Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates.

The synthesis of potential "combined prodrugs" where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N4 position of 2',3'-dideoxy-3'-thiacytidine (BCH-189) is described. The anti-HIV-1 activity of 11 analogues which included carboxylic ester or phosphoric ester linkages of PFA or PAA to BCH-189 was determined in MT-4 cells. Of these compounds, the IC50 of analogues 3, 4, 6, and 7 ranged from 0.2 to 100 microM, while IC50 for BCH-189 in this system was 0.1 microM. In vitro hydrolysis of the various esters or amides in human plasma indicated that these agents were relatively stable in the presence of plasma esterases with t1/2 values of up to 120 min. Moreover, lipophilicity of these compounds (partition coefficient) was determined in order to establish correlation between lipophilicity and diffusion of BCH-189 analogues into the cells. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agent BCH-189, but intrinsic anti-HIV-1 activity of some of PAA and PFA adducts, themselves, may also be involved.

Synthesis and antiviral activity of new carbonylphosphonate 2',3'-dideoxy-3'-thiacytidine conjugates.

The synthesis of new potential PFA-BCH-189 conjugate analogues is described and their molecular structure clearly identified through NMR and mass spectra techniques. The anti-HIV-1 activity was determined according to the inhibition of syncytium formation in MT-4 cells, while the anti-HBV activity was determined in infected duck hepatocytes. Both antiviral activities of the PFA-BCH-189 conjugates were much lower than those of the parent BCH-189 (2',3'-dideoxy-3'-thiacytidine) (1). Whereas a prodrug effect, following cleavage and release of the free BCH-189 and PFA, cannot be ruled out, poor cellular permeation of the drug seems to be the most likely reason for the reduced activities against HIV and DHBV. The presence of the PFA moiety appears to be detrimental for both the anti-HIV and anti-DHBV activity of PFA-BCH-189 cases.

A model allowing the design of modified nucleosides as HIV-RT inhibitors.

A chemical, structural, molecular electrostatic potential (MEP) analysis of modified nucleosides allows the understanding of how nucleosides interact with different receptors. The interaction with kinases is sensitive to base modifications, while the interaction with the reverse transcriptase receptor HIV active site is more affected by ribose modifications. The model herein indicates a geometrical lower limit in the width of the modified sugar that corresponds to the 3' erythro position. This characteristic allows one to predict a potential activity of the 3' substituted compounds. The 4'-hydroxymethyl group position with respect to the nucleic base is also important for antiviral activity. The model gives the geometric parameters of this position (related to kinetic effects) that corresponds to an increase in the activation energy required to fit the active site of the kinases and the RT. Our model is compatible with the 3D structure of the HIV RT active site. It allows the design of potent new active compounds where the sugar can be substituted by any group answering to the defined parameters.

[Doppler echocardiographic evaluation of the efficacy of fibrinolytic treatment of pulmonary embolism]. / Evaluation de l'efficacité du traitement fibrinolytique de l'embolie pulmonaire par échocardiographie Doppler.

The efficacy of the fibrinolytic therapy in pulmonary embolism was studied by Doppler echocardiography: the evolution of the cardiac and angiographic changes could be studied in parallel. Thirty patients with severe pulmonary embolism and vascular obstruction greater than 40% (67.2 +/- 9.9%) were examined prospectively by Doppler echocardiography before and after thrombolysis. The following parameters were studied: systolic pulmonary artery pressure calculated from the jet of tricuspid regurgitation and left and right ventricular diameters for the calculation of the ratio of the ventricular dimensions. All patients underwent Doppler echocardiography and pulmonary angiography immediately after thrombolysis. The average improvement of the percentage vascular obstruction was 37%. The hemodynamic and echocardiographic changes were globally favourable. The pulmonary artery systolic pressure fell from 51 +/- 10 to 33 +/- 6.7 to 25.3 +/- 6.3 mm and the ratio of ventricular dimension from 0.87 +/- 0.3 to 0.60 +/- 0.16 (p less than 0.001). Only 4 patients had pulmonary artery systolic pressures over 40 mmHg after therapy compared with 26 before therapy. However, the hemodynamic and angiographic correlations were poor (r = 0.37; p less than 0.001). In the 6 patients in whom treatment was ineffective according to angiographic criteria (less than 20% improvement of vascular obstruction), the echocardiographic changes were small or absent, the improvement in the ratio of ventricular dimensions being less than 20%. However, a satisfactory correlation was observed between the percentage improvement of the ratio of ventricular dimensions and that of vascular obstruction (r = 0.59; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnosis and evaluation of mitral endocarditis complicating obstructive cardiomyopathy using cardiac echo-Doppler]. / Diagnostic et bilan d'une endocardite mitrale compliquant une cardiomyopathie obstructive par écho-Doppler cardiaque.

