[Hyperprolactinemic ovulation disorders].

Cytochrome P450 (P450) 3A4, the major catalyst involved in human drug oxidation, displays substrate- and reaction-dependent homotropic and heterotropic cooperative behavior. Although several models have been proposed, these mainly rely on steady-state kinetics and do not provide information on the contribution of the individual steps of P450 catalytic cycle to the observed cooperativity. In this work, we focused on the kinetics of substrate binding, and the fluorescent properties of bromocriptine and alpha-naphthoflavone allowed analysis of an initial ligand-P450 3A4 interaction that does not cause a perturbation of the heme spectrum. The binding stoichiometry for bromocriptine was determined to be unity using isothermal titration calorimetry and equilibrium dialysis methods, suggesting that the ligand bound to the peripheral site during the initial encounter dissociates subsequently. A three-step substrate binding model is proposed, based on absorbance and fluorescence stopped-flow kinetic data and equilibrium binding data obtained with bromocriptine, and evaluated using kinetic modeling. The results are consistent with the substrate molecule binding at a site peripheral to the active site and subsequently moving toward the active site to bind to the heme and resulting in a low to high spin iron shift. The last step is attributed to a conformational change in the enzyme active site. The later steps of binding were shown to have rate constants comparable with the subsequent steps of the catalytic cycle. The P450 3A4 binding process is more complex than a two-state system, and the overlap of rates of some of the events with subsequent steps is proposed to underlie the observed cooperativity.

Bromocriptine↗

PubMed2005

Frontotemporal dementia--part III. Clinical diagnosis and treatment.

The authors report a comprehensive publication consisting of three parts going into the details of history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, and pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The third part of the present review focuses on the clinical diagnosis and treatment of FTD. The diagnosis of FTD is problematic even today. Mental status, psychometric testing as well as imaging studies such as PET and SPECT, and laboratory examinations may be helpful in the diagnosis. Unfortunately, bedside tests are generally insensitive to mild executive deficits. Most of FTDs do not have characteristic laboratory abnormalities or brain atrophy sufficient to set up the diagnosis; these only allow to rule out other disorders and assume the diagnosis of FTD. An effective treatment for FTD is still to be established. The improvement of serotonin metabolism has been proposed as a biological treatment. Recent studies suggest that bromocriptine may improve selective frontal symptoms, but this and the efficacy of other dopaminergic drugs need further evaluation. Drugs that prevent the expression or accumulation of tau seem to be the most promising causal approach. In aphasia behavioral therapy may be attempted. In addition, caregiver management is essential, because as with those of Alzheimer's dementia patients, they also carry a significant psychosocial stress.

Bromocriptine↗