RESUMEN
Statins are a group of extremely successful drugs that lower cholesterol levels in blood; decreasing the risk of heath attack or stroke. In recent years, statins have also been reported to have other biological activities and numerous potential therapeutic uses. Natural statins are lovastatin and compactin, while pravastatin is derived from the latter by biotransformation. Simvastatin, the second leading statin in the market, is a lovastatin semisynthetic derivative. Lovastatin is mainly produced by Aspergillus terreus strains, and compactin by Penicillium citrinum. Lovastatin and compactin are produced industrially by liquid submerged fermentation, but can also be produced by the emerging technology of solid-state fermentation, that displays some advantages. Advances in the biochemistry and genetics of lovastatin have allowed the development of new methods for the production of simvastatin. This lovastatin derivative can be efficiently synthesized from monacolin J (lovastatin without the side chain) by a process that uses the Aspergillus terreus enzyme acyltransferase LovD. In a different approach, A. terreus was engineered, using combinational biosynthesis on gene lovF, so that the resulting hybrid polyketide synthase is able to in vivo synthesize 2,2-dimethylbutyrate (the side chain of simvastatin). The resulting transformant strains can produce simvastatin (instead of lovastatin) by direct fermentation.
Asunto(s)
Aspergillus/metabolismo , Lovastatina/biosíntesis , Aciltransferasas/genética , Aciltransferasas/metabolismo , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapéutico , Aspergillus/enzimología , Aspergillus/genética , Biotecnología , Fermentación , Lovastatina/análogos & derivados , Lovastatina/uso terapéutico , Pravastatina/biosíntesis , Simvastatina/metabolismoRESUMEN
Recent evidence suggests that statins improve the status of patients with coronary artery disease not only by reducing cholesterol levels, but also by acting at the level of the endothelium-smooth muscle unit. Previous results from our laboratory showed that these drugs interact with the vascular wall by partially inhibiting calcium-dependent, agonist-induced contractions in rat aortas. To evaluate whether this effect is also extended to the coronary vasculature, we assessed the effect of statins on serotonin (5-HT) induced contractions of left and right coronary arteries of swine. Concentration-response curves for the 5-HT-induced contractions (from 0.1 nmol/l to 100 micromol/l) were calculated on rings from both coronaries in the presence and absence of either (5 micromol/l) pravastatin, mevastatin, simvastatin, lovastatin, or atorvastatin. After a 45-min incubation period, all statins significantly reduced the Emax for the 5-HT-induced contractions, ranging from 51.9 +/- 1.9% (simvastatin) to 15.9 +/- 2.0% (pravastatin) in the left coronary artery and from 48.8 +/- 2.0% (simvastatin) to 17.8 +/- 2.5% (pravastatin) in the right coronary artery. The EC50 values for the 5-HT-induced contractions were 0.150 +/- 0.005 micromol/l for the left coronary artery and 0.171 +/- 0.010 micromol/l for the right coronary artery. These values significantly changed after incubation with statins, ranging from 1.240 +/- 0.101 micromol/l (for simvastatin) to 0.081+/- 0.008 micromol/l (for pravastatin) in the left coronary artery and from 1.410 +/- 0.075 micromol/l (for simvastatin) to 0.084 +/- 0.008 micromol/l (for pravastatin) in the right coronary artery. This evidence supports the possibility that, beyond their lipid-lowering properties, statins may provide a beneficial effect in atherosclerotic patients by reducing the tone in the coronary vasculature, facilitating blood flow to the myocardium.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Serotonina/farmacología , Vasoconstricción/efectos de los fármacos , Animales , Atorvastatina , Vasos Coronarios/fisiología , Relación Dosis-Respuesta a Droga , Ácidos Heptanoicos/farmacología , Humanos , Técnicas In Vitro , Lovastatina/análogos & derivados , Lovastatina/farmacología , Masculino , Pravastatina/farmacología , Pirroles/farmacología , Simvastatina/farmacología , Porcinos , Factores de TiempoRESUMEN
N-glycosylation of proteins is required for the intra-erythrocytic schizogony of Plasmodium falciparum. In eukaryotic cells, this process involves the transfer of oligosaccharides from a dolichyl pyrophosphate derivative to asparagine residues. We have identified dolichol, dolichyl phosphate and dolichyl pyrophosphate species of 11 and 12 isoprenoid residues by metabolic labelling with [(3)H]farnesyl pyrophosphate, [(3)H]geranylgeranyl pyrophosphate and [(14)C]acetate in the different intra-erythrocytic stages of P. falciparum. This is the first demonstration of short-chain dolichols in the phylum Apicomplexa. The results demonstrate the presence of an active isoprenoid pathway in the intra-erythrocytic stages of P. falciparum. Parasites treated with mevastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, show depressed biosynthesis of dolichol, dolichyl phosphate and isoprenoid pyrophosphate. This effect is observed in all intra-erythrocytic stages of the parasite life cycle, but is most pronounced in the ring stage. N-linked glycosylation of proteins was inhibited in the ring and young-trophozoite stages after mevastatin treatment of parasite cultures. Therefore the isoprenoid pathway may represent a different approach to the development of new anti-malarial drugs.
