Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

Comparison of the apoptotic effects of topically applied papaverine, diltiazem, and nitroprusside to internal thoracic artery

Abstract Objective: To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside. Methods: Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis. Results: Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups. Conclusion: The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

TeleCondutas: fissura anal / TeleGuides: anal fissure

A fissura anal é uma laceração do revestimento do canal anal inferior. É uma das patologias benignas anorretais mais comuns e, em muitos casos, resolve-se espontaneamente. Sua prevalência é igual entre os sexos e é mais comum em adultos jovens. A grande maioria das fissuras são primárias e causadas por trauma local, como constipação, diarreia ou sexo anal. Fissuras secundárias são encontradas em pacientes com Doença de Crohn, malignidades (neoplasia epidermoide do canal anal, leucemia), tuberculose ou doenças sexualmente transmissíveis (HIV, sífilis, clamídia). Esta guia apresenta informação que orienta a conduta para casos de fissura anal no contexto da Atenção Primária à Saúde, incluindo: classificação, avaliação clínica, diagnóstico, tratamento clínico, tratamento cirúrgico e encaminhamento para especialista.

Development and validation of a stability indicating HPLC method to determine diltiazem hydrochloride in tablets and compounded capsules

ABSTRACT A stability indicating HPLC method to determine diltiazem hydrochloride (DTZ) in tablets and compounded capsules was developed and validated according to Brazilian and the International Conference on Harmonization (ICH) guidelines. The separation was carried out on a Purospher Star® C18 (150 x 4.6 mm i.d., 5 µm particle size, Merck Millipore) analytical column. The mobile phase consisted of a 0.05% (v/v) trifluoroacetic acid aqueous solution and a 0.05% trifluoroacetic acid methanolic solution (44:56, v/v). The flow rate was 1.0 mL.min-1 with a run time of 14 minutes. The detection of DTZ and degradation products (DP) was performed at 240 nm, using a diode array detector. The method proved to be linear, precise, accurate, selective, and robust, and was adequate for stability studies and routine quality control analyses of DTZ in tablets and compounded capsules.

Effects of intraoperative diltiazem infusion on flow changes in arterial and venous grafts in coronary artery bypass graft surgery / Efeitos da infusão intraoperatória de diltiazem sobre as mudanças do fluxo em enxertos arteriais e venosos em cirurgia de revascularização do miocárdio

AbstractObjective:This study aimed to show the effects of intra-operative diltiazem infusion on flow in arterial and venous grafts in coronary artery bypass graft surgery.Methods:Hundred fourty patients with a total of 361 grafts [205 (57%) arterial and 156 (43%) venous] underwent isolated coronary surgery. All the grafts were measured by intraoperative transit time flow meter intra-operatively. Group A (n=70) consisted of patients who received diltiazem infusion (dose of 2.5 microgram/kg/min), and Group B (n=70) didn't receive diltiazem infusion.Results:Mean graft flow values of left internal mammary artery were 53 ml/min in Group A and 40 ml/min in Group B (P<0.001). Pulsatility index (PI) values of left internal mammary artery for Group A and Group B were 2.6 and 3.0 respectively (P<0.001). No statistically significant difference was found between venous graft parameters.Conclusion:We recommend an effect of diltiazem infusion in increasing graft flows in coronary artery bypass graft operations.

ResumoObjetivo:Este estudo teve como objetivo mostrar os efeitos da infusão de diltiazem intraoperatória no fluxo arterial e enxertos venosos em cirurgia de revascularização do miocárdio.Métodos:Cento e quarenta pacientes com um total de 361 enxertos [205 (57%) arteriais e 156 (43%) venosos] passaram por uma cirurgia coronária isolada. Todos os enxertos foram medidos pelo medidor de fluxo de tempo de trânsito intraoperatório. Grupo A (n=70), formado por pacientes que receberam infusão de diltiazem (dose de 2,5 micrograma/kg/min), e Grupo B (n=70), por aqueles que não receberam infusão de diltiazem.Resultados:Os valores médios de fluxo de enxerto de artéria mamária interna esquerda foram 53 ml/min no grupo A e 40 ml/min no Grupo B (P<0,001). Valores do índice de pulsatilidade da artéria mamária interna esquerda para o Grupo A e do Grupo B foram de 2,6 e 3,0, respectivamente (P<0,001). Não houve diferença estatisticamente significativa entre os parâmetros do enxerto venoso.Conclusão:Sugerimos um efeito da infusão de diltiazem em aumentar os fluxos de enxerto em operações de bypass de artéria coronária.

