy (HDP) living in this country is unclear. A population-based birth cohort study including 4262 women was conducted to describe the pattern of use of cardiovascular agents and acetylsalicylic acid between women with and without HDP in the 2015 Pelotas (Brazil) Birth Cohort. The prevalence of maternal and perinatal outcomes in this population was also assessed. HDP were classified according to Ministry of Health recommendations. Medications were defined using the Anatomical Therapeutic Chemical Classification System and the substance name. In this cohort, 1336 (31.3%) of women had HDP. Gestational hypertension was present in 636 (47.6%) women, 409 (30.6%) had chronic hypertension, 191 (14.3%) pre-eclampsia, and 89 (6.7%) pre-eclampsia superimposed on chronic hypertension. Approximately 70% of women with HDP reported not using any cardiovascular medications. Methyldopa in monotherapy was the most frequent treatment (16%), regardless of the type of HDP. Omega-3 was the medication most frequently reported by women without HDP. Preterm delivery, caesarean section, low birth weight, and neonatal intensive care admissions were more prevalent in women with HDP. Patterns of use of methyldopa were in-line with the Brazilian guidelines as the first-line therapy for HDP. However, the large number of women with HDP not using medications to manage HDP requires further investigation.

Prescripción de metildopa en el tratamiento de pacientes con enfermedad hipertensiva en el embarazo / Methyldopa prescription in patients with hipertensive disease during pregnancy

Se realizó un estudio descriptivo y transversal, de utilización de medicamentos, de tipo indicación-prescripción, de 67 gestantes con enfermedad hipertensiva en el embarazo, atendidas en el Hospital Materno Sur Mariana Grajales Coello de Santiago de Cuba, desde julio de 2015 hasta junio de 2016, con vistas a caracterizar la prescripción de metildopa en estas pacientes. En la casuística predominó el uso de este fármaco en las pacientes que tenían situaciones asociadas con las formas más graves de la enfermedad, tales como la edad avanzada, la nuliparidad y el antecedente de hipertensión arterial. Las principales dificultades correspondieron a la combinación de medicamentos con riesgo de interacciones con la metildopa y al empleo de esta a dosis elevadas(AU)

A descriptive cross-sectional indication-prescription study of medications use, of 67 pregnant women with hipertensiv disease during pregnancy, assisted in Mariana Grajales Coello Southern Maternal Hospital was carried out in Santiago de Cuba, from July, 2015 to June, 2016, aimed at characterizing methyldopa prescription in these patients. The use of this medicine prevailed in the case material in patients that had situations associated with the most serious forms of the disease, such as advanced age, nonpariity and hypertension history. The main difficulties corresponded to the combination of medicines with risk of methyldopa interactions and its use at a high dose(AU)

Prescripción de metildopa en el tratamiento de pacientes con enfermedad hipertensiva en el embarazo / Methyldopa prescription in patients with hipertensive disease during pregnancy

Se realizó un estudio descriptivo y transversal, de utilización de medicamentos, de tipo indicación-prescripción, de 67 gestantes con enfermedad hipertensiva en el embarazo, atendidas en el Hospital Materno Sur Mariana Grajales Coello de Santiago de Cuba, desde julio de 2015 hasta junio de 2016, con vistas a caracterizar la prescripción de metildopa en estas pacientes. En la casuística predominó el uso de este fármaco en las pacientes que tenían situaciones asociadas con las formas más graves de la enfermedad, tales como la edad avanzada, la nuliparidad y el antecedente de hipertensión arterial. Las principales dificultades correspondieron a la combinación de medicamentos con riesgo de interacciones con la metildopa y al empleo de esta a dosis elevadas

A descriptive cross-sectional indication-prescription study of medications use, of 67 pregnant women with hipertensive disease during pregnancy, assisted in Mariana Grajales Coello Southern Maternal Hospital was carried out in Santiago de Cuba, from July, 2015 to June, 2016, aimed at characterizing methyldopa prescription in these patients. The use of this medicine prevailed in the case material in patients that had situations associated with the most serious forms of the disease, such as advanced age, nonpariity and hypertension history. The main difficulties corresponded to the combination of medicines with risk of methyldopa interactions and its use at a high dose

