Recomendaciones para la intercambiabilidad de medicamentos antiepilépticos disponibles en Argentina

Los fármacos antiepilépticos (FAE) son un grupo heterogéneo de compuestos con respecto a estructura química, mecanismo de acción e indicaciones. Durante las últimas décadas, el vencimiento de las patentes de muchos FAE ha conducido a la aparición de formulaciones genéricas para varios de estos. Por ello, en muchos países, para el tratamiento de la epilepsia -como en otras áreas de la farmacoterapia- se recurre a la utilización de medicamentos antiepilépticos genéricos. Un supuesto fundamental para la utilización de un medicamento antiepiléptico genérico es que este es bioequivalente al producto original o innovador -también denominado “de marca” en los países que tienen medicamentos genéricos- y que brinda un efecto terapéutico similar al de este. Por lo tanto, ambos productos se pueden utilizar indistintamente (Bialer, 2007). A pesar de que internacionalmente se acepta que los medicamentos genéricos son intercambiables si demuestran equivalencia terapéutica mediante estudios de bioequivalencia in vivo, principalmente, la disponibilidad de medicamentos antiepilépticos genéricos ha generado serias dudas y controversias respecto a su eficacia, seguridad, calidad e intercambiabilidad, las cuales aún no se han resuelto definitivamente. Así, la prescripción de medicamentos genéricos bioequivalentes para pacientes con epilepsia es un problema para el cual no hay aún consenso (Bramley, 2014). Nuestro país no escapa a la problemática de la intercambiabilidad de medicamentos antiepilépticos que contienen el mismo FAE, en igual dosis, igual forma farmacéutica y vía de administración. Pero, a diferencia de lo que ocurre en otros países, no existen formulaciones genéricas de FAE, porque en nuestro país no existe la figura del medicamento genérico. La falta de armonización en la definición del medicamento genérico es una problemática en América Latina. Existe una diversidad de definiciones -o su ausencia- en los países de la región (OPS, 2011). En lugar de medicamento genérico, la Organización Mundial de la Salud (OMS) utiliza el término “producto farmacéutico multifuente” y lo define como un equivalente farmacéutico o una alternativa farmacéutica que puede o no ser equivalente terapéutico. Los productos farmacéuticos multifuente que son equivalentes terapéuticos son considerados intercambiables (OPS, 2011). A este respecto, cabe recordar que, en Argentina, están vigentes las definiciones de producto similar, equivalentes farmacéuticos, alternativas farmacéuticas, alternativas terapéuticas y equivalentes terapéuticos, pero no existen los medicamentos genéricos. Además, todas las especialidades farmacéuticas se registran como especialidades únicas: con una determinada forma farmacéutica, potencia o concentración, presentación comercial o tamaño de envase (unidades o volumen) y poseen un nombre comercial o de marca, aunque este sea el nombre genérico (o la denominación común argentina, DCA) seguido del fabricante (nombre del laboratorio productor). En la Tabla 1 se presentan definiciones de las categorías de medicamentos antes mencionadas, situaciones de sustitución posibles y ejemplos ilustrativos de cada una.Fil: Sperandeo, Norma Rebeca.Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Ciencias Farmacéuticas; Argentina.Fil: Uema, Sonia Andrea Naeko. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Ciencias Farmacéuticas; Argentina

Spectroscopic, thermal and X-ray structural study of the antiparasitic and antiviral drug nitazoxanide

Nitazoxanide [2-(acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide, NTZ] is a potent antiparasitic and antiviral agent recently approved. The anti-protozoal activity of NTZ is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme dependent electron transfer reaction. As drug– enzyme interactions are governed by the three-dimensional stereochemistry of both participants, the crystal structure of NTZ was determined for the first time to identify the conformational preferences that may be related to biological activity. NTZ crystallizes as the carboxamide tautomer in the orthorhombic system, space group Pna21 with the following parameters at 100(2) K: a = 14.302(2) Å, b = 5.2800(8) Å, c = 33.183(5) Å, V = 2505.8(6) Å3 , Z = 8, Dx = 1.629 g cm3 , R = 0.0319, wR2 = 0.0799 for 5121 reflections. In addition, the spectroscopic and thermal properties were determined and related to the molecular structure. The 13C CPMAS NMR spectra showed resolved signals for each carbon of NTZ, some signals being broad due to residual dipolar interaction with quadrupolar 14N nuclei. In particular, the resonance at about 127 ppm showed multiplicity, indicating more than one molecule in the asymmetric unit and this is consistent with the crystallographic data. The DSC and TG data revealed that NTZ shows a single DSC melting peak with extrapolated onset at 201 C which is accompanied by a TG weight loss, indicating that NTZ melts with decomposition.Fil: Bruno, Flavia Paola. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Caira, Mino R.. University of Cape Town; SudáfricaFil: Monti, Gustavo Alberto. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; ArgentinaFil: Kassuha, Diego Enrique. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Sperandeo, Norma Rebeca. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentin

