Aripiprazole in the treatment of schizophrenia: a consensus report produced by schizophrenia experts in Italy

Schizophrenia is generally a chronic and disabling mental illness. Pharmacological therapy, which is used for relief of acute psychotic episodes and prevention of subsequent relapse, is essential for the effective management of schizophrenia. In order to alleviate the positive symptoms of schizophrenia, all antipsychotic agents act on the dopaminergic system. However, strong, high-affinity dopamine D(2)-receptor blockade may also be responsible for debilitating extrapyramidal symptoms (EPS) and hyperprolactinaemia. Unlike conventional antipsychotic agents, atypical antipsychotics also exert activity at other receptors, and it is generally acknowledged that, compared with conventional antipsychotics, atypical agents are associated with a broader spectrum of clinical efficacy and are better tolerated. However, other adverse effects such as weight gain and metabolic changes are cause for concern with some atypical antipsychotics. The novel atypical antipsychotic agent aripiprazole is a partial agonist at D(2) receptors that has been shown in clinical trials to be effective in treating both the positive and the negative symptoms of schizophrenia, and to be well tolerated, with a low propensity for EPS and no clinically significant weight gain, hyperprolactinaemia or corrected QT-interval prolongation. Aripiprazole thus provides clinicians with another treatment option, and in October 2005, schizophrenia experts participated in an expert consensus meeting that aimed to agree on a set of guidelines for best-practice use of aripiprazole in the acute and long-term management of schizophrenia in Italy. This report describes the outcome of the meeting. Our recommendations for dosage and administration of aripiprazole are in agreement with the manufacturer's prescribing information. Ideally, optimal dosing should be evaluated on an individual basis, taking into account patients' characteristics such as the presence or absence of agitation. Overall, in our experience, aripiprazole is generally a well accepted, well tolerated, safe and broadly effective first-line antipsychotic agent. Switching to aripiprazole from maintenance therapy with another antipsychotic also works well, provided the change is made gradually, involving tapering of the original medication.     

A pharmacokinetic interaction between clarithromycin and sirolimus in kidney transplant recipient

Bacterial infection is a frequent event in renal transplant recipients and often requires the use of antimicrobial agents. In this paper it is reported an evidence of pharmacokinetic interaction between clarithromycin and sirolimus in a kidney transplanted woman, suffering from pulmonary infection sustained by a bacterial pathogen, in particular Hemophilus Influenzae. In the present case report, the concomitant administration of clarithromycin and sirolimus determined impressive increase of sirolimus trough blood concentrations from 6.2 up to 54 ng/mL and this increase was associated with an acute impairment of renal function, almost completely reversed upon both drugs discontinuation. This drug-drug interaction is due to a likely inhibition of activity of both cytochrome P450 3A4 and P-glycoprotein. Although this interaction could be predicted, it represents the first reported clinical evidence.     

Impaired reduction of enhanced levels of dehydroepiandrosterone by oral dexamethasone in anorexia nervosa

Allopregnanolone and dehydroepiendrosterone (DHEA) have been supposed to be involved in some psychiatric disorders including anorexia nervosa (AN). The secretion of DHEA and allopregnanolone occurs in both the brain and the adrenal gland, where it is under the control of the corticotrophin-releasing factor (CRF)/adrenocorticotrophin hormone (ACTH) system, and, according to the increased CRF/ACTH drive found in AN, we previously reported enhanced morning levels of both DHEA and allopregnanolone in underweight anorexic patients. To further characterize the physiology of these neurosteroids in AN, we measured plasma levels of cortisol, DHEA and allopregnanolone after the oral administration of 1 mg dexamethasone at 800h in six underweight AN women and ten age-matched healthy females. We found that, before dexamethasone administration, both cortisol and DHEA plasma concentrations were significantly increased in anorexic patients as compared to controls, whereas plasma allopregnanolone levels although increased in the former did not reach a statistical significance. Moreover, while cortisol levels after dexamethasone administration were suppressed in AN to values similar to normal controls, DHEA concentrations, although significantly decreased, remained higher than in normal controls. These data support the view that in AN, the increased production of DHEA may be linked to mechanisms other than the enhanced CRF/ACTH drive.     

IL-12 and Th1 immune responses in human Peyer's patches

Oral tolerance is a well-characterized phenomenon in animals and is highly effective when induced as a treatment for experimental autoimmune disease. However, its use as a therapeutic modality for the treatment of autoimmune disease in humans has been disappointing. Much of the rationale for its use in humans is based on the finding that feeding antigen to rodents elicits regulatory T cells in Peyer's patches (PPs) that secrete immunosuppressive cytokines such as transforming growth factor (TGF)-beta. By contrast, human antigen-specific PP T-cell responses, and mucosal T-cell responses in general, are strongly biased towards T helper 1 (Th1) cells, which are pro-inflammatory rather than immunosuppressive. This is caused by the high local levels of interleukin (IL)-12 in PPs.     

Repetitive growth hormone-releasing hormone administration restores the attenuated growth hormone (GH) response to GH-releasing hormone testing in normal aging

The plasma GH response to human pituitary GH (hpGH)-releasing hormone-40 (hpGHRH-40; 1 microgram/kg BW) was significantly lower in seven healthy aged men (age range, 65-78 yr) than in seven healthy young men (age range, 18-31 yr) 30, 60, and 90 min after acute hpGHRH-40 administration (P less than 0.0001, by Student's unpaired t test). To verify whether a priming regimen might be able to reverse the reduced GH response to GHRH, elderly subjects underwent repetitive administration of hpGHRH-40 and placebo in a double blind design (100 micrograms hpGHRH-40 or volume-matched saline iv as a single morning dose, every 2 days for 12 days). After the hpGHRH-40-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points after placebo treatment. These findings suggest that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response.