Sensory multiple mononeuropathy induced by pravastatin use: from a case report to literature's review / Mononeuropatia múltipla sensitiva induzida pelo uso de pravastatina: de um relato de caso à revisão de literatura

Statins are frequently prescribed in clinical practice for their proven efficacy in prevention of cardiovascular and cerebrovascular diseases. Despite the recognized beneficial effects of this class of drugs, in recent years, many studies published in medical literature have shown a wide range of adverse effects as a consequence of this therapy, including the risk of peripheral neuropathy. The purpose of this article is to report a case in which clinical features consistent with multiple mononeuropathy probably secondary to use of pravastatin were observed. The case report is followed by a review of the relevant literature.

As estatinas são frequentemente prescritas na prática clínica por sua comprovada eficácia na prevenção de doenças cardiovasculares e cérebrovasculares. Apesar dos reconhecidos efeitos benéficos dessa classe medicamentosa, nos últimos anos, diversos estudos publicados na literatura médica vem evidenciando uma ampla variedade de efeitos colaterais como consequência desta terapia, incluindo o risco de neuropatias periféricas. O objetivo deste artigo é relatar um caso no qual foram observadas manifestações clínicas compatíveis com o diagnóstico de mononeuropatia múltipla sensitiva, provavelmente secundária ao uso de pravastatina. O relato de caso é acompanhando de uma revisão de dados pertinentes da literatura.

Pravastatin induces cell cycle arrest and decreased production of VEGF and bFGF in multiple myeloma cell line / Pravastatina induz parada no ciclo celular e diminuição na produção de VEGF e bFGF em linhagem de Mieloma Multiplo

Abstract Multiple myeloma (MM) is a B cell bone marrow neoplasia characterized by inflammation with an intense secretion of growth factors that promote tumor growth, cell survival, migration and invasion. The aim of this study was to evaluate the effects of pravastatin, a drug used to reduce cholesterol, in a MM cell line.Cell cycle and viability were determinate by Trypan Blue and Propidium Iodide. IL6, VEGF, bFGF and TGFβ were quantified by ELISA and qRT-PCR including here de HMG CoA reductase. It was observed reduction of cell viability, increase of cells in G0/G1 phase of the cell cycle and reducing the factors VEGF and bFGF without influence on 3-Methyl-Glutaryl Coenzyme A reductase expression.The results demonstrated that pravastatin induces cell cycle arrest in G0/G1 and decreased production of growth factors in Multiple Myeloma cell line.

Resumo O Mieloma Múltiplo é uma neoplasia de linfócitos B da medula óssea, caracterizada por inflamação com uma intensa secreção de fatores de crescimento que promovem o aumento do volume do tumor, sobrevivência celular, migração e invasão. O objetivo deste estudo foi avaliar os efeitos da pravastatina, uma droga usada para reduzir o colesterol, em um linhagem de MM. O ciclo celular e viabilidade foram determinadas por Trypan Blue e iodeto de propídio. IL6, VEGF, bFGF e TGF foram quantificadas por ELISA e qRT-PCR, incluindo aqui de HMG CoA redutase. Observou-se a redução da viabilidade das células, aumento de células na fase G0/G1 do ciclo celular e redução no VEGF e bFGF, sem influência na expressão da enzima 3-Metil-Glutaril Coenzima A redutase. Os resultados demonstraram que a pravastatina induz parada no ciclo celular em G0/G1 e diminuição da produção de fatores de crescimento em várias linhas de células de Mieloma.

Liberación de pravastatina sódica formulada en matrices poliméricas a base de Quitosan/Pluronic F ̶ 127 / Release of pravastine sodium formulated in polymer chitosan/pluronic f-127 matrices