Modificación de formas farmacéuticas sólidas: relevamiento en un hospital de la provincia de Córdoba

Introducción: La modificación de formas farmacéuticas (FF) sólidas (comprimidos y cápsulas) es una práctica común en el ámbito hospitalario. Esta práctica puede afectar a sus características fisicoquímicas y biofarmacéuticas, al efecto farmacológico y a veces provocar la aparición de efectos secundarios indeseables. Objetivos: Identificar los medicamentos cuya FF es modificada en un Hospital de Córdoba (Argentina), la manera en que dichas modificaciones son efectuadas y establecer si las mismas eran procedentes o no. Métodos: Se analizaron retrospectivamente las prescripciones efectuadas entre el 5 y 11 de mayo de 2012 y se identificaron las que solicitaban alteración de la FF. Se realizaron entrevistas abiertas a enfermeros y visitas a cada servicio del hospital para determinar cómo se modificaban las FF. Resultados: Se analizaron 700 prescripciones correspondientes a 113 pacientes. A 61 pacientes (54 %) se les modificó la FF (49 por indicación médica; 7 porque tenían sonda nasogástrica, 3 por decisión del paciente y 2 por decisión de enfermería). A 23 de los medicamentos prescriptos se les manipuló la FF, pero solo 12 de ellos fueron correctamente manipulados. Las principales modificaciones fueron la división de comprimidos y la pulverización-dispersión en agua de comprimidos y cápsulas. Conclusión: La FF de varios medicamentos es alterada en el hospital analizado, muchas veces sin indicación médica y sin justificación científica. Sería adecuado realizar cursos formativos y establecer una colaboración más estrecha entre Farmacia y las Unidades de Enfermería del hospital investigado.Background: In the hospital setting is frequent to manipulate solid dosage forms (SDF, tablets 16and capsules), which can affect their physicochemical and biopharmaceutical properties, the pharmacoloeffect and sometimes to cause the appearance of undesirable side effects. Objectives: To identify the medicines whose SDF is altered in a Hospital of Cordoba (Argentina), to determine how these modifications are made and to establish whether they were properly performed or not. Methods: We retrospectively analyzed the prescriptions made between the 5th and the 11th of March of 2012 and identified impaired requesting SDF modifications. Open interviews were held with nurses and service visits to each hospital to determine how they manipulated the SDF. Results: We analyzed 700 prescriptions for 113 patients, of which 61 (54%) had manipulations of the received SDF (49 for medical prescription, 7 because they had nasogastric tubes, 3 due to patient choice and 2 by nursing decision). Twenty three medicines were manipulated, but only 12 were correctly manipulated. The major changes were partition of tablets and grinding of tablets or microgranules and dispersible in water. Conclusion: The SDF of several medicines is altered in the analyzed hospital, many times without medical indication and scientific justification. It would be appropriate to conduct training courses and establish closer collaborations between pharmacy and nursing units in the investigated hospital.Fil: Parisia, Luciana R.. Provincia de Córdoba. Hospital J. B. Iturraspe; ArgentinaFil: Olivera, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Sperandeo, Norma Rebeca. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentin

Trapped lipopolysaccharide and LptD intermediates reveal lipopolysaccharide translocation steps across the Escherichia coli outer membrane

