Development of Poly (Methyl vinyl ether-alt-maleic acid) Microneedles for Transdermal Delivery of Atorvastatin Calcium.

AIMS: Biodegradable polymeric microneedles containing atorvastatin calcium were developed in order to improve the percutaneous absorption of the drug, useful for the treatment of hypercholesterolemia. BACKGROUND: The use of physical enhancers like microneedles have shown good results to increase the delivery of drugs through the skin, the use of microneedles has very important advantages for transdermal drug delivery, for example, they are painless, easy to use and safe, they increase time interval of drug activity, dose, and reductions in adverse reactions, they also offer, the facility to remove the system instantly of the skin. OBJECTIVE: Develop polymer microneedles loaded with a calcium atorvastatin and evaluate them by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, postwetting- bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies to demonstrate the use of microneedles atorvastatin is able to cross the skin. METHODS: The microneedles were made with poly (methyl vinyl ether-alt-maleic acid) as biodegradable polymer using the technique of casting in solution in a mold. After solidification these microneedles were characterized by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, post-wetting-bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies. RESULTS: In general, the performances were satisfactory for optimal formulation in terms of DSC with no interactions between drug and excipients, SEM shows microneedles with a conical shape, bioadhesion of 1570 g.f, post wetting-bioadhesion of 1503.4 g.f, breaking strength of 1566.7g.f that is sufficient to disrupt Stratum corneum, good drug release and a flux of 33.4 µg/cm2*h with a tLag of 15.14 h for the in vitro percutaneous absorption. CONCLUSION: The results indicate that it is possible to generate microneedles to increase the percutaneous absorption of calcium atorvastatin transdermally, with the potential to be used as an alternative to the oral route for the treatment of dyslipidemias.

HMGCR rs17671591 SNP Determines Lower Plasma LDL-C after Atorvastatin Therapy in Chilean Individuals.

Lipid-lowering response to statin therapy shows large interindividual variability. At a genome-wide significance level, single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR have been implicated in this differential response. However, the influence of these variants is uncertain in the Chilean population. Hence, we aimed to evaluate the contribution of PCSK9 rs7552841 and HMGCR rs17671591 SNPs as genetic determinants of atorvastatin response in Chilean hypercholesterolaemic individuals. One hundred and one hypercholesterolaemic patients received atorvastatin 10 mg/day for 4 weeks. Plasma lipid profile (TC, HDL-C, LDL-C and TG) was determined before and after statin treatment, and SNPs were identified by allelic discrimination using TaqMan(®) SNP Genotyping Assays. Adjusted univariate and multivariate analyses' models were used for statistical analyses, and a p-value <0.05 was considered significant. From baseline (week 0) to the study end-point (week 4), significant reductions were observed in plasma TC, LDL-C and TG (p < 0.001), while HDL-C levels were increased (p < 0.001). Multivariate analysis showed no association between lipid levels and atorvastatin therapy for the PCSK9 variant. However, the HMGCR rs17671591 T allele contributed to basal HDL-C concentration variability along with a higher increase in this lipid fraction after statin medication. In addition, this allele determined greater plasma LDL-C reductions after therapy with atorvastatin. Our data suggest that the HMGCR rs17671591 polymorphism can constitute a genetic marker of lower plasma LDL-C and enhanced HDL-C concentration after atorvastatin therapy in the Chilean population.