Introducción: el desarrollo de medicamentos transdérmicos manifiesta gran interés en los últimos años debido a las ventajas que ofrece; sin embargo, muchos de los sistemas desarrollados utilizan componentes solubles lo cual podría llevar a una ineficacia terapéutica si la matriz polimérica del sistema se solubiliza muy rápido, por ello se ensayan polímeros insolubles que permitan modular la liberación de un ingrediente farmacéuticamente activo. Objetivo: evaluar la liberación de pravastatina sódica en matrices poliméricas insolubles de quitosan/PF-127 con el método de paleta sobre disco para obtener su perfil cinético de liberación, con la finalidad de proponerse como matrices viables para la elaboración de parches transdérmicos. Métodos: se realizaron estudios de contenido químico, diámetro y espesor de las películas, calorimetrías de barrido diferencial y estudios de liberación. La cuantificación del principio activo se realizó mediante espectrofotometría UV-Vis a 238 nm. Resultados: se obtuvieron parches transdérmicos con buena uniformidad de contenido, espesor, diámetro, con una buena estabilidad en base a los estudios de calorimetría. El uso de PF-127 incrementó o retardó la liberación de pravastatina de la matriz polimérica dependiendo de su concentración y al realizarse los perfiles cinéticos de liberación las formulaciones se ajustaron a una cinética de orden 0 que describe el comportamiento de algunos sistemas transdérmicos. Conclusiones: los resultados manifiestan la posibilidad de usar esta matriz polimérica insoluble de quitosana con PF-127 para modular la liberación de pravastatina sódica y de fármacos con estructura similar a la misma por vía transdérmica, lo que generará de esta manera nuevas alternativas a las formas farmacéuticas orales para el tratamiento de padecimientos y enfermedades(AU)

Introduction: the development of transdermal drugs has aroused great interest in recent years due to their advantages, however many of the drug delivery systems use soluble matrix components which could trigger therapeutic problems due to a rapid release of the active ingredient. Therefore, insoluble polymers are being tested that can modulate the release of a pharmaceutically active ingredient. Objective: to evaluate the release of pravastatin sodium in insoluble polymer chitosan/PF-127 matrices by VER to obtain kinetic profile of release in order to submit them as viable systems for the manufacture of transdermal patches. Methods: studies on the chemical content, diameter and thickness of films, differential scanning calorimetry and release studies were performed. The UV-Vis spectrophotometry at 238 nm allowed quantitating the active principle. Results: transdermal patches with adequate uniform drug content, suitable thickness and diameter with good stability, based on calorimetric studies, were obtained. The use of PF-127 increased or delayed the release of pravastatin sodium from the polymeric matrix depending on concentration. When performing the kinetic profiles of release, the formulations were regulated to zero kinetic that describes the behavior of some transdernal systems. Conclusions: the results demonstrated the possibility of using these insoluble polymer chitosan/PF-127 matrices to modulate the release of pravastin sodium and of other structurally similar drugs, thus creating new alternatives to existing pharmaceutical oral forms for treatment of diseases(AU)

Las estatinas afectan la viabilidad de líneas celulares de leucemia y linfoma humanas in vitro / Statins affect the viability of leukemia cell lines in vitro and human lymphoma

Se ha propuesto que las estatinas inducen apoptosis sobre células tumorales. Para probar dicha hipótesis, se analizó el efecto de las estatinas atorvastatina, fluvastatina, lovastatina, mevastatina, pravastatina y simvastatina en el rango de concentraciones de 1 pM hasta 100 µM, sobre la viabilidad de las líneas celulares humanas Jurkat E6.1, Jurkat D1.1 (Linfoma T) , Daudi (Linfoma B), U937 (leucemia monocítica) y HL-60 (leucemia promielomonocítica) in vitro en cultivos de 48 horas, analizados por la técnica de hidrolización del compuesto bromuro de 3-(4,5-dimetiltiazol-2-il)-2,5-difenilltetrazolio (MTT). Lovastatina y mevastatina son los más potentes inductores de muerte celular independientemente del tipo celular (Ic 50 entre 12 y 50 µM). Para las otras estatinas se observan diferencias en el Ic50 según la línea celular atorvastatina (38,1 y 48,6 µM Jurkats, 55,3 µM Daudi y 100 µM para las otras líneas), pravastatina (25 µM HL-60, 55,6 y 60,7 µM Jurkats y > 100 µM Daudi y U937), simvastatina (25,1 µM Jurkat D1.1, 50,2 µM Jurkat E6.1, 45,2 µM Daudi y 51,3 µM HL-60, y > 100 µM U937) y para fluvastatina en todos los casos > 100 µM. La disminución de la viabilidad celular se revierte completamente cuando las células son incubadas con 10 µM mevalonato. Se concluye que la lovastatina y mevastatina son las más potentes inductoras de muerte seguida por atorvastatina, pravastatina y simvastatina cuyo efecto depende del tipo de línea celular y la fluvastatina no tiene efectos importantes en la viabilidad de las líneas celulares estudiadas

