Efficacy of diltiazem 2% rectal gel in the treatment of chronic anal fissure: a retrospective observational study.

OBJECTIVE: The aim of this study is to describe the effectiveness and safety of a magistral formulation of diltiazem 2% rectal gel as a treatment for chronic anal fissure. MATERIAL AND METHODS: A retrospective observational study of all patients that began treatment with diltiazem 2% gel during 2019. The primary endpoint of the study was anal fissure healing. We also looked for differences in effectiveness between those initiating treatment and those who had been previously treated, long-term effectiveness through a 2-year follow-up and frequency of adverse effects. RESULTS: Of the 166 patients included in the study, anal fissure healed in 72.9%. We detected adverse effects in 12 patients, the most common was local irritation. After 2 years of follow-up, 88% of patients did not relapse. CONCLUSION: In this study, use of topical diltiazem 2% has been shown to be effective and safe in the treatment of anal fissure and should be considered as the first line of therapy.

OBJETIVO: El objetivo de este estudio es describir la efectividad y la seguridad de una fórmula magistral de diltiazem 2% gel rectal, como tratamiento de la fisura anal crónica. MATERIAL Y MÉTODOS: Un studio observacional retrospectivo de todos los pacientes que comenzaron a ser tratados con diltiazem 2% gel durante el año 2019. La variable principal del estudio fue la cicatrización de la fisura anal. También se buscaron diferencias de efectividad entre aquellos que iniciaban el tratamiento y los que ya habían sido tratados previamente, efectividad a largo plazo mediante un seguimiento de 2 años y frecuencia de aparición de efectos adversos. RESULTADOS: De los 166 pacientes incluidos en el estudio, el 72,9% cicatrizaron la fisura anal. No detectamos diferencias estadísticamente significativas de efectividad entre los pacientes naive y aquellos que ya habían sido tratados. Detectamos efectos adversos en 12 pacientes, siendo el más frecuente la irritación local. Tras 2 años de seguimiento, el 88% de los pacientes no presentaron ninguna recaída. CONCLUSIÓN: En este estudio, el uso de diltiazem 2% tópico ha mostrado ser efectivo y seguro en el tratamiento de la fisura anal y debería considerarse como primera línea terapéutica.

SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.

In skeletal muscle (SM), inward Ca2+-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca2+-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca2+-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca2+-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca2+-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca2+-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca2+-uptake. 5) The denaturation profile of the SERCA Ca2+-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca2+-binding domain, affecting SR Ca2+-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.

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.

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.

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.

Randomized clinical trial with topical diltiazem for post-hemorrhoidectomy wound healing. / Ensayo clínico aleatorizado con diltiazem tópico para la cicatrización de heridas posthemorroidectomía.

Anal sphincter spasm contributes to the delay in surgical wound healing after hemorrhoidectomy. A prospective, experimental, randomized, double-blind trial was conducted on two groups of patients that underwent closed hemorrhoidectomy. There were 26 patients in each group. Group A received topical diltiazem in the anal region three times a day. Group B received a placebo. Cicatrization time was documented for 6 weeks through digital photography. Mean healing time for the group treated with diltiazem was 3.19 weeks (22.33±0.884 days) and 3.92 weeks (27.44±1.130 days) for the control group (p=0.012 95% CI). At week three, the wounds in 73.07% of the patients in the diltiazem group had healed, compared with 46.15% of the patients in the control group.

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.

Cardioprotección farmacológica en anestesia cardiovascular. Diltiazem vs nitroglicerina / Pharmacological cardioprotection in cardiovascular anesthesia. Diltiazem vs nitroglycerin

Introducción: en pacientes cardiópatas isquémicos se han diseñado diversas estrategias preventivas farmacológicas para limitar el daño por isquemia- reperfusión, con el fin de optimizar el balance en el consumo miocárdico de oxigeno. Objetivos: determinar qué estrategia cardio-protectora (nitroglicerina o diltiazem) es más efectiva en la revascularización coronaria.Métodos: se realizó un estudio comparativo aleatorio para evaluar el efecto cardio protector de la nitroglicerina y el diltiazem en pacientes intervenidos con el corazón latiendo. Resultados: se estudiaron 175 pacientes; los de nitroglicerina, grupo N=90 pacientes y los de diltiazem, grupo D=85. La isquemia miocárdica sostenida, en el grupo D fue del 20 por ciento vs N con 12 por ciento; p= 0,04. Primó el infra desnivel del ST[a1] . En el grupo N fue 10 % vs grupo D de 39 por ciento; p=0,002. La alteración segmentaria más frecuente fue la hipocinesia en el 36 por ciento de los pacientes. La acinesia fue superior en el grupo D, 9,4 por ciento v/s grupo N 4,4 por ciento; p=0,05. El valor promedio de tensión arterial media intraoperatoria fue en el grupo N=80 mm/Hg vs grupo D= 61,4 mm/Hg; p= 0,003. La frecuencia cardiaca media en el grupo N=63 lpm vs grupo D=50 lpm; p=0,006. La arritmia más frecuente fue la fibrilación auricular 28 por ciento, en el grupo N 34 por ciento vs grupo D 21 por ciento, p=0,037. El valor medio de la troponina Tus a las 24 h, en el grupo D=125 pg/ml, vs grupo N=97,7 pg/ml; p=0,042. Los efectos adversos fueron mínimos. La hipotensión arterial sostenida, en el grupo D fue 30 por ciento vs grupo N 5,5 por ciento; p=0,002. El bloqueo AV[a2] se observó en el grupo N 4 por ciento vs grupo D 15 por ciento; p=0,01. El IMA [a3] perioperatorio fue 2,2 veces más frecuente con diltiazem, que con nitroglicerina.Conclusiones: la infusión perioperatoria de nitroglicerina provee un mejor efecto cardio protector que el diltiazem en la prevención de eventos isquémicos ... (AU)

