Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities

Tamoxifen Is Effective in the Treatment of Leishmania amazonensis Infections in Mice

Leishmaniasis is an antropozoonotic disease with a wide range of clinical manifestations. In humans, signs of disease vary from skin and mucosal ulcers to enlargement of internal organs such as the liver and spleen. The unicellular parasite Leishmania amazonensis is able to infect humans and cause localized or diffuse skin lesions. The treatment for this disease is difficult, as it requires prolonged and painful applications of toxic drugs that are poorly tolerated. Therefore, a key area in leishmaniasis research is the study of new therapeutic schemes and less toxic drugs. The present report is based on the investigation of tamoxifen's activity (a compound that has been in clinical use since the 1970s for the treatment of breast cancer) in the treatment of mice experimentally infected with L. amazonensis. We observed that infected mice treated with 20 mg/kg/day of tamoxifen for 15 days showed a significant clinical and parasitological response, with reduction in the size of lesions and ulcers and decreased numbers of parasites. These promising results pave the way for further testing of this drug as a new alternative in the chemotherapy of leishmaniasis

Tamoxifen-elicited uterotrophy: cross-species and cross-ligand analysis of the gene expression program

<p>Abstract</p> <p>Background</p> <p>Tamoxifen (TAM) is a well characterized breast cancer drug and selective estrogen receptor modulator (SERM) which also has been associated with a small increase in risk for uterine cancers. TAM's partial agonist activation of estrogen receptor has been characterized for specific gene promoters but not at the genomic level <it>in vivo</it>.Furthermore, reducing uncertainties associated with cross-species extrapolations of pharmaco- and toxicogenomic data remains a formidable challenge.</p> <p>Results</p> <p>A comparative ligand and species analysis approach was conducted to systematically assess the physiological, morphological and uterine gene expression alterations elicited across time by TAM and ethynylestradiol (EE) in immature ovariectomized Sprague-Dawley rats and C57BL/6 mice. Differential gene expression was evaluated using custom cDNA microarrays, and the data was compared to identify conserved and divergent responses. 902 genes were differentially regulated in all four studies, 398 of which exhibit identical temporal expression patterns.</p> <p>Conclusion</p> <p>Comparative analysis of EE and TAM differentially expressed gene lists suggest TAM regulates no unique uterine genes that are conserved in the rat and mouse. This demonstrates that the partial agonist activities of TAM extend to molecular targets in regulating only a subset of EE-responsive genes. Ligand-conserved, species-divergent expression of carbonic anhydrase 2 was observed in the microarray data and confirmed by real time PCR. The identification of comparable temporal phenotypic responses linked to related gene expression profiles demonstrates that systematic comparative genomic assessments can elucidate important conserved and divergent mechanisms in rodent estrogen signalling during uterine proliferation.</p

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Epidemiological studies at the human - animal - ecosystem interface. Factors related to the risk of infection by zoonotic pathogens

One of the most important social phenomena in recent years is the close coexistence between animals -domestic companion or production, synanthropic and wild- and people, fulfilling various functions: social, cultural or economic and representing a relevant component of the welfare of community.\nThe fast and poorly planned urbanization and industrialization of agri-food production have favored the expression of risk factors for pathogen infection. At the same time, wild species, after altering their habitat, modify their range of action, being able to contact domestic species and humans. In order to analyze environmental variables and the risk of pathogen infection in the human-animal-ecosystem interface, we conducted studies in Buenos Aires city, in the Costanera Sur Ecological Reserve (RECS), in close relationship with precarious urbanized areas with high epidemiological risk -Barrio Rodrigo Bueno- considering as a model the study of Leptospira spp. Currently, studies are being carried out in areas where contact would be established in the human-animal-ecosystem interface of wild and domestic reservoirs with an impact on public and animal health due to their productive condition, considering as multi-host pathogenic models such as Cryptosporidium spp. and Giardia spp. in protected areas -Ciervo de los Pantanos National Park and Iberá National Park- and in the urban-rural area of the Exaltación de la Cruz district. These studies are fundamental since they contribute new aspects to the knowledge of the epidemiology of these diseases and innovative forms of monitoring using sentinel species to detect the risk of infection early and propose tools to incorporate into the health systems.Fil: Berra, Y. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Berra, Y. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Berra, Y. CONICET. Buenos Aires, ArgentinaFil: Graciano, L. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Graciano, L. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Graciano, L. Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (ANPCyT). Buenos Aires, ArgentinaFil: Bravo, J. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Bravo, J. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Orozco, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Buenos Aires, ArgentinaFil: Orozco, M. CONICET - Universidad de Buenos Aires. Instituto de Ecología, Genética y Evolución de Buenos Aires (IEGEBA). Buenos Aires, ArgentinaFil: Marcos, E. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Marcos, E. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Degregorio, O. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Degregorio, O. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaUno de los fenómenos sociales más importantes de los últimos años es la estrecha convivencia entre los animales -domésticos de compañía o producción, sinantrópicos y silvestres- y las personas, cumpliendo variadas funciones: sociales, culturales o económicas y significando un componente relevante del bienestar de la comunidad.\nLa rápida y escasamente planificada urbanización e industrialización de la producción agroalimentaria han favorecido la expresión de factores de riesgo de infección de patógenos. A la vez, especies silvestres, tras la alteración de su hábitat, modifican su rango de acción, pudiendo contactar con especies domésticas y con los humanos. Con el fin de analizar variables ambientales y el riesgo de infección de patógenos en la interfase humano-animal-ecosistema, realizamos estudios en la Ciudad de Buenos Aires, en la Reserva Ecológica Costanera Sur, (RECS), en estrecha relación con áreas urbanizadas precarias y de alto riesgo epidemiológico -Barrio Rodrigo Bueno- considerando como modelo el estudio de Leptospira spp. Actualmente, se desarrollan estudios en áreas donde se establecería el contacto en la interfase humanoanimal-ecosistema de reservorios silvestres y domésticos con impacto en salud pública y animal por su condición productiva, considerando como modelos patógenos multihospedadores como Cryptosporidium spp. y Giardia spp. en áreas protegidas -Parque Nacional Ciervo de los Pantanos y Parque Nacional Iberá- y en el área urbano-rural del partido de Exaltación de la Cruz. Estos estudios son fundamentales ya que aportan nuevos aspectos al conocimiento de la epidemiología de estas enfermedades e innovadoras formas de monitoreo empleando especies centinela para detectar precozmente el riesgo de infección y proponer herramientas para incorporar al sistemas de salud

