Giorgio Basile

Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis.

ObjectiveThis study aimed to compare the efficacy and safety of quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis in a randomized, open-label, blinded-rater, parallel group trial. MethodsForty-five patients with Parkinson disease (PD) and psychosis induced by antiparkinsonian drugs were randomly assigned to receive either quetiapine or clozapine. The duration of the trial was 12 weeks. Forty patients, 20 in each treatment group, completed the study. The final dose of quetiapine (mean ± SD) was 91 ± 47 mg/d and that of clozapine 26 ± 12 mg/d. The severity of psychosis was assessed using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale–Severity Subscale (CGI-S). The Unified Parkinson’s Disease Rating Scale (UPDRS) III was used to assess motor conditions during the study period. The Abnormal Involuntary Movement Scale (AIMS) was performed to evaluate dyskinesias. ResultsForty patients, 20 on clozapine and 20 on quetiapine, completed the study. The psychopathologic state improved significantly (P < 0.001) from baseline in both treatment groups. No differences were found between clozapine and quetiapine at any assessment time. Motor conditions remained unchanged after clozapine and quetiapine. Dyskinesias decreased significantly (P < 0.05) in both groups. Side effects were mild, generally transient, and well tolerated. ConclusionsQuetiapine and clozapine appear equally efficacious for treatment of dopaminergic psychosis in patients with PD.

Increased Plasma Neutrophil Gelatinase-Associated Lipocalin Levels Predict Mortality in Elderly Patients with Chronic Heart Failure

Chronic congestive heart failure (CHF) is associated with an increase in cytokines and inflammatory markers, particularly in elderly patients in whom chronic inflammation is generally present per se. In the present pilot study, neutrophil gelatinase-associated lipocalin (NGAL), a recently discovered cytokine, was analyzed together with different clinical and laboratory parameters in a small cohort of 46 elderly patients with CHF of various degrees. NGAL levels in the cohort were found to be significantly higher than in healthy age-balanced controls (458.5 [62.5-1212.4] vs. 37.8 [15.9-46.5] ng/mL; p = 0.0001). Furthermore, NGAL values increased in parallel with the clinical severity of CHF (New York Heart Association [NYHA] classification), the highest levels being reached in class IV patients (p = 0.0001). After a 2-year follow up, Kaplan-Meier curves indicated that patients with baseline NGAL > 783 ng/mL (best receiver operating characteristic [ROC]-derived cut-off value) had a significantly higher mortality (p = 0.001; log-rank test) and 4.08 hazards ratio (95% confidence interval [CI], 1.29-12.96) for death than the other subjects considered. Although preliminary, our findings suggest that NGAL plays a pivotal role in the systemic adaptation to chronic heart failure in elderly patients. Moreover, they indicate, for the first time, that measurement of NGAL may be of important prognostic value in the assessment of survival, thus extending the predictive properties of this cytokine beyond the clinical field of renal disease.

Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity

Longevity and aging are two sides of the same coin, as they both derive from the interaction between genetic and environmental factors. Aging is a complex, dynamic biological process characterized by continuous remodeling. One of the most recent theories on aging focuses on immune response, and takes into consideration the activation of subclinical, chronic low-grade inflammation which occurs with aging, named “inflammaging”. Long-lived people, especially centenarians, seem to cope with chronic subclinical inflammation through an anti-inflammatory response, called therefore “anti-inflammaging”. In the present review, we have focused our attention on the contrast between inflammaging and anti-inflammaging systems, by evaluating the role of cytokines and their impact on extreme longevity. Cytokines are the expression of a network involving genes, polymorphisms and environment, and are involved both in inflammation and anti-inflammation. We have described the role of IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IL-22, IL-23, TNF-α, IFN-γ as pro-inflammatory cytokines, of IL-1Ra, IL-4, IL-10, TGF-β1 as anti-inflammatory cytokines, and of lipoxin A4 and heat shock proteins as mediators of cytokines. We believe that if inflammaging is a key to understand aging, anti-inflammaging may be one of the secrets of longevity.

Quetiapine versus clozapine: a preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson's disease.

Abstract. This study investigated the efficacy and safety of quetiapine versus clozapine in parkinsonian patients with dopaminergic psychosis. All patients fulfilling the inclusion criteria were randomly assigned to receive either quetiapine or clozapine. The duration of the trial was 12 weeks. The severity of psychosis was assessed using the BPRS and the Clinical Global Impression Scale-Severity subscale (CGI-S). The UPDRS III was used to monitor the progression of PD during the study period. Twenty patients, 10 on clozapine, and 10 on quetiapine, completed the study. The psychopathological state, as assessed by the BPRS and by the CGI-S, improved significantly (p<0.001) from baseline in both treatment groups. No differences were found between clozapine and quetiapine at each assessment time. The UPDRS score decreased significantly (p<0.05) in the clozapine group, while was almost unchanged in the quetiapine group.

Smoking, aging and the centenarians.