Pharmacokinetics of diltiazem hydrochloride delay-onset sustained-release pellet capsules in healthy volunteers

The pharmacokinetics (PK) of ordinary tablets and sustained release capsules of diltiazem hydrochloride in human clinical trials had been studied. The PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules, a new dosage form, has not been reported, although it is very important to clinical use. In this paper, we investigated the PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules and the food influence in Chinese healthy volunteers. The PK parameters indicated that the diltiazem hydrochloride delay-onset sustained-release pellet capsules appeared marked characteristics of delayed and controlled release. An opened-label, randomized and parallel clinical trial was conducted in 36 Chinese healthy volunteers with single oral dose (90 mg, 180 mg or 270 mg) and a multiple oral dose (90 mg d-1×6 d) administration. The effect of food on the PK of one single oral dose (360 mg) was investigated in 24 healthy Chinese volunteers. Plasma diltiazem concentration was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and the main pharmacokinetic parameters were analyzed by PKSolver (Ver 2.0). All clinical studies were conducted in the Clinical Pharmacological Center (No. JDX1999064) of Xiangya Hospital Affiliated Central South University, China. The PK parameters suggested that the new formulation had marked characteristics of delayed and controlled release of diltiazem, and food intake did not alter significantly diltiazem pharmacokinetic parameters.

Embora a farmacocinética (PK) do cloridrato de diltiazem nas formas de comprimidos de liberação imediata e cápsulas de liberação modificada em ensaios clínicos já tenha sido relatada, a pesquisa da PK do cloridrato de diltiazem na forma de cápsulas com peletes de liberação retardada e sustentada ainda é muito importante. Neste trabalho, propusemos avaliar a farmacocinética do cloridrato de diltiazem administrado através desta nova forma farmacêutica em voluntários chineses sadios, assim como a influência da ingestão de alimentos neste perfil farmacocinético. Foi realizado um ensaio clínico aberto, randomizado e paralelo em 36 voluntários, que receberam dose oral única de 90 mg, 180 mg ou 270 mg e dose múltiplas (90 mg/d × 6 d) pela mesma via de administração. Para avaliar o efeito da ingestão de alimentos sobre a PK do diltiazem foi realizada a administração de dose única (360 mg) em 24 voluntários chineses sadios. A concentração plasmática do diltiazem foi determinada por Cromatografia Liquida de Alta Eficiência em fase reversa (CLAE-FR) e os principais parâmetros farmacocinéticos foram analisados através do emprego do software PKSolver (Ver 2.0). O ensaio de farmacocinética clínica foi conduzido na clínica Pharmacological Center (No.JDX1999064) do Hospital de Xiangya, Central South University, China. Os parâmetros PK obtidos indicaram que a nova formulação de cápsulas de liberação retardada e sustentada de cloridrato de diltiazem possue marcantes características de liberação retardada e controlada do fármaco.

Diltiazem como alternativa ao betabloqueador na angiotomografia de artérias coronárias / Diltiazem as an alternative to beta-blocker in coronary artery computed tomography angiography

FUNDAMENTO: A redução da frequência cardíaca (FC) na angiografia por tomografia das artérias coronarianas (ATCCor) é fundamental para a qualidade de imagem. A eficácia dos bloqueadores de cálcio como alternativas para pacientes com contraindicações aos betabloqueadores não foi definida. OBJETIVOS: Comparar a eficácia na redução da FC e variabilidade RR do metoprolol e diltiazem na ATCCor. MÉTODOS: Estudo prospectivo, randomizado, aberto, incluiu pacientes com indicação clínica de ATCCor, em ritmo sinusal, com FC>70bpm e sem uso de agentes que interferissem com a FC. Cinquenta pacientes foram randomizados para grupos: metoprolol IV 5-15 mg ou até FC≤60 bpm(M), e diltiazem IV 0,25-0,60mg/kg ou até FC≤60 bpm (D). Pressão arterial (PA) e FC foram aferidas na condição basal, 1min, 3min e 5min após agentes, na aquisição e após ATCCor. RESULTADOS: A redução da FC em valores absolutos foi maior no grupo M que no grupo D (1, 3, 5min, aquisição e pós-exame). A redução percentual da FC foi significativamente maior no grupo M apenas no 1 min e 3 min após início dos agentes. Não houve diferença no 5 min, durante a aquisição e após exame. A variabilidade RR percentual do grupo D foi estatisticamente menor do que a do grupo M durante a aquisição (variabilidade RR/ FC média da aquisição). Um único caso de BAV, 2:1 Mobitz I, revertido espontaneamente ocorreu (grupo D). CONCLUSÃO: Concluímos que o diltiazem é uma alternativa eficaz e segura aos betabloqueadores na redução da FC na realização de angiografia por tomografia computadorizada das artérias coronarianas. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

