Salvatore Gentile

Impairment of insulin secretion in man by nifedipine

SummaryThe effect of nifedipine, a calcium antagonist, on carbohydrate metabolism and insulin secretion was evaluated in patients who required treatment with this drug. 20 subjects underwent two oral glucose tolerance tests (100 g), one under basal conditions, and the other after ten days of treatment with nifedipine 30 mg/day by mouth, in three divided doses. 10 subjects had normal glucose tolerance; in them nifedipine administration reduced the insulin response to oral glucose in the first 60 min, but improved glucose tolerance. The other 10 subjects had impaired glucose tolerance and nifedipine treatment resulted in a further reduction both of insulin secretion and glucose tolerance. No such effects were seen in the placebo (weight- and disease-matched) group. The mechanism by which nifedipine influences carbohydrate metabolism and insulin secretion is discussed.

Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: A systematic review

OBJECTIVE In weighing the risk and benefits of pharmacological treatment of depression during pregnancy it is important to consider risks of long-term as well as short-term implications for children from exposure. Hence, this article examines the evidence to date of studies which have examined longer-term neurodevelopment teratogenic effects on child outcomes (including cognitive, motor and behavioral outcome measures) following in utero exposure to antidepressants. METHOD A systematic review of published literature between January, 1973 and February, 2010 was conducted using the following key-words: pregnancy, child/infant development/neurodevelopment, antidepressants. All studies (N = 12) that reported primary data on neurodevelopmental outcome of infants exposed prenatally to antidepressants were assessed and analyzed. RESULTS The identified studies varied considerably in their own methodology, including the age of the children studied, the scales and assessments used, and the different aspects of neurodevelopment (such as cognitive, motor and behavioral outcomes) that were examined. Despite these limitations, the majority of studies found no difference between those exposed and controls on the various neurodevelopmental outcome measures, whereas only two studies identified statistically significant differences in motor function. CONCLUSIONS These preliminary reassuring results must be confirmed by larger studies with longer period of follow-up and providing more robust measures of neurodevelopmental outcome, in order to definitively exclude any potential risk of neurodevelopmental teratogenicity associated with antidepressant exposure in utero.

SSRIs in pregnancy and lactation: emphasis on neurodevelopmental outcome.

The aim of this review was to assess existing information about the long-term neurocognitive development of children whose mothers took SSRIs during pregnancy and/or breastfeeding. The available literature consists of 11 studies (examining a total of 306 children) that demonstrate no impairment of infant neurodevelopment following prenatal and/or postnatal exposure to SSRIs, and two studies (examining 81 children) that suggest possible unwanted effects of fetal SSRI exposure. These unwanted effects included subtle effects on motor development and motor control.Thus, the available data are not unanimous in excluding possible long-term detrimental neurodevelopmental sequelae of intrauterine exposure to SSRIs. However, it is clear that the research suggesting a lack of adverse events on infants’ neurocognitive development is much more numerous and methodologically better conducted than the studies showing possible unwanted effects. Nevertheless, all reviewed studies had procedural inadequacies, and the screening instruments used have limitations, especially in the evaluation of infants. Furthermore, it is not advisable to extend the generalisations emerging from the findings of a few trials to every infant. Some infants may experience difficulties in metabolising the drugs and/or their metabolites, so the benign outcome described for most infants may not occur.Thus, the findings emerging from the reports are inconclusive and are not able to fully clarify the repercussions of maternal SSRI treatment on infants’ long-term neurocognitive development. Further large, simple and well designed, randomised, prospective studies will be required for this purpose. These should also be of adequate length and performed using reproducible neurophysiological parameters in order to firmly establish the safety of these medications

Association of Fasting Plasma Free Fatty Acid Concentration and Frequency of Ventricular Premature Complexes in Nonischemic Non-Insulin-Dependent Diabetic Patients