The authors report a case of mitral endocarditis diagnosed by cardiac echo-Doppler and complicating an obstructive cardiomyopathy (OCM) in a 37-year-old woman. Despite the high degree of sub-aortic obstruction and the existence of an apparently severe mitral leak by Doppler analysis, the patient remained totally asymptomatic and the outcome was favourable with appropriate antibiotics. A review of the literature revealed 11 cases of endocarditis in a context of OCM, documented by echocardiography. Echo-Doppler enables precise evaluation of this grave and often poorly tolerated complication of OCM.

[Massive pulmonary embolism disclosing thrombocytopenia induced by low molecular weight heparin. Therapeutic success of prostacyclin]. / Embolie pulmonaire massive révélant une thrombopénie induite par héparine de bas poids moléculaire. Succès thérapeutique d'une prostacycline.

The authors report a case of massive pulmonary embolism revealing thrombocytopenia induced by a low molecular weight heparin (LMWH) initially proposed for the treatment of superficial phlebitis. The diagnosis was confirmed by in vitro aggregation tests and a fall in the platelet count when the LMWH was reintroduced. The outcome was clinically, angiographically and hematologically satisfactory in response to in situ treatment with prostaglandin, subsequently replaced by Vitamin K antagonists.

[Doppler echocardiography under dipyridamole after thrombolyzed early myocardial infarction. Comparison with coronarographic data]. / Echocardiographie Doppler sous dipyridamole après infarctus du myocarde inaugural thrombolysé. Comparaison aux données de la coronarographie.

The reliability and safety of Doppler echocardiography with dipyridamole (0.84 mg/kg in 10 min) were evaluated in 63 patients an average of 7 days after a thrombolysed early lateral infarct and 24 hours before follow-up coronary arteriography. The aims of the test were the detection of tight stenoses (diameter reduced by more than 75%) affecting the artery responsible for the infarct as well as the other coronary vessels, using the vasodilator action of dipyridamole. The echocardiographic manifestation of induced coronary steal consisted of transitory asynergism in the territory of the artery involved. Clinical tolerability of the test was good. The brief onset of anginal pain was nevertheless seen in 6 patients. Analysis of the zone corresponding to the necrosed area was possible in only 43 cases. Sensitivity of the test for detection of a post-infarction residual stenosis was 64% (39-89) and specificity 90% (79-100). Study of other territories was possible in 59 cases. Sensitivity of the test for the diagnosis of multiple vessel disease was 70% (42-98) and specificity 94% (88-100). In the population as a whole, Doppler study of variations in anterograde mitral flow revealed a sensitivity of 40% (27-53) and specificity of 87% (78-96). Variations in sub-aortic flow were analysed only in the final 27 patients, with a sensitivity and specificity of 100%. The specificity of dipyridamole echocardiography after infarction is good, both for the detection of residual stenosis and that of multiple vessel disease, the chief limiting factor being the impossibility of analysis of the infarcted region in the presence of initial akinesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and biological properties of the four optical isomers of 5-o-carboranyl-2',3'-didehydro-2',3'-dideoxyuridine.

The four isomers of the 5-o-carboranyl-2',3'-didehydro-2',3'-dideoxyuridine (d4CU) were synthesized and their antiviral activity and cytotoxicity in normal and cancer human cells determined. Coupling of silylated 5-o-carboranyluracil with the protected D/L 2,3-dideoxy-2-phenylselenenylribosylacetates provided after oxidative elimination and deprotection, the desired compounds. The presence of the electron deficient 5-o-carboranyl moiety on uracil influenced the yield of the various isomers. In general, the compounds demonstrated weak anti-human immunodeficiency virus activity in primary human lymphocytes. No marked difference in the biological profile was noted for the various optical isomers, suggesting that the high lipophilicity of these nucleosides imparted by the carboranyl moiety overrides stereochemical considerations in the 2',3'-didehydro-2',3'-dideoxyaglycon moiety.