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São Paulo; s.n; s.n; 2020. 144 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-1290792


O guia Q8(R2) do guia ICH descreve Qualidade por Design (QbD) como "uma abordagem sistemática para desenvolvimento farmacêutico que começa com objetivos predefinidos e enfatiza produto, entendimento e controle dos processos, baseado em dados científicos sólidos e gestão do risco da qualidade". Os métodos analíticos são considerados parte integrante do desenvolvimento farmacêutico. Assim, a Qualidade por Design Analítico (AQbD) é justificável e recomendada para obter flexibilidade regulatória, reduzir os resultados fora de especificação, obter um alto grau de robustez e um método analítico econômico. O Planejamento de Experimentos (DoE) é um conjunto de ferramentas estatísticas que inclui delineamentos de triagem e otimização, no qual os fatores são sistematicamente variados para determinar seus efeitos nas respostas, o que permite a determinação de quais fatores são os mais significantes, a identificação de qual configuração de fatores resulta em respostas otimizadas e a identificação de interações entre os fatores. As abordagens QbD e AQbD permitem a melhoria contínua ao longo do ciclo de vida do produto farmacêutico e do método analítico, inclusive para reduzir a variabilidade do produto, melhorar o desempenho do processo, reduzir resultados fora da especificação, melhorar o desempenho analítico, entre outros. O Cloridrato de Verapamil foi escolhido como molécula teste para desenvolvimento do projeto. Na primeira etapa do estudo foi realizado uma triagem com 13 fatores e 20 experimentos, utilizando o delineamento Plackett-Burman, seguiu-se para a próxima etapa com 7 fatores e 16 experimentos através do delineamento fatorial fracionado (Res.: IV). A etapa de otimização foi realizada com 3 fatores e 20 experimentos utilizando o delineamento central composto. Após todas as etapas do estudo, as seguintes condições foram consideradas ideais: Fase móvel A - Tampão formiato de amônio 10 mM pH 3,0, Fase móvel B - Amoníaco 2,0% em acetonitrila, eluição do tipo gradiente, coluna cromatográfica XSelect CSH C18 (100mm x 4,6mm x 3,5 µm), fluxo de 0,7 mL/min, volume de injeção de 2 µL para teor e 10 µL para produtos de degradação. Os métodos desenvolvidos são robustos, validados e indicativos de estabilidade

The ICH guide Q8 (R2) describes Quality by Design as "a systematic approach to pharmaceutical development that begins with predefined goals and emphasizes product, understanding and control of processes, based on solid scientific data and Quality Risk Management ". Analytical methods are considered an integral part of pharmaceutical development. Thus, the application of QbD approach to analytical method development is justifiable and a recommended strategy to attain regulatory flexibility, to reduce out-of-specification results, to achieve a high degree of robustness and a cost-effective analytical method. DoE is a set of statistical tools which include screening designs and optimization designs. In DoE approach, the controlled input factors are systematically varied to determine their effects on the output responses, which allows the determination of the most important input factors, the identification of input factors setting leading to optimized output responses, and the identification of interactions between input factors. The QbD and AQbD approach allows the continuous improvement throughout the lifecycle of pharmaceutical product and analytical method, including to reduce product variability, to improve process performance, to reduce out-of-specification results, to improve analytical performance, among others. Verapamil Hydrochloride was chosen as a test molecule for the development of the project. In the first phase of the study, a 13-factor and 20-experiment screening was performed using the Plackett-Burman design, followed by the 7-factor and 16-experiment next stage through fractional factorial design (Res .: IV). The optimization step was performed with 3 factors and 20 experiments using the composite central design. After performing all the study steps, the following conditions were considered ideal: Mobile Phase A - 10 mM ammonium formate buffer pH 3.0, Mobile Phase B - 2.0% ammonia in acetonitrile, gradient elution, column chromatographic XSelect CSH C18 (100mm x 4.6mm x 3.5µm), flow rate of 0.7ml / min, injection volume of 2µL for assay and 10µL for degradation products. The methods developed are robust, validated and stability indicating

Analytical Methods/methods , Drawing , Methods , Acetonitriles/adverse effects , Pharmaceutical Preparations , Verapamil , Mass Screening , Drug Development/instrumentation
Article in English | WPRIM | ID: wpr-719635


Most diabetic patients experience diabetic mellitus (DM) urinary bladder dysfunction. A number of studies evaluate bladder smooth muscle contraction in DM. In this study, we evaluated the change of bladder smooth muscle contraction between normal rats and DM rats. Furthermore, we used pharmacological inhibitors to determine the differences in the signaling pathways between normal and DM rats. Rats in the DM group received an intraperitoneal injection of 65 mg/kg streptozotocin and measured blood glucose level after 14 days to confirm DM. Bladder smooth muscle contraction was induced using acetylcholine (ACh, 10⁻⁴ M). The materials such as, atropine (a muscarinic receptor antagonist), U73122 (a phospholipase C inhibitor), DPCPX (an adenosine A1 receptor antagonist), udenafil (a PDE5 inhibitor), prazosin (an α₁-receptor antagonist), papaverine (a smooth muscle relaxant), verapamil (a calcium channel blocker), and chelerythrine (a protein kinase C inhibitor) were pre-treated in bladder smooth muscle. We found that the DM rats had lower bladder smooth muscle contractility than normal rats. When prazosin, udenafil, verapamil, and U73122 were pre-treated, there were significant differences between normal and DM rats. Taken together, it was concluded that the change of intracellular Ca²⁺ release mediated by PLC/IP3 and PDE5 activity were responsible for decreased bladder smooth muscle contractility in DM rats.