Asunto(s)
Dolicoles/metabolismo , Eritrocitos/parasitología , Plasmodium falciparum/metabolismo , Animales , Dolicoles/análogos & derivados , Glicoproteínas/antagonistas & inhibidores , Glicoproteínas/biosíntesis , Lovastatina/análogos & derivados , Lovastatina/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrolloAsunto(s)
Hipercolesterolemia/tratamiento farmacológico , Adulto , Anciano , Anticolesterolemiantes/uso terapéutico , Enfermedad Coronaria/mortalidad , Femenino , Humanos , Lovastatina/análogos & derivados , Lovastatina/uso terapéutico , Masculino , Persona de Mediana Edad , Factores de Riesgo , SimvastatinaRESUMEN
OBJECTIVES: The present study was conducted to investigate endothelium-dependent relaxation in hypercholesterolemic rabbits after treatment with two HMG-CoA reductase inhibitors: Simvastatin and Pravastatin. METHODS: Thirty male New Zealand rabbits were randomly assigned to Control, Simvastatin and Pravastatin groups and fed a diet supplemented with lipids and cholesterol (coconut oil 10% and cholesterol 1%) for 8 weeks. The drugs were administered in dosages of 10 mg/kg from the fourth to seventh weeks; at the end of the seventh week, plasma cholesterol was determined, and the Pravastatin dosage adjusted to 15 mg/kg to obtain similar levels of plasma cholesterol for the two experimental groups. At the end of the 8th week, the animals were killed and aorta removed for histologic examination and the measurement of cholesterol content, as well as for the conduction of endothelium-dependent relaxation studies. RESULTS: At the end of the study serum cholesterol was reduced by 57.1% in the Pravastatin group and 58.4% in the Simvastatin group, with the aortic cholesterol content in the former being significantly lower than that of the Simvastatin and Control groups (p < 0.05). Histologic examination also revealed a significant decrease in volume fractions of foam cells in Pravastatin-treated animals, whereas endothelium-dependent relaxation in response to ACh was significantly impaired in the Simvastatin group. No significant difference was found in relaxation induced by nitroprusside. CONCLUSIONS: In spite of the similar reduction in plasma cholesterol obtained by different doses, it seems that Pravastatin preserves the endothelium-dependent relaxation of aortic rings of hypercholesterolemic rabbits more effectively than does Simvastatin.
Asunto(s)
Anticolesterolemiantes/farmacología , Endotelio Vascular/fisiología , Hipercolesterolemia/fisiopatología , Lovastatina/análogos & derivados , Pravastatina/farmacología , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Técnicas In Vitro , Lovastatina/farmacología , Masculino , Conejos , SimvastatinaRESUMEN
Estatinas säo drogas derivadas de microorganismos e que eficientemente interferem na síntese celular de colesterol por inibiçäo competitiva da enzima HMG-CoA-redutase. Näo obstante, as estatinas reduzem a colesterolemia por induzirem formaçäo de receptores que captam as LDL do plasma e por diminuirem a síntese de VLDL no fígado. Esta última explica o efeito parcial na queda da trigliceridemia. A eficiência das estatinas na diminuiçäo da colesterolemia é comparável à das resinas seqüestradoras de ácidos biliares, porém superios à dos fibrates e ácido nicotínico. Estatinas säo melhor toleradas do que estas últimas duas drogas, mas inferiores quanto à capacidade de diminuirem os triglicérides e de aumentarem o HDL-colesterol. Seletividade tissular varia entre as diversas estatinas, mas esta é uma questäo irrelevante tendo em vista a raridade dos efeitos colaterais. Conseqüentemente, estas drogas devem ser prescritas em razäo da potência farmacológica e do fator custo. Cinecoronarioangiografia seqüencial em pacientes com coronariopatia tratados com placebo em comparaçäo a estatinas isoladamente, indica que a doença arterial regride por métodos farmacológicos.