Tratamento farmacológico e intervencionista do sistema nervoso simpático / Pharmacological and interventional treatment of sympathetic system

o sistema nervoso autônomo contribui diretamente para uma série de atividades biológicas e está envolvido em inúmeras doenças. A hiperatividade simpática é um dos vários mecanismos envolvidos na patogênese da hipertensão arterial sistêmica (HAS) primária. A transmissão da informação nervosa através de sinapses é mediada por agentes químicos específicos conhecidos como neurotransmissores, representados pela acetilcolina e pelas catecolaminas. O bloqueio dos receptores pré e pós-sinapse permite que a ação de fárrnacos alcance sua plenitude no controle dos portadores de hiperati vidade simpática. Um percentual significativo de hipertensos são resistentes ao tratamento farrnacológico. A denervação simpática renal surgiu como estratégia terapêutica adjunta no controle de hipertensos resistentes ao tratamento clínico. Nos últimos cinco anos, diversos estudos demonstraram resultados consistentes na redução da pressão arterial. Diversas outras condições clínicas associam-se à hiperatividade do sistema adrenérgico, tais como a insuficiência cardíaca, o diabetes mellitus, a doença renal crônica, a síndrome da apneia e hipopneia obstrutiva do sono e as arritmias cardíacas. Nestes contextos, a redução da atividade simpática renal também mostrou-se ser benéfica em estudos clínicos iniciais. Uma variedade de dispositivos dedicados foram e estão sendo desenvolvidos com o objetivo de ampliar a segurança e a eficácia do método, além de facilitar o procedimento. Estudos multicêntricos, prospectivos, randomizados e controlados em andamento investigam desfechos como mortalidade cardiovascular, infarto agudo do miocárdio e acidente vascular cerebral em longo prazo.

The autonomic nervous system contributes directly to a number of biological activities and is involved in numerous diseases. Sympathetic hyperactivity is one of several mechanisms involved in the pathogenesis of primary hypertension. The transmission through the nerve synapses is mediated by specific chemical agents known as neurotransmitters represented by the acetylcholine and catecholarnine. Blockade of specific pre-and post-synapse receptors allows the treatment of patients with sympathetic hyperactivity. A large proportion of hypertensive patients are resistant to pharmacological treatment. Renal sympathetic denervation emerged as adjunctive therapeutic strategy in controlling hypertension resistant to medical treatrnent. ln the last five years, several studies have shown consistent results in lowering blood pressure. Several other clinica! conditions are associated with hyperactivity of the adrenergic system such as heart failure, diabetes mellitus, chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome and cardiac arrhythrnias. ln these contexts, the reduction in renal sympathetic activity also proved to be beneficial in initial clinical studies. A substantial variety of dedicated devices have been developed in order to reduce variability between operators, reduce renal artery manipulation, improve vessel contact, reduce radiation exposure and procedure time, and therefore improving safety and efficacy. Mu!ticenter, prospective, randomized, controlled trials are ongoing to investigate long term outcomes such as cardiovascular mortality, acute myocardial infarction and stroke.

Development of a HPLC/MS/MS methodology for determining 3-O-methyldopa in human plasma and its application in a bioequivalence study / Desenvolvimento de metodologia baseada em HPLC/MS/MS para a determinação de 3-O-metildopa em plasma humano e sua aplicação a estudos de bioequivalência

A simple, sensitive and specific HPLC/MS/MS methodology was developed and it was validated for determining 3-O-methyldopa, the major metabolite of dopamine, in human plasma. The separation was achieved on Atlantis T3 C18 analytical column (5 μm; 150 x 4.6 mm i.d.) using a mobile phase consisted of a solution of water and methanol (85:15, v/v) and containing formic acid 0.05 %. The extraction from the analyte and the internal standard sample was performed using a simple protein plasma precipitation with perchloric acid. The detection was conducted on a triple quadrupole tandem mass spectrometer with a positive multiple reaction monitoring mode (MRM). The monitored fragmentation transitions were m/z 212.0  m/z 166.0 for 3-O-methyldopa and m/z 227.10  m/z 181.0 for carbidopa (internal standard). The calibration curves were linear in the range of 50–4000 ng/mL for 3-O-methyldopa. The methodology presented a good precision and accuracy in accordance to the criteria for biomedical analysis. And it was successfully applied to the bioequivalence study of two formulations levodopa + benserazide (200 + 50 mg) in plasma samples from healthy human volunteers, following the ANVISA guidelines.(AU)