Acetylcholine , Animals , Atropine , Blood Glucose , Calcium Channels , Humans , Injections, Intraperitoneal , Muscle, Smooth , Papaverine , Prazosin , Protein Kinase C , Rats , Receptor, Adenosine A1 , Receptors, Muscarinic , Streptozocin , Type C Phospholipases , Urinary Bladder , Verapamil
Yonsei Medical Journal ; : 1157-1163, 2019.
Article in English | WPRIM | ID: wpr-762069


PURPOSE: Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection. MATERIALS AND METHODS: We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY). RESULTS: In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at $487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at $638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost $834 and $830/QALY, respectively. The cost-effectiveness threshold of all drugs was lower than $30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios. CONCLUSION: Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same.

Amiodarone , Atenolol , Atrial Fibrillation , Betaxolol , Bisoprolol , Compliance , Cost-Benefit Analysis , Diltiazem , Flecainide , Humans , Insurance, Health , Korea , Markov Chains , Mortality , National Health Programs , Propafenone , Propranolol , Quality-Adjusted Life Years , Sotalol , Verapamil
The Korean Journal of Pain ; : 256-263, 2019.
Article in English | WPRIM | ID: wpr-761714


BACKGROUND: Antinociceptive anti-inflammatory drugs have many adverse effects. The goal of this investigation is to study the probable anti-inflammatory and analgesic effects of verapamil and N-acetylcysteine (NAC) in experimental rats. METHODS: Adult male Wistar rats were randomly divided into 4 groups in the antinociceptive study, each containing 6 rats; the normal control group, which received saline (1 mL/kg); the diclofenac group, which received diclofenac sodium (5 mg/kg); the NAC group, which received NAC (125 mg/kg); and the verapamil group, which received verapamil (8 mg/kg). In the anti-inflammatory study, 5 groups were used, the 4 previous groups with the addition of an edema control group, received saline and were subjected to formalin test. Hot plate latency time was recorded for antinociceptive evaluation. Paw edema thickness and biochemical parameters were recorded for anti-inflammatory evaluation. RESULTS: Administration of NAC showed significant prolongation of hot plate latency time at 1 hour when compared to the control group while verapamil showed a significant prolongation of hot plate latency time at 1 and 2 hours when compared to the control group and NAC group values. Administration of NAC and verapamil significantly decreased paw edema thickness at 2, 4, and 8 hours when compared to edema control values. Regarding biochemical markers, NAC and verapamil significantly decreased serum nitric oxide synthase, C-reactive protein, and cyclooxygenase-2 levels compared to the edema control value. In accordance, a marked improvement of histopathological findings was observed with both drugs. CONCLUSIONS: NAC and verapamil have antinociceptive and anti-inflammatory effects comparable to diclofenac sodium.

Acetylcysteine , Adult , Animals , Anti-Inflammatory Agents , Biomarkers , C-Reactive Protein , Cyclooxygenase 2 , Diclofenac , Edema , Humans , Male , Nitric Oxide Synthase , Pain Measurement , Rats , Rats, Wistar , Verapamil
Rev. Soc. Cardiol. Estado de Säo Paulo ; 28(3): 276-285, jul.-ago. 2018. tab, ilus, graf
Article in English, Portuguese | LILACS | ID: biblio-916531


As taquicardias de QRS estreito apresentam origem supraventricular. O histórico clínico, exame físico e eletrocardiograma na sala de emergência constituem-se nas principais ferramentas para o tratamento do quadro. As taquicardias que apresentam instabilidade hemodinâmica devem ser, imediatamente, revertidas através de cardioversão elétrica sincronizada. Aquelas que se apresentam como estáveis hemodinamicamente podem, se regulares, ser tratadas através de manobras vagais ou através do uso de fármacos endovenosos. Se irregulares, podem caracterizar fibrilação e flutter atrial, sendo, então, avaliados a duração do episódio e o risco de tromboembolismo para determinar não apenas a necessidade de anticoagulação, mas também a estratégia para tratamento do quadro, seja através do controle da frequência cardíaca ou do controle do ritmo, este último podendo ser alcançado através do uso de fármacos (propafenona oral ou amiodarona endovenosa) ou da cardioversão elétrica sincronizada. Dessa forma, o papel do clínico na sala de emergência é fundamental para garantir a condução adequada dos episódios de taquicardia supraventricular, especialmente, na prevenção ou pronta intervenção em caso de deterioração hemodinâmica relacionada ao quadro

Narrow QRS tachycardias are supraventricular in origin. The clinical history, physical exam, and electrocardiogram in the emergency room are the main tools used to manage this condition. Tachycardias that present haemodynamic instability must be promptly reverted through synchronized electrical cardioversion. Those that present haemodynamic stability may be treated with vagal maneuvers or intravenous drugs. If irregular, they may take the form of atrial fibrillation or atrial flutter, and in this case, the duration of the episode and the thromboembolic risk are evaluated to determine not only the need for anticoagulation, but also the treatment strategy, whether through heart rate or rhythm control. The latter may be achieved through the use of drugs (oral propafenone or intravenous amiodarone) or synchronized electrical cardioversion. The role of the clinician in the emergency room is therefore fundamental in ensuring adequate conduct of episodes of supraventricular tachycardia, especially in prevention or prompt intervention in case of haemodynamic deterioration related to the condition