Asunto(s)
Humanos , Lovastatina/farmacología , Pravastatina/farmacología , Hipercolesterolemia/metabolismo , Lovastatina/análogos & derivados , Hidroximetilglutaril-CoA Reductasas/efectos de los fármacos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Lipoproteínas , Lipoproteínas/metabolismoRESUMEN
Statins are microorganism derived drugs that greatly impair the cell synthesis of cholesterol by competitively inhibiting the activity of the enzyme HMG-CoA reductase. Statins, however lower the blood level of cholesterol chiefly by increasing the number of high affinity receptors that recognize plasma LDL and by diminishing the VLDL synthesis rate in the liver. The latter explains the mild triglyceride reducing effect of these drugs. Statins efficiency in lowering the plasma cholesterol concentration is comparable to that of the bile acid binding polymers, but is better than that of the fibrates and nicotinic acid. Statins are better tolerated than the latter two drugs but are less efficient in lowering plasma triglycerides and in increasing the HDL-cholesterol concentrations. Tissue selectivity varies for the different statins but this is a secondary issue when the rarity of side effects is taken into account. Statins should be prescribed considering solely their pharmacologic efficiency and cost. Coronary angiography studies in coronary heart disease patients treated with placebo as compared to statins alone, or combined to other lipid lowering drugs, indicate that coronary artery disease regression can be achieved by pharmacological means.
Asunto(s)
Hipercolesterolemia/metabolismo , Lovastatina/farmacología , Pravastatina/farmacología , Humanos , Hidroximetilglutaril-CoA Reductasas/efectos de los fármacos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Lipoproteínas/efectos de los fármacos , Lipoproteínas/metabolismo , Lovastatina/análogos & derivadosRESUMEN
Feeding a 0.5% diosgenin plus 0.02% simvastatin diet to rats increases biliary cholesterol concentration and saturation to levels generally found in human native supersaturated bile. By using preparative ultracentrifugation, gel filtration chromatography, and electron microscopy, we isolated, purified, and identified lamellar structures (unilamellar vesicles and multilamellae) as a major biliary cholesterol transport in supersaturated human and rat bile. It was estimated that more than 60% of biliary cholesterol is transported in these lamellar carriers, which were identified by transmission electron microscopy as unilamellar vesicles and multilamellar bodies within bile canaliculi of rats with cholesterol supersaturated bile. By SDS-PAGE, a characteristic and constant protein profile was found associated to the purified lamellar carriers. One of these proteins, a 130-kDa protein, was isolated from human biliary lamellae and used for preparation of a rabbit polyclonal antibody, which cross-reacted with the homologous rat protein. By Western blotting, it was established that the purified low density fraction of bile-Metrizamide gradients, containing lamellae, was enriched with the 130-kDa protein. The 130-kDa protein was characteristically detected at the canalicular membrane by Western blotting of hepatic subcellular fractions and by immunohistochemistry of rat and human liver biopsies. Amino acid sequencing of the amino terminus of the 130-kDa protein demonstrated a complete identity with aminopeptidase N, a canalicular transmembrane hydrophobic glycoprotein. These studies show that biliary lipids may acquire an ordered multilamellar structure that is present in the canaliculi of rats with supersaturated bile. These biliary lamellae are similar to lamellar bodies and surfactant-like material frequently found in other epithelia, suggesting common biogenetic, structural, and functional properties. The identification of aminopeptidase N associated with biliary lamellae is consistent with the involvement of the canalicular membrane in the secretory mechanism of biliary lipids.
Asunto(s)
Aminopeptidasas/análisis , Bilis/química , Proteínas Portadoras/análisis , Colesterol/metabolismo , Secuencia de Aminoácidos , Aminopeptidasas/química , Aminopeptidasas/aislamiento & purificación , Animales , Bilis/metabolismo , Antígenos CD13 , Proteínas Portadoras/química , Proteínas Portadoras/aislamiento & purificación , Centrifugación por Gradiente de Densidad , Diosgenina/farmacología , Humanos , Immunoblotting , Inmunohistoquímica , Hígado/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Lovastatina/análogos & derivados , Lovastatina/farmacología , Masculino , Metrizamida , Microscopía Electrónica , Datos de Secuencia Molecular , Proteínas/metabolismo , Conejos , Ratas , Ratas Wistar , SimvastatinaRESUMEN