BACKGROUND: Reducing heart rate (HR) in CT angiography of the coronary arteries (CTACor) is critical to image quality. The effectiveness of calcium channel blockers as alternatives for patients with contraindications to beta-blockers has not been established. OBJECTIVES: To compare the efficacy in the reduction of HR and RR variability of metoprolol and diltiazem in CTACor. METHODS: Prospective, randomized, open study that included patients with clinical indication of CTACor in sinus rhythm with HR > 70 bpm and no use of agents that could interfere with HR. Fifty patients were randomized to the groups: metoprolol IV 5-15 mg or up to HR ≤ 60 bpm (M), and diltiazem IV 0.25 to 0.60 mg/kg or up to HR ≤ 60 bpm (D). Blood pressure (BP) and HR were measured at baseline, 1 minute, 3 minutes and 5 minutes after the agents, at the acquisition and after CTACor. RESULTS: HR reduction in absolute values was higher in group M than in group D (1, 3, 5 min, acquisition and post-test). The percentage reduction of HR was significantly higher in group M only 1 min and 3 min after the start of the agents. There was no difference in 5 min at acquisition and after examination. The percentage RR variability in group D was lower than that in group M during acquisition (RR variability/mean HR of acquisition). A single case of AVB, 2:1 Mobitz I occurred, which was spontaneously reverted (group D). CONCLUSION: We conclude that diltiazem is an effective and safe alternative to beta-blockers in the reduction of HR when performing computed tomography angiography of coronary arteries. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

Comparison of the efficacy and safety of topical diltiazem and nitroglycerine for pain relief during transrectal ultrasound guided biopsy of the prostate

INTRODUCTION AND OBJECTIVE: Transrectal ultrasound biopsy of prostate is a painful procedure. The introduction of the rectal probe is one of the major contributors to the pain associated with this procedure. Drugs that relax the anal sphincter should theoretically decrease this pain. This study was done to compare the efficacy and safety of two topical medications that relax the anal sphincter, diltiazem and nitroglycerine, in decreasing the pain associated with transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS: 66 patients who were to undergo their first prostate biopsy were randomized to receive either 2 mL of 2% topical diltiazem or 2 mL of 0.2% topical nitroglycerine or placebo 20 minutes before prostate biopsy. All patients also received 15 mL of intrarectal lignocaine. A 10-point visual analogue score was used to record the pain immediately after the insertion of the probe, during biopsy and at the end of the procedure. RESULTS: The pain scores due to probe insertion, during biopsy and at the end of the procedure in patients who received topical diltiazem or nitroglycerine were significantly lower compared to the placebo group (p < 0.001). There were no significant differences in the pain scores between the patients receiving diltiazem compared to those receiving nitroglycerine. Higher incidence of headache and fall in blood pressure was noted in patients who received nitroglycerine compared to those receiving diltiazem. CONCLUSION:Topical diltiazem and nitroglycerine are equally effective in reducing the pain associated with transrectal prostatic biopsy. Diltiazem is safer compared to nitroglycerine.

Biodegradable microparticulate drug delivery system of diltiazem HCl

The efficacy of a drug in a specific application requires the maintenance of appropriate drug blood level concentration during a prolonged period of time. Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. The objective of this work is to prepare and evaluate diltiazem HCl loaded albumin microparticles using a factorial design. Albumin (natural polymer) microparticles were prepared by emulsion heat-stabilization method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance for entrapment efficiency indicates that entrapment efficiency is best fitted to a response surface linear model. Surface morphology was studied by scanning electron microscopy. Scanning electron microscopy of the microparticles revealed a spherical, nonporous and uniform appearance, with a smooth surface. The geometric mean diameter of the microparticles was found to be 2-9 µm, which more than 75% were below 3.5 µm and drug incorporation efficiency of 59.74 to 72.48% (w/w). In vitro release profile for formulations containing diltiazem HCl loaded BSA microparticles with heat stabilization technique shows slow controlled the release of the drug up to 24 hours. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microparticles exhibited a prolonged release for almost 24 hours. On comparing regression-coefficient (r²) values for Hixson Crowel, Higuchi and Peppas kinetic models, different batches of microparticles showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D:P ratio. From the statistical analysis it was observed that as the drug:polymer (D:P) ratio increased, there was a significant increase in the encapsulation efficiency. Based on the particle size, entrapment efficiency and physical appearance, DTM-3 formulations were selected for in vivo release study and stability study. The in vivo result of drug loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 ºC. In present study, diltiazem HCl loaded BSA microparticles were prepared and targeted to various organs to satisfactory level and were found to be stable at 4 ºC.

