Bioequivalencia de una dosis de levofloxacina de laboratorios Leti (LL) comprimidos de 500 mg frente a levofloxacina de laboratorios sanofi aventis: tavanic® (LSA) tabletas de 500 mg, administrados en dosis única en voluntarios sanos / Bioequivalence of a dose of levofloxacin Leti laboratories (LL) tablets of 500 mg versus levofloxacin Sanofi Aventis laboratorie: tavanic® (LSA) tablets of 500 mg administered in single dose in healthy volunteers

Evaluar la Bioequivalencia en 12 voluntarios sanos de la Levofloxacina de Laboratorios LETI (LL) comprimidos de 500 mg en dosis única, producto test, con la del producto de referencia: Levofloxacina de Laboratorios SANOFI AVENTIS, Tavanic® (LSA) tabletas de 500 mg. El grupo test recibió un comprimido de Levofloxacina de Laboratorios LETI (LL) de 500 mg, y el grupo de referencia recibió una tableta de Levofloxacina de Laboratorios SANOFI AVENTIS: Tavanic® (LSA) de 500 mg. Terminada esta primera fase de tratamiento, los voluntarios no recibieron medicación por 6 días consecutivos (período de lavado). Luego se procedió al cruce de los tratamientos, los voluntarios del grupo test recibieron la medicación del grupo referencia y viceversa. La extracción de sangre venosa se realizó a la hora 0, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8, 14, 18 y 24 horas. Se determinaron los niveles plasmáticos de Levofloxacina de las muestras plasmáticas procedentes del estudio clínico, mediante el método cromatográfico por HPLC desarrollado y validado. Se obtuvo una Cmax de 1253.40+/-562.58 μg/mL para LL vs. 1317.42+/-439.64 μg/mL para LSA, el AUC0-24 fue de 9188.43+/-2406.64 μg/mL/h vs 8780.22+/-2305.99 μg/mL/h; y para el AUC0-∞ el resultado fue de 9933.17+/-2488.52 μg/mL/h vs. 9433.47+/-2399.71 μg/mL/h respectivamente. Las medias y sus intervalos de confianza para la Cmax y el AUC0-24 y AUC0-∞ se mantuvieron en los rangos aceptados para la demostración de bioequivalencia. Ambos productos son bioequivalentes y por lo tanto intercambiables.

To evaluated the bioequivalence in 12 healthy volunteers of the LETI Laboratories Levofloxacin (LL) tablets 500 mg single dose, test product with the product Reference: SANOFI AVENTIS Laboratories Levofloxacin, Tavanic® (LSA) 500 mg tablets. The test group received one tablet of levofloxacin LETI Laboratories (LL) of 500 mg, and the control group received a tablet Levofloxacin SANOFI AVENTIS Laboratories: Tavanic® (LSA) of 500 mg. After this first treatment phase, volunteers received no medication for 6 consecutive days (washout period). Then he proceeded to the crossing of the treatments, the volunteers of the group test group received the medication reference and viceversa. The venous blood collection was performed at time 0, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8, 14, 18 and 24 hours. We determined plasma levels of levofloxacin in plasma samples from the clinical study, using HPLC chromatographic method developed and validated. Cmax of 1253.40 + / -562.58 μg/mL for the LL vs. 1317.42 + / -439.64 μg/mL for LSA, the AUC0-24 was 9188.43 + / -2406.64 μg/mL/h vs. 8780.22 + / -2305.99 μg/mL/h, and the AUC0-∞ the result was 9933.17 + / -2488.52 μg/mL/h vs. 9433.47 + / -2399.71 μg/mL/h, respectively. The mean and confidence intervals for Cmax and AUC0-24 and AUC0-∞ were maintained in the range accepted for the demonstration of bioequivalence. Both products are bioequivalent and therefore interchangeable.

Bioequivalencia de una dosis de levofloxacina de laboratorios Leti: proxime® (LL) comprimidos de 500 mg frente a levofloxacina de laboratorios Sanofi Aventis: tavanic® (LSA) tabletas de 500 mg, administrados en dosis única en voluntarios sanos / Bioequivalence of dose of levofloxacin Leti laboratories: proxime® (LL) 500 mg tablets of levofloxacin aganist Sanofi Aventi: tavanic® (LSA) 500 mg tablets given as a single dose in healthy volunteers

Evaluar la Bioequivalencia en 12 voluntarios sanos de la Levofloxacina de Laboratorios LETI: Proxime® (LL) comprimidos de 500 mg en dosis única, producto test, con la del producto de referencia: Levofloxacina de Laboratorios SANOFI AVENTIS, Tavanic® (LSA) tabletas de 500 mg. El grupo test recibió un comprimido de Levofloxacina de Laboratorios LETI: Proxime® (LL) de 500 mg, y el grupo de referencia recibió una tableta de Levofloxacina de Laboratorios SANOFI AVENTIS: Tavanic® (LSA) de 500 mg. Terminada esta primera fase de tratamiento, los voluntarios no recibieron medicación por 6 días consecutivos (período de lavado). Luego se procedió al cruce de los tratamientos, los voluntarios del grupo test recibieron la medicación del grupo referencia y viceversa. La extracción de sangre venosa se realizó a la hora 0, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8, 14, 18 y 24 horas. Se determinaron los niveles plasmáticos de Levofloxacina de las muestras plasmáticas procedentes del estudio clínico, mediante el método cromatográfico por HPLC desarrollado y validado. Se obtuvo una Cmax de 1253.40+/-562.58 para la LL vs. 1317.42+/-439.64 para LSA, el AUC 0-24 fue de 9188.43+/-2406.64 vs 8780.22+/-2305.99; y para el AUC 0-∞ el resultado fue de 9933.17+/-2488.52 vs. 9433.47+/-2399.71 respectivamente.Las medias y sus intervalos de confianza para la Cmax yel AUC 0-24 y AUC 0-∞ se mantuvieron en los rangos aceptados para la demostración de bioequivalencia. Ambos productos son bioequivalentes y por lo tanto intercambiables

