Comparative in vitro dissolution and in vivo bioavailability of commercial amlodipine tablets

Purpose: To evaluate the in vivo and in vitro behavior of amlodipine immediate release products.Methods: Three Mexican amlodipine products and the innovator (Norvasc®) were evaluated. Three bioequivalence studies were performed in 24 healthy male and female volunteers each. Plasma concentrations were determined using a liquid chromatographic method coupled with tandem mass spectrometry (LC/MS/MS). Dissolution profiles were evaluated using USP type apparatus 2 at 75 rpm and 500 mL of HCl 0.1N, pH 4.5 and pH 6.8. Also, the dissolution behavior of different lots of the innovator product was evaluated using apparatus 1 or 2 and 900 mL of buffer pH 6.8.Results: All the generic products under study were bioequivalent to the innovator. In vitro data showed that although at pH 1.2 and 4.5, the products met the specifications for very rapidly dissolving products but at pH 6.8, neither the innovator nor the test products complied with the criteria for rapidly dissolving products. When the study was performed at pH 6.8 in 900 mL of medium, the innovator showed a rapid dissolution behavior.Conclusion: The results show that the use of WHO conditions (900 mL of media, apparatus 2 at 75 rpm) are more adequate to predict the in vivo behavior of the amlodipine products.Keywords: Biopharmaceutics Classification System (BCS), Dissolution, Bioequivalence, Solubility, Permeabilit

Farmacogenética de reacciones adversas a fármacos antiepilépticos

PLANTEAMIENTO:Las reacciones adversas a medicamentos (RAM) son un problema de salud pública y una importante causa de morbimortalidad a nivel mundial. En el caso de los fármacos antiepilépticos (FAE), la presencia de RAM puede ser un impedimento para lograr el éxito terapéutico al dificultar la adherencia al tratamiento e impactar la calidad de vida del paciente. La farmacogenética busca la identificación de variantes genéticas asociadas a la seguridad de los fármacos. En este artículo se revisan los genes que codifican para enzimas metabolizadoras y transportadores de fármacos, así como en el sistema HLA asociados a RAM inducidas por FAE. DESARROLLO: A la fecha, se ha reportado la asociación de los alelos CYP2C9*2 y *3, que codifican para enzimas de actividad reducida, con efectos neurotóxicos por fenitoína (PHT); alelos nulos de GSTM1 asociados con hepatotoxicidad inducida por carbamazepina (CBZ) y ácido valproico (VPA); polimorfismos genéticos de EPHX1 en la teratogénesis inducida por PHT; variantes genéticas de ABCC2 asociadas con RAM neurológicas por CBZ y VPA, y también diversos alelos de HLA (p. ej., HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) asociados con RAM de tipo cutáneas. CONCLUSIONES: Los hallazgos publicados muestran que existen RAM con base farmacogenética con una alta variabilidad interétnica, lo que refleja la necesidad de que se realicen estudios en distintas poblaciones para poder obtener resultados que sean de utilidad a un número mayor de pacientes. La búsqueda de biomarcadores que permitan la predicción de RAM a FAE podría mejorar la farmacoterapia en la epilepsia.BACKGROUND: Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients’ quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. DEVELOPMENT: To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. CONCLUSIONS: Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy.• Consejo Nacional de Ciencia y Tecnología (México). Subvención #167261 • Consejo Nacional de Ciencia y Tecnología (México). Subvención #369708, para investigación doctoral de Ingrid Fricke GalindopeerReviewe

Characterization and comparability of biosimilars: A filgrastim case of study and regulatory perspectives for Latin America

Background: Developing countries have an estimate of ten times more approved biosimilars than developed countries. This disparity demands the need of an objective regulation that incorporates health policies according to the technological and economical capabilities of each country. One of the challenges lies on the establishment of comparability principles based on a physicochemical and biological characterization that should determine the extent of additional non-clinical and clinical studies. This is particularly relevant for licensed biosimilars in developing countries, which have an extensive clinical experience since their approval as generics, in some cases more than a decade. To exemplify the current status of biosimilars in Mexico, a characterization exercise was conducted on licensed filgrastim biosimilars using pharmacopeial and extended characterization methodologies. Results: Most of the evaluated products complied with the pharmacopeial criteria and showed comparability in their Critical Quality Attributes (CQAs) towards the reference product. These results were expected in accordance with their equivalent performance during their licensing as generics. Accordingly, a rational approval and registration renewal scheme for biosimilars is proposed, that considers the proper identification of CQAs and its thoroughly evaluation using selected techniques. Conclusions: This approach provides support to diminish uncertainty of exhibiting different pharmacological profiles and narrows or even avoids the necessity of comparative clinical studies. Ultimately, this proposal is intended to improve the accessibility to high quality biosimilars in Latin America and other developing countries

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel

(S)-(+)-cis-4′-Benzyloxypraziquantel

The asymmetric unit of the title compound, C26H30N2O3 {systematic name (S)-(+)-2-[cis-4-(benzyloxy)cyclohexanecarbonyl]-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one}, consists of two independent molecules in which the O= Camide group is syn to the N—C(C=Olactam) moiety, making dihedral angles of 2.0 (8) and 3.7 (8)°. The conformation of the 1,4-disubstituted cyclohexane ring is cis in each independent molecule, with the carbonyl group occupying an equatorial position and the benzyloxy group an axial position. In one molecule, two C and one O atom of the benzyloxy group are disordered over two sets of sites, with a refined occupancy ratio of 0.772 (8):0.228 (8). In the crystal, molecules are linked by C—H...O interactions, forming ribbons parallel to the b-axis direction

In Vitro Effects of Albendazole Sulfoxide and Praziquantel against Taenia solium and Taenia crassiceps Cysts

We investigated the minimum exposure times of prazicuantel (PZQ) and albendazole sulfoxide (ABZSO) required for their activities against Taenia cysts in vitro as well as the 50 and 99% effective concentrations. The results showed that although the effects of both drugs are time and concentration dependent, ABZSO acts much slower and is less potent than PZQ