Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Here, we report novel cationic lysine-based surfactants (hydrochloride salts of N¿- and N¿-acyl lysine methyl ester) that differ in the position of the positive charge and the length of the alkyl chain. Amino acid-based surfactants could be promising novel biomaterials in drug delivery systems, given their biocompatible properties and low cytotoxic potential. We examined their ability to disrupt the cell membrane in a range of pH values, concentrations and incubation times, using a standard hemolysis assay as a model of endosomal membranes. Furthermore, we addressed the mechanism of surfactant-mediated membrane destabilization, including the effects of each surfactant on erythrocyte morphology as a function of pH. We found that only surfactants with the positive charge on the ¿-amino group of lysine showed pH-sensitive hemolytic activity and improved kinetics within the endosomal pH range, indicating that the positive charge position is critical for pH-responsive behavior. Moreover, our results showed that an increase in the alkyl chain length from 14 to 16 carbon atoms was associated with a lower ability to disrupt cell membranes. Knowledge on modulating surfactant-lipid bilayer interactions may help us to develop more efficient biocompatible amino acid-based drug delivery devices.

Early use of TIPS in patients with cirrhosis and variceal bleeding.

Background Patients with cirrhosis in ChildPugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic porto - systemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. Methods We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapyEBL group, 31 patients). Results During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapyEBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapyEBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapyEBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapyEBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapyEBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapyEBL group than in the early-TIPS group. No significant diferences were observed between the two treatment groups with respect to serious adverse events. Conclusions In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with signif icant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)

In vitro susceptibility to pentavalent antimony in Leishmania infantum strains is not modified during in vitro or in vivo passages but is modified after host treatment with meglumine antimoniate

Background: Leishmaniasis is a common parasitic disease in Southern Europe, caused by Leishmania infantum. The failures of current treatment with pentavalent antimonials are partially attributable to the emergence of antimony-resistant Leishmania strains. This study analyses the in vitro susceptibility to pentavalent antimony of intracellular amastigotes from a range of L. infantum strains, derived from the same infected animal, during in vitro and in vivo passages and after host treatment with meglumine antimoniate. Results: SbV-IC50 values for strains from two distinct isolates from the same host and one stock after two years of culture in NNN medium and posterior passage to hamster were similar (5.0 ± 0.2; 4.9 ± 0.2 and 4.4 ± 0.1 mgSbV/L, respectively). In contrast, a significant difference (P < 0.01, t test) was observed between the mean SbV-IC50 values in the stocks obtained before and after treatment of hosts with meglumine antimoniate (4.7 ± 0.4 mgSbV/L vs. 7.7 ± 1.5 mgSbV/L). Drug-resistance after drug pressure in experimentally infected dogs increased over repeated drug administration (6.4 ± 0.5 mgSbV/L after first treatment vs. 8.6 ± 1.4 mgSbV/L after the second) (P < 0.01, t test). Conclusions: These results confirm previous observations on strains from Leishmania/HIV co-infected patients and indicate the effect of the increasing use of antimony derivatives for treatment of canine leishmaniasis in endemic areas on the emergence of Leishmania antimony-resistant strains.

Actividad antibacteriana de la Bencidamina HCl

En el presente trabajo se valora la eficacia antibacteriana del colutorio Tantum verde® y la de su, presuntamente, único principio activo, la bencidamina clorhidrato. Para ello, se ensayó la actividad in vitro de la bencidamina HCl y del Tantum verde mediante la obtención de las correspondientes CMI (Concentración Mínima Inhibitoria) siguiendo la técnica de la dilución en medio sólido. Inicialmente, se estudiaron ocho cepas de uso común en el laboratorio y, posteriormente, el estudio fue ampliado a cepas de patógenos bucales aisladas de muestras clínicas. Los estudios realizados, demuestran una eficacia bactericida real frente a patógenos bucales pertenecientes a géneros tales como Actinomyces, Bacillus, Actinobacillus, Veillonella o Streptococcus. Además, el Tantum verde como colutorio posee, en general, una mayor actividad antibacteriana que la demostrada por su principal principio activo, la bencidamina HCl, por lo que cabe pensar que la presencia de etanol a baja concentración, en su composición contribuye de forma notable a la acción antibacteriana.

¿Las patentes aceleran o retrasan la comercialización de nuevos medicamentos en los países en desarrollo?

Este trabajo analiza el impacto de las patentes en la dinámica de introducción de nuevos medicamentos en diferentes mercados nacionales. El estudio de un conjunto de mercados de medicamentos contra el VIH/SIDA en una muestra de países en desarrollo indica que las patentes sólo aceleran significativamente la introducción de los nuevos medicamentos después de que hayan pasado entre 1 y 4 años desde su lanzamiento mundial. Las patentes impiden que se introduzcan copias locales de los nuevos medicamentos comercializados por las grandes multinacionales, y la falta de competencia y los mayores precios de introducción resultantes ofrece a las multinacionales mayores ingresos en la comercialización de nuevos medicamentos mientras dura la patente. Sin embargo, el incentivo económico que debería acelerar la disponibilidad de nuevos medicamentos parece operar con cierto retraso

Drug price differentials caused by de-listing and price cap policies

This paper analyses the behaviour of pharmaceutical companies that face the threat of having their drugs excluded from reimbursement and the markets characterised also by price caps. We conclude that price elasticity of demand and cost differentials cause the price discounts which drug firms offer to health care organisations. Additionally, we conclude that price cap regulations affect the time path of prices, resulting in higher prices for new products and lower prices for old products.