Statins have been proposed to induce apoptosis of tumor cells. In order to test this hypothesis, the effect of atorvastatin, fluvastatin, lovastatin, mevastatin, pravastatin, simvastatin on cell viability was assessed by in vitro culture for 48 hr, at concentrations ranging from 1 pM to 100 µM on human cell lines Jurkat E6.1, Jurkat D1.1 (T cell lymphoma), Daudi (B cell lymphoma), U937 (monocitic leukemia) and HL-60 (pro mielomonocitic leukemia) and analyzed the oxidation of (3-(4.5-Dimethylthiazol-2-yl)-2.5- diphenyltetrazolium bromide (MTT). Lovastatin and mevastatin are the most potent inductors of cell death independently of the cell type (Ic 50 between 12 and 50 µM). Differences in the Ic50 are observed depending on the cell line: atorvastatina (38.1 and 48.6 µM Jurkats, 55.3 µM Daudi y 100 µM for the others lines), pravastatin (25 µM HL-60, 55.6 y 60.7 µM Jurkats and > 100 µM Daudi and U937), simvastatin (25.1 µM Jurkat D1.1, 50.2 µM Jurkat E6.1, 45.2 µM Daudi and 51,3 µM HL-60, and > 100 µM U937) and for fluvastatin > 100 µM in all cases. The decrease in cell viability is reverted completely when the cells were incubated with 10 µM mevalonate. It is concluded that lovastatin and mevastatin are the most potent inductors of cell death followed by atorvastatin, pravastatin and simvastatin whose effect depends upon the cell type and fluvastatin does not have any important effects on cell viability on the cell lines studied

Fatores de risco em pacientes idosos selecionados por médicos da comunidade para tratamento hipolipemiante / Risk Factors in Elderly Patients Selected by Primary Care Physicians for a Hypolipemic Treatment Protocol

OBJETIVO- avaliar a influência da idade sobre a conduta e a resposta para terapêutica com pravastina, em pacientes seguidos por médicos da comunidade.MÉTODOS- Conforme a faixa etária, 873 pacientes foram divididos em três grupos:grupo A com idades entre 45e 59 anos(n=544), grupo B com idades entre 60 e 64 anos (n=182) e grupo C com idades entre 65 e 70 anos (n=147).Após quatro semanas recebendo apenas orientaçäo dietética, os pacientes receberam 10mg/dia de pravastatina por período de 12 semanas.RESULTADOS- Observou-se prevalência maio em faixas etárias mais idosas de fatores de risco, como hipertensäo arterial (45,7 por cento, 54,1 por cento nos grupos A, B e C, respctivamente, p=0,0165), diabetes mellitus (9,3 por cento, 17,6 por cento e 25,8 por cento grupos A,B,C, respectivamente, p<0,0001), e doenças cardíacas prévia (23,1 por cento, 34,3 por cento e 34,7,Grupos A,B e C, respectivamente, p<0,001).Durante o período de orientaçäo dietética houve reduçäo nos níveis de colesterol total em cerca de 10 por cento e de LDL colesterol de 10,5 por cento, resposta semelhante nos três grupos.Com a administraçäo de pravastina, a reduçäo foi mais importante, atingindo percentual médio de 30,0 por cento, o mesmo sendo obeservado com o LDL colesterol com níveis de 31,7 por cento, sem diferenças entre os grupos.Os níveis de colesterol de alta densidade (HDL) aumentaram, significativamente, com a introduçäo da pravastatina (12,7 por cento).Com a introduçäo da terapêutica, o aumento percentural nos níveis de HDL colesterol foi maior nos pacientes com HDL prévio baixo (_<35mg/dL) nos três grupos.A intervençäo terapêutica foi bem tolerada nos três grupos.CONCLUSAO- Em Pacientes selecionados por médicos da comunidade para terapêutica hipolipemiante, o aumento da idade relacionou-se com frequência a fatores de risco e cardiopatia.Independentemente da idade, houve boa resposta à terapêutica com pravastatina

