Equivalencia terapéutica in vitro de tabletas de enalapril maleato 20 mg de producción nacional / In vitro therapeutic equivalence of 20 mg enalapril maleate tablets of national production

Los ensayos de equivalencia terapéutica tienen como objetivo demostrar que los medicamentos genéricos aportan la misma cantidad de principio activo en comparación con el medicamento innovador. El objetivo de la investigación fue evaluar la equivalencia terapéutica del medicamento enalapril maleato en tabletas de 20 mg, según la clasificación biofarmacéutica que le corresponde, ya que este es un medicamento representativo de la clase III, para demostrar que tienen un perfil de tolerabilidad adecuado y que son eficaces para su prescripción médica. Por otro lado, al demostrarse la equivalencia terapéutica se puede recurrir con toda seguridad al medicamento genérico y reducir los costos de los tratamientos, con lo cual la población tendrá una oferta de medicamentos confiables, seguros y a precios económicos. Se utilizó un medicamento innovador y tres de los ocho medicamentos genéricos de fabricación y comercialización nacional, a los cuales se les determinó perfiles de disolución (F2: 45.41, 92.42, 71.04), uniformidad de contenido (AV: 7.37, 2.97, 2.50) y valoración de principio activo (%: 107.14, 98.89, 101.71) para determinar la cantidad de principio activo en las muestras. Los análisis se realizaron con base en los criterios establecidos en la Farmacopea de los Estados Unidos. Se aplicó un modelo estadístico independiente, y se estableció que dos de los tres lotes analizados de los medicamentos genéricos son equivalentes terapéuticos con el lote del medicamento innovador. Con las pruebas de disolución in vitro realizadas a lo largo de este estudio, se puede concluir que los tres lotes analizados de dos medicamentos genéricos pueden ser considerados intercambiables con respecto al lote del medicamento innovador.

The therapeutic equivalence essays to demonstrate that generic medicine can provide the same amount of active ingredient compared to the innovative medicine. The objective of this research was to evaluate the therapeutic equivalence of enalapril maleate 20 mg, according to the biopharmaceutical classification, given that this is a representative class III drug. This to demonstrate that it has an acceptable tolerability profile and that it is effective for medical prescription. Once the therapeutic equivalence is stablished, the use of therapeutic bioequivalence products can reduce treatment costs, so that the general public can have access to reliable, safe and affordable medicines. For this study an innovative medicine and three of the eight generic medicines of national manufacture and commercialization were used for each medicine, the dissolucion profiles (F2: 45.41, 92.42, 71.04), the uniformity of content (AV: 7.37, 2.97, 2.50) and percentage of active ingredient (%: 107.14, 98.89, 101.71) were determined. The essays were performed based on the criteria established in The United States Pharmacopeia and were satisfactory in all the analyzed batches. An independent statistical model was carried out it was established, that two of the three analyzed batches for generic medicine are therapeutic equivalents with the batch of the innovative drug. In vitro dissolution tests obtained throughout this study, concluded that the three analyzed batches of two generic medicines can be considered interchangeable in respect to the batch of the innovative medicine.

Intracardiac tromboembolism during liver transplantation. / Tromboembolismo intracardíaco durante trasplante hepático.

We describe a case of intraoperative cardiac trombosis during orthotopic liver transplant surgery that resulted in intraoperative death. By using transesophageal echocardiography, the cause of the descompensation of the patient could be determined and the mechanism of trombus migration from thrombi from the venous circulation to the left heart was accurately observed.

Systemic air embolism as a complication of percutaneous computed tomography guided transthoracic lung biopsy.

A 57-year-old man underwent prone position computed tomography (CT) guided percutaneous transthoracic lung biopsy. After removal of the 18-gauge biopsy needle, the patient lost consciousness and developed shock. CT showed signs of air embolism in descending aorta and left atrium. Cardiopulmonary resuscitation was unsuccessful. A postmortem CT scan confirmed a massive air embolism in the descending aorta, left ventricle and brain. Systemic air embolism occurs in around 0.001-0.003% of lung biopsy procedures. Recommendations to reduce the risk include requesting the patient to stop breathing during the procedure and preventing the exposure of the outer cannula of a coaxial biopsy needle to the atmosphere.

Synthesis and biological activity of fluorinated combretastatin analogues.

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.

Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity.

In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 microM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.

Reversible carnitine palmitoyltransferase inhibitors with broad chemical diversity as potential antidiabetic agents.

A series of carnitine related compounds of general formula XCH(2)CHZRCH(2)Y were evaluated as CPT I inhibitors in intact rat liver (L-CPT I) and heart mitochondria (M-CPT I). Derivative 27 (ZR = -HNSO(2)R, R = C(12), X = trimethylammonium, Y = carboxylate, (R) form) showed the highest activity (IC(50) = 0.7 microM) along with a good selectivity (M-CPT I/L-CPTI IC(50) ratio = 4.86). Diabetic db/db mice treated orally with 27 showed a significant reduction of serum glucose levels.

Formation of micelles and liposomes from carnitine amphiphiles.

Esterification of the carboxy and/or the hydroxy groups of (R)-carnitine (3-hydroxy-4-trimethylammonium butanoate) produces interesting classes of (cationic or zwitterionic) surfactants whose CMC values are in general predictable from their molecular structure. In fact similar relationships between CMC and the number of carbon atoms, Cn, have been found for three classes of such surfactants. However the sensitivity of CMC to Cn for the diesters is considerably lower than that calculated from literature values for the monoesters (either in their cationic or zwitterionic forms). The CMC values for the diesters have been determined by tensiometric, conductimetric and spectrophotometric methods, both in pure water and in 0.154 M NaCl solutions, at 25 degrees C. In particular the tensiometric results provide evidence that double-chain diesters undergo self assembly into structures more complex than simple micelles if the two chains are of comparable length. EPR and electron microscopy experiments show that the aggregates spontaneously formed by these surfactants are a mixture of multilamellar vescicles.