The smoke of cigarettes represents an important accelerator of the aging process, both directly through complex mechanisms mediated prevalently by excessive formation of free radicals, and indirectly by favoring the appearance of various pathologies in which smoke is a recognized risk factor. This means that smoke compromises not only life expectancy, but also the quality of the life, favoring the occurrence of non-autosufficiency. Smoking is an important risk factor for many diseases, such as cancer, cardiovascular and respiratory diseases. These are also the main causes of death in the industrialized Countries, where the habit of smoking is also largely diffused. Non-smokers have a much higher life expectancy than smokers, and the suspension of smoking is accompanied, even in the elderly, by an increase in the survival time due to the reduction of smoke-induced biological damage. Therefore, cigarette smoking is opposing the longevity, particularly the extreme one, as it is confirmed by the observations obtained on centenarians. Among them, smoking is extremely rare, and even when it occurs among them, it is correlated almost exclusively to bad health conditions and non-autosufficiency, indicating that it compromises health status and the quality of life even in extremely long living subjects. Considering the demonstrated beneficial effects of suspension of smoking, all practitioners and geriatricians in particular, should promote the abstinence from smoking as a behavioral norm for a correct life style. Non-smokers can delay the appearance of diseases and of the aging process, thus attaining longevity; further, non-smoking habit allows genetically predisposed subjects to reach the extreme longevity and maintain an acceptable health status and autosufficiency.

Increased circulating Interleukin-18 levels in centenarians with no signs of vascular disease: another paradox of longevity?

Interleukin (IL)-18 is highly expressed in macrophages from human atherosclerotic plaques, suggesting its involvement in ischemic syndromes. We evaluated IL-18 and IL-18 binding protein (BP) in healthy centenarians, as longevity is characterized by a reduced incidence of ischemic events. For comparison, patients with chronic ischemic syndromes (CIS) were evaluated. Serum IL-18 and IL-18BP levels were measured by non-cross-reacting ELISA in 16 healthy centenarians and in two age-control populations, each of 18 healthy individuals aged 55.9+/-1.43 and 74.3+/-1.35, respectively, as well as in 23 CIS patients, and another cohort of 23 healthy subjects that were age- and sex-matched with CIS patients. Centenarians displayed significantly higher total IL-18 serum levels compared to each control group. Elevated IL-18 levels were also present in CIS patients. However, centenarians had a significant higher level of IL-18BP compared to the cohort of 23 controls (P=0.0014), and compared to CIS patients (P=0.043); as a result centenarians exhibited a lower level of free IL-18 than CIS patients. The present results indicate that quenching of IL-18 by IL-18BP may explain the apparent paradox of elevated serum IL-18 with no vascular signs in centenarians.

Age-related modifications in circulating IL-15 levels in humans.

Aging is associated to a progressive establishing of a chronic inflammatory state linked to a continuous long exposure to antigens. Since IL-15 stimulates the proliferation of memory T cells and the immunosenescence is characterized by accumulation of memory T cells and exhaustion of naive T cells, we analyzed IL-15 levels in sera from 30 ultralongeval subjects with respect to those from young and old adults. IL-15 levels were assayed by immunoenzymatic methods. Ultralongeval subjects displayed significantly higher IL-15 levels with respect to both young and old controls. No statistical difference was found between old and young controls. These findings may explain, at least in part, the characteristic increase of memory cells in immunosenescence and the capacity of the immune system of centenarians to defend itself from infections through immune-inflammatory responses.

Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus

Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552(∗)] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552(∗) alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3β phosphorylation that is observed after wild-type APPL1 transfection. These findings-linking APPL1 mutations to familial forms of diabetes-reaffirm the critical role of APPL1 in glucose homeostasis.

Continuous apomorphine infusion and neuropsychiatric disorders: a controlled study in patients with advanced Parkinson's disease.

Abstract.The aim of this study was to asses whether patients with Parkinson’s disease (PD) develop cognitive and psychiatric complications more frequently during prolonged therapy with continuous apomorphine infusion compared with standard oral treatment. Thirty consecutive PD patients with severe motor fluctuations were included in the study. Twelve patients accepted the treatment with subcutaneous continuous apomorphine infusion, while the remaining 18 preferred to continue with oral dopaminergic therapy. The two groups were evaluated with neuropsychological, psychiatric, and motor tests at baseline and after 1 year. The off daily duration and the levodopa dosage were significantly reduced in infused patients. The neuropsychiatric assessment did not change in both groups compared with baseline, except for a significant improvement of mood in the apomorphine group.

Candesartan cilexetil-induced severe hepatotoxicity

We report a case of severe hepatotoxicity associated with ductopenia in a 61-year-old woman. The patient developed jaundice, vomiting, and abdominal pain a few weeks after the beginning of treatment with candesartan cilexetil, 16 mg/d, for essential hypertension. Liver biopsy showed parenchymal bilirubinostasis with portal cholangitis and ductopenia. The drug was immediately withdrawn, and in the following weeks, aminotransferases and serum bilirubin returned to normal levels. The clinical-histologic data and the exclusion of known causes of liver disease led us to make a diagnosis of drug-induced cholestasis. To our knowledge, this is the first description of severe hepatotoxicity associated with ductopenia caused by an adverse reaction to candesartan cilexetil.