Pharmacokinetics of experimental pentavalent antimony after intramuscular administration in adult volunteers.

BACKGROUND: Pentavalent antimony (SbV) has demonstrated therapeuticeffectiveness against clinical manifestations of leishmaniasis, an infection caused by Leishmania, a genus of flagellate protozoa comprising parasites of worldwide distribution. Approximately 1.8 million new cases are reported annually. OBJECTIVE: The aim of this study was to assess the pharmacokinetics of the investigational generic SbV, Ulamina (pentachloride of antimony + N-methylglucamine), in healthy adult volunteers. METHODS: In this study, SbV was administered IM as a single 5-mg/kg dose.Blood samples were collected at 0.25, 0.75, 1, 2, 4, 8, 12, and 24 hours after administration; urine samples were collected at 6-hour intervals during the 24-hour postadministration period. Determination of trivalent antimony, SbV, and total antimony concentrations in blood and urine samples was carried out using atomic absorption spectrometry. Clinical history was reviewed and the subjects were monitored before and after administration of SbV using physical examination, weight, and hepatic- and renal-function studies. The pharmacokinetic parameters calculated were Cmax, Tmax, absorption constant (Ka), elimination constant (Kel), AUC2-24h, AUC0-∞, elimination phase (t½ß), volume of distribution (Vd), and urinary excretion rate. RESULTS: Five subjects (3 men, 2 women; mean age, 28 years [range, 18-34 years]) were included in the study. One hour after drug administration the following values were obtained: Cmax, 1.1 µg/mL; Tmax, 1.3 hours; Ka, 1.87 hours; Kel, 0.043 hours; AUC0-24h, 12.26 µg/mL · h; AUC0-∞, 19.84 µg/mL · h; t½ß, 17.45 hours; Vd, 6.6 L/kg; and urinary excretion rate, 2.8 µg/h; these were mean values for the entire study group. The single dose was well tolerated by all subjects. CONCLUSIONS: The investigational generic SbV, Ulamina, was associated with linearelimination after IM administration of a single 5-mg/kg dose. A 2-compartment pharmacokinetic model was observed in these volunteers; the mean t½ß, was 17.45 hours and the mean Vd was 6.6 L/kg.

Population structure of the dengue viruses, Aragua, Venezuela, 2006-2007. Insights into dengue evolution under hyperendemic transmission.

During the past three decades there has been a notable increase in dengue disease severity in Venezuela. Nevertheless, the population structure of the viruses being transmitted in this country is not well understood. Here, we present a molecular epidemiological study on dengue viruses (DENV) circulating in Aragua State, Venezuela during 2006-2007. Twenty-one DENV full-length genomes representing all of the four serotypes were amplified and sequenced directly from the serum samples. Notably, only DENV-2 was associated with severe disease. Phylogenetic trees constructed using Bayesian methods indicated that only one genotype was circulating for each serotype. However, extensive viral genetic diversity was found in DENV isolated from the same area during the same period, indicating significant in situ evolution since the introduction of these genotypes. Collectively, the results suggest that the non-structural (NS) proteins may play an important role in DENV evolution, particularly NS1, NS2A and NS4B proteins. The phylogenetic data provide evidence to suggest that multiple introductions of DENV have occurred from the Latin American region into Venezuela and vice versa. The implications of the significant viral genetic diversity generated during hyperendemic transmission, particularly in NS protein are discussed and considered in the context of future development and use of human monoclonal antibodies as antivirals and tetravalent vaccines.