Lipopolysaccharide (LPS) is a main component of the outer membrane of Gram-negative bacteria, which is essential for the vitality of most Gram-negative bacteria and plays a critical role for drug resistance. LptD/E complex forms a N-terminal LPS transport slide, a hydrophobic intramembrane hole and the hydrophilic channel of the barrel, for LPS transport, lipid A insertion and core oligosaccharide and O-antigen polysaccharide translocation, respectively. However, there is no direct evidence to confirm that LptD/E transports LPS from the periplasm to the external leaflet of the outer membrane. By replacing LptD residues with an unnatural amino acid p-benzoyl-L-phenyalanine (pBPA) and UV-photo-cross-linking in E.coli, the translocon and LPS intermediates were obtained at the N-terminal domain, the intramembrane hole, the lumenal gate, the lumen of LptD channel, and the extracellular loop 1 and 4, providing the first direct evidence and “snapshots” to reveal LPS translocation steps across the outer membrane

Efficacy of a food supplement based on S-adenosyl methionine and probiotic strains in subjects with subthreshold depression and mild-to-moderate depression: A monocentric, randomized, cross-over, double-blind, placebo-controlled clinical trial

Depression is one of the most serious chronic psychiatric disorders affecting people worldwide. Subthreshold depression (SD) is a form of subclinical depression with increased risk of major depressive disorder (MDD). Patients diagnosed with SD may not be eligible for antidepressant drugs and, particularly in the case of MDD, these antidepressants may have adverse effects which outweigh their therapeutic effects, leading to discontinuation of therapy. Food supplements could provide an alternative strategy. The aim of this study is to demonstrate the efficacy of a food supplement based on a combination of S-adenosyl methionine (SAMe, 200 mg/day) and probiotics (Lactobacillus helveticus Rosell®−52, Bifidobacterium longum Rosell®−175, 3 ×109 CFU/day) in reducing depression symptoms in a monocentric, randomised, double-blind, placebo-controlled, cross-over clinical trial. 80 Subjects were recruited and offered the food supplement or placebo daily for three months, according to a cross-over clinical trial design, followed by a six-week follow-up period. The efficacy of the food supplement was measured by means of the “Hamilton Depression Rating Scale” (HAM-D) and "Patient Health Questionnaire-9" (PHQ-9), using a mixed analysis of variance model, with random intercept, for statistical analysis. The food supplement showed a significant decrease of PHQ-9 and HAM-D scores resulting in reduced SD and MDD symptoms as compared to placebo. In conclusion, the daily intake of the food supplement based on SAMe and probiotic strains for a period of three months is effective in improving the quality of life of SD subjects who are not eligible for antidepressant therapies, and patients suffering from mild-to-moderate depression who are not sensitive or cannot tolerate conventional drugs

The Escherichia coli Lpt transenvelope protein complex for lipopolysaccharide export is assembled via conserved structurally homologous domains

Lipopolysaccharide is a major glycolipid component in the outer leaflet of the outer membrane (OM), a peculiar permeability barrier of Gram-negative bacteria that prevents many toxic compounds from entering the cell. Lipopolysaccharide transport (Lpt) across the periplasmic space and its assembly at the Escherichia coli cell surface are carried out by a transenvelope complex of seven essential Lpt proteins spanning the inner membrane (LptBCFG), the periplasm (LptA), and the OM (LptDE), which appears to operate as a unique machinery. LptC is an essential inner membrane-anchored protein with a large periplasm-protruding domain. LptC binds the inner membrane LptBFG ABC transporter and interacts with the periplasmic protein LptA. However, its role in lipopolysaccharide transport is unclear. Here we show that LptC lacking the transmembrane region is viable and can bind the LptBFG inner membrane complex; thus, the essential LptC functions are located in the periplasmic domain. In addition, we characterize two previously described inactive single mutations at two conserved glycines (G56V and G153R, respectively) of the LptC periplasmic domain, showing that neither mutant is able to assemble the transenvelope machinery. However, while LptCG56V failed to copurify any Lpt component, LptCG153R was able to interact with the inner membrane protein complex LptBFG. Overall, our data further support the model whereby the bridge connecting the inner and outer membranes would be based on the conserved structurally homologous jellyroll domain shared by five out of the seven Lpt components

The Escherichia coli Lpt Transenvelope Protein Complex for Lipopolysaccharide Export Is Assembled via Conserved Structurally Homologous Domains