Humans , Male , Female , Middle Aged , Aged , Arrhythmias, Cardiac/diagnosis , Therapeutics , Tachycardia, Supraventricular/diagnostic imaging , Emergencies , Atrial Fibrillation , Propafenone/adverse effects , Propafenone/therapeutic use , Bundle-Branch Block/diagnosis , Electric Countershock/methods , Diagnostic Imaging/methods , Heparin/adverse effects , Heparin/therapeutic use , Verapamil/adverse effects , Verapamil/therapeutic use , Adenosine/adverse effects , Adenosine/therapeutic use , Prevalence , Electrocardiography/methods , Amiodarone/therapeutic use
Rev. Soc. Cardiol. Estado de Säo Paulo ; 28(3): 291-295, jul.-ago. 2018. graf
Article in English, Portuguese | LILACS | ID: biblio-916538


Um dos grandes desafios no atendimento dos pacientes nas unidades de emergência é o tratamento das arritmias ventriculares, principalmente, quando sustentadas e recorrentes, pois são de difícil tratamento e estão associadas à alta mortalidade. O principal mecanismo envolvido na sustentação das taquicardias ventriculares é o mecanismo de reentrada, devido às cicatrizes miocárdicas secundárias a diversas cardiopatias estruturais. A tempestade elétrica pode ser séria quando ocorre em portadores de desfibriladores automáticos, provocando múltiplos choques correspondentes fora do ambiente hospitalar. Nesses casos é necessária a internação hospitalar, onde medidas específicas e escalonadas de tratamento são realizadas, indo desde o manejo clínico até intervenções específicas, como programação de dispositivos eletrônicos, intervenções eletrofisiológicas ou cirúrgicas

One of the biggest challenges in the care of patients in emergency units is the treatment of ventricular arrhythmias, particularly when sustained and relapsing, as they are difficult to treat and are associated with high mortality. The main mechanism involved in the maintenance of ventricular tachycardias is the mechanism of reentry, due to myocardial scars secondary to various structural heart diseases. The electrical storm may be serious when it occurs in patients with automatic defibrillators, causing multiple corresponding shocks outside the hospital setting. In these cases, admission to hospital is necessary, where specific and stepwise treatment measures are performed, ranging from clinical management to specific interventions, such as programming of electronic devices, and electrophysiological or surgical interventions

Humans , Male , Female , Pacemaker, Artificial , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/therapy , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/therapy , Propranolol/therapeutic use , Quinidine/therapeutic use , Verapamil/therapeutic use , Electric Stimulation Therapy/methods , Defibrillators , Diagnosis, Differential , Electrocardiography/methods , Brugada Syndrome/diagnosis , Brugada Syndrome/therapy , Heart , Heart Diseases/diagnosis , Amiodarone/therapeutic use
Biol. Res ; 51: 38, 2018. graf
Article in English | LILACS | ID: biblio-1038781


BACKGROUND: Hydrogen sulfide has been shown to improve the quality of oocytes destined for in vitro fertilization. Although hydrogen sulfide is capable of modulating ion channel activity in somatic cells, the role of hydrogen sulfide in gametes and embryos remains unknown. Our observations confirmed the hypothesis that the KATP and L-type Ca2+ ion channels play roles in porcine oocyte ageing and revealed a plausible contribution of hydrogen sulfide to the modulation of ion channel activity. RESULTS: We confirmed the benefits of the activation and suppression of the KATP and L-type Ca2+ ion channels, respectively, for the preservation of oocyte quality. CONCLUSIONS: Our experiments identified hydrogen sulfide as promoting the desired ion channel activity, with the capacity to protect porcine oocytes against cell death. Further experiments are needed to determine the exact mechanism of hydrogen sulfide in gametes and embryos.

Animals , Female , Oocytes/drug effects , Calcium Channels/physiology , Cellular Senescence/physiology , Potassium Channels, Calcium-Activated/physiology , Hydrogen Sulfide/pharmacology , Oocytes/metabolism , Phenotype , Swine , Calcium Channel Blockers/pharmacology , Verapamil/pharmacology , Calcium Channels/drug effects , Signal Transduction/drug effects , Adenosine Triphosphate , Potassium Channels, Calcium-Activated/drug effects , Minoxidil/pharmacology
Article in English | WPRIM | ID: wpr-727866


Bladder dysfunction is a common complication of diabetes mellitus (DM). However, there have been a few studies evaluating bladder smooth muscle contraction in DM in the presence of pharmacological inhibitors. In the present study, we compared the contractility of bladder smooth muscle from normal rats and DM rats. Furthermore, we utilized pharmacological inhibitors to delineate the mechanisms underlying bladder muscle differences between normal and DM rats. DM was established in 14 days after using a single injection of streptozotocin (65 mg/kg, intraperitoneal) in Sprague-Dawley rats. Bladder smooth muscle contraction was induced electrically using electrical field stimulation consisting of pulse trains at an amplitude of 40 V and pulse duration of 1 ms at frequencies of 2–10 Hz. In this study, the pharmacological inhibitors atropine (muscarinic receptor antagonist), U73122 (phospholipase C inhibitor), DPCPX (adenosine A₁ receptor antagonist), udenafil (PDE5 inhibitor), prazosin (α₁-receptor antagonist), verapamil (calcium channel blocker), and chelerythrine (protein kinase C inhibitor) were used to pretreat bladder smooth muscles. It was found that the contractility of bladder smooth muscles from DM rats was lower than that of normal rats. In addition, there were significant differences in percent change of contractility between normal and DM rats following pretreatment with prazosin, udenafil, verapamil, and U73122. In conclusion, we suggest that the decreased bladder muscle contractility in DM rats was a result of perturbations in PLC/IP₃-mediated intracellular Ca²⁺ release and PDE5 activity.

