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A volunteer participating in a study of eproxindine, a new antiarrhythmic agent, had a sudden cardiorespiratory arrest and died. Subsequently it became known that he had received a depot injection of flupenthixol on the day before his death; an interaction between these two drugs seems likely. This incident illustrates that it is impossible to guarantee absolute safety in volunteer studies if details of medical history are withheld.

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Twenty-four subjects participated in this placebo-controlled, double-blind study. Eighteen were randomized to receive active enoxacin capsules (400 mg twice daily for 14 days) and the remaining six received placebo therapy. Steady state was reached in four days or less, with an average minimum concentration of 1.25 mg/l and the average concentration achieved 1.5 h after the dose was 3.53 mg/l. Five of 18 (28%) subjects who received active enoxacin and two of six (33%) subjects who received placebo reported adverse events, which were generally mild and of short duration. No rash or pruritus were reported. Haematology, biochemistry and urinalyses revealed no untoward effect.

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In a double-blind, placebo-controlled three-way cross over study, the efficacy of Ro 15-1788 200 mg, a new benzodiazepine antagonist, in blocking the amnesic, cognitive, psychomotor and subjective effects of diazepam 20 mg, was investigated in a group of six healthy male volunteers. The amnesic effects of diazepam were markedly attenuated by the combined administration of Ro 15-1788. The psychomotor and subjective effects of diazepam by mouth were most pronounced 2.5 h after administration. Concurrent oral administration of Ro 15-1788 completely prevented these effects at 2.5 h. Plasma diazepam concentrations observed after administration of the combination of diazepam and the antagonist did not differ from those observed following diazepam alone.

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Changes in platelet serotonin uptake and content were investigated following administration of a single oral dose of 3-cyano-imipramine to healthy volunteers. The uptake of 3H-serotonin by platelets harvested from these subjects was almost completely inhibited 4 h after dose administration. This inhibition continued for at least 24 h. Plasma taken from the subjects inhibited the uptake of 3H-serotonin by platelets isolated from non-treated subjects. A small but significant reduction in platelet serotonin content was observed 3.75 h after dosing and was still evident after 24 h.

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PK 5078 is a recently developed compound which inhibits specifically the neuronal reuptake of serotonin and enhance its release. PK 5078 was administered to healthy male volunteers in single and multiple oral doses and the effects on platelet serotonin uptake and content were examined. A significant dose-related inhibition of 3H-serotonin uptake by platelets was observed following single oral doses of PK 5078 (25-150 mg), with maximal inhibition at 75 mg. This was evident 2 h after dosing and was still marked after 10 h. Plasma collected from the subjects after dosing also had a considerable dose-related effect on the uptake of 3H-serotonin by untreated platelets. No significant alteration in platelet serotonin content was observed after single doses of PK 5078. When PK 5078 (50 mg) was administered twice daily for 9 days there was a rapid and sustained reduction in 3H-serotonin uptake by platelets, which returned to pretreatment levels 2 days after discontinuation of the drug. A similar response was observed when plasma from these subjects was incubated with untreated platelets. The rate of depletion of endogenous platelet serotonin was much slower with minimum levels being attained on the morning after the final dose. The recovery following withdrawal was also slow with serotonin levels approaching pre-dose values 14 days after the final dose of PK 5078.

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In a double blind, placebo-controlled study the effects of daily oral administration of 3-cyano-imipramine on the 3H-serotonin uptake capacity of platelets were investigated in healthy volunteers. The initial dose was 1 mg, rising to 3 mg daily for 7 days. A rapid and profound inhibition of 3H-serotonin uptake was observed in platelets isolated from the treated subjects. During repeated administration, uptake was reduced to less than 10% of pre-drug values. Five days after the final dose uptake had only partially recovered, to 53% of pre-drug values. A similar inhibition profile was observed when serum from the treated subjects was incubated with normal platelets and 3H-serotonin. The results establish 3-cyano-imipramine as a potent inhibitor of platelet serotonin uptake in humans.

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The benzodiazepines are typified by a profile of side effects which includes drowsiness, ataxia and incoordination. Ro 15-1788, an imidazodiazepine derivative, exhibits marked antagonism of the behavioural and biochemical effects of the benzodiazepines in animals and man. It is devoid of any behavioural activity in animals, except at very high doses. In the present study the effects of single rising oral doses of Ro 15-1788 on cognitive, psychomotor and subjective function in man have been assessed using a battery of psychometric tests designed to identify the sedative action of the benzodiazepines. At all doses up to 600 mg, Ro 15-1788 demonstrated none of the classical behavioural effects of the benzodiazepines.