Frequency of common variants in genes involved in lipid-lowering response to statins in Chilean subjects with hypercholesterolemia / Frecuencia de polimorfismos en genes relacionados a la respuesta terapéutica a estatinas en individuos chilenos con hipercolesterolemia

Interindividual differences in activity and expression of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp, encoded by ABCB1 gene) contribute considerably to lipid-lowering efficacy of statin treatment in subjects with hypercholesterolemia. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. However, the available data indicate that the frequencies of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms differ significantly across populations. Thus, the aim of the present study was to determine the allelic frequency of three common variants of these genes in Chilean individuals with primary hypercholesterolemia (HC) and controls. A total of 135 unrelated patients (44 +/- 7 years old) with diagnosis of hypercholesterolemia (Total cholesterol 240 mg/dL) and 120 normolipidemic healthy controls (40 +/- 10 years old; total cholesterol 200 mg/dL) were included in this study. The 3435C>T (MDR1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) gene polymorphisms were analyzed by PCR-RFLP. The genotype distribution for 3435C>T variant of ABCB1 in HC patients (CC: 49 percent, CT: 37 percent, TT: 14 percent) and controls (CC: 41 percent, CT: 48 percent, TT: 11 percent) was comparable (P=0.186). Similarly, the genotype distribution for -290A>G polymorphism of CYP3A4 in HC subjects (AA: 73 percent, AG: 27 percent, GG: 0 percent) and controls (AA: 71 percent, AG: 29 percent, GG: 0 percent) was equivalent (P = 0.863). Finally, the genotype distribution for 6986A>G variant of CYP3A5 in HC individuals (AA: 4 percent, AG: 41 percent, GG: 55 percent) and controls (AA: 4 percent, AG: 47 percent, GG: 49 percent) was similar (P=0.594). The allelic frequencies of 3435C>T (ABCB1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) polymorphisms are similar between Chilean HC patients and controls, and comparable to frequencies found in Asian populations.

Polimorfismos de los genes CYP3A4, CYP3A5 y ABCB1 se han asociado a variaciones en la respuesta a fármacos hipolipemiantes, como las estatinas; principales medicamentos utilizados para disminuir los niveles plasmáticos de colesterol (CT). Sin embargo, la frecuencia de estas variantes genéticas puede variar entre las poblaciones. Así, el objetivo de este trabajo fue evaluar la frecuencia de tres polimorfismos de los genes CYP3A4, CYP3A5 y ABCB1, relacionados previamente a la respuesta a estatinas, en individuos chilenos hipercolesterolémicos (HC) y controles. Se analizaron 135 sujetos con diagnóstico de hipercolesterolemia primaria (CT 240 mg/dL) y 120 controles (CT 200 mg/dL) pertenecientes a la Región de La Araucanía (Chile). La genotipificación de las variantes genéticas se efectuó mediante la técnica de reacción en cadena de la polimerasa seguido de restricción enzimática (PCR-RFLP). La distribución de genotipos para la variante 3435C>T del gen ABCB1 en los individuos HC (CC: 49 por ciento, CT: 37 por ciento, TT: 14 por ciento) y controles (CC: 41 por ciento, CT: 48 por ciento, TT: 11 por ciento) fue semejante (P = 0,186). De forma similar, la distribución de genotipos para el polimorfismo -290A>G del gen CYP3A4 en los pacientes HC (AA: 73 por ciento, AG: 27 por ciento, GG: 0 por ciento) y controles (AA: 71 por ciento, AG: 29 por ciento, GG: 0 por ciento) fue equivalente (P = 0,863). Del mismo modo, la distribución de genotipos para la variante 6986A>G del gen CYP3A5 en el grupo HC (AA: 4 por ciento, AG: 41 por ciento, GG: 55 por ciento) y grupo control (AA: 4 por ciento, AG: 47 por ciento, GG: 49 por ciento) fue similar (P = 0,594). En resumen, nuestro estudio demuestra que las frecuencias de los polimorfismos 3435C>T (ABCB1), -290A>G (CYP3A4) y 6986A>G (CYP3A5) no difieren entre individuos HC y controles, y son comparables a las frecuencias encontradas en poblaciones asiáticas. Su efecto sobre el tratamiento con estatinas en la población chilena debe ser...

Enantioselectivity in the pharmacokinetic interaction between fluvastatin and lercanidipine in healthy volunteers.