Animals , Atropine , Diabetes Mellitus , Muscle, Smooth , Phosphotransferases , Prazosin , Rats , Rats, Sprague-Dawley , Streptozocin , Type C Phospholipases , Urinary Bladder , Verapamil
Article in Chinese | WPRIM | ID: wpr-813186


To evaluate the anti-cicatricial and anti-restenosis effect of verapamil on anterior urethral stricture.
 Methods: A total of 32 patients received anterior urethral stricture were enrolled in this study. They were divided into 4 blocks according to the duration of previous urethral operations and dilations. Every block was further randomly divided into an experimental group and a control group. Experimental groups received 2 mL injection of verapamil around the anastomosis site of urethra before and after the surgery (2, 4, 6, 8, and 10 weeks after the surgery), while the control groups only received the anastomosis surgery. After surgery, maximal urinary flow rate (Qmax) was examined for all patients once the catheter was removed. In addition, they were also conducted palpation of urethral scar range. The sum of long transverse diameters of urethral scar was measured, and the narrowest urethral inner diameter was examined. The Qmax was rechecked and the urethral scar range was assessed by penis color Doppler elastography after 12 weeks of surgery. The above 4 indexes were used to evaluate the inhibitory effect of verapamil on urethral scar.
 Results: The length of palpated urethral scar in the Block 1 to 4 of the experimental groups was (22.75±1.03), (21.25±0.25), (20.75±1.03), and (20.0±0.58) mm, respectively; and those in the control groups (26.00±0.82), (24.5±1.04), (25.75±1.65), and (28.25±1.75) mm, respectively. The Qmax rates in the Block 1 to 4 of the experimental groups were (11.85±0.77), (11.33±0.81), (10.23±0.26), and (10.35±0.17) mL/s, respectively; and those in the control groups were (10.85±0.39), (10.50±0.76), (10.53±1.00), (12.60±0.39) mL/s, respectively. The Qmax rates in the Block 1 to 4 of the experimental groups were (11.73±0.87), (10.65±0.25), (10.23±0.19), and (10.35±0.29) mL/s, respectively; and those in the control groups were (8.05±0.28), (7.73±0.68), (7.53±0.92), and (9.60±0.32) mL/s, respectively. The narrowest diameters of urethral in the Block 1 to 4 of the experimental groups were (9.00±0.58), (7.50±2.89), (7.00±0.10), and (7.00±0.41) mm, respectively; and those in the control groups were (5.50±0.29), (5.00±0.41), (4.75±0.48), and (6.75±0.48) mm, respectively. The ultrasound strain ratio in the Block 1 to 4 of the experimental groups were 6.10±0.22, 6.10±0.17, 5.10±0.16, and 6.90±0.19, respectively; and those in the control groups were 8.00±0.25, 10.60±0.29, 11.30±0.16, and 8.90±0.33, respectively. Compared with the control groups, the experimental groups displayed smaller urethral scar range, less severe scarring, improved Qmax rates and wider inner diameters (all P<0.05).
 Conclusion: Urethral regional injection of verapamil intraoperatively or postoperatively can prevent overgrowth of urethral scar tissues after the transperineal anastomosis surgery, and reduce the tendency of postoperative restenosis of anterior urethral stricture.

Anastomosis, Surgical , Cicatrix , Diagnostic Imaging , Drug Therapy , Dilatation , Humans , Male , Penis , Diagnostic Imaging , Postoperative Complications , Diagnostic Imaging , Drug Therapy , Secondary Prevention , Ultrasonography , Urethra , Diagnostic Imaging , General Surgery , Urethral Stricture , General Surgery , Urination , Urological Agents , Therapeutic Uses , Verapamil , Therapeutic Uses
Article in English | WPRIM | ID: wpr-715249


BACKGROUND/OBJECTIVE: This study was designed to investigate how a Portulaca oleracea L. extract (POE) stimulates insulin secretion in INS-1 pancreatic β-cells. MATERIALS/METHOD: INS-1 pancreatic β-cells were incubated in the presence of various glucose concentrations: 1.1 or 5.6, 16.7 mM glucose. The cells were treated with insulin secretagogues or insulin secretion inhibitor for insulin secretion assay using an insulin ELISA kit. In order to quantify intracellular influx of Ca2+ caused by POE treatment, the effect of POE on intracellular Ca2+ in INS-1 pancreatic β-cells was examined using Fluo-2 AM dye. RESULTS: POE at 10 to 200 µg/mL significantly increased insulin secretion dose-dependently as compared to the control. Experiments at three glucose concentrations (1.1, 5.6, and 16.7 mM) confirmed that POE significantly stimulated insulin secretion on its own as well as in a glucose-dependent manner. POE also exerted synergistic effects on insulin secretion with secretagogues, such as L-alanine, 3-isobutyl-1-methylxanthine, and especially tolbutamide, and at a depolarizing concentration of KCl. The insulin secretion caused by POE was significantly attenuated by treatment with diazoxide, an opener of the K+ ATP channel (blocking insulin secretion) and by verapamil (a Ca2+ channel blocker). The insulinotropic effect of POE was not observed under Ca2+-free conditions in INS-1 pancreatic β-cells. When the cells were preincubated with a Ca2+ fluorescent dye, Fluo-2 (acetoxymethyl ester), the cells treated with POE showed changes in fluorescence in red, green, and blue tones, indicating a significant increase in intracellular Ca2+, which closely correlated with increases in the levels of insulin secretion. CONCLUSIONS: These findings indicate that POE stimulates insulin secretion via a K+ ATP channel-dependent pathway in INS-1 pancreatic β-cells.