L-carnitine esters as "soft", broad-spectrum antimicrobial amphiphiles.

A new class of antimicrobial, "soft", quaternary ammonium l-carnitine esters, of the type (CH3)3N+-CH2-CHOCO(R1)-CH2-COO(R2) Cl-, has been designed, with R1 and R2 being in general long-chain alkyl substituents. The series shows good activity against a wide range of bacteria, yeasts, and fungi. Lipophilicity has been measured by RP-HPLC method to give the logarithm of the experimental capacity factor (log k'), and a quantitative relationship has been determined between log k' and the theoretical partition coefficient (CLOGP); also, bond-dipole descriptors have been introduced into calculations by accounting for polar moieties present within the apolar cores of the molecules, giving a more refined calculated capacity factor (log k'calcd). Finally the latter has been related to the antimicrobial activity (MIC values). The proposed models are predictive for the best broad-spectrum antimicrobial compound within the series.

[Pollution by mites and/or mold spores in work environments and the risk of occupational respiratory pathology]. / Inquinamento da acari e/o micofiti in ambienti di lavoro e rischio di patologia respiratoria professionale.

In recent years the measurement of mold spore concentrations in working environments where workers spend long periods of time has acquired considerable importance because of the diffusion of diseases caused by fungi. On this basis, the aim of the research was to evaluate the level of environmental fungal pollution and contamination by mites in three factories producing seasoned foods, i.e., hams, sausages and cheeses. We also studied the occurrence of fungal species in the upper respiratory tract of workers operating in the washing and brushing areas, which was compared with the environmental concentrations in these areas, where contamination with fungal spores was visibly high. The results showed high and widespread fungal pollution in most of the working environments sampled and a significant presence of the same species in the upper respiratory tract of the workers. The data obtained indicate that the environments sampled can constitute a possible health risk factor for workers.

Effect of the addition of electrolytes on the partition coefficients, activity coefficients, and acid dissociation constants of carnitine and its acetyl and propionyl derivatives.

The partition coefficients, P, between n-octanol and water of carnitine, acetylcarnitine, propionylcarnitine, and tetraethylammonium pentacyanopropenides have been determined spectrophotometrically at 20 degrees C. The value of P increases upon addition of electrolytes, the increase produced by LiCl being particularly high. The carnitine cations are 'salted-out' by electrolytes as shown by the variation of their 'single-ion' activity coefficients (relative to that of the tetraethylammonium ion) with electrolyte concentration. These cations are appreciably more hydrated than the reference tetraethylammonium ion. The considered carnitine cations are at least one pKa (where Ka is the acid dissociation constant) unit more acidic than butanoic acid in water at 25 degrees C. Electrolyte addition somewhat increases the pKa of these cationic acids.

The influence of fetal calf serum on interferon-gamma induced HLA-DR expression on U937 cells.

The induction of HLA-DR antigen expression on U937 cells by interferon-gamma (IFN-gamma) is positively influenced by amount of fetal calf serum (FCS) added to the tissue culture medium. A transient alkalinization of FCS before its addition to the medium, dramatically decreased the immunomodulating activity of IFN-gamma. FCS was also found to be a dose-dependent enhancer of the IFN-gamma-induced 2',5'-oligoadenylate (2-5A) synthetase production. Our findings suggest the need for a serum factor(s), labile at basic pH values, to support at least two of the multiple IFN-gamma activities.

Flow cytometric indirect immunofluorescence assay with high sensitivity and specificity for the detection of antibodies to HSV-1 and HSV-2.

Cells infected with HSV-1 or HSV-2 develop viral antigens which can be detected by immunofluorescence. We developed a flow cytometric indirect immunofluorescence assay to detect and quantitate antibodies to HSV-1 and HSV-2 in human sera. Results obtained by flow cytometry for detecting antibodies against HSV-1, when compared with results obtained by ELISA, showed an index of overall agreement of 100%. The correlation between the antibody titers obtained with each method was found to be highly significant. An index of overall agreement equal to 94.1% was observed between results obtained by flow cytometry and by immunofluorescence as concerns the discrimination of HSV-2 positive from negative samples. However, the correlation between antibody titers was found to be not statistically significant. The flow cytometric assay proved to be type-specific.

Semisynthetic beta-lactam antibiotics. III. Cephalosporin derivatives in the furyl series. Chemical and microbiological properties.

The synthesis of a series of 7-acylamido cephalosporins having a substituted furyl moiety in the side chain is described. These new cephalosporins were examined in vitro for antibacterial activity and evaluated for resistance to inactivation by beta-lactamases.

Semisynthetic beta-lactam antibiotics. II Cephalosporin derivatives in the naphthalene series. Chemical and microbiological properties.

A seris of new 7-acylamidocephalosporins, containing a substituted naphthalene moiety in the side chain, has been prepared and tested for their in vitro antibacterial activity. Some observations are made on the structure-activity relationships.

Synthesis of 7-acylamidodesacetoxycephalosporanic acids and corresponding pivaloyloxymethyl esters. Chemical and microbiological properties.

A series of 7-acylamidodesacetoxycephalosporanic acids and analogous pivaloyloxymethyl esters have been prepared and tested in vitro for antibacterial activity. Those acids which exhibited a significant in vitro activity, were also studied in vivo and compared with the corresponding esters. Experiments performed on laboratory animals showed that, after oral administration, the esters were absorbed more efficiently than the corresponding acids.