Uma metodologia específica, simples e sensível baseado em HPLC/MS/MS foi desenvolvida e validada para realizar a determinação de 3-o-metildopa, o principal metabolito da dopamina, em plasma humano. A separação foi realizada em coluna analítica Atlantis T3 C18 (5 μm; 150 x 4,6 mm i.d.), utilizando-se uma fase móvel composta por uma solução de água e metanol (85:15, v/v), e contendo 0,05 % de ácido fórmico. A extração do analito e da amostra padrão interno foi executada utilizando-se uma simples precipitação proteica no plasma com ácido perclórico. A detecção foi realizada por meio de espectrômetro de massa triplo quadrupolo, em modo de monitoramento de reações múltiplas (MRM) positivo. A transição monitorizada foi m/z 212,0  m/z 166,0 para 3-O-metildopa e m/z 227,1  m/z 181,0 para carbidopa (padrão interno). As curvas de calibração foram lineares na faixa de 50 a 4000 ng/mL para 3-O-metildopa. A metodologia apresentou boa precisão e exatidão de acordo com os critérios para análises biomédicas e esta foi aplicada com sucesso no estudo de bioequivalência de duas formulações contendo levodopa + benserazida (200 + 50 mg) em amostras de plasmas humanos.(AU)

Development and validation of a simple spectrophotometric method for the determination of methyldopa in both bulk and marketed dosage formulations

A simple, precise, sensitive, rapid, specific and economical spectrophotometric method was developed to determine methyldopa (MTD) content in bulk and pharmaceutical dosage formulations. The proposed method was based on the formation of a colored product from the nitrosation reaction of MTD with sodium nitrite in an acid medium. The resultant nitroso derivative species reacts further with sodium hydroxide and is converted it into a more stable compound. This yellow nitrosation product exhibited an absorption maximum at 430 nm. Beer's Law was obeyed in a concentration range of 6.37 to 82.81 μg mL-1 MTD with an excellent coefficient of determination (R 2 = 0.9998). No interference was observed from common excipients in formulations. The results showed the method to be simple, accurate and readily applied for the determination of MTD in pure form and in pharmaceutical preparations. The analytical results obtained for these products using the proposed method are in agreement with those of the Brazilian Pharmacopoeia procedure at a 95% confidence level.

Desenvolveu-se método espectrofotométrico simples, preciso, sensível, rápido, específico e econômico para a determinação do teor de metildopa (MTD) em matéria-prima e em formulações farmacêuticas. O método proposto baseia-se na formação de um produto colorido resultante da reação de nitrosação da MTD com nitrito de sódio em meio ácido. A espécie resultante (nitroso derivado) reage com hidróxido de sódio e é convertida a um composto mais estável de cor amarela. Este produto exibiu máximo de absorção a 430 nm. A lei de Beer foi obedecida na faixa de concentração de 6,37 a 82,81 μg mL-1 de MTD com excelente coeficiente de determinação (R 2 = 0,9998). Não se observou interferência de excipientes comumente encontrados em formulações farmacêuticas comerciais. Os resultados demonstraram que o método proposto apresenta simplicidade, excelentes precisão e exatidão e pode ser aplicado para a determinação de MTD na sua forma pura e em preparações farmacêuticas. Os resultados analíticos obtidos pelo método proposto estão de acordo com aqueles obtidos pelo método oficial descrito na Farmacopéia Brasileira, a um nível de confiança de 95%.

A single oral dose of fructose induces some features of metabolic syndrome in rats: role of oxidative stress.