We investigated the association between free fatty acid (FFA) concentration and ventricular premature complexes (VPCs) in nonischemic patients with non-insulin-dependent diabetes mellitus using 3 approaches: cross-sectional analysis (n = 142), intervention including induction of elevated FFA levels with Intralipid heparin (n = 15), and reduction in FFA levels with Acipimox (n = 34) and a longitudinal follow-up study (n = 59). Patients at the third tertile of fasting plasma FFA concentration had the strongest increase in VPCs. Independently of age, sex, body mass index (BMI), waist/hip ratio, left ventricular mass index, glycated hemoglobin, fasting plasma insulin and triglyceride concentration, and daily physical activity, FFA concentration and VPCs were significantly correlated (r = 0.21 p <0.01). At multiple logistic regression analysis independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, glycated hemoglobin, fasting plasma insulin, triglycerides and potassium concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity, plasma FFA concentration was a significant determinant of VPCs (odds ratio 1.2, 95% confidence interval 1.0 to 2.3). Intralipid infusion (10% in 24 hours) (n = 15) and acipimox administration (250 mg, 4 times/day) (n = 34) increased, and decreased fasting plasma FFA concentration, respectively. In those studies, change in VPCs paralleled the effects on plasma FFA. In the longitudinal study (n = 59), plasma FFA concentration predicted the development of VPCs (RR 1.4 95% confidence interval 1.0 to 1.9) independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, fasting plasma triglyceride concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity. In conclusion, in nonischemic patients with non-insulin-dependent diabetes mellitus, plasma FFA concentration is associated with the frequency of ventricular premature complexes.

Adverse effects associated with second-generation antipsychotic long-acting injection treatment: a comprehensive systematic review.

As second‐generation antipsychotic long‐acting injections (SGA‐LAIs) are rapidly replacing depot first‐generation antipsychotics as first‐line agents in treating schizophrenia spectrum disorders, a systematic assessment of their adverse effects is timely. English‐language, peer‐reviewed articles reporting original data on the safety and tolerability of SGA‐LAIs were identified electronically by searching the MEDLINE, EMBASE, PsycINFO, and DARE databases and the Cochrane Library (January 2001–April 2013). In addition to second‐generation (atypical) antipsychotics and long‐acting injection (depot) antipsychotics, a separate search was performed for each available drug: aripiprazole LAI, olanzapine pamoate, paliperidone palmitate, and risperidone LAI. Articles were excluded if they were review articles, post hoc analyses, analyses of subsets of patients enrolled in previous trials, single case reports, case series studies, small naturalistic studies (involving less than 50 patients), studies providing no safety data, and studies lasting less than 8 weeks. Of 181 articles identified from the search, 140 were excluded; thus, 41 articles met the inclusion criteria. Predictably, the reviewed information revealed that SGA‐LAIs have safety profiles consistent with their oral parent formulations. However, they seem to also show unforeseen and worrisome safety signals. Indeed, the routine use of olanzapine‐LAI in clinical practice could be limited not only by the well‐known risk of postinjection syndrome, whose clinical management remains a matter of concern, but also by the risk of worsening of psychosis. The reviewed information seems to suggest that worsening of psychotic symptoms and depression could also be associated with both risperidone‐LAI and paliperidone palmitate. The leading cause of death among patients enrolled in risperidone‐LAI studies was suicide. Given the exponential growth in the clinical use of SGA‐LAIs, further studies must be urgently performed in order to confirm or exclude the potential safety signals associated with such drugs.

Atypical antipsychotics for the treatment of bipolar disorder: more shadows than lights.

Atypical antipsychotics are utilised more frequently for the treatment of bipolar disorder than first-generation antipsychotics because of their improved neurological tolerability. Furthermore, recent studies suggest that psychiatric outcomes are improved in patients treated with atypical agents. The aim of this article is to review the studies evaluating the effectiveness of atypical antipsychotics in treating acute bipolar episodes (bipolar mania, bipolar depression and mixed episodes), as well as those investigating the effectiveness of atypical antipsychotics as maintenance treatment for the disorder.Because of several relevant methodological limitations affecting the vast majority of clinical trials, evidence-based information about the effectiveness of atypical antipsychotics in treating bipolar disorder is somewhat discouraging. Moreover, data indicating effectiveness in managing the acute manic phase and in long-term maintenance treatment are quantitatively robust only for olanzapine. However, olanzapine seems to have no advantages in terms of tolerability and therapy compliance when compared with classical mood stabilisers or first-generation antipsychotics. In addition, only a few studies have investigated the efficacy of atypical antipsychotics for treating bipolar depression. Hence, information regarding the effectiveness of such medications in treating this specific phase of bipolar disorder should be considered as still preliminary.Given this situation, further independent and well-designed studies are urgently needed before definitive conclusions on the effectiveness of most atypical antipsychotics in the different clinical situations characterising the natural course of bipolar disorder can be drawn.