To evaluated the bioequivalence in 12 healthy volunteers of the LETI Laboratories Levofloxacin: Proxime® (LL) tablets 500 mg single dose, test product with the product Reference: SANOFI AVENTIS Laboratories Levofloxacin, Tavanic® (LSA) 500 mg tablets. The test group received one tablet of levofloxacin LETI Laboratories: Proxime® (LL) of 500 mg, and the control group received a tablet Levofloxacin SANOFI AVENTIS Laboratories: Tavanic® (LSA) of 500 mg. After this first treatment phase, volunteers received no medication for 6 consecutive days (washout period). Then he proceeded to the crossing of the treatments, the volunteers of the group test group received the medication reference and viceversa. The venous blood collection was performed at time 0, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8, 14, 18 and 24 hours. We determined plasma levels of levofloxacin in plasma samples from the clinical study, using HPLC chromatographic method developed and validated. Cmax of 1253.40 + / -562.58 for the LL vs. 1317.42 + / -439.64 for LSA, the AUC 0-24 was 9188.43 + / -2406.64 vs. 8780.22 + / -2305.99, and the AUC 0-∞ the result was 9933.17 + / -2488.52 vs. 9433.47 + / -2399.71, respectively. The mean and confidence intervals for Cmax and AUC 0-24 and AUC 0-∞ were maintained in the range accepted for the demonstration of bioequivalence. Both products are bioequivalent and therefore interchangeable

In vitro activities of ER-119884 and E5700, two potent squalene synthase inhibitors, against Leishmania amazonensis: antiproliferative, biochemical, and ultrastructural effects.

ER-119884 and E5700, novel arylquinuclidine derivatives developed as cholesterol-lowering agents, were potent in vitro growth inhibitors of both proliferative stages of Leishmania amazonensis, the main causative agent of cutaneous leishmaniasis in South America, with the 50% inhibitory concentrations (IC(50)s) being in the low-nanomolar to subnanomolar range. The compounds were very potent noncompetitive inhibitors of native L. amazonensis squalene synthase (SQS), with inhibition constants also being in the nanomolar to subnanomolar range. Growth inhibition was strictly associated with the depletion of the parasite's main endogenous sterols and the concomitant accumulation of exogenous cholesterol. Using electron microscopy, we identified the intracellular structures affected by the compounds. A large number of lipid inclusions displaying different shapes and electron densities were observed after treatment with both SQS inhibitors, and these inclusions were associated with an intense disorganization of the membrane that surrounds the cell body and flagellum, as well as the endoplasmic reticulum and the Golgi complex. Cells treated with ER-119884 but not those treated with E5700 had an altered cytoskeleton organization due to an abnormal distribution of tubulin, and many were arrested at cytokinesis. A prominent contractile vacuole and a phenotype typical of programmed cell death were frequently found in drug-treated cells. The selectivity of the drugs was demonstrated with the JC-1 mitochondrial fluorescent label and by trypan blue exclusion tests with macrophages, which showed that the IC(50)s against the host cells were 4 to 5 orders of magnitude greater that those against the intracellular parasites. Taken together, our results show that ER-119884 and E5700 are unusually potent and selective inhibitors of the growth of Leishmania amazonensis, probably because of their inhibitory effects on de novo sterol biosynthesis at the level of SQS, but some of our observations indicate that ER-119884 may also interfere with other cellular processes.

Quinuclidine derivatives as potential antiparasitics.

There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.

Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole.

There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca(2+) homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca(2+) homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.

In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi.

Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K(i) values in the low nanomolar to subnanomolar range in the absence or presence of 20 microM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.

Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi.

We present the results of the first detailed study of the molecular and cellular basis of the antiproliferative effects of the bisphosphonate risedronate (Ris) on Trypanosoma cruzi, the causative agent of Chagas' disease. Ris and related compounds, which block poly-isoprenoid biosynthesis at the level of farnesyl pyrophosphate synthase, are currently used for the treatment of bone resorption disorders, but also display selective activity against trypanosomatid and apicomplexan parasites. Ris induced a dose-dependent effect on growth of the extracellular epimastigote form of T. cruzi; complete growth arrest and cell lysis ensued at 150 microM. Growth inhibition was associated with depletion of the parasite's endogenous sterols, but complete growth arrest and loss of cell viability took place before full depletion of these compounds, suggesting that disappearance of other essential poly-isoprenoids is involved in its anti-parasitic action. Ris had a variety of effects on cellular ultrastructure, including mitochondrial swelling, disorganisation of other organelles, such as reservosomes and the kinetoplast, together with the appearance of autophagic vesicles and progressive vacuolization of the cytoplasm. Ris had selective antiproliferative effects against the clinically relevant amastigote form of T. cruzi, and at 100 microM, was able to prevent completely the development of T. cruzi infection of murine muscle heart or Vero cells, and to cure cultures which were already infected. Ris induced drastic ultrastructural alterations in the intracellular parasites and blocked amastigote to trypomastigote differentiation, with no biochemical or ultrastructural effects on the host cells, which fully recovered their normal structure and activity after treatment. Ris is, therefore, a promising lead compound for the development of new drugs against T. cruzi.