BACKGROUND AND AIMS: To determine if a single oral dose of fructose to rats reproduces some features of metabolic syndrome observed after chronic administration and if so, to investigate its mechanisms. METHODS AND RESULTS: Systolic blood pressure was measured in rats before and after oral administration of fructose, and in animals pretreated with lipoic acid, methyldopa, losartan or streptozotocin. In other rats, glucose, insulin, uric acid, and insulin sensitivity index, were determined before and after fructose or lipoic acid plus fructose. Glutathione was measured in liver before and after fructose administration. In aortic rings from other rats, incubation with mannitol, fructose, or fructose plus lipoic acid was evaluated on the relaxation by acetylcholine. Fructose produced a moderate increase in blood pressure, which was prevented by lipoic acid or streptozotocin. Methyldopa and losartan decreased the pressor response minimally. Fructose increased oxidized glutathione, plasma glucose, insulin and uric acid, and diminished the insulin sensitivity index, and the reduced glutathione. Lipoic acid prevented hyperglycemia and hyperuricemia, and improved the insulin sensitivity index. Finally, endothelial dysfunction was prevented by lipoic acid. CONCLUSION: A single dose of fructose reproduces some of the features of metabolic syndrome, most changes were caused by oxidative stress and insulin resistance.

[Takayasu's arteritis in pregnancy: report seven cases]. / Arteritis de Takayasu en el embarazo: reporte de siete casos.

Takayasu's arteritis is a chronic and non-specific disease of young women in reproductive age that primarily affects the aorta, its branches and the pulmonary artery. Ramirez Cueto G. and Fernandez Del Castillo C. et al. published a case of pregnancy in Mexico and Takayasu's arteritis in 1968. There are no reports of this disease in pregnancy since. The purpose of this study is to describe the clinical course and perinatal outcome of seven pregnant patients with known diagnosis of Takayasu arteritis. The clinical course, laboratory findings, angiographic findings and perinatal outcomes were assessed in retrospect in seven pregnant patients with diagnosis of Takayasu's arteritis seen at the National Institute of Perinatology Isidro Espinosa Reyes (Mexico) during the period 2002-2010. The results of the conducted follow-up of 7 patients pregnant with Takayasu's arteritis were: 3 patients were complicated with pre-eclampsia and 2 newborn presented intrauterine growth restriction. Disease activity wasn't observed during pregnancy. No cases of congestive heart failure, brain ischemia or maternal deaths were presented. There were no fetal deaths. We didn't observed induced activity during pregnancy in the cases presented. The most common mother complication was type renovascular hypertension with added severe preeclampsia, which determined the presence of intrauterine growth restriction. There were no maternal or perinatal deaths.

Different culture media containing methyldopa for melanin production by Cryptococcus species.

INTRODUCTION: Melanin production by species of Cryptococcus is widely used to characterize C. neoformans complex in mycology laboratories. This study aims to test the efficacy of methyldopa from pharmaceutical tablet as a substrate for melanin production, to compare the production of melanin using different agar base added with methyldopa, and to compare the melanin produced in those media with that produced in Niger seed agar and sunflower seed agar by C. neoformans, C. laurentii, and C. albidus. Two isolates of each species, C. neoformans, C. laurentii, and C. albidus, and one of Candida albicans were used to experimentally detect conditions for melanin production. METHODS: The following media were tested: Mueller-Hinton agar (MHA), brain and heart infusion agar (BHIA), blood agar base (BAB), and minimal medium agar (MMA), all added with methyldopa, and the media Niger seed agar (NSA) and sunflower seed agar (SSA). RESULTS: All isolates grew in most of the culture media after 24h. Strains planted on media BAB and BHIA showed growth only after 48h. All isolates produced melanin in MMA, MHA, SSA, and NSA media. CONCLUSIONS: Methyldopa in the form pharmaceutical tablet can be used as a substrate for melanin production by Cryptococcus species; minimal medium plus methyldopa was more efficient than the BAB, MHA, and BHIA in the melanin production; and NSA and SSA, followed by MMA added with methyldopa, were more efficient than other media studied for melanin production by all strains studied.