Further Findings Linking SSRIs During Pregnancy and Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn (PPHN) is a rare but potentially life-threatening neonatal condition. Several authors have suggested that late pregnancy exposure to selective serotonin reuptake inhibitors (SSRIs) may increase the risk of PPHN. This association has been investigated in seven published studies that have shown mixed findings based on diverse methods. Several methodological limitations may account for the diversity of findings, which include, in some studies, a lack of control for well established risk factors for PPHN. The methodological improvement in the most recent study tentatively suggests that infants prenatally exposed to SSRIs are approximately twice as likely to suffer PPHN. Further research on the biological mechanisms involved is required. Clinicians should consider late pregnancy exposure to SSRIs as one of several possible risks for PPHN, which has implications for both prescribing SSRIs to pregnant women and for neonatal care of SSRI-exposed infants.

Modulation by verapamil of insulin and glucagon secretion in man.

SummaryThe present investigation was designed to evaluate the effect of acute and protracted verapamil administration on insulin and glucagon secretion in man. For this purpose, 14 normal subjects received two consecutive glucose pulses (5 g i.v. in less than 20 sec or 20 g i.v. in less than 1 min, 7 subjects for each group), 70 or 90 min apart, before and during an infusion of verapamil (160 μg/min). Seven additional normal subjects received two consecutive arginine pulses (5 g i.v.), 70 min apart. In 14 inpatients with coronary heart disease, we investigated the effect of protracted verapamil administration. Seven of these subjects underwent two oral glucose tolerance tests (100 g) and the other 7 two arginine tests (30 g) before and after a 10-day treatment with verapamil, 240 mg/die p.o. divided into three doses; the last dose, 80 mg, was given orally 1 h before the performance of the post-treatment test. Verapamil significantly inhibited the acute insulin response (AIR, mean change from 3–10 min) to glucose (5 g), as well as the AIR and AGR (acute glucagon response) to arginine (5 g). By contrast, verapamil failed to alter significantly the AIR to the higher glucose pulse. There was no significant change of oral glucose tolerance after verapamil, nor was there a change in insulin response to oral glucose. By contrast, insulin and glucagon responses to arginine infusion were significantly reduced by the drug.

Topiramate in pregnancy and breastfeeding.

Recent information suggests that use of the antiepileptic drug topiramate in pregnancy may raise some concerns, especially if used in polytherapy. Moreover, data on the safety of this antiepileptic drug for the breastfed infant are very limited. However, use of topiramate may be unavoidable in women who wish to become pregnant but who have already experienced severe adverse reactions to antiepileptic medications considered relatively safe in this female condition. Hence, we describe the healthy outcome of a male infant exposed to topiramate through the placenta and maternal milk and who was conceived while the mother was undergoing folic acid supplementation.

Prevention of left ventricular hypertrophy by ACE-inhibitor, ramipril in comparison with calcium-channel antagonist, felodipine

This perspective study was performed to demonstrate the prevention of left ventricular hypertrophy by ACE-inhibitor, ramipril, in hypertensives of recent onset. Thirty-four hypertensive patients, treated with ramipril (group I), and 32 controls who received another frequently employed drug (the calcium channel-antagonist, felodipine (group II), were evaluated. Neither of two groups received any anti-hypertensive drug and did not suffer from left ventricular hypertrophy. All selected patients underwent M-mode echocardiography for measuring the following parameters: diastolic diameter of left ventricle, (DDLV); systolic diameter of left ventricle (SDLV); inter-ventricular septum (IVS); thickness of the posterior wall (PW); and left ventricular mass index (LVMI). Two anti-hypertensive drugs reduce systemic hypertension the same way. But, in hypertensives receiving ramipril (group I), the echocardiographic parameters of the left ventricle increased non-significantly. On the other hand, in those treated with felodipine (II group), these parameters significantly changed. The mechanisms of non-increase in cardiac and non-cardiac proteins, due to the ACE-inhibitors, are illustrated.