1-Methyl-3-isobutylxanthine , Adenosine Triphosphate , Alanine , Calcium Channels , Diabetes Mellitus , Diazoxide , Enzyme-Linked Immunosorbent Assay , Fluorescence , Glucose , Insulin , Portulaca , Tolbutamide , Verapamil
Article in Korean | WPRIM | ID: wpr-715165


PURPOSE: Intravenous lipid emulsion (ILE) has been shown to have significant therapeutic effects on calcium channel blocker overdose in animal studies and clinical cases. In this preliminary experiment, we investigated the hemodynamic changes and survival in a rat model of verapamil intoxication. METHODS: Fourteen male Sprague-Dawley rats were sedated and treated with ILE or normal saline (control), followed by continuous intravenous infusion of verapamil (20 mg/kg/h). Mean arterial pressure and heart rate of rats were monitored during the infusion. In addition, the total dose of infused verapamil and the duration of survival were measured. RESULTS: Survival was prolonged in the ILE group (32.43±5.8 min) relative to the control group (24.14±4.3 min) (p=0.01). The cumulative mean lethal dose of verapamil was higher in the ILE group (4.3±0.7 mg/kg) than in the control group (3.2±0.5 mg/kg; p=0.017). CONCLUSION: ILE pretreatment prolonged survival and increased the lethal dose in a rat model of verapamil poisoning.

Animals , Arterial Pressure , Calcium Channels , Heart Rate , Hemodynamics , Humans , Infusions, Intravenous , Male , Models, Animal , Poisoning , Rats , Rats, Sprague-Dawley , Therapeutic Uses , Verapamil
São Paulo; s.n; s.n; 2017. 85p tab, graf, ilus.
Thesis in English | LILACS | ID: biblio-878498


Polímeros naturais têm sido amplamente utilizados como excipientes farmacêuticos, principalmente por serem biocompatíveis e renováveis. O objetivo deste estudo foi investigar a aplicação da resina poliuretânica derivada do óleo de mamona (RPDOM) em formas farmacêuticas gastrorretentivas de liberação controlada. O trabalho aqui apresentado está dividido em quatro capítulos. O capítulo 1 trata-se de uma visão geral sobre a aplicação dos poliuretanos como sistemas de liberação de fármacos, enfatizando os estudos contendo poliuretanos do óleo de mamona. O capítulo 2 trata-se de uma revisão sistemática sobre sistemas gastrorretentivos de liberação de fármacos. O capítulo 3 trata do desenvolvimento e da caracterização da RPDOM contendo fármaco na sua matriz. Domperidona e cloridrato de verapamil foram escolhidos como fármacos modelos devido ao potencial uso desses em formulações gastrorretentivas. Os estudos físico-químicos mostraram que parte da domperidona interagiu quimicamente com a RPDOM. Visto que não é possível a quebra dessa ligação química durante o estudo de dissolução, parte do fármaco ficou indisponível para liberação. Por outro lado, o verapamil foi incorporado com sucesso na RPDOM pelo método de evaporação do solvente. O verapamil interagiu através de forças intermoleculares com o polímero e esse sistema mostrou um promissor perfil de dissolução. O capítulo 4 trata do desenvolvimento de matrizes monolíticas flutuantes, contendo verapamil como fármaco modelo, espuma de polipropileno como excipiente de baixa densidade e um blend da RPDOM e da celulose microcristalina como sistema matricial. A capacidade de flutuação in vitro das matrizes e o controle da liberação do fármaco foram demonstrados. Por fim, a RPDOM mostrou-se um polímero promissor para o uso em sistemas de liberação controlada de fármacos devido a sua hidrofobicidade e para o uso em sistemas gastrorretentivos flutuantes devido à sua baixa densidade

Natural polymers have been extensively used as pharmaceutical excipients mainly due to their biocompatibility and renewability. The aim of this study was to investigate the application of polyurethane resin from castor oil (PU) in controlled release gastroretentive dosage forms. The work presented herein is divided in four chapters. Chapter 1 is an overview of the application of polyurethanes as drug delivery systems, emphasizing studies containing castor oil-based polyurethanes. Chapter 2 is a systematic review of gastroretentive drug delivery systems. Chapter 3 is about the development and characterization of the PU containing drug in its matrix. Domperidone and verapamil hydrochloride were chosen as model drugs due to their potential use in gastroretentive formulations. Physicochemical studies showed that part of domperidone interacted chemically with PU. Since it is not possible a cleavage of the chemical bond between domperidone and the polyurethane during the dissolution study, part of the drug was not available for release. On the other hand, verapamil was successfully incorporated into PU by solvent evaporation method. Verapamil interacted by intermolecular forces with the polymer and this system showed a promising drug dissolution profile. Chapter 4 shows the development of floating monolithic matrices, containing verapamil as model drug, polypropylene foam as low-density excipient and a blend of PU and microcrystalline cellulose as matrix-forming polymers. The in vitro buoyancy capability of the matrices and the ability to control drug release were demonstrated. Finally, PU proved to be a potential polymer to be used in controlled drug delivery systems due to its hydrophobicity and in gastroretentive floating systems due to its low density

Drug Liberation , Polyurethanes/administration & dosage , Castor Oil , Domperidone/chemistry , Verapamil/chemistry
Braz. j. med. biol. res ; 50(11): e6353, 2017. tab, graf
Article in English | LILACS | ID: biblio-888951


This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.