Farmacocinética de la ulamina administrada en perros como prueba aguda intravenosa e intramuscular / Pharmacokinetic disposition of ulamina in dogs administered as intravenous and intramuscular acute test

Se realizó una investigación con el objeto de describir la disposición farmacocinética del antimonial pentavalente genérico ulamina en 8 perros sanos, como prueba aguda intravenosa e intramuscular, después de administrar una dosis de 25 mg/kg. Las curvas obtenidas para ambas vías muestran un descenso de las concentraciones plasmáticas de 184,91± 86,06 μg/mL a 86,06±39,24 μg/mL y 164,61 ± 23,80 μg/mL a 100,94 ± 45,3 μg/mL, hasta la hora 4,0 para las vía IV e IM, respectivamente, que corresponden a la fase alfa de distribución. Seguidamente se aprecia un descenso lento, con antimonio detectable más allá de la hora 24 para ambas vías, denominada fase beta o de eliminación. La droga se absorbe rápidamente y mostró alta biodisponibilidad. La vida media (t1/2β) IV fue de 8,1 horas y t1/2 β IM fue 13,35 horas. El volumen de distribución (Vd) IV fue de 0,17 L/Kg e IM fue de 0,23 L/Kg. No se encontraron diferencias significativas al comparar AUC y t1/2β, después de administrar ulamina IV e IM, proponiéndose esta última como ruta de administración por resultar más práctica y segura. La ulamina constituiría una opción terapéutica para el tratamiento de la leishmaniasis humana y canina, por lo que se sugiere la aplicación de ensayos con dosis múltiples para evaluar la fase de eliminación y determinar si hay acumulación de antimonio, lo cual justificaría una disminución de la dosis.

A study was carried out to describe the pharmacokinetic disposition of pentavalent antimony generic ulamina in 8 healthy dogs in acute intravenous and intramuscular test after a dose of 25mg/Kg. The curves obtained for both routes show a decrease in plasma concentrations of 184.91 ± 86.06 μ g / mL to 86.06 ± 39.24 μ g / mL and 164.61 ± 23.80 μ g / mL to 100.94 ± 45.3, μ g / mL to 4.0 hours for the IM and IV, respectively, corresponding to the alpha phase distribution. There was a decrease slowly, with antimony detectable beyond 24.0 hours for both routes, called beta or disposal. The drug is rapidly absorbed and showed high bioavailability. The half life (t1/2β) IV was 8.1 hours and t1/2β IM was 13.35 hours. The volume of distribution (Vd) IV was 0.17 L /Kg and MI was 0.23 L /Kg. No significant differences were found when comparing AUC, and t1/2β, after IV and IM administration ulamina, proposing the latter as a more practical and safe administration route. The ulamina may be a therapeutic option for the treatment of human and canine leishmaniasis, as it is suggested by the application of multiple dose trials to evaluate the phase of removal and to determine if there is an accumulation of antimony, which would warrant a dose reduction.

Antiproliferative and leishmanicidal effect of ajoene on various Leishmania species: ultrastructural study.

Ajoene [(E,Z)-4,5,9 trithiadodeca 1,6,11 triene 9-oxide], the major bioactive compound derived from garlic, shows a potent trypanolytic and antimicotic activity. In this paper we evaluate its effect on Leishmania mexicana(Lm:MHOM/VE/80/NR), L eishmania mexicana venezuelensis (Lmv: MHOM/VE/80/H16), L eishmania mexicana amazonensis (Lma: M112, IFLA/BR/67/PH8) and L eishmania donovani chagasi (Ldch: MHOM/BR/74/PP75). Ajoene showed a potent leishmanicidal activity in vitro against all species studied. Concentrations higher than 0.3 microM led to total inhibition of growth, and 10 microM induced 100% lysis of Leishmaniaafter 96 h of incubation in a chemically defined culture medium. The 50% inhibitory concentration (IC(50)) for lysis, for all species, was about to 2 microM. The effect was dose-dependent and a threefold increase in concentration (30 microM) produced 100% lysis of cultured forms after 72 h. Ultrastructural studies showed a time- and dose-dependent morphological alteration of the mitochondrial membrane and nuclear envelope, as well as the formation of large autophagic vacuoles.