Different culture media containing methyldopa for melanin production by Cryptococcus species / Avaliação de diferentes meios de cultura contendo metildopa para a produção de melanina por espécies de Cryptococcus

INTRODUCTION: Melanin production by species of Cryptococcus is widely used to characterize C. neoformans complex in mycology laboratories. This study aims to test the efficacy of methyldopa from pharmaceutical tablet as a substrate for melanin production, to compare the production of melanin using different agar base added with methyldopa, and to compare the melanin produced in those media with that produced in Niger seed agar and sunflower seed agar by C. neoformans, C. laurentii, and C. albidus. Two isolates of each species, C. neoformans, C. laurentii, and C. albidus, and one of Candida albicans were used to experimentally detect conditions for melanin production. METHODS: The following media were tested: Mueller-Hinton agar (MHA), brain and heart infusion agar (BHIA), blood agar base (BAB), and minimal medium agar (MMA), all added with methyldopa, and the media Niger seed agar (NSA) and sunflower seed agar (SSA). RESULTS: All isolates grew in most of the culture media after 24h. Strains planted on media BAB and BHIA showed growth only after 48h. All isolates produced melanin in MMA, MHA, SSA, and NSA media. CONCLUSIONS: Methyldopa in the form pharmaceutical tablet can be used as a substrate for melanin production by Cryptococcus species; minimal medium plus methyldopa was more efficient than the BAB, MHA, and BHIA in the melanin production; and NSA and SSA, followed by MMA added with methyldopa, were more efficient than other media studied for melanin production by all strains studied.

INTRODUÇÃO: A produção de melanina por espécies de Cryptococcus é uma característica amplamente utilizada em laboratórios de micologia para caracterização do complexoC. neoformans. O objetivo deste estudo foi verificar a eficácia da metildopa na forma farmacêutica de comprimido, como substrato para a produção de melanina por Cryptococcus, comparar diferentes bases de meios de cultura acrescidas de metildopa para produção de melanina e comparar o pigmento produzido nestes meios com o produzido em ágar Níger e ágar girassol por C. neoformans, C. laurentii e C. albidus. MÉTODOS: Foram testados dois isolados de cada uma das espécies, C. neoformans, C.laurentii e C.albidus, e um de C. albicans para avaliar a produção de melanina nos meios de cultura ágar Müeller-Hinton (MH), ágar brain heart infusion (BHI), ágar base sangue (BS), meio mínimo (MM), todos acrescidos de metildopa, e ainda ágar girassol e ágar Níger. RESULTADOS: Todos os isolados cresceram na maioria dos meios após 24h. O crescimento nos meios BS e BHI somente ocorreu após 48h. Todos os isolados produziram melanina nos meios MM, MH, girassol e Niger. CONCLUSÕES: A metildopa de origem farmacêutica pode ser utilizada como substrato para a produção de melanina por espécies de Cryptococcus; o MM acrescido de metildopa mostrou-se mais eficiente na produção de melanina do que os meios BS, MH e BHI; ágar girassol e ágar Níger seguidos de MM acrescido de metildopa foram os mais eficientes na produção de melanina pelos isolados estudados.

Development and validation of a high-performance liquid chromatography-electrospray ionization-MS/MS method for the simultaneous quantitation of levodopa and carbidopa in human plasma.

A sensitive and fast high-performance liquid chromatography-electrospray ionization-MS/MS method for the simultaneous quantitation of levodopa and carbidopa in human plasma was developed and validated. A simple protein precipitation step with perchloric acid was used for the cleanup of plasma, and methyldopa was added as an internal standard. The analyses were carried out using an ACE C(18) column (50 × 4.6 mm i.d.; 5 µm particle size) and a mobile phase consisting of 0.2% formic acid and acetonitrile (90:10). The triple-quadrupole mass spectrometer equipped with an electrospray source in positive mode was set up in the selective reaction monitoring mode to detect the ion transitions m/z 198.1 → m/z 107.0, m/z 227.2 → m/z 181.0, and m/z 212.1 → m/z 139.2 for levodopa, carbidopa, and methyldopa, respectively. The method was validated and proved to be linear, accurate, and precise over the range 50-5000 ng/mL for levodopa and 3-600 ng/mL for carbidopa. The proposed method was successfully applied in a pharmacokinetic study with a levodopa/carbidopa tablet formulation in healthy volunteers.