Hypertension and dyslipidemia are independent risk factors for cardiovascular mortality and are frequently present in the same patient. Fluvastatin (FV), used to reduce cholesterol levels, and lercanidipine (LER), used to control blood pressure, are marketed as racemic mixtures. Therapeutic activities are 30-fold higher for (+)-3R, 5S-FV and 100- to 200-fold higher for S-LER compared with their respective antipodes. The present study describes the enantioselective pharmacokinetic interaction between LER and FV in healthy volunteers. A crossover randomized study was conducted in 3 phases on 8 volunteers treated with a single oral racemic dose of LER (20 mg) or FV (40 mg) or LER plus FV. Serial blood samples were collected from 0 to 24 hours. Plasma concentrations of the LER and FV enantiomers were determined by liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were evaluated using the WinNonlin software. The Wilcoxon and Mann-Whitney tests (P < .05) were used to analyze enantiomer ratios and the pharmacokinetic drug interaction. Data are expressed as medians. In monotherapy, the kinetic disposition of both FV and LER was enantioselective. AUC values were significantly higher for (-)-3S,5R-FV than for (+)-3R,5S-FV (358.20 vs 279.68 ng.h/mL) and for S-LER compared with R-LER (13.90 vs 11.88 ng.h/mL). The pharmacokinetic parameters of FV were not enantioselective when combined with LER (AUC: (-)-3S,5R-FV: 325.21; (+)-3R,5S-FV: 316.44 ng.h/mL). There was a significant reduction in S-LER (8.06 vs 13.90 ng.h/mL) and R-LER (6.76 vs 11.88 ng.h/mL) AUC values when FV was coadministered. In conclusion, the interaction between FV-LER might be clinically relevant because AUC values of (+)-3R,5S-FV were increased when LER was coadministered, and AUC values of the 2 LER enantiomers were reduced when FV was coadministered.

Comparison of composition and absorption of sugarcane policosanols.

Policosanols (PC) exist as very-long-chain alcohols derived from sugarcane currently used in many countries as a cholesterol-lowering therapy. PC purity and relative percentage composition have been suggested as primary reasons why the original Cuban PC (OPC) supplements possess lipid-lowering efficacy. The purpose of the present study was, first, to compare the relative percentage purity and PC composition of both OPC and alternative sources of PC (APC). A second objective was to feed Syrian hamsters a diet containing 0.275 mg PC/g of either the OPC or an APC product (APC1) and compare subsequent tissue, plasma and faecal PC levels. Five animals from the APC1 dietary group received a diet containing ten times the original amount of PC. Results indicate that the APC formulations have a composition that is highly consistent with the OPC supplement, with octacosanol being present within the cited 60-70 % range. PC were undetectable in the small intestine, liver, adipose or plasma in animals fed either source. Hamsters fed OPC excreted octacosanol (C28) more rapidly (P < 0.05) than hamsters receiving APC1. If the cholesterol-lowering efficacy of PC mixtures is dependent on their purity and composition, then sugarcane-derived APC products should possess similar therapeutic properties as the OPC supplement.

Ezetimiba: farmacocinética e terapêutica / Ezetimibe: pharmacokinetics and therapeutics

Ezetimiba é um inibidor da absorção do colesterol que é glucuronidado no fígado após sua rápida absorção nos enterócitos, onde juntamente com os seus metabólitos, exerce as suas ações hipolipidêmicas, reduzindo a absorção do colesterol através da inibição do transporte do colesterol por enzimas transportadoras específicas. Esta droga pode ser utilizada uma vez ao dia, em função de sua meia-vida plasmática prolongada e normalmente é muito bem tolerada. A eliminação da ezetimiba e de seus metabólitos é feita principalmente pela excreção fecal. Em geral, o uso da ezetimiba isolada promove modestos efeitos no LDL plasmático, entretanto, quando combinada às estatinas, importantes mudanças no perfil lipídico podem ser observadas.

[Ezetimibe--pharmacokinetics and therapeutics]. / Ezetimiba--farmacocinética e terapêutica.