Epidemiological studies of tick-borne bacterial pathogens in urban and peri-urban areas of the Metropolitan Area of Buenos Aires

Urbanization has created a new geography, where there are no longer metropolitan areas surrounded by well-defined rural areas. Urban, semi-urban and semi-rural areas create an urban-rural interface, and in turn converge with natural areas (in some cases areas protected) in an urban-wild interface. All these areas are interrelated, allowing a large circulation of people, domestic animals, food products, and traffic of fauna (legal and illegal), providing new opportunities for the dispersal of pathogens and vectors. The increase of human and animal cases of infections caused by tick-borne pathogens in urban and peri-urban areas in recent years, together with the appearance and / or presence of infectious agents originating in natural areas, is closely related with these interfaces. In this sense, most domestic and wild animals (especially synanthropic) present in urban and peri-urban environments can act as hosts for some species of ticks and, in turn, be exposed to a variety of pathogens to which they may be susceptible. To analyze the richness of tick species in the urban-natural interface, in the Autonomous City of Buenos Aires, with emphasis on protected urban areas and neighboring neighborhoods, studies were carried out in the Rodrigo Bueno neighborhood (with high epidemiological risk and in close relationship with the Costanera Sur Ecological Reserve) and in the Ciudad Universitaria - Costanera Norte Ecological Reserve, both in the environment and in companion animals. Studies are currently being carried out on ticks and associated pathogens in areas of urban-rural-natural interfaces in the Exaltación de la Cruz district (Province of Buenos Aires). These studies contribute to the knowledge about the epidemiology of microorganisms transmitted by ticks in urban and peri-urban environments, within the framework of the "One Health" concept.Fil: González, S. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Estadística. Buenos Aires, ArgentinaFil: González, S. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Graciano, L. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Graciano, L. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Labanchi Alurralde, M. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Cicuttin, G.L. Universidad de Buenos Aires Facultad de Ciencias Veterinarias, Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Cicuttin, G.L. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Cicuttin, G.L. Gobierno de la Ciudad Autónoma de Buenos Aires. Ministerio de Salud. Instituto de Zoonosis Luis Pasteur. Buenos Aires, ArgentinaFil: Marcos E. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Marcos E. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Degregorio, O. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Degregorio, O. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaLa urbanización ha creado una nueva geografía, donde ya no hay áreas metropolitanas rodeadas de zonas\nrurales bien definidas. Áreas urbanas, semiurbanas y semirurales crean una interfase urbana-rural, y confluyen a su vez con áreas naturales (en algunos casos áreas protegidas) en una interfase urbana-silvestre. Todas estas áreas están relacionadas entre sí, posibilitando una gran circulación de personas, animales domésticos, productos alimenticios, y el tráfico (legal e ilegal) de fauna, proporcionando nuevas oportunidades para la dispersión de patógenos y vectores. El incremento en la ocurrencia de casos, humanos y animales, de infecciones causadas por patógenos transmitidos por garrapatas, en áreas urbanas y periurbanas en los últimos años, junto a la aparición y/o presencia de agentes infecciosos originados en áreas naturales, está íntimamente relacionado con estas interfases. En ese sentido, la mayoría de los animales domésticos y silvestres (especialmente sinantrópicos) presentes en entornos urbanos y periurbanos pueden actuar como hospedadores para algunas especies de garrapatas, y a su vez, exponerse a una variedad de patógenos a los que pueden ser susceptibles. Para analizar la riqueza de especies de garrapatas en la interfase urbana-natural en la Ciudad Autónoma de Buenos Aires, con énfasis en las áreas urbanas protegidas y los barrios aledaños, se realizaron estudios en el Barrio Rodrigo Bueno (de alto riesgo epidemiológico y en estrecha relación con la Reserva Ecológica Costanera Sur) y en la Reserva Ecológica Ciudad Universitaria ? Costanera Norte, tanto en el ambiente como en animales de compañía. Actualmente, se desarrollan estudios sobre garrapatas y patógenos asociados en áreas de interfases urbano-rural natural en el partido de Exaltación de la Cruz (Provincia de Buenos Aires). Estos estudios aportan al conocimiento sobre la epidemiología de los microorganismos transmitidos por garrapatas en ambientes urbanos y periurbanos en el marco del concepto de "Una Salud"

Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract and tolerability in postmenopausal women

OBJECTIVE: To compare ospemifene and raloxifene regarding their effects on hormones, lipids, genital tract, and tolerability in postmenopausal women. DESIGN: A randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) of ospemifene or 60 mg (n = 29) of raloxifene for 3 months. RESULTS: There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters. CONCLUSIONS: Ospemifene, at the dose of 90 mg/day, was more estrogenic than raloxifene, as shown by changes in serum follicle-stimulating hormone and sex hormone-binding globulin levels. Neither agent stimulated endometrium, but in contrast to raloxifene, ospemifene had a clear estrogenic effect in the vagina. Further studies with ospemifene are needed in subjects with vaginal atrophy