A eficácia terapêutica de um fármaco depende da manutenção de seu nível plasmático adequado em determinado intervalo de tempo. Nesse sentido, a liberação modificada de fármacos está disponível em muitas vias de administração e oferece muitas vantagens (como micropartículas e nanopartículas) quando comparada às formulações de liberação imediata. Essas vantagens incluem reduzida frequência da dosagem, melhor controle terapêutico e menos efeitos colaterais. Assim sendo, esses produtos apresentam maior aceitação pelos pacientes. Os avanços na ciência dos materiais, na engenharia das partículas, em manufatura e em nanotecnologia permitiram a introdução no mercado de vários produtos de liberação modificada e vários outros se encontram em desenvolvimento pré-clínico e clínico. O objetivo do presente trabalho foi preparar e avaliar o fármaco cloridrato de diltiazem associado a micropartículas de albumina utilizando planejamento fatorial. As micropartículas de albumina, um polímero natural, foram preparadas por método de emulsão empregando estabilização por calor. As formulações selecionadas foram caracterizadas no que se refere à sua eficiência de encapsulamento, tamanho médio de partículas, morfologia de superfície e perfil de liberação do fármaco. A análise de variância relativa à eficiência de encapsulamento indicou superfície de resposta linear. Com referência à morfologia superficial, essa foi avaliada empregando microscopia eletrônica de varredura. Essa análise revelou micropartículas esféricas, não porosas e de aparência uniforme, com superfície lisa. O diâmetro médio das micropartículas foi entre 2 e 9 µm, sendo que mais de 75% das micropartículas se apresentaram abaixo de 3,5 µm. Além disso, a eficiência de encapsulamento foi entre 59,74 e 72,48%. Quanto ao ensaio para avaliação do perfil de liberação in vitro do fármaco associado às micropartículas, as formulações apresentaram liberação lenta até 24 horas. O comportamento foi caracterizado por liberação inicial (efeito burst) seguida por liberação lenta. Todas as fórmulas selecionadas apresentaram liberação prolongada por aproximadamente 24 horas. Na comparação entre os valores de coeficientes de regressão (R²), os modelos propostos por Hixson Crowel, Higuchi e Peppas, para diferentes formulações de micropartículas, demonstraram cinética de liberação de acordo com modelo Fickiano e não-Fickiano. O mecanismo de liberação do fármaco foi regulado pela razão entre o fármaco e o polímero. A análise estatística revelou significativo aumento da eficiência de encapsulamento quando essa razão aumentou. As avaliações relativas à análise dimensional das micropartículas, à eficiência de encapsulamento do fármaco e à morfologia permitiram a seleção da formulação DTM-3 para os ensaios de liberação in vivo e para o estudo da estabilidade. O ensaio de liberação in vivo do fármaco associado às micropartículas demonstrou sítio-alvo preferencial no fígado, seguido pelos pulmões rins e baço. No presente estudo, as micropartículas de albumina contendo cloridrato de diltiazem foram adequadamente preparadas e orientadas satisfatoriamente para vários órgãos. Além disso, a formulação selecionada apresentou estabilidade físico-química a 4 ºC.

Atenuación de la respuesta presora a la laringoscopia e intubación entre diltiazem y esmolol en pacientes hipertensos controlados / Attenuation of the pressor response to laryngoscopy and tracheal intubation with intravenous diltiazem and esmolol intravenous in controlled hypertensive surgical patients

Introduction. Tachycardia and hypertension are well documented sequels of laryngoscopy and endotracheal intubation which is transient, highly variable and is generally well tolerated in healthy patients. In hypertensive patients, cardiovascular response to laryngoscopy and intubation is exaggerated. The aim of this study intended to find a better alternative by comparision amongst diltiazem and esmolol to attenuate the pressor response to laryngoscopy and intubation in Kasmiri Population. Materials & Methods. Randomized placebo controlled double blind study. One hundred fifty hypertensive patients of both sexes (ASA II), controlled on antihypertensive drugs, between age hinrange of 40-60 years scheduled for routine surgical procedures were divided into 3 groups Group A (10 ml of 5 % Dextrose), Group B (Diltiazem 0.2 mg/Kg) and Group C (Esmolol 1.5 mg/Kg). Baseline parameters, i.e. heart rate, systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and rate pressure product were noted at baseline level, at 1 min., 3min. and 5min after tracheal intubation. Results. Both Esmolol and Diltiazem showed statistically significant attenuation of rise in systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and rate pressure product when compared to control. However Diltiazem failed to attenuate rise in heart rate. Conclusions. We conclude that Esmolol is a very effective agent in attenuating the pressor response to laryngoscopy and intubation in controlled hypertensive patients.

Introducción. La taquicardia e hipertensión son efectos bien documentados de la laringoscopia e intubación orotraqueal que son transitorios, muy variables y generalmente bien toleradas en los pacientes sanos. Sin embargo, en los pacientes hipertensos, la respuesta cardíaca a la laringoscopia e intubación es exagerada. El objetivo de este estudio es encontrar la mejor alternativa entre diltiazem y esmolol para atenuar la respuesta presora a la laringoscopia e intubación en una población de Cachemira. Materiales y métodos. Estudio aleatorizado controlado doble ciego. Ciento cincuenta pacientes hipertensos de ambos sexos (ASA II), controlados con drogas antihipertensivas con edades entre los 40 y 60 años programados para cirugías rutinarias fueron divididos en tres grupos, grupo A (10 ml de dextrosa al 5 %), grupo B (diltiazem 0,2 mg por kilo), y grupo C (esmolol 1,5 mg por kilo). Los parámetros de base como frecuencia cardíaca, presión arterial sistólica, presión arterial diastólica, presión arterial media y doble producto, fueron anotados al inicio al minuto 1 al minuto 3 y al minuto 5 después de la intubación traqueal. Resultados. Tanto el esmolol como el diltiazem demostraron atenuación estadísticamente significativa de la presión arterial sistólica, diastólica y media, y del doble producto, cuando se compararon al control. Sin embargo el diltiazem no pudo evitar un aumento de la frecuencia cardíaca. Conclusiones. Concluimos que el esmolol es un agente muy efectivo para atenuar la respuesta presora a la laringoscopia e intubación en pacientes hipertensos controlados.