Introduction: in the cases of ischemic cardiopathy patients, different preventive strategies have been designed to limit the damage for ischemia-reperfusion, in order to optimize the balance in myocardial oxygen consumption. Objectives: To determine what cardio-protective (nitroglycerin or diltiazem) strategy is more effective in coronary revascularization. Methods: A randomized therapeutic trial was conducted to assess the cardio-protective effect of diltiazem and nitroglycerin in patients intervened with heart beating. Results: 175 patients were studied: the nitroglycerin group N=90 patients and the diltiazem group D=85. Sustained myocardial ischemia in group D was 20 percent vs. 12 percent in N; p=0.04. ST infra-imbalance prevailed. It was 10 percent in the N group vs 39 percent in group D; p = 0.002. The most frequent alteration was segmental hypokinesia in 36 percent of the patients. Akinesia was higher in group D, 9.4 percent vs. group N 4.4 percent; p = 0.05. The average value of mean intraoperative blood pressure was 80 mm/Hg in the group N vs.61.4 mm/Hg in group D; p = 0.003. The average heart rate in the group N was 63 bpm vs Group D which was 50 bpm; p = 0.006. The most common arrhythmia was atrial fibrillation 28 percent, in the N group 34 percent vs. group D 21 percent, p = 0.037. The average value of troponin after 24 h was 125 pg/ml in group D vs.97.7 pg/ml in group N; p = 0.042. Adverse effects were minimal. Sustained hypotension in group D was 30 percent vs 5.5 percent in group N; p = 0.002. AV block was observed in the group N 4 percent vs 15 percent in group D; p = 0.01. Perioperative IMA was 2.2 times more frequent with diltiazem than with nitroglycerin. Conclusions: Perioperative infusion of nitroglycerin provides better cardioprotective effect then diltiazem in preventing sustained ischemic events, associated with less release of T troponin and better hemodynamic stability. Diltiazem is associated with a decreased risk of postoperative ...(AU)

Topical diltiazem for pain after closed hemorrhoidectomy. / Diltiazem tópico en el dolor postoperatorio de hemorroidectomía con técnica cerrada.

BACKGROUND: Anal sphincter spasm contributes to the appearance of postoperative pain following hemorrhoidectomy. AIM: To determine the efficacy of topical diltiazem in the control of post-hemorrhoidectomy pain. MATERIAL AND METHODS: A randomized, prospective, experimental, double-blind study was conducted on 2 groups of patients in the postoperative period of closed hemorrhoidectomy. Each group consisted of 17 patients. Group A received topical diltiazem in the anal region 3 times a day and group B received a placebo. Ketorolac was administered to both groups as rescue therapy. RESULTS: In group A, the mean score on the visual analog scale was 2.97±1.18cm at 24h, 1.51±1.18cm at 48h, and 0.84±0.92cm at 72h. In group B, it was 6.82±1.9cm at 24h, 5.3±1.66cm at 48h, and 4.32±2.13cm at 72h (P<.001, 95% CI). The mean number of analgesic doses in group A was 2.41±0.87 at 24h, 1.11±0.85 at 48h, and 0.94±0.96 at 72h. In group B, it was 3.82±0.52 at 24h, 3.64±0.70 at 48h, and 2.88±1.26 at 72h (P<.001, 95% CI). CONCLUSIONS: In this study, topical administration of diltiazem resulted in a statistically significant reduction of postoperative pain in patients that underwent closed hemorrhoidectomy.

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.

Cardiac microvascular rarefaction in hyperthyroid rats is reversed by losartan, diltiazem, and propranolol.