Índices de sensibilidad insulínica (homa y quicki): en escolares y adolescentes sanos en Valera: estado Trujillo-Venezuela / Insuline sensibility index among healthy children and adolescents in Valera: Trujillo state-Venezuela

La resistencia a la insulina contribuye a la fisiopatología de la diabetes tipo 2 y es la antesala de la obesidad, el síndrome metabólico y muchas enfermedades cardiovasculares, de allí la importancia de su detección temprana. Evaluar el grado de sensibilidad insulinica mediante los índices HOMA y QUICKI y la asociación de la insulinosensibilidad basal con algunas variables biológicas (edad, sexo, estado nutricional). Se realizó un estudio descriptivo de corte transversal en escolares y adolescentes entre 6 y 18 años, entre marzo y julio de 2005. Se calculó el IMC y se emplearon las curvas percentiles de FUNDACREDESA para su categorización. Se extranjeron 5mL de sangre para detectar los valores de glucosa e insulina. La sensibilidad insulínica basal se calculó mediante los índices HOMA [glicemia en ayunas (mmol/l) x insulina en ayunas (mU/l)]/22,5 y QUICKI (1/(Log glicemia ayuno (mg/dl)+Log insulina ayuno (µU/ml). Se calcularon los estadísticos descriptivos y las diferencias fueron estudiadas mediante la prueba Chi², considerando significativo a todo valor de p<0,05. 269 niños tenían peso normal (84,5 por ciento), 29 presentaron sobrepeso (9,11 por ciento) y 20 eran obesos (6,28 por ciento). No se encontró asociación significativa entre la sensibilidad insulínica y el estado nutricional. Hubo diferencia significativa en las glicemias en ayunas entre escolares y adolescentes eutróficos y con sobrepeso (p<0.001). No hubo insulino resistencia en escolares ni adolescentes. El índice HOMA alcanzó un valor cercano a 1, y el índice de QUICKI se mantuvo alrededor de 0,40 independientemente del estado nutricional.

Insulin resistance contributes to the physiopathology of diabetes and is the previous step to obesity, metabolic syndrome and many cardiovascular disease, therefore the importance of its early detection. To evaluate the degree of insulin sensitivity by means of the indexes HOMA and QUICKI and the association with some biological variables (age, gender, nutritional state). The study is descriptive of transverse cut type and included children and adolescents between 6 and 18 years. Body Mass Index was calculated and the categorization was performed by Fundacredesa's charts. Glucose and insulin were measured in blood. Basal insulin sensitivity was calculated by means of the indexes HOMA, [blood fasting sugar (mmol/1) x fasting insulin (mU/1)]/22,5 and QUICKI (1/(Log fasting blood sugar (mg/dl) + Log fasting blood insulin (µU/ml). Descriptive statistic were calculated and differences were studied by means of the test X², considering as significant, values under 0.05. There were 269 children with normal weight (84,5%), 29 were overweight (9,11%) and obese (6,28%). There was no significant association between insulin sensitivity and nutritional state. There were significant differences in fasting blood sugar between normal and overweight children and adolescents (p<0,001). There were neither children nor adolescents with insulin resistance the HOMA index reached a value of 1 and the QUICKI index was near 0,40 independently of the nutritional state.

Influence of gentaminice on the pharmacokinetic of a pentavalent antimonial compound glucantime influence of gentaminice on glucantime kinetic

Se estudiaron los parámetros farmacocinéticos del antimoniato de meglumina Glucantime® después de su administración solo y en combinación con gentamicina, a objeto de determinar el efecto del aminoglucósido sobre las concentraciones plasmáticas y los parámetros farmacocinéticos del metal. Se inyectaron cuatro perros con una dosis única/día de Glucantime® (25.65 mgkg-1) durante 5 días y Glucantime® + gentamicine (25.65 mg kg-1 y 5 mg kg-1, respectivamente). Se colectaron muestras de sangre 0.25, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 y 24.0 horas post-tratamiento. Las determinaciones de antimonio se realizaron usando espectroscopia de absorción atómica. Los resultados demuestran que la combinación modificó la depuración del metal y disminuyó sus concentraciones plasmáticas. Solo ClB mostró una diferencia significativa (0.353 ± 0.110 a 0.733 ± 0.33 mLh-1kg-1), sugiriendo menor persistencia tisular con la administración conjunta. En el futuro debe aclararse si la gentamicina interfiere en el análisis de las concentraciones de antimonio o viceversa.