Lipopolysaccharide is a major glycolipid component in the outer leaflet of the outer membrane (OM), a peculiar permeability barrier of Gram-negative bacteria that prevents many toxic compounds from entering the cell. Lipopolysaccharide transport (Lpt) across the periplasmic space and its assembly at the Escherichia coli cell surface are carried out by a transenvelope complex of seven essential Lpt proteins spanning the inner membrane (LptBCFG), the periplasm (LptA), and the OM (LptDE), which appears to operate as a unique machinery. LptC is an essential inner membrane-anchored protein with a large periplasm-protruding domain. LptC binds the inner membrane LptBFG ABC transporter and interacts with the periplasmic protein LptA. However, its role in lipopolysaccharide transport is unclear. Here we show that LptC lacking the transmembrane region is viable and can bind the LptBFG inner membrane complex; thus, the essential LptC functions are located in the periplasmic domain. In addition, we characterize two previously described inactive single mutations at two conserved glycines (G56V and G153R, respectively) of the LptC periplasmic domain, showing that neither mutant is able to assemble the transenvelope machinery. However, while LptCG56V failed to copurify any Lpt component, LptCG153R was able to interact with the inner membrane protein complex LptBFG. Overall, our data further support the model whereby the bridge connecting the inner and outer membranes would be based on the conserved structurally homologous jellyroll domain shared by five out of the seven Lpt components.Chemistry and Chemical Biolog

Adaptation and Preadaptation of Salmonella enterica to Bile

Bile possesses antibacterial activity because bile salts disrupt membranes, denature proteins, and damage DNA. This study describes mechanisms employed by the bacterium Salmonella enterica to survive bile. Sublethal concentrations of the bile salt sodium deoxycholate (DOC) adapt Salmonella to survive lethal concentrations of bile. Adaptation seems to be associated to multiple changes in gene expression, which include upregulation of the RpoS-dependent general stress response and other stress responses. The crucial role of the general stress response in adaptation to bile is supported by the observation that RpoS− mutants are bile-sensitive. While adaptation to bile involves a response by the bacterial population, individual cells can become bile-resistant without adaptation: plating of a non-adapted S. enterica culture on medium containing a lethal concentration of bile yields bile-resistant colonies at frequencies between 10−6 and 10−7 per cell and generation. Fluctuation analysis indicates that such colonies derive from bile-resistant cells present in the previous culture. A fraction of such isolates are stable, indicating that bile resistance can be acquired by mutation. Full genome sequencing of bile-resistant mutants shows that alteration of the lipopolysaccharide transport machinery is a frequent cause of mutational bile resistance. However, selection on lethal concentrations of bile also provides bile-resistant isolates that are not mutants. We propose that such isolates derive from rare cells whose physiological state permitted survival upon encountering bile. This view is supported by single cell analysis of gene expression using a microscope fluidic system: batch cultures of Salmonella contain cells that activate stress response genes in the absence of DOC. This phenomenon underscores the existence of phenotypic heterogeneity in clonal populations of bacteria and may illustrate the adaptive value of gene expression fluctuations

Structural insights into cardiolipin transfer from the Inner membrane to the outer membrane by PbgA in Gram-negative bacteria

The outer membrane (OM) of Gram-negative bacteria is a unique asymmetric lipid bilayer in which the outer leaflet is composed of lipopolysaccharide (LPS) and the inner leaflet is formed by glycerophospholipid (GPL). The OM plays a fundamental role in protecting Gram-negative bacteria from harsh environments and toxic compounds. The transport and assembly pathways for phospholipids of bacterial OM are unknown. Cardiolipin (CL) plays an important role in OM biogenesis and pathogenesis, and the inner membrane (IM) protein PbgA, containing five transmembrane domains and a globular domain in periplasm has been recently identified as a CL transporter from the IM to the OM with an unknown mechanism. Here we present the first two crystal structures of soluble periplasmic globular domain of PbgA from S. typhimurium and E. coli, which revealed that the globular domains of PbgA resemble the structures of the arylsulfatase protein family and contains a novel core hydrophobic pocket that may be responsible for binding and transporting CLs. Our structural and functional studies shed an important light on the mechanism of CL transport in Gram-negative bacteria from the IM to the OM, which offers great potential for the development of novel antibiotics against multi-drug resistant bacterial infections