Prices of medicines: a case-study on the impact of the rate-of-return regulation in the United Kingdom

This work carries out an empirical evaluation of the impact of the main mechanism for regulating the prices of medicines in the UK on a variety ofpharmaceutical price indices. The empirical evidence shows that the overall impact of the rate of return cap appears to have been slight or even null, and in any case that the impact would differ across therapeutic areas. These empiricalfindings suggest that the price regulation has managed to encourage UK-based firms¿ diversification in many therapeutic areas

Efectos del clobazam sobre la memoria, atención y tiempo de reacción

A través de un diseño intrasujeto contrabalanceado, y sobre una base de doble ciego, se han estudiado, en relación al placebo, 1os efectos de una dosis única de 20 mg. de clobazam sobre la memoria, atencion y tiempo de reaccion medidos a traves de pruebas de laboratorio. Se ha utilizado una muestra de 9 sujetos, universitarios voluntarios, sin patologia orgánica conocida y con puntuaciones medias en 10s factores neuroticismo y extroversión del E.P.I. No se han encontrado diferencias significativas entre el clobazam y el placebo, salvo en la prueba de Tolouse-Pieron, la cua1 pone de manifiesto un efecto detrimental del clobazam. Por otra parte, aunque no estadisticamente significativas, se han apreciado dos tendencias. En primer lugar, el clobazam tiende a disminuir el rendimiento mnemico y de atencion y a incrementar la rapidez de respuesta en comparación con el placebo; en segundo lugar, el clobazam inhibe el efecto de practica en las aplicaciones sucesivas de las pruebas de atención y memoria y 10 potencia en el caso del tiempo de reaccion. Por todo ello se requiere una investigacion adicional con mas sujetos y un diseño experimental más complejo.

Solid-phase synthesis and DNA binding studies of dichloroplatinum(II) conjugates of dicarba analogues of octreotide as a new anticancer drugs

The first dichloroplatinum(II) conjugates of dicarba analogues of octreotide , which is expected to act as a"tumour-targeting device", have been efficiently synthesized following a stepwise solid-phase approach; these compounds emulate the mechanism of cisplatin since they form a 1,2-intrastrand cross-link with two consecutive guanines of an oligonucleotide.

Efectos del clobazam sobre la memoria, atención y tiempo de reacción

A través de un diseño intrasujeto contrabalanceado, y sobre una base de doble ciego, se han estudiado, en relación al placebo, 1os efectos de una dosis única de 20 mg. de clobazam sobre la memoria, atencion y tiempo de reaccion medidos a traves de pruebas de laboratorio. Se ha utilizado una muestra de 9 sujetos, universitarios voluntarios, sin patologia orgánica conocida y con puntuaciones medias en 10s factores neuroticismo y extroversión del E.P.I. No se han encontrado diferencias significativas entre el clobazam y el placebo, salvo en la prueba de Tolouse-Pieron, la cua1 pone de manifiesto un efecto detrimental del clobazam. Por otra parte, aunque no estadisticamente significativas, se han apreciado dos tendencias. En primer lugar, el clobazam tiende a disminuir el rendimiento mnemico y de atencion y a incrementar la rapidez de respuesta en comparación con el placebo; en segundo lugar, el clobazam inhibe el efecto de practica en las aplicaciones sucesivas de las pruebas de atención y memoria y 10 potencia en el caso del tiempo de reaccion. Por todo ello se requiere una investigacion adicional con mas sujetos y un diseño experimental más complejo.

Technological, biopharmaceutical and pharmacokinetic advances: new formulations of application on the skin and oral mucosa

Currently a growing interest to improve the pharmacological therapy exists, not only by the production and the appearance of new drugs, but guaranteeing that the uses of those which already exist, become more effective. In fact, the conventional pharmaceutical formulations of different drugs present a few secondary effects due to oral administration. In order to avoid these undesired side effects, the purpose of current therapeutic is the development and research of formulations as an alternative to others routes of administration. Therefore, in spite of the undoubtedly complete parenteral absorption, the transdermal and transbuccal routes appear to be a rather attractive alternative to provide an efficient absorption. In this chapter a new technological, biopharmaceutical and pharmacokinetic approach of strategies for application on skin and buccal mucosa are reported. In the future new transdermal drug delivery systems will emerge to be more effective, equipped with an improved aesthetic appearance, better adherence and greater diffusion. But to reach these aims, it is necessary previous knowledge of histology and physiology of skin, and factors involved in the penetration of drugs through it.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Antifungal compounds from plants

Due to the increase of the incidence of fungal infections in humans and the limitations of the available antimycotic drugs, among which the emergence of resistant strains, there is a need for the discovery of new antifungal agents. Plants, especially those used in Traditional Medicine, linked to an unmatched chemical diversity, either as pure compounds or as plant extracts, provide unlimited opportunities for the development of new antifungals. Inrecent years, compounds from different phytochemical groups have been described as having antifungal activity, including polyphenols, saponins, or peptides, among others, as well asessential oils and their constituents. After screening of ethnopharmacologically selected plants, mainly from Latin-America, followed by bio-guided isolation, our group hasdescribed the antifungal activity of different types of plant constituents, such as sesquiterpenes, triterpenes, flavonoids, lignans, fatty acids and essential oils.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.