Calcinosis cutis extensa en pacientes adultos con dermatomiositis: a propósito de dos casos / Extensive calcinosis cutis in adult patients with dermatomyositis: two case reports

La calcinosis cutis es el término empleado para describir una serie de trastornos caracterizados por presentar depósitos de sales de calcio a nivel subcutáneo o de la dermis, ocurriendo tanto en hipercalcemia como en normocalcemia y en ocasiones se asocia a un trastorno subyacente. El pronóstico suele ser benigno y el tratamiento, tanto médico como quirúrgico, presenta resultados variables. Presentamos dos casos de pacientes adultos con diagnóstico de dermatomiositis que desarrollaron extensas zonas de calcificación subcutánea.

Calcinosis cutis is the term used to describe a group of disorders characterized by calcium deposits in the skin, occurring in hypercalcemia or normocalcemia and sometimes associated to an underlying disorder. It has a benign evolution and the treatment, both medical and surgical, present variable outcomes. We report the cases of two adult patients with diagnosis of dermatomyositis that developed extensive areas of calcium deposit.

Formulation and in vitro evaluation of taste-masked oro-dispersible dosage form of diltiazem hydrochloride

Diltiazem hydrochloride is a calcium channel blocker generally indicated for the treatment of angina and hypertension, and it is extensively metabolized due to the hepatic metabolism. Formulation of diltiazem hydrochloride into an oro-dispersible dosage form can provide fast relief with higher bioavailability. The bitter taste of the drug should be masked to formulate it in a palatable form. In the present work, an attempt was made to mask the taste by complexation technique, with a formulation into an oro-dispersible dosage form, using superdisintegrants Doshion P544, crospovidone (CP) and sodium starch glycolate (SSG). The complexes of diltiazem hydrochloride with β-CD (1:1 molar ratio) were prepared by kneading, co-evaporation, co-grounding, freeze-drying and melting methods. Phase solubility showed stability constant 819.13M-1. Prepared inclusion complexes were evaluated for taste masking and characterized by I.R, XRD, DSC. Using the drug β-CD complex, oro-dispersible tablets were prepared and evaluated for hardness, friability, weight variation, thickness, disintegrating time (DT), dissolution rate and taste. Formulations with 4 percent Doshion, 8 percent CP and 4 percent SSG showed DT of 0.54, 0.35 and 1.23 minutes, respectively.

O cloridrato de diltiazem é bloqueador do canal de cálcio geralmente indicado para o tratamento de angina e de hipertensão e é extensamente biotransformado devido ao metabolismo hepático. A formulação do cloridrato de diltiazem em orodispersão pode prover rápida liberação com maior biodisponibilidade. O sabor amargo do fármaco deve ser mascarado para ser formulado em forma palatável. No presente trabalho tentou-se mascarar o sabor pela técnica de complexação, com uma orodispersão, usando superdesintegrantes, como Doshio P544, crospivodina (CP) e glicolato de amido sódico (SSG). Os complexos de cloridrato de diltiazem com β-CD (razão molar 1:1) foram preparados por mistura, coevaporação, comoagem, liofilização e métodos de fusão. A solubilidade de fase mostrou estabilidade constante de 819,13 M-1. Os complexos de inclusão preparados foram avaliados com relação ao mascaramento do sabor e caracterizados por IV, Difração de Raios X e DSC. Empregando-se o fármaco complexado com β-CD, prepararam-se comprimidos dispersíveis e avaliaram-se os mesmos quanto à dureza, friabilidade, variação de peso, espessura, tempo de desintegração (DT), taxa de dissolução e sabor. Formulações com 4 por cento de Doshion, 8 por cento de CP e 4 por cento de SSG mostraram DT de 0,54, 0,35 e 1,23 minutos, respectivamente.