Animals , Male , Female , Adjuvants, Pharmaceutic/pharmacology , Curcumin/analogs & derivatives , Curcumin/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Intestinal Absorption , Intestine, Small/metabolism , Reference Values , Time Factors , Uncoupling Agents/pharmacology , Verapamil/pharmacology , Probenecid/pharmacology , Reproducibility of Results , Chromatography, High Pressure Liquid/methods , Rats, Sprague-Dawley , ATP-Binding Cassette Transporters/antagonists & inhibitors , 2,4-Dinitrophenol/pharmacokinetics , Curcumin/chemistry , Multidrug Resistance-Associated Proteins/analysis , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Emulsions , Perfusion Imaging/methods , Intestinal Absorption/drug effects , Intestine, Small/drug effects
Article in English | WPRIM | ID: wpr-107202


Paclitaxel (PTX) is one of the most frequently used anticancer agent for treating refractory ovarian cancer, metastatic breast cancer and non-small cell lung cancer. However, its oral administration is impeded by very low bioavailability (<5%) due to the P-glycopprotein (P-gp) efflux pump effect. This study investigated in vitro and in vivo P-gp inhibitory effects of adamantyl derivatives AC-603 and AC-786 in rats. Two adamantyl derivatives tested in this study increased the cytotoxicity of daunomycin (DNM) in P-gp overexpressed cell line by inhibiting P-gp efflux function. Pharmacokinetics of PTX with orally co-administered P-gp inhibitors were assessed in rats to improve PTX absorption. The pharmacokinetic parameters of PTX were determined in rats after intravenous (2 mg/kg) or oral (25 mg/kg) administration in the presence or absence of verapamil (a positive control), AC-603 or AC-786 (0.5 mg/kg or 5 mg/kg). Compared to control group (PTX alone), experimental groups (PTX with AC-603 or AC-786) significantly increased the area under the plasma concentration-time curve of PTX following oral administration by 1.7–2.2 fold. The volume of distribution and total clearance of PTX were decreased, while other parameters were not significantly changed. In conclusion, co-administration of AC-603 or AC-786 enhanced the relative bioavailability of orally administered PTX as compared to control.

Absorption , Administration, Oral , Animals , Biological Availability , Breast Neoplasms , Carcinoma, Non-Small-Cell Lung , Cell Line , Daunorubicin , In Vitro Techniques , Ovarian Neoplasms , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Paclitaxel , Pharmacokinetics , Plasma , Rats , Verapamil
Article in Korean | WPRIM | ID: wpr-19891


Concealed bypass tract (CBT) results from incomplete development of the atrioventricular (AV) annulus. CBT conducts only in a retrograde direction, and therefore does not cause pre-excitation on standard electrocardiograms. The most common tachycardia associated with CBT is an orthodromic atrioventricular reentrant tachycardia (AVRT): a pathway involving anterograde circuitry through the AV node and His Purkinje system and retrograde conduction over the accessory pathway. Orthodromic AVRT accounts for approximately 90%-95% cases of AVRT. Most incidences of CBT occur at the left free wall. Vagal maneuvers and/or intravenous (IV) adenosine are recommended for first line acute management of AVRT. However, pharmacological therapy with IV diltiazem, verapamil, or beta blockers can also be effective for acute treatment for orthodromic AVRT in patients who do not show pre-excitation on their resting ECG during sinus rhythm. The first-line ongoing therapy for AVRT is catheter ablation of CBT; when catheter ablation is not indicated or preferred, oral beta blockers, diltiazem, verapamil, flecainide, propafenone, or amiodarone are recommended.

Adenosine , Amiodarone , Atrioventricular Node , Catheter Ablation , Diltiazem , Electrocardiography , Flecainide , Humans , Incidence , Propafenone , Tachycardia , Tachycardia, Supraventricular , Verapamil
Article in English | WPRIM | ID: wpr-185794


An 8-month old female presented with spontaneous subarachnoid hemorrhage and was treated successfully with endovascular coil embolization of the ruptured aneurysm. Transcranial Doppler ultrasound performed four days later demonstrated middle cerebral artery (MCA) velocities greater than 350 cm/sec on the right and greater than 200 cm/sec on the left, despite medical management. The patient demonstrated no focal neurological deficits, though examination was limited by our patient's sedation and intubation. Angiography revealed severe vasospasm of the supraclinoid internal carotid and MCA territories, bilaterally. The vasospasm was refractory to the administration of intra-arterial verapamil. Balloon angioplasty was attempted, but the device could not be advanced safely due to the small size of the patient's vessels and the stiffness of the device. A microcatheter (0.0165" diameter) was advanced over a J-shaped soft microwire (0.014" diameter) to perform mechanical angioplasty in the internal carotid artery and MCA vessels bilaterally. Dramatic improvement was seen angiographically and on transcranial Doppler, and no complications were seen.

