Metabolic drug interactions with new psychotropic agents

New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and 'third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s).     

Biological factors and age-dependence of primary motor cortex experimental plasticity

To evaluate whether the age-dependence of brain plasticity correlates with the levels of proteins involved in hormone and brain functions we executed a paired associative stimulation (PAS) protocol and blood tests. We measured the PAS-induced plasticity in the primary motor cortex. Blood levels of the brain-derived neurotrophic factor (BDNF), estradiol, the insulin-like growth factor (IGF)-1, the insulin-like growth factor binding protein (IGFBP)-3, progesterone, sex hormone-binding globulin (SHBG), testosterone, and the transforming growth factor beta 1 (TGF-β1) were determined in 15 healthy men and 20 healthy women. We observed an age-related reduction of PAS-induced plasticity in females that it is not present in males. In females, PAS-induced plasticity displayed a correlation with testosterone (p = 0.006) that became a trend after the adjustment for the age effect (p = 0.078). In males, IGF-1 showed a nominally significant correlation with the PAS-induced plasticity (p = 0.043). In conclusion, we observed that hormone blood levels (testosterone in females and IGF-1 in males) may be involved in the age-dependence of brain plasticity.     

Nutritional and racial determinants of the increase in plasma homocysteine levels after methionine loading

Background: Low circulating plasma levels of total homocysteine (tHcy) are associated with a lower prevalence of coronary heart disease among black people than among white people living in Burkina Faso.Objective: The purpose of this study was to provide a rationale for a possible mechanism for the decrease in plasma tHcy levels among black people compared with white people living in Burkina Faso.Methods: Healthy, black, adult, lifelong inhabitants of Burkina Faso and healthy, white adults born in Italy but living in Burkina Faso ≥5 years were eligible for enrollment. Controlled diets were assigned to all subjects for 2 weeks before the study. After an overnight (12-hour) fast, a methionine-loading test was performed in all subjects. Plasma levels of tHcy, cysteine, glutathione, and cysteinylglycine were measured simultaneously using high-performance liquid chromatography after fasting (baseline) and at either 4 and 8 hours (n = 30) or 2, 4, 6, and 8 hours (n = 4) after methionine loading. During the 12 hours after loading, the clinical conditions and adverse events of subjects were monitored. Results were analyzed using the Student t test and Mann-Whitney U test.Results: Seventeen black adults (9 males, 8 females; median age, 21 years) and 17 white adults (8 males, 9 females; median age, 35 years) were enrolled. Mean plasma levels of tHcy, cysteine, and glutathione increased from mean baseline levels more slowly in the black group than in the white group and peaked 8 hours after methionine loading (16.8 ± 3.0 μmol/L, 130.4 ± 25.7 μmol/L, and 68.3 ± 21.2 μmol/L, respectively). In the white group, these levels peaked 4 hours after loading (16.1 ± 4.0 μmol/L, 215.8 ± 18.6 μmol/L, and 38.6 ± 12.4 μmol/L, respectively). Only the mean plasma cysteinylglycine level decreased significantly (from 35.7 ± 11.4 μmol/L to 19.0 ± 6.1 μmol/L; P < 0.01) in the black group after 4 hours. This decrease was followed by an increase after 8 hours (29.6 ± 12.0 μmol/L). In the white group, a less remarkable change in mean cysteinylglycine level was observed, with a peak after 4 hours (16.3 ± 4.3 μmol/L).Conclusions: The findings of this study suggest that, in addition to lower plasma tHcy levels, the metabolism of plasma tHcy is different in black people than in white people after methionine loading. This difference may be due to different alimentary habits associated with a reduced dietary availability of methionine. Moreover, the higher plasma levels of glutathione before and after methionine loading appear to occur exclusively in black people compared with whites and correspond with the variation of cysteinylglycine, suggesting that, in addition to nutritional factors, a racial component may contribute to the difference in plasma levels of tHcy. This difference also might explain, in part, the lower prevalence of coronary heart disease in black people living in Burkina Faso compared with that in other populations.     

Morris syndrome: description of a case characterized by partial androgen insensitivity

The Morris syndrome is a X-linked recessive condition due to a complete or partial insensitivity to androgens, resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete or partial depending on the amount of residual androgen receptor function. The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia to mildly undervirilized male external genitalia. We describe a case of Partial Androgen Insensitivity Syndrome in a 21-year-old patient with a 46, XY karyotype, bilateral inguinal masses, clitoral enlargement and partial posterior labial fusion. Surgical care consisted of bilateral orchiectomy and plastic surgery of external genitalia. The patient underwent estrogen replacement therapy.     

Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia: a randomized, placebo-controlled trial

Antidepressant drugs have often been used as an augmentation strategy for those patients who have demonstrated a suboptimal response to clozapine. The present 16-week double-blind, randomized, placebo-controlled trial study aimed to explore the efficacy and tolerability of duloxetine add-on pharmacotherapy on clinical symptomatology and executive cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments, the patients were randomly allocated to receive, in a double-blind design, at a dose of 60 mg per day of duloxetine or a placebo. A final sample of 33 patients completed the study. The results obtained indicate that duloxetine added to stable clozapine treatment showed a beneficial effect on the negative and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. With regard to executive cognitive functions, duloxetine augmentation of clozapine had no significant effects. The findings provide evidence that duloxetine augmentation of clozapine treatment is safe and well tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy.     

Multiple sclerosis and anti-Plasmodium falciparum innate immune response

Several epidemiological investigations conducted in Sardinia, insular Italy, indicate that the strong selective pressure of malaria along the centuries may have concurred to the elevated genetic MS-risk in this region. To test such hypothesis in an experimental setting, we have compared the immune response to P. falciparum (the causative agent of malaria) in Sardinian MS patients relative to their ethnic healthy controls and control MS patients of different ethnicity. To this purpose, the P. falciparum-driven peripheral mononuclear cell proliferation, the production of pro-inflammatory cytokines of the innate immunity such as TNF-alpha, IL-6 and IL-12 and the ability to inhibit the parasite growth have been tested in relation to HLA-DR alleles and TNF promoter polymorphisms known of being associated to MS. We found that P. falciparum-induced proliferation, cytokine production and parasite killing are significantly augmented in Sardinian MS patients as compared to controls (p<0.01). Additionally, a correlation is found with genes associated to Sardinian MS, namely the TNF(-376A) promoter polymorphism and the class II HLA-DRB1*0405 allele. In conclusion, we have found evidences that some genetic traits formerly selected to confer a protective responses to P. falciparum now partially contribute to the elevated MS susceptibility amongst Sardinians.     

The Effect of a Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study

Oxidative stress leads to chronic liver damage. Silybin has been conjugated with vitamin E and phospholipids to improve its antioxidant activity. Eighty-five patients were divided into 2 groups: those affected by nonalcoholic fatty liver disease (group A) and those with HCV-related chronic hepatitis associated with nonalcoholic fatty liver disease (group B), nonresponders to treatment. The treatment consisted of silybin/vitamin E/phospholipids. After treatment, group A showed a significant reduction in ultrasonographic scores for liver steatosis. Liver enzyme levels, hyperinsulinemia, and indexes of liver fibrosis showed an improvement in treated individuals. A significant correlation among indexes of fibrosis, body mass index, insulinemia, plasma levels of transforming growth factor-β, tumor necrosis factor-α, degree of steatosis, and γ-glutamyl transpeptidase was observed. Our data suggest that silybin conjugated with vitamin E and phospholipids could be used as a complementary approach to the treatment of patients with chronic liver damage. Other members of the Real Sud Group: L. Cimino, Federico II University, Naples; V. De Girolamo and A. Marone, Ascalesi Hospital, Naples; C. De Stefano, S. Carlo Hospital, Potenza; G. De Stefano, Madonna delle Grazie Hospital, Matera; D. Disalvo and B. Provenzano, Villa D’Agri Hospital, Potenza; P. Esposito and A. Simonetti, Second University, Naples; M. D. Iannece and R. Pempinello, Cotugno Hospital, Naples; R. Iorio, Giugliano Hospital, Naples; S. Monastra and M. Di Pierro, S. Gennaro Hospital, Naples.     

Typing of the immunological system in human embryos by coelocentesis

Coelocentesis offers a new opportunity for gaining access to the human embryos from 28 d postfertilization. However, while some studies about its biochemical composition have been reported, our knowledge about immunological pattern of this compartment is still limited. For this reason, we studied the human coelomic fluids sampled from 6.6 to 10 wk of gestation. The majority of cellular population consisted in mesenchymal/epithelial cells. In fluids sampled before 10 wk we found only a preT Cell Receptor expression and an absence or a very low frequency of B lymphocytes, T lymphocytes and NK (natural killer) antigens. These preliminary data suggest that the immunological system in human embryos could be in the ideal conditions to start a process of tolerance induction.