Cardiac microvascular rarefaction appears to be involved in hyperthyroidism-induced left ventricular hypertrophy and dysfunction. We investigated the effects of losartan, an AT1 receptor antagonist; diltiazem, a calcium channel blocker; and propranolol, a ß-adrenergic receptor antagonist, on cardiac function and structural microcirculatory cardiac alterations in an experimental model of l-thyroxin-induced hyperthyroidism in rats. Hyperthyroidism (HYPER) was induced by intraperitoneal injections of l-thyroxin for 35 days (600 µg/kg/day; n = 32). The euthyroid group was treated with distilled water (EUT + VEH; n = 8). On the 14th day, the HYPER group was divided into four groups that received an oral treatment for 21 days with saline (HYPER + VEH; n = 8), losartan (10 mg/kg/day; HYPER + LOS, n = 8), diltiazem (10 mg/kg/day; HYPER + DILT, n = 8), or propranolol (10 mg/kg/day; HYPER + PROP, n = 8). An echocardiographic study was performed at baseline, at the beginning and at the end of the pharmacological treatment protocol (35th day). The structural capillary density in the left ventricle (LV) was analyzed using histochemical analysis with fluorescein isothiocyanate-conjugated Griffonia simplicifolia lectin. HYPER + VEH (182 ± 5 mmHg; P < 0.001) presented higher systolic blood pressure (SBP) compared with EUT + VEH (132 ± 3 mmHg). HYPER + LOS (144 ± 2 mmHg), HYPER + DILT (147 ± 3 mmHg) and HYPER + PROP (153 ± 4 mmHg) presented lower SBP compared with HYPER + VEH (P < 0.001). Chronic treatment with losartan, diltiazem, and propranolol reversed cardiac structural microvascular rarefaction (HYPER + VEH 0.16 ± 0.01; EUT + VEH 0.35 ± 0.02; HYPER + LOS 0.46 ± 0.03; HYPER + DILT 0.49 ± 0.02; HYPER + PROP 0.58 ± 0.04 (Vv[cap]/Vv[fib]); P < 0.001) and enhanced the LV ejection fraction of hyperthyroid rats (HYPER + VEH 71 ± 3; EUT + VEH 85 ± 2; HYPER + LOS 90 ± 3; HYPER + DILT 85 ± 3; HYPER + PROP 86 ± 2%; P < 0.05). In conclusion, chronic treatment with losartan, diltiazem, and propranolol improved the cardiac microcirculation and function in an experimental model of hyperthyroidism in rats.

Effects of intraoperative diltiazem infusion on flow changes in arterial and venous grafts in coronary artery bypass graft surgery.

OBJECTIVE: 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.

Spray-dried O-carboxymethyl chitosan as potential hydrophilic matrix tablet for sustained release of drug.

OBJECTIVE: The aim of the present investigation was to evaluate the use of spray-dried O-carboxymethyl chitosan (OCMCS) as potential hydrophilic matrix excipient for sustained release of drug. METHODS: The polymer was synthesized from chitosan, then spray-dried and characterized. Tablets with different OCMCS concentrations (80, 50, 30, 5 and 2% w/w), containing diltiazem (DTZ) as model drug, were prepared for direct compression (DC) and after the wet granulation method (WG). RESULTS: The spray-dried OCMCS powder was spherical, with a smooth surface and an average size of 2.2 µm. The tablets prepared for WG disintegrated in time less than 30 min. The tablets obtained for DC presented high retention of the drug, with zero order or Higuchi release kinetic. There was a direct relationship between the OCMCS concentration and the release ratio, swelling degree and water uptake behavior. DC tablets containing 80% OCMCS presented behavior as an effective swelling-control system. The DC tablets with 5% OCMCS showed a similar release profile at formulations with 30% HPMC. CONCLUSION: Spray-dried OCMCS showed great potential as hydrophilic matrices for drug-sustained release.

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.

Copper-induced intracellular calcium release requires extracellular calcium entry and activation of L-type voltage-dependent calcium channels in Ulva compressa.

The marine alga Ulva compressa exposed to 10 µM copper showed a triphasic increase of intracellular calcium with maximal levels at 2, 3 and 12 h involving the activation of ryanodine-, Ins(1,4,5)P3- and NAADP-sensitive calcium channels. In order to analyze the requirement of extracellular calcium entry for intracellular calcium release as well as the activation of voltage-dependent calcium channels (VDCC) and phospholipase C, U. compressa was treated with EGTA, a non-permeable calcium chelating agent, with verapamil, nipfedipine and diltiazem, inhibitors of L-type VDCC, and with neomycin and U731222, inhibitors of phospholipase C. The release of intracellular calcium was partially inhibited with EGTA at 2 and 3 h and completely inhibited at 12 h of copper exposure and decreased with inhibitors of L-type VDCC and phospholipase C. Thus, copper-induced intracellular calcium release depends on calcium entry and activation of L-type VDCC and phospholipase C. An integrative model of copper-induced cellular responses in U. compressa is presented.

Diltiazem as an alternative to beta-blocker in coronary artery computed tomography angiography.

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.