In a contribution to a prolonged multicenter study 15 patients with primary hypercholesterolemia were treated with simvastatin, a competitive inhibitor of HMG-CoA reductase. The first part of the study was done in a double-blind fashion comparing the effect of this new drug with that of gemfibrozil during 12 weeks, and after this period on open-label treatment was started with the administration to all the patients of simvastatin in doses ranging from 2.5 to 40 mg q.p.m. Persistent and significant reductions (P less than 0.001) were achieved for total serum cholesterol (TC), LDL-cholesterol (LDL-C), apo B and triglycerides: by 38, 49, 44 and 33%, respectively, after 40 weeks of the open-label extension. From week 12, LDL-C levels were maintained at a cut point less than or equal to 140 mg/dl in every patient throughout the study. At week 40, cholesterol values of HDL subfractions showed a significant increase in HDL2-C (28%, P less than 0.01) and a concomitant reduction in HDL3-C (12%, P less than 0.01) in spite of a nonsignificant elevation of total HDL-C (by 6%). The HDL2-C/HDL3-C ratio rose by 47% (P less than 0.001) and the TC/HDL-C ratio was significantly reduced by 43%: from 6.1 +/- 1.2 to 3.5 +/- 0.7 (mean +/- SD, P less than 0.001). No adverse effects were detected. Our results suggest a conversion of HDL3 into HDL2, which could imply a beneficial effect of simvastatin upon the so-called reverse cholesterol transport, in addition to the striking reduction in atherogenic lipoproteins.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , HDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia/sangre , Lovastatina/análogos & derivados , Anciano , Anticolesterolemiantes/efectos adversos , Apolipoproteínas/sangre , Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Femenino , Gemfibrozilo/uso terapéutico , Humanos , Hipercolesterolemia/tratamiento farmacológico , Lovastatina/efectos adversos , Lovastatina/uso terapéutico , Masculino , Persona de Mediana Edad , Simvastatina , Triglicéridos/sangreAsunto(s)
Enfermedad de Acumulación de Colesterol Éster/tratamiento farmacológico , Resina de Colestiramina/uso terapéutico , Lovastatina/análogos & derivados , Preescolar , Quimioterapia Combinada , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Lovastatina/uso terapéutico , Masculino , SimvastatinaRESUMEN
Simvastatin, 10-40 mg/d (n = 11), bezafibrate, 600 mg/d (n = 6), and gemfibrozil, 1200 mg/d (n = 5) were administered for 12 weeks after a 4-week placebo period to subjects with initial plasma levels (mg/100 ml. mean +/- SD) of cholesterol (346 +/- 77), and of triglycerides (180 +/- 54). Total LDL-C plasma concentration was lowered 32% by simvastatin and 35% by bezafibrate, but only bezafibrate diminished the triglyceride (41%) and increased HDL-C plasma levels (35%). Plasma lipoprotein fractions obtained by discontinuous gradient ultracentrifugation, namely, VLDL, lighter LDL (LDL-1), heavier LDL (LDL-2) and bulk HDL were chemically analyzed. Simvastatin and bezafibrate significantly diminished the quantity of VLDL and LDL-1 particles, although barely modifying their composition. Neither drug influenced the LDL-2 plasma concentration. Bezafibrate increased the total plasma HDL level little interfering with its chemical composition. Gemfibrozil was the least effective of all drugs but decreased the lipid and protein contents and their ratios in VLDL and LDL-2.
Asunto(s)
Bezafibrato/uso terapéutico , Gemfibrozilo/uso terapéutico , Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteínas/sangre , Lovastatina/análogos & derivados , Adulto , Anciano , Apolipoproteínas/sangre , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Femenino , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Lipoproteínas/química , Lovastatina/uso terapéutico , Masculino , Persona de Mediana Edad , SimvastatinaRESUMEN
PURPOSE: To evaluate the efficacy and tolerability of simvastatin, a new and potent HMG-CoA reductase inhibitor, in the treatment of hypercholesterolemia in elderly patients. PATIENTS AND METHODS: Twenty patients, 14 female and 6 male, aged 65 to 72 years (x = 69 +/- 3), with total cholesterol (TC) above 260 mg/dl and triglycerides below 350 mg/dl were studied. All patients presented clinical evidences of atherosclerotic disease and were followed up for 6 months. Monthly visits were required for clinical and laboratory evaluation. The initial dosage of simvastatin was 10 mg/day; dosage was titrated up to 10 mg/day or to a minimum of 5 mg/day in intervals of at least 4 weeks, in order to maintain LDL-cholesterol below 140 mg/dl. To evaluate the changes on plasma lipid levels, the mean value of determinations during the placebo baseline period was compared to the mean value of determinations during the active treatment period. RESULTS: There were significant reductions of total cholesterol (-26.4%), triglycerides (-16.0%), LDL-cholesterol (-35.2%), VLDL-cholesterol (-15.4%), TC/HDL-C (-30.7%), and LDL/HDL-C (-39.5%). There was significant elevation of HDL-cholesterol (+5.2%), although this response was not uniform. The drug was well tolerated: only five patients reported transient clinical adverse experiences that subsided spontaneously. Two patients had elevation of CPK and one of TGP. The drug did not have to be discontinued in any case. Ophthalmological examinations performed before treatment compared to examinations at the end of the study showed no signficant alterations. CONCLUSION: Simvastatin in elderly patients appeared to be a potent TC and LDL-C lowering drug and presented mild but significant effect on the elevation of HDL-C. There was good tolerability, with low incidence of adverse experiences. This fact is important when one considers drug therapy for hypercholesterolemia in this age group.