Simultaneous quantitation of levodopa and 3-O-methyldopa in human plasma by HPLC-ESI-MS/MS: application for a pharmacokinetic study with a levodopa/benserazide formulation.

A sensitive and simple method was developed for the quantitation of levodopa and its metabolite 3-O-methyldopa, in human plasma, after oral administration of tablet formulations containing levodopa (200 mg) and benserazide (50 mg). The analytes were extracted by a protein precipitation procedure, using carbidopa as an internal standard. A mobile phase consisting of 0.2% formic acid and acetonitrile (94:6, v/v) was used and chromatographic separation was achieved using ACE C(18) column (50 mm×4.6 mm i.d.; 5 µm particle size). Selected reaction monitoring was performed using the fragmentation transitions m/z 198→m/z 107, m/z 212→m/z 166 and m/z 227→m/z 181 for levodopa, 3-O-methyldopa and carbidopa, respectively. Calibration curves were constructed over the range 50.0-6000.0 ng/mL for levodopa and 25.0-4000.0 ng/mL for 3-O-methyldopa. The method shown to be specific, precise, accurate and provided recovery rates higher than 85% for all analytes. No matrix effect was detected in the samples. The validated method was applied in a pharmacokinetic study with a levodopa/benserazide tablet formulation in healthy volunteers.

Preparation and evaluation of a new nano pharmaceutical excipients and drug delivery system based in polyvinylpyrrolidone and silicate.

PURPOSE: This work describes the preparation of new nanocomposites based on lamellar silicates (AAM-alkyl ammonium montmorillonite) obtained by the intercalation of PVP K30 and glyceril monostearate. METHODS: By XRD, TGA and DSC analysis the AAM was characterized and its compactation characteristics, functionality and toxicity were also tested. The AAM/PVP K-30 and AAM/GME nanocomposite obtained were evaluated to identify the interlamellar spacing values by XRD diffratograms. Tablets were prepared using methyldopa and theophylline as model drugs and the dissolution tests were carried out in simulated gastric fluid and simulated enteric fluid. RESULTS: AAM showed a good compactability and compressibility characteristics for tablets preparation. The intercalation yields (approximately 25%) of the nanocomposites were efficient. The AAM/PVP K-30 nanocomposites were successfully tested as dissolution enhancers and sustained release matrixes. CONCLUSIONS: The results also suggested the promising use of AAM (viscogel B8) and the new nanocomposite prepared by clay/PVP K-30 intercalation as a new matrix for sustained release and the feasibility of using these new nanocomposites as dissolution enhancer.

A novel support for laccase immobilization: cellulose acetate modified with ionic liquid and application in biosensor for methyldopa detection.

A material based on cellulose acetate (CA) and the room temperature ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (BMI·N(Tf)(2)) was developed and characterized by scanning electron microscopy, electron dispersive spectroscopy and infrared analysis. Laccase (Lac) from Aspergillus oryzae was immobilized in this material to investigate the behavior of methyldopa by square-wave voltammetry. Under optimized conditions, the Lac biosensor based on CA/BMI·N(Tf)(2) exhibited an excellent electrocatalytic performance: the analytical curve showed good linear range for methyldopa concentrations from 34.8 to 370.3 µM with a detection limit of 5.5 µM. This sensor demonstrated acceptable stability (ca. 60 days; at least 350 determinations), good repeatability and reproducibility (relative standard deviations of 1.5 and 4.3%, respectively). The recovery study of methyldopa in pharmaceutical formulations ranged from 94.1 to 105.9%. The determination of this substance using the biosensor compared favorably with that using a spectrophotometry procedure at the 95% confidence level, and indicated potential application to methyldopa determination in pharmaceutical samples.