Purpose - To evaluate the influence of age on response to pravastatin treatment in patients treated by community physicians. Methods - According to age, 873 patients were divided in three groups: group A with ages ranging from 45 to 59 years (n=55), group B with ages from 60 to 64 years (n=182) and group C with ages from 65 to 70 years (n=143). After four weeks only with diet orientation, patients received 10mg/day of pravastatin for 12 weeks. Results - There was a greater prevalence of risk factors in elderly patients: hypertension (45.7%, 54.4% and 57.1% in groups A, B and C respectivelly p=0.0165), diabetes mellitus (9.3%, 17.6% and 25.8% respectivelly in groups A, B and C p<0.0001), and previous heart disease (23.1%, 34.3% and 34.7% in groups A, B and C respectivelly p<0.001). During the period of diet orientation there was a similar total cholesterol reduction in the three groups (about 10.5%), the reduction reached 30.0% with the introduction of pravastatin for 12 weeks. Low density cholesterol level decreased during the diet period in the three groups (about 10.5%), pravastatin prescription induced further reduction (about 31.7%). The high density cholesterol level (HDL) increased significantly with pravastatin treatment (12.7%). After pravastatin treatment the increase in HDL levels was more significantly among those patients with initial low levels of HDL (<35mg/dL) in the three groups. Conclusion - In patients selected by community physicians to receive lipid lowering therapy, increased age was associated with greater prevalence of risk factors and heart disease. Regardless of age, there was a good response to pravastatin treatment, however less than half of patients had received treatment prior to the protocol

Estudo comparativo do gemfibrozil versus pravastatina no tratamento de portadores de doença arterial coronária e níveis reduzidos de HDL-colesterol / Comparative study of gemfibrozil versus pravastatin in the treatment of patients with coronary artery disease and low HDL cholesterol levels

PURPOSE--To evaluate the effects of gemfibrozil and pravastatin in coronary artery disease patients with HDL-cholesterol (HDL-C) < 35 mg/dl). METHODS--Twenty-nine patients (20 males, 60 +/- 9) were divided in a gemfibrozil group (G) (1200 mg/day n = 15) and a pravastatin group (P) (10 or 20 mg n = 10 and 4, respectively). The plasma lipid profile (LP) e.g. total cholesterol (TC), fractions and triglycerides (TG) was determined at 4 and 12 weeks of treatment. RESULTS--HDL-C was not affected in P, TC and LDL-cholesterol (LDL-C) reductions were superior to those in G (31.3 vs 13.4 and 38.7 and 11.5, p < 0.05 and < 0.01 respectively). In G HDL-C raised by 50 (12th week p < 0.01). Gemfibrozil reduced TG levels in 44.7 while in P it varied -32.2 (12th week p < 0.01 and < 0.05 respectively). CONCLUSION--Gemfibrozil is more effective in reducing TG and raising HDL-C than pravastatin. On the other hand, pravastatin was more potent in reducing LDL-C levels.

Objetivo - Comparar os efeitos do gemfibrozil e pravastatina no perfil lipídico (PL) de pacientes coronarianos com HDL-colesterol (HDL-C) <35 mg/dl Métodos - Vinte e nove pacientes (20 homens, 60 9 anos) divididos em grupo gemfibrozil (G) (1200mg/dia n=15) e grupo pravastatina (P) (10mg e 20mg, 10 e 4 pacientes, respectivamente). O perfil lipídico plasmático [colesterol total (CT), frações e triglicérides (TG)] foi avaliado a 4 e 12 semanas de tratamento. Resultados - Em P, o HDL-C não se alterou, as reduções de CT e LDL-colesterol (LDL-C) foram superiores às de G (31,3% vs 13,4% e 38,7 e 11,5%, respectivamente p<0,05 e <0,01). Em G. o HDL-C elevou-se em até 50% (12º semana, p<0,01). O gemfibrozil reduziu os TG em 44,7% (p<0,01) enquanto que em P, a variação foi de -32,2% na 12º semana (p<0,05). Conclusão - O gemfibrozil é mais eficaz que a pravastatina para reduzir os TG e elevar o HDL-C, porém a pravastatina é um redutor mais potente do LDLC

Efeitos da pravastatina nas lipoproteínas, Lp(a), apo B e apo A-I em pacientes com hipercolesterolemia primária / Effects of Pravastatin on Lipoproteins, Lp(a), apo B and apo A-I in Patients with Primary Hypercholesterolemia

