Aims To examine whether the antidepressant venlafaxine, a novel serotoninnoradrenaline re-uptake inhibitor (SNRI), can modify a-adrenoceptor-mediated venoconstriction in man. The effects of venlafaxine were compared with those of desipramine, a tricyclic antidepressant with noradrenaline uptake inhibiting properties, and paroxetine, a selective serotonin re-uptake inhibitor (SSRI), on noradrenalineand methoxamine-evoked venoconstriction using the dorsal hand vein compliance technique. Methods Fifteen healthy male volunteers participated in five weekly experimental sessions. Each session was associated with a clinically effective dose of an antidepressant or placebo. The following oral dosages were used: venlafaxine 75 mg, venlafaxine 150 mg, desipramine 100 mg, paroxetine 20 mg, or placebo. A doubleblind, cross-over, balanced design was used. In each session, dose-response curves to both locally infused noradrenaline acid tartrate (0.1-33.33 ng min Conclusions These results show that, similarly to desipramine 100 mg, venlafaxine 150 mg can potentiate venoconstrictor responses to noradrenaline, consistent with venlafaxine's ability to block noradrenaline uptake in man. The importance of noradrenaline uptake blockade in these observations is confirmed by the lack of effect of the antidepressants on methoxamine-evoked venoconstriction and the failure of paroxetine to modify noradrenaline-evoked venoconstriction.
The effects of a single oral dose (100 mg) of amitriptyline on noradrenaline- and methoxamine-evoked venoconstriction were compared, using the dorsal hand vein compliance technique, in 8 healthy male volunteers. Both noradrenaline and methoxamine produced dose-dependent venoconstriction; the geometric mean ED50 for noradrenaline was 4.15 ng min-1 and for methoxamine was 1143.54 ng min-1; the potency ratio (noradrenaline/methoxamine) was 277. Amitriptyline shifted the dose-response curve for noradrenaline to the left (ANOVA: P < 0.025; dose-ratio: 0.38) consistent with potentiation, and the dose-response curve for methoxamine to the right (ANOVA: P < 0.025; dose ratio: 2.72) consistent with antagonism. The potentiation is likely to be due to noradrenaline uptake blockade, whereas the antagonism is likely to reflect the blockade of post-junctional alpha 1-adrenoceptors.
Using the stem cell survival model and a detailed computerized man model, distribution effectiveness factors (DEF) have been estimated for the bone marrow system for proton exposure conditions typical of manned space flight. The DEF is a dose-modifying factor which attempts to provide a common basis for risk assessment for some body organs under differing radiation depth-dose patterns. The regime of parameters for which the effect of nonuniform dose distribution in bone marrow may be significant is indicated. It is concluded that the DEF can be neglected for typical manned missions in low earth orbit, except possibly for the combination of relatively large doses, (greater than 40 rads) and relatively soft proton spectra.
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