Ezetimibe is an inhibitor of cholesterol absorption that is liver glucuronized after its rapid absorption, and is mobilized to the enterocytes, where together with its metabolites it exerts hypolipidemic effects, avoiding the absorption of cholesterol, through the reduction of specific cholesterol-transporter enzymes in the gut. This drug can be given once daily due to its prolonged plasma half-life, and is usually very well-tolerated. Elimination of ezetimibe and its metabolites is mainly via fecal excretion. In general, the use of ezetimibe alone promotes modest effects on plasma LDL-c, however, when combined with statins, a remarkable change in the lipid profile can be observed.

Stereoselective analysis of fluvastatin in human plasma for pharmacokinetic studies.

Fluvastatin, an inhibitor of cholesterol biosynthesis, is commercialized as a racemic mixture of the (+)-3R,5S and (-)-3S,5R stereoisomers, although inhibition of HMG-CoA reductase mainly resides in the (+)-(3R,5S)-fluvastatin isomer. The aim of the present study was to analyze fluvastatin isomers in human plasma with application to studies on kinetic disposition. Plasma samples of 1 ml were eluted into 3 ml LC-18 Supelclean (Supelco) columns equilibrated with methanol and water. The columns were washed with water and acetonitrile and then eluted with methanol containing 0.2% diethylamine. The (+)-3R,5S and (-)-3S,5R isomers were separated by HPLC on a Chiralcel OD-H chiral phase column and detected by fluorescence (lambda(ex) 305 nm; lambda(em) 390 nm). The quantification limit was 0.75 ng for each isomer/ml plasma and linearity was observed up to 625 ng/ml. The relative standard deviations obtained for intra- and inter-assay precision were lower than 10% and the recovery was higher than 80% for both enantiomers. Application of the method to a stereoselective study on the pharmacokinetics of fluvastatin administered as a single oral dose (Lescol, 20 mg) to a healthy volunteer revealed stereoselectivity, with the highest plasma concentrations being observed for the (-)-3S,5R isomer (Cmax 92.4 vs. 60.3 ng/ml, AUC(0-infinity) 133.3 vs. 97.4 ng h/ml, Cl/f 150.2 vs. 205.2 l h(-1) and Vd/f 4.4 vs. 6.0 l/kg).

Eficacia, seguridad y tolerabilidad de la fluvastatina sódica 40 mg en pacientes con hiperlipidemia tipo IIA / The use of 40 mg of fluvastatin sodium in patients with type IIA hyperlipidemia

La fluvastatina sódica es el primer inhibidor sintético de la reductasa de 3-hidroxi-3mentilglutaril coenzima A. Actúa inhibiendo en forma reversible la síntesis de colesterol y aumentando la catálisis de colesterol de las lipoproteínas de baja densidad y la expresión de receptores LDL en hepatocitos. Para evaluar la eficacia, tolerabilidad y seguridad de la fluvastatina sódica, 40 mg una vez al día, se estudiaron 40 pacientes con dislipidemia tipo IIA. Se observó una disminución significativa en colesterol total: 20.7 por ciento (p<0.01), en colesterol de las lipoproteínas de baja densidad: 29.5 por ciento (p<0.01), en triglicéridos: 10.53 por ciento (p N.S.), en colesterol de las lipoproteínas de muy baja densidad: 10.53 por ciento (p N.S.) y en C-CLDL:C-HDL: 33.7 por ciento (p<0.01). Asimismo, se obtuvo un aumento del colesterol de las lipoproteínas de alta densidad de 2.8 por ciento, después de 12 semanas de tratamiento. No se reportaron efectos secundarios y los exámenes de laboratorio de seguridad no tuvieron ningún cambio. Se concluye, que la fluvastatina sódica 40 mg, una vez al día, es eficaz, bien tolerada y segura en el tratamiento de dislipidemia tipo IIA