PURPOSE--To evaluate the effects of pravastatin on lipoproteins, Lp (a), apo B and apo A-I and its tolerability in primary hypercholesterolemic patients in our outpatient lipid clinic. METHODS--Twenty-two primary hypercholesterolemic patients were evaluated. They had all been treated previously with other hypocholesterolemic drugs, including the statins, forming a specific and homogeneous group with hypercholesterolemia and definite coronary risk. After 7 weeks with American Heart Association phase I diet and placebo drug, pravastatin was administered during 12 weeks. All patients received an initial daily dose of 10 mg for six weeks. After this period, this dose was increased to 20 mg. The levels of cholesterol, triglycerides, high-density lipoprotein, lipoprotein (a) and apolipoproteins A-1 and B were determined. RESULTS--No changes occurred with diet and placebo, but pravastatin at a daily dose of 10 mg, reduced significantly cholesterol level (7.22 per cent) LDL-cholesterol (13.08 per cent) and increased HDL-cholesterol (7.8 per cent). The results were better with 20 mg, achieving a reduction of (28.21 per cent) in cholesterol, (36.88 per cent) in LDL-cholesterol, (17.06 per cent) in apo B level and an increase of (10.06 per cent) in HDL-cholesterol. The smaller effect observed with the more commonly used dosage (10 mg/day) was most probably due to the characteristics of the sample with already established hypercholesterolemia, being thus dependent of higher concentrations of medications, as observed in previous treatments in our outpatient clinic. Side affects with this drug were rare. No biochemical changes were observed that would interrupt the continuation of therapy. CONCLUSION--Pravastatin was well tolerated and promoted favorable changes in the total cholesterol, LDL, apo B and cholesterol/HDL and LDL/HDL ratios of primary hypercholesterolemic patients

Avaliação da eficácia e segurança da pravastatina em portadores de hipercolesterolemia primária: estudo aberto multicêntrico brasileiro / An evaluation of the efficacy and safety of pravastatin in patients with primary hypercholesterolemia: a Brazilian open multicenter study

Objetivo - Avaliar a resposta terapêutica e a segurança da pravastatina em portadores de hipercolesterolemia primária. Casuística e Métodos - 1.850 pacientes com hipercolesterolemia primária da clínica privada ou ambulatorial foram submetidos após quatro semanas de dieta padronizada, a tratamento com 10mg de pravastatina uma vez ao dia por período de 12 semanas. Resultados - Reduções médias superiores a 25%foram observadas para colesterolemia total e para LDL-C, sendo que individualmente elas foram consideradas ótimas e boas (diminuições superiores a 20%) em aproximadamente 70% dos pacientes. Também foram observadas elevações importantes superiores a 10% de HDL-C em 51% dos pacientes. A aderência à droga foi excelente, pois somente 118 (6,4%) apresentaram distúrbios clínicos atribuíveis ao uso do medicamento, mas a sua interrupção só foi necessária em 18 (0, 9°/0), dos quais 9 por queixas musculares, 3 por sintomas digestivos, 2 por manifestações cutâneas e 4 por manifestações gerais. Não houve interferência de condições clínicas (diabetes melito, obesidade, hipertensão arterial) na resposta hipolipemiante. A resposta a pravastatina não foi estatisticamente diferente, independente de um tratamento antilipêmico prévio. Pacientes responsivos ou não a esquemas terapêuticos prévios responderam igualmente a pravastatina. Conclusão - Considerando os efeitos expressivos sobre adversos e facilidade de utilização, a pravastatina entra como droga de primeira linha no arsenal terapêutico hipolipemiante

Purpose: To evaluate the efficacy and safety of pravastatin in patients with primary hypercholesterolemia Patients and Methods: In an open-label multicenter uncontrolled study under the usual conditions of clinical practice 1,850 patients with primary hypercholesterolemia were submitted, after one month of placebo control and low fat/low cholesterol diet, to 12 weeks of treatment with pravastatin 10mg o.d. Results: Significant reductions higher than 25% were obtained in plasma levels of total cholesterol and low density lipoprotein (LDL) cholesterol associated with an increase > 10% in the HDL cholesterol plasma concentration in 51% of the patients. The individual results were classified as satisfactory (higher than 20% decrease) in 70% of the studied population. The compliance of pravastatin was excellent, since 118 patients (6.4%) developed adverse reactions, but interruption of the treatment was necessary in only 18 (0.9%); 9 patients due to muscular pain, 3 by gastrointestinal symptoms, 2 by cutaneous reactions and 4 due to general complaints.The clinical conditions of diabetes, obesity, hypertension did not modify the efficacy of the drug. Previousinsatisfactory hypolipidemic treatment did not alter the results of the efficacy. Conclusion: The satisfactory results in efficacy and safety and the facility of the pravastatin use, make this drug as afirst line agent in the hypolipidemic treatment