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1 In a double-blind, placebo controlled study, the efficacy of Ro 15-1788, a new benzodiazepine antagonist, in blocking the cognitive, psychomotor and subjective effects of diazepam, was investigated in a group of six healthy male volunteers. 2 The central effects of orally administered diazepam (40 mg) were most pronounced 1 h after dosing and persisted for 9 h with decreasing severity. 3 Concurrent oral administration of Ro 15-1788 (200 mg) completely prevented the impairment in cognitive and psychomotor function observed after diazepam alone. 4 The duration of action of Ro 15-1788 was shorter than that of diazepam. 5 Plasma diazepam levels after administration of the diazepam/antagonist combination were very similar to those observed following diazepam alone.

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Experiments are presented to determine whether Rana pipiens gastrula cells differentiate in vitro as they do in vivo with respect to rate, morphology and spreading characteristics. Comparisons are made between presumptive germ layer cells isolated at late blastula, cultured for 24 h, and the same cell types form late gastrula cultured for 1 h (LeBlanc and Brick, 1981a). These cells are chronologically similar and should be morphologically similar at the end of their respective culture periods if in vivo and in vitro differentiation are proceeding in the same direction and rate. Five hour cultures of the same cell types were compared to 1 h cultures in media with enhanced Ca2+ (LeBlanc and Brick, 1981b) to study the role of Ca2+ as a modulator of spreading and production of cell protrusions, and the rate at which these occur, as these relate to morphogenetic movements. The data and inferences can be summarized as follows: (1) Some Rana pipiens late blastula and gastrula cells appear to differentiate morphologically in vitro similarly to their differentiation in vivo. (2) In vitro differentiation is autonomous indicating that determination occurred prior to late blastula, mid-gastrula or late gastrula depending on when cells were isolated. (3) The presence of two sub-populations is some germ layer cell isolate indicates determinative interactions had occurred prior to isolation. (4) Morphologic similarity of cells in standard culture for 5 h to the same cells in culture with additional Ca2+ for 1 h suggests that Ca2+ modulates spreading and projection formation and the rate at which these occur. (5) The upper cell surface of these cells may provide adhesive sites for plasmalemma projections from adjacent cells.

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50 patients with actinic keratosis were studied over four months of treatment with either etretinate ('Tigason') or placebo. Each treatment was given for two months and the order of administration was randomised. The clinical response to treatment was assessed by direct measurement and photographs of the lesions at monthly intervals. Of the 44 patients who completed treatment with etretinate 37 had a complete or partial response. Of the 42 patients who completed treatment on placebo only 2 showed a complete or partial response. The response to treatment occurred within the first month of therapy and was maintained even when the dose was reduced because of toxicity.

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Cell locomotion involves several structural-functional activities: membrane extensibility, microfilament regulation and adhesive interactions. There is evidence for Ca2+ requirement in all of these. Our data may clarify the role of Ca2+ in locomotion and adhesion. Morphologic and spreading responses of isolated blastula--late gastrula Rana pipiens germ layer cells to varying molar concentrations of Ca2+; 0-Ca2+, Standard Ca2+ (Barth's X solution), 1.5 x and 2.0 x Std Ca2+ were viewed by S.E.M. after 1 h in culture. Ionic strength and pH were constant. All cells showed quantitative relationships between Ca2+ concentration and surface extensibility, projection formation and presumably adhesion, but with tissue- and stage-specific variations. Cells in Ca2+-free medium fail to adhere (50%), flatten or form surface projections. Cells in media with increasing Ca2+ generally formed more numerous and extensive surface projections, spread and adhered to a greater extent. In some cases there were no quantitative differences in response between 1.5x and 2.0x standard Ca2+. Cells in suspension for 1 h in standard solution remained spherical, forming no projections. We infer from these results that both Ca2+ and contact with a physical substratum, cell--cell of cell--glass are required for mobilization of the various systems involved in locomotion and adhesion. In addition, components of these systems are quantitatively activated by increased availability of Ca2+.

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By means of SEM we have examined spreading and adhesive behavior of cells isolated from superficial and deep regions of germ layers from blastula to late gastrula in Rana pipiens embryos. Each of the cell populations sampled show adhesive and spreading characteristics distinctive for each region and stage which we interpret as demonstrating the following: (1) From blastula through late gastrula, cells from each region have already acquired the ability to express surface morphologic and adhesive features independently of their association with their neighbors, i.e. autonomously. (2) The distinctive spreading and adhesive characteristics for each tissue sub-population suggest kinetic properties seemingly related to their in vivo morphogenetic movements, epiboly or invagination. (3) The appearance within germ layers of two subpopulations between blastula to mid-gastrula, suggests early intratissue inductive interactions. (4) The outermost, superficial cells from each germ layer show proximal and distal surface differences which may reflect adhesive differentials as postulated by Steinberg (1970) for presumptive ectoderm cells. (5) With the exception of superficial cell proximal and distal differentiation, freshly disaggregated cells do not show morphologic characteristics seen in corresponding cells spreading for one hour.

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