Anemia hemolítica secundaria a metildopa / Hemolytic secondary anemia to methyldopa

Se presentó el caso de una paciente de sesenta y dos años, hipertensa esencial desde hace veinte años. Después de recibir tratamiento con metildopa, dos gramos diarios durante cuatro meses, presenta anemia hemolítica y trombocitopenia, con prueba de Coombs directa positiva. Se discutieron los mecanismos fisiopatológicos posibles, y se reseñaron las drogas capaces de producir esta enfermedad, así como los mecanismos de acción de la metildopa y los efectos hematológicos adversos (AU)

A case of a sixty two year-old patient, essential hypertensive for twenty years is presented. After receiving treatment with methyldopa, two daily grams during four months, showed hemolytic anemia and thrombocytopenia, with the positive direct Coombs´test. Possible physiopathologic mechanisms were discussed, the drugs able to produce this disease, the action mechanisms of methyldopa and the hematologic side effects were pointed out (AU)

Anemia hemolítica secundaria a metildopa / Hemolytic secondary anemia to methyldopa

Se presentó el caso de una paciente de sesenta y dos años, hipertensa esencial desde hace veinte años. Después de recibir tratamiento con metildopa, dos gramos diarios durante cuatro meses, presenta anemia hemolítica y trombocitopenia, con prueba de Coombs directa positiva. Se discutieron los mecanismos fisiopatológicos posibles, y se reseñaron las drogas capaces de producir esta enfermedad, así como los mecanismos de acción de la metildopa y los efectos hematológicos adversos.

A case of a sixty two year-old patient, essential hypertensive for twenty years is presented. After receiving treatment with methyldopa, two daily grams during four months, showed hemolytic anemia and thrombocytopenia, with the positive direct Coombs´test. Possible physiopathologic mechanisms were discussed, the drugs able to produce this disease, the action mechanisms of methyldopa and the hematologic side effects were pointed out.

Tratamento anti-hipertensivo na gravidez baseado em evidências / Evidence-based anti-hypertensive treatment in pregnancy

As síndromes hipertensivas representam uma das alterações que ocorrem com maior freqüência na gravidez, encontrando-se entre as principais causas de morte materna e perinatal no mundo. A terapêutica anti-hipertensiva neste grupo de pacientes ainda permanece incerta. Realizou-se uma revisão da literatura com o objetivo de descrever as peculiaridades do tratamento anti-hipertensivo na gravidez baseado nas evidências científicas disponíveis. Nas gestantes com hipertensão/pré-eclâmpsia leve, recomenda-se a não utilização de drogas anti-hipertensivas de manutenção, mesmo nas pacientes com hipertensão crônica leve sabidamente conhecida antes da gestação e que faziam uso da terapia. Nas pacientes hipertensas com fatores de risco associados, a terapia anti-hipertensiva de manutenção é recomendada. Na emergência hipertensiva, é consenso que o tratamento deva ser instituído, embora não exista consenso sobre a melhor droga a ser utilizada com essa finalidade. Da mesma forma, não está estabelecida a real necessidade do tratamento anti-hipertensivo de manutenção, ou seja, diário, nas gestantes com pré-eclâmpsia grave, em termos de efeitos benéficos para o binômio mãe-feto.

The hypertensive syndromes are one of the most common disorders of pregnancy and are one of the main causes of maternal and perinatal death around the world. Anti-hypertensive treatment in this group of patients remains unclear. A literature review was performed with the objective of describing the singularities of anti-hypertensive treatment in pregnancy based on current scientific evidence. In pregnant women with mild hypertension or preeclampsia the use of anti-hypertensive drugs is not recommended, even in patients with mild chronic hypertension diagnosed before pregnancy that previously used these drugs. In hypertensive pregnant women with associated risk factors the therapy is recommended. There is consensus about the need of treatment of hypertensive emergencies but there is no agreement on which drug should be used. In addition, the need of daily anti-hypertensive treatment in patients with severe preeclampsia is not established in terms of real beneficial effects for mothers and fetuses.