Aneurysm , Aneurysm, Ruptured , Angiography , Angioplasty , Angioplasty, Balloon , Carotid Artery, Internal , Embolization, Therapeutic , Female , Humans , Infant , Intubation , Middle Cerebral Artery , Subarachnoid Hemorrhage , Ultrasonography , Vasospasm, Intracranial , Verapamil
Int. braz. j. urol ; 42(5): 1005-1009, Sept.-Oct. 2016. tab
Article in English | LILACS | ID: lil-796900


ABSTRACT Objectives: To compare the response to tiocolchicine and verapamil injection in the plaque of patients with Peyronie's disease. Materials and Methods: Prospective, single-blind, randomized study, selecting patients who have presented Peyronie's disease for less than 18 months. Thiocolchicine 4mg or verapamil 5mg were given in 7 injections (once a week). Patients who had received any treatment for Peyronie's disease in the past three months were excluded. The parameters used were the International Index of Erectile Function (IIEF-5) score, analysis of the curvature on pharmaco-induced erections and size of the plaque by ultrasonography. Results: Twenty-five patients were randomized, 13 received thiocolchicine and 12 were treated with verapamil. Both groups were statistically similar. The mean curvature was 46.7° and 36.2° before and after thiocolchicine, respectively (p=0.019) and 50.4° and 42.08° before and after verapamil, respectively (p=0.012). The curvature improved in 69% of patients treated with thiocolchicine and in 66% of those who received verapamil. Regarding sexual function, there was an increase in the IIEF-5 from 16.69 to 20.85 (p=0.23) in the thiocolchicine group. In the verapamil group the IIEF-5 score dropped from 17.50 to 16.25 (p=0.58). In the thiocolchicine group, the plaque was reduced in 61% of patients. In the verapamil group, 8% presented decreased plaque size. No adverse event was associated to thiocolchicine. Conclusion: The use of thiocolchicine in Peyronie's disease demonstrated improvement on penile curvature and reduction in plaque size. Thiocolchicine presented similar results to verapamil in curvature assessment. No significant side effects were observed with the use of tiocolchicine.

Humans , Male , Adult , Aged , Penile Induration/drug therapy , Vasodilator Agents/administration & dosage , Verapamil/administration & dosage , Colchicine/analogs & derivatives , Time Factors , Penile Erection/drug effects , Injections, Intralesional , Single-Blind Method , Colchicine/administration & dosage , Prospective Studies , Reproducibility of Results , Treatment Outcome , Middle Aged
Arq. bras. cardiol ; 107(3): 223-229, Sept. 2016. graf
Article in English | LILACS | ID: lil-796033


Abstract Background: Despite the important biological effects of jabuticaba, its actions on the cardiovascular system have not been clarified. Objectives: To determine the effects of jabuticaba hydroalcoholic extract (JHE) on vascular smooth muscle (VSM) of isolated arteries. Methods: Endothelium-denuded aortic rings of rats were mounted in isolated organ bath to record isometric tension. The relaxant effect of JHE and the influence of K+ channels and Ca2+ intra- and extracellular sources on JHE-stimulated response were assessed. Results: Arteries pre-contracted with phenylephrine showed concentration-dependent relaxation (0.380 to 1.92 mg/mL). Treatment with K+ channel blockers (tetraethyl-ammonium, glibenclamide, 4-aminopyridine) hindered relaxation due to JHE. In addition, phenylephrine-stimulated contraction was hindered by previous treatment with JHE. Inhibition of sarcoplasmic reticulum Ca2+ ATPase did not change relaxation due to JHE. In addition, JHE inhibited the contraction caused by Ca2+ influx stimulated by phenylephrine and KCl (75 mM). Conclusion: JHE induces endothelium-independent vasodilation. Activation of K+ channels and inhibition of Ca2+ influx through the membrane are involved in the JHE relaxant effect.

Resumo Fundamentos: Embora a jabuticaba apresente importantes efeitos biológicos, suas ações sobre o sistema cardiovascular ainda não foram esclarecidas. Objetivos: Determinar os efeitos do extrato de jabuticaba (EHJ) sobre o músculo liso vascular (MLV) em artérias isoladas. Métodos: Aortas (sem endotélio) de ratos foram montadas em banho de órgãos isolados para registro de tensão isométrica. Foram verificados o efeito relaxante, a influência dos canais de K+ e das fontes de Ca2+ intra- e extracelular sob a resposta estimulada pelo EHJ. Resultados: Artérias pré-contraídas com fenilefrina apresentaram relaxamento concentração-dependente (0,380 a 1,92 mg/mL). O tratamento com bloqueadores de canais de K+ (tetraetilamônio, glibenclamida, 4-aminopiridina) prejudicaram o relaxamento pelo EHJ. A contração estimulada com fenilefrina também foi prejudicada pelo tratamento prévio com EHJ. A inibição da Ca2+ATPase do reticulo sarcoplasmático não alterou o relaxamento pelo EHJ. Além disso, o EHJ inibiu a contração causada pelo influxo de Ca2+ estimulado por fenilefrina e KCl (75 mM). Conclusão: O EHJ induz vasodilatação independente do endotélio. Ativação dos canais de K+ e inibição do influxo de Ca2+ através da membrana estão envolvidas no efeito relaxante do EHJ.