Histologic alterations of rat kidneys perfused with a Euro-Collins diltiazem solution / Alterações histológicas ocorridas em rins de ratos perfundidos com solução de Euro-Collins associada à diltiazem

PURPOSE: Analyse the histologic changes of rat kidneys perfused with isotonic saline solution (ISS), Euro-Collins solution (ECS) and Euro-Collins solution with diltiazem (ECSD). METHODS: Thirty-six Wistar rats were used divided equally, as follow: group A (ISS), group B (ECS) and group C (ECSD). Through a catheter placed into the abdominal aorta, a renal perfusion was performed using a solution according to the group to which the animal belonged. After the complete perfusion, bilateral nephrectomy was performed and the organs were preserved under hypothermia for five distinct periods of time. Glomerulus and tubule were evaluated through optical microscopy. RESULTS: Renal perfusion with ECS and ECSD proved effectiveness in the preservation of the organs up to 36 hours and an increase in the percentage of injured glomeruli was noticed only in the period of 48 hours. CONCLUSIONS: The results showed that exists an association between the tubular injury and the glomeruli lesion degree; kidneys with a higher degree of tubular damage were related to severe glomerular lesion. Also, the addition of a calcium channel blocker, diltiazem, to the ECS for the renal perfusion does not decrease the percentage of glomerular lesion.

OBJETIVO: Analisar as alterações histológicas nos rins de ratos perfundidos com solução salina isotônica (ISS), solução Euro-Collins (ECS) e solução Euro-Collins com diltiazem (ECSD). MÉTODOS: Foram divididos, de forma igual, 36 ratos Wistar, como se segue: grupo A (ISS), grupo B (ECS), grupo C (ECSD). Através de um cateter localizado na aorta abdominal, foi realizada a perfusão renal com a solução de acordo com o grupo ao qual o animal pertencia. Após a perfusão total, realizou-se nefrectomia bilateral com a preservação dos órgãos sob hipotermia por cinco períodos distintos de tempo. Glomérulos e túbulos foram avaliados por microscopia óptica. RESULTADOS: Tanto a perfusão renal com ECS quanto a com ECSD provaram sua efetividade na preservação dos órgãos em até 36 horas e aumento da porcentagem de glomérulos injuriados foi notada apenas no período de 48 horas. CONCLUSÕES: Os resultados mostraram haver uma correlação entre a injúria tubular e o grau de lesão glomerular; rins com um maior grau de dano tubular foram relacionados com lesão glomerular severa. Além disso, a adição de um bloqueador de canal de cálcio, diltiazem, à ECS para a perfusão renal não diminui a porcentagem de lesão glomerular.

Influence of diltiazem in combination with a sucrose-rich diet on gingival alterations in rats

The aim of this study was to evaluate the influence of diltiazem in combination with a sucrose-rich diet on gingival alterations in rats. One hundred and twenty male Holtzman rats were randomly assigned to 10 groups (n = 12), being 2 control groups treated with saline and 8 test groups treated with diltiazem in daily doses of 5, 25, 50 and 100 mg/kg during 40 or 60 days. Afterwards, the mandibles were removed for macroscopic, histologic and histometric analyses of the buccal gingiva of the mandibular right first molar. No macroscopic characteristic of gingival overgrowth was observed in any of the groups. The microscopic analysis showed characteristics of normality with inflammatory cells only adjacent to the crevicular epithelium in all groups for both periods. The histometric analysis showed significant differences only for the epithelial tissue area in the 40-day period (Kruskal-Wallis; P = 0.032). Comparing the periods, significant differences regarding the connective and epithelial tissue areas were observed only in the group treated with a 25 mg/kg dose (Mann-Whitney; P = 0.004 and P = 0.007, respectively). Oral administration of diltiazem in combination with a sucrose-rich diet did not induce gingival alterations in rats.

Vasorreactividad a adenosina en los pacientes con hipertensión pulmonar arterial: prevalencia y respuesta clínica, funcional y hemodinámica al tratamiento con diltiazem / Acute vasodilatador test using adenosine in patients with pulmonary arterial hypertension: prevalence and clinical, functional and hemodynamic response after diltiazem treatment

Pulmonary arterial hypertension (PAH) is a severe and progressive disease. Invasive hemodynamic study (HS) is required to confirm the diagnosis of PAH and to perform the vasodilator test (VT) with adenosine. Vasodilator acute responders (VAR) may have a sustained benefit with diltiazem. There is not national information regarding these issues. All patients with probable PAH were evaluated with HS and VT. VAR were treated with diltiazem and followed up with functional class score (FC) and 6 minute walk test. After 6 months, a second HS was performed. Results: Between 2003 and 2008, 6/54 (11%) were VAR. All were women, 45 +/- 14 years old, 4 with idiopathic PAH, 4 in FCIII and 2 in FCII. After two years of treatment, all patients clinically improved. Walked distance significantly increased by 83 and 87 m at month 12 and 24 respectively. Hemodynamic parameters also improved. Therapy with diltiazem is effective in VAR patients supporting the convenience to perform the VT.

