The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

Mifepristone in Italy: the case of a drug trapped between ethics and clinical practice

In Italy mifepristone is not yet marketed. Gynaecologists in our hospital asked to use this medication as a less traumatic method for voluntary abortions. We followed the standard procedure defined by the Italian Health Ministry (IMH) for purchasing drugs from abroad but encountered several unexpected barriers. Starting from this case, this paper is aimed at identifying these barriers which we found to be not only professional, but also ethical, religious and moral.     

Cadmium induction of renal and hepatic ornithine decarboxylase activity in the rat. Effects of sex hormones and involvement of the renin-angiotensin system.

We investigated the effect of sex hormones on the sex-dependent response of rat kidney ornithine decarboxylase (ODC) activity to cadmium (Cd) administration and the involvement of the renin-angiotensin system in mediating stimulation of the liver enzyme by the metal. The response of renal ODC to Cd, which occurs in intact adult males but not in females, is also detectable in prepubertal and castrated males. Upon treatment with 17 beta-estradiol, the basal levels of enzyme activity in intact or castrated adult males were enhanced and Cd administration failed to increase them further. In adult females the kidney enzyme became responsive after ovariectomy. Also, in prepubertal females renal ODC was induced by Cd, and this was prevented by treatment with 17 beta-estradiol. Under the same conditions, changes in the levels of Cd accumulation within the kidney, that might account for variations in the response of ODC activity, did not occur. Cd caused an increase in renin activity starting minutes after its injection. Captopril, which specifically inhibits the conversion of angiotensin I to angiotensin II, prevented completely the induction of liver ODC by this metal; stimulation of the enzyme by Co was not affected by the drug. A similar inhibitory effect was exerted by propranolol. Adrenalectomy had no influence on the response of hepatic ODC to Cd; the decarboxylase was unaffected by aldosterone administration. It is suggested that Cd may induce liver ODC through the increase in angiotensin II following stimulation of renin by the metal.     

Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia.

BACKGROUND: Metabotropic glutamate receptors (mGlus) may be involved in the pathophysiology of schizophrenia. Group II mGlus (mGlu2 and mGlu3) have attracted considerable interest since the development of potent specific agonists that exhibit atypical antipsychotic-like activity and reports of a genetic association between the mGlu3 gene and schizophrenia. METHODS: In this postmortem study, mGlu3 protein levels in Brodmann area 10 of prefrontal cortex from schizophrenic (n = 20) and control (n = 35) subjects were analyzed by western immunoblotting using a novel specific mGlu3 antibody and an antibody for the vesicular glutamate transporter 1 (VGluT1). RESULTS: We report a significant decrease in the dimeric/oligomeric forms of mGlu3 in schizophrenic patients compared with control subjects, whereas total mGlu3 and VGluT1 levels were not altered significantly. CONCLUSIONS: This is the first experimental evidence that mGlu3 receptor levels are altered in schizophrenia and supports the hypothesis that neurotransmission involving this particular excitatory amino acid receptor is impaired in schizophrenia.