Animals , Male , Vasodilator Agents/pharmacology , Plant Extracts/pharmacology , Myrtaceae/chemistry , Muscle, Smooth, Vascular/drug effects , Aorta, Thoracic/drug effects , Time Factors , Vasoconstriction/drug effects , Vasodilation/drug effects , Calcium Channel Blockers/pharmacology , Verapamil/pharmacology , Calcium Channels/drug effects , Potassium Channels/drug effects , Cell Membrane/drug effects , Reproducibility of Results , Rats, Wistar , Potassium Channel Blockers/pharmacology
Rev. chil. cir ; 68(1): 32-37, feb. 2016. ilus, tab
Article in Spanish | LILACS | ID: lil-780530


Abstract Introduction: Keloids and hypertrophic scars are dermal fibro-proliferative disorders unique to humans. Their treatment is a true challenge with multiple options, but not all the time with good results. Unfortunatelythis problem is not uncommon in patients with history of burn injury. Aim: To evaluate use of verapamil andpressure garments in patients with hypertrophic or keloid scar caused by burn injury. methods: We includedpatients with a hypertrophic or keloid scar caused by burn injury that report non-response to treatment withpressure garment. The pathologic scars were evaluated by serial photographic records, Vancouver and Posasscales. The scales of Vancouver and Posas were compared with t Student. Results: We included 13 scars in11 patients. Four scars were located in the legs, 4 in the arms, 4 in the face-neck and 1 in the abdomen. Thedose of verapamil was calculated 0.03 mg per kg. Injections were scheduled every 7 to 10 days until complete 6 sessions. Taking in count Posas scale, patients referred improvement in pigmentation (0.01), thickness(0.005), pliability (0.01), pruritus (0.003) and irregular surface (0.004). In the Vancouver scale the observers mentioned improvement in elevation (0.008), pigmentation (0.014), vascularity (0.022) and flexibility (0.014).No adverse effects were found in verapamil injection. Conclusion: Verapamil was useful in conjunction withpressure garment to improve the condition of the keloid and hypertrophic scar caused by burn.

Resumen Introducción: La cicatriz queloide o la cicatriz hipertrófica son desórdenes fibro-proliferativos únicos de los humanos, cuyo tratamiento representa un reto en donde existen pocas opciones con buenos resultados.Objetivo: Evaluar el uso de verapamilo y las prendas de compresión en pacientes con cicatrización patológicacomo consecuencia de quemadura. material y método: Incluimos pacientes con cicatrización patológica,ya sea queloide o hipertrófica, causada por quemadura que mencionaron no haber tenido beneficio con el usode prendas de compresión. La cicatriz fue evaluada con fotografías seriadas, escala de Vancouver y Posas.Los resultados fueron comparados con la prueba de t de Student. Resultados: Incluimos 13 cicatrices en 11pacientes. La localización de las cicatrices fue en brazos 4, piernas 4, cara y cuello 1, y abdomen 1. La dosisde verapamilo se calculó a 0,03 mg por kg. Las inyecciones se aplicaron intralesionales y se administraroncada 7 a 10 días hasta completar 6 sesiones. Encontramos mejoría en los siguientes parámetros de la escalade Posas: pigmentación (0,01), pliabilidad (0,01), endurecimiento o grosor (0,005), prurito (0,003) e irregular (0,004). En la escala de Vancouver elevación (0,008), pigmentación (0,014), vascularidad (0,022) yflexibilidad (0,014). No encontramos efectos adversos con la administración de verapamilo. Conclusión: Elverapamilo fue útil en conjunto con las prendas de compresión para mejorar las condiciones de la cicatrizqueloide e hipertrófica causadas por lesiones por quemadura.

Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Verapamil/therapeutic use , Cicatrix, Hypertrophic/therapy , Compression Bandages , Keloid/therapy , Burns/complications , Prospective Studies , Cicatrix, Hypertrophic/etiology , Keloid/etiology
Braz. j. med. biol. res ; 49(2): e4800, 2016. tab, graf
Article in English | LILACS | ID: lil-766979


β-Citronellol is an alcoholic monoterpene found in essential oils such Cymbopogon citratus (a plant with antihypertensive properties). β-Citronellol can act against pathogenic microorganisms that affect airways and, in virtue of the popular use of β-citronellol-enriched essential oils in aromatherapy, we assessed its pharmacologic effects on the contractility of rat trachea. Contractions of isolated tracheal rings were recorded isometrically through a force transducer connected to a data-acquisition device. β-Citronellol relaxed sustained contractions induced by acetylcholine or high extracellular potassium, but half-maximal inhibitory concentrations (IC50) for K+-elicited stimuli were smaller than those for cholinergic contractions. It also inhibited contractions induced by electrical field stimulation or sodium orthovanadate with pharmacologic potency equivalent to that seen against acetylcholine-induced contractions. When contractions were evoked by selective recruitment of Ca2+ from the extracellular medium, β-citronellol preferentially inhibited contractions that involved voltage-operated (but not receptor-operated) pathways. β-Citronellol (but not verapamil) inhibited contractions induced by restoration of external Ca2+ levels after depleting internal Ca2+ stores with the concomitant presence of thapsigargin and recurrent challenge with acetylcholine. Treatment of tracheal rings with L-NAME, indomethacin or tetraethylammonium did not change the relaxing effects of β-citronellol. Inhibition of transient receptor potential vanilloid subtype 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptors with selective antagonists caused no change in the effects of β-citronellol. In conclusion, β-citronellol exerted inhibitory effects on rat tracheal rings, with predominant effects on contractions that recruit Ca2+ inflow towards the cytosol by voltage-gated pathways, whereas it appears less active against contractions elicited by receptor-operated Ca2+ channels.

Animals , Male , Calcium Channel Blockers/pharmacology , Monoterpenes/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Trachea/drug effects , Analysis of Variance , Calcium Channel Blockers/administration & dosage , Enzyme Inhibitors/pharmacology , Indomethacin/pharmacology , Inhibitory Concentration 50 , Monoterpenes/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Parasympatholytics/administration & dosage , Rats, Wistar , Tetraethylammonium/pharmacology , Thapsigargin/pharmacology , Verapamil/pharmacology