La Hipertensión Pulmonar Arterial (HAP) es una entidad grave y progresiva. El estudio hemodinámica (EH) permite certificar el diagnóstico y evaluar la vasorreactividad mediante adenosina. Los pacientes vaso-reactivos podrían responder a terapia con diltiazem. No existe información nacional al respecto. En nuestro programa todo paciente con sospecha de HAP es sometido a EH diagnóstico y de vasorreactividad. Los positivos son tratados con diltiazem y seguidos semestralmente según capacidad funcional (CF) y con test de caminata. Al 6º mes se efectúa un 2º EH. Entre 2003-2008, 6/54 (11%) de los pacientes con HAP fueron vasorreactivos. Todas mujeres, 45 +/- 14 años, 4 con HPA idiopática, 4 en CFIII y 2 en CFII. A los 2 años, todos mejoraron clínicamente. La distancia recorrida aumentó significativamente en los meses 12 y 24 en 83 y 87 m respectivamente. Todas las variables hemodinámicas mejoraron. La terapia con diltiazem es efectiva en los pacientes vaso-reactivos lo que justifica usar el test de vasorreactividad.

Neuroprotective effects of diltiazem in rabbits with occluded aorta

OBJECTIVE: In the present study, we aimed to determine the protective effect of the perfusion of the distal aorta with diltiazem and ringer lactate solution on the spinal cord. METHODS: Twenty-seven New Zealand rabbits were used in which spinal cord ischemia was provided by occlusion of the aorta for thirty minutes. Experimental animals were divided into four groups: group A (n=4), the sham operation group; group B (n=8) in which intraaortic balloon occlusion alone was applied; group C (n=7), ringer lactate group in which ringer lactate was perfused into distal aorta at a rate of 40 ml/kg, hr, following intraaortic balloon occlusion; group D (n=8) diltiazem group in which diltiazem 40 mg/kg, hr, in Ringer lactate was perfused into distal aorta following intraaortic balloon occlusion. Motor function of hind limbs was evaluated by Tarlov's scoring system. After observation, spinal cords were removed for histopathological evaluation. RESULTS: The degree of histopathological injury was well correlated with neurological function. The most severe histopathological injury and neurological dysfunction occurred in group B, followed by group C, D and A respectively. No injury or neurological dysfunction occurred in the sham group. CONCLUSIONS: The protective effect of diltiazem on both histopathological injury and neurological function was significant in comparison with control groups.

OBJETIVO: O objetivo do presente trabalho é determinar o efeito protetor da perfusão na aorta distal com diltiazem e solução de Ringer lactato na medula espinal. MÉTODOS: Foram usados 27 coelhos da raça New-Zeland, nos quais se provocou isquemia da medula espinal por meio de oclusão da aorta durante 30 minutos. Os animais experimentais foram divididos em quatro grupos: grupo A (n=4), o grupo de cirurgia simulada (pseudocirurgia); o grupo B (n=8) no qual se aplicou somente a oclusão do balão intraaórtico; grupo C (n=7), o grupo do Ringer lactato, no qual a solução de Ringer lactato foi perfundida na aorta distal após oclusão do balão intra-aórtico; grupo D (n=8), grupo do dialtiazem, no qual 40 mg/kg/h de diltiazem, em solução de Ringer lactato, foram perfundidas na aorta distal após oclusão do balão intra-aórtico. A função motora dos membros posteriores foi avaliada pelo sistema de escore de Tarlov. Após observação, as medulas espinais foram removidas para avaliação histopatológica. RESULTADOS: O grau de lesão histopatologica estava bem correlacionado com a função neurológica. Lesões histopatológicas e disfunções neurológicas mais graves ocorreram no grupo B, seguido pelos grupos C, D e A, respectivamente. Não ocorreu nenhuma lesão ou disfunção neurológica no grupo de cirurgia simulada. CONCLUSÕES: O efeito protetor do diltiazem na lesão histopatológica e na função neurológica foi significativo em comparação com os grupos-controle.

Aspectos técnicos na esqueletização da artéria torácica interna com bisturi ultra-sônico / Technical aspects in skeletonization of the internal thoracic artery using an ultrasonic scalpel

OBJETIVO: Descrever a técnica e avaliar os resultados imediatos da utilização do bisturi ultra-sônico nas esqueletizações da artéria torácica interna, na cirurgia de revascularização do miocárdio. MÉTODO: Foram operados com essa técnica 188 pacientes submetidos à cirurgia de revascularização do miocárdio, no período de janeiro de 2000 a outubro de 2006. Setenta e um (37,8 por cento) pacientes eram do sexo feminino. A idade variou de 28 a 81 anos. A técnica utilizada na dissecação consistiu em expor toda artéria torácica interna, abrindo-se a fáscia endotorácica com tesoura o mais próximo possível da adventícia da artéria. Com o bisturi ultra-sônico é feita a secção dos ramos colaterais e sua respectiva hemostasia, dispensando-se o uso de "clips" metálicos na artéria torácica interna. RESULTADOS: As artérias torácicas internas esqueletizadas com bisturi ultra-sônico apresentaram fluxos excelentes, não sendo necessárias manipulações intraluminais para vasodilatação. No pós-operatório imediato, dois pacientes apresentaram paralisia temporária da hemicúpula diafragmática esquerda. Não houve infecção do esterno nesta série. O tempo de dissecação foi de aproximadamente 33 minutos, mas com o aumento da experiência esse tempo pôde ser reduzido. CONCLUSÃO: Essa técnica facilita e abrevia o procedimento da esqueletização da artéria torácica interna, não promove espasmos e a cauterização dos ramos colaterais com o bisturi ultra-sônico é eficiente, dispensando o uso de "clips" metálicos. É um procedimento de fácil reprodução, podendo ser recomendado para sua realização de maneira preferencial.

OBJECTIVE: To describe the technique and evaluate the immediate results of using an ultrasonic scalpel in the skeletonization of the internal thoracic artery for coronary artery bypass grafting surgery. METHODS: From January 2000 to October 2006, 188 patients were submitted to coronary artery bypass grafting with the internal thoracic artery skeletonized using an ultrasonic scalpel. Seventy-one patients (37.8 percent) were women. The patients' ages varied from 28 to 81 years old. The entire internal thoracic artery was exposed opening the endothoracic fascia using scissors as close as possible to the arterial adventitia. An ultrasonic scalpel was used to transect and coagulate all the intercostal branches, thereby minimizing the use of metallic clips. RESULTS: The skeletonized internal thoracic arteries presented with excellent flow, obviating the need for intraluminal manipulation for vasodilatation. In the immediate postoperative period, two patients were found to have temporary left-sided diaphragmatic paralysis. There were no sternal wound infections in this series. The dissection can be performed in approximately 33 minutes however with more experience this time may be reduced. CONCLUSION: This technique facilitates and shortens the internal thoracic artery skeletonization procedure and does not cause arterial spasms. Cauterization of the collateral branches with an ultrasonic scalpel is efficient and the use of metallic clips is almost unnecessary. It is a procedure that is easy to reproduce and may be recommended as the first-choice technique for the dissection of the internal thoracic artery.

Ponte miocárdica multiarterial: apresentações clínica e anatômica incomuns / Multi-arterial myocardial bridge: uncommon clinical and anatomical presentations

Homem de 42 anos, sem fatores de risco para doença arterial coronariana, internado com precordialgia atípica. Eletrocardiograma após a introdução de nitrato endovenoso evidenciou supradesnivelamento do segmento ST de V1 a V4. Cineangiocoronariografia demonstrou ponte miocárdica nas três artérias coronárias além de extensão incomum na descendente anterior (80 mm). A evolução foi satisfatória com a suspensão do nitrato e instituição de betabloqueador e antagonista de canais de cálcio.

We report the case of a 42-year-old man with no risk factors for coronary artery disease admitted with atypical chest pain. The electrocardiogram performed after intravenous injection of nitrate revealed ST-segment elevation in leads V1 to V4. The coronary angiography showed myocardial bridges in the three coronary arteries, besides an unusual length of the left anterior descending artery (80 mm). The patient progressed well following the discontinuation of nitrate use and introduction of beta-blockers and calcium channel antagonists.

Efecto del diltiazem sobre los lípidos séricos y lesiones ateroscleróticas en conejos hipercolesterolemicos / Effect of the diltiazem on the seric lipids and atherosclerotics lesions in hypercholesterolemics rabbits

El propósito de este estudio fue evaluar si la administración de diltiazem (30mg/día(vía oral), disminuye la hipercolesterolemia e inhibe la aterosclerosis en 38 conejos machos hipercolesterolemicos. Control: Conejarina por doce semanas, A: dieta rica con 0,3 por ciento de colesterol (DH) por doce semanas. B: DH por doce semanas y desde la tercera semana hasta la dodécima diltiazem, Grupo C: DH por dos semanas y Conejarina + diltiazem desde la tercera semana hasta la duodécima y D: DH por dos semanas y Conejaría desde la tercera hasta la duodécima semana. Se determinaron Colesterol Total (CT), LDL-colesterol (LDLc) y Triglicéridos (Tg) por métodos enzimáticos. A la duodécima semana, se sacrificaron los conejos y el estudio histológico fue realizado por los siguientes métodos: 1. Hematoxilina Eosina evaluó la presencia de lesiones, 2. Gomori's: evaluó la profundidad de las lesiones 3. Computarizado: midió la extensión de las lesiones. En el grupo A y B aumentaron significativamente el CT, LDLc y Tg en relación al control en todos los periodos, a excepción de los Tg a la duodécima semana. Respectoa las lesiones ateroscleróticas, los grupos A y B presentaron lesiones tipo II, III, IV y V, el porcentaje promedio de área lesionada fue: Grupo A: 47,20 por ciento, Grupo B: 57, 60 por ciento. Estos resultados permiten concluir que el diltiazem ejerce un efecto hipolipidemiante cuando se administra junto con una dieta rica en 0,3 por ciento colesterol, se confirma que una dieta adecuada es una buena estrategia para prevenir las displidemías y que el diltiazem no previno, ni indujo regresión de las lesiones ateroscleróticas.