1,720,963 research outputs found
Pharmacogenomics: state of research and prospectives in clinical application
No full textThe person-to-person variability of drug response is a major problem in clinical practice and in drug development. It can lead to therapeutic failure or adverse drug reactions (ADRs) in individuals or subpopulation of patients. In addition to the high occurence of ADRs and the associated morbidity and mortality, substantial costs are incurred. Potential risk factors for drug inefficacy or toxicity include drug-drug interactions, the patient's age, renal and liver functions or other disease factors, and lifestyle variables such as smoking and alcohol consumption. In addition, it has become clear in recent years that genetic factors may also significantly modify drug responses or increase the risk for ADRs. Genetic variations in genes (polymorphisms) for drug-metabolizing enzymes, drug receptors, and drug transporters have been associated with individual variability in the efficacy and toxicity of drugs. It is now widely accepted that migraine is a polygenic and multifactorial disorders, thus considered to be a genetic complex disease. Genetic studies on migraine suggested a role of CACNA1A and DRD2 genes as susceptibility genes in this disorde
Evaluation of lithium response in episodic cluster headache: a retrospective case series
No full textObjective.- In this study, we attempted to evaluate the response to lithium treatment and its tolerability in the prevention of episodic cluster headache (CH) and to identify clinical predictors of response. Background.- Verapamil and lithium are the most widely used drugs in the prevention of CH attacks. Lithium is considered a second-line treatment in part because of its potentially severe adverse drug reactions (ADRs). Evidence for the efficacy of lithium in CH prevention is greater in chronic than in episodic patients. In addition, because of its narrow therapeutic window and ADRs (which can be significantly reduced with proper periodical monitoring of blood levels), lithium is recommended only in chronic CH, when other drugs are ineffective or potentially harmful. Methods.- Our primary aim was to determine whether lithium reduced the number of attacks per day (attack frequency). We compared attack frequency in 3 periods: run-in, the first, and the second week of lithium treatment. Responders were defined as patients showing at least a 50% reduction in attack frequency. Results.- Lithium response was evaluated in 26 patients. Treatment led to a significant reduction in attack frequency within 2 weeks in a percentage of 77% of responders and 23% of nonresponders. Responders and nonresponders did not differ in terms of demographic and clinical characteristics. Only 15% of patients experienced mild ADRs. Conclusion.- Our study provides additional evidence on the effectiveness of lithium in the prevention of episodic CH. It also shows the tolerability of lithium, given the short duration of treatment and low dosage
Mixture analysis of age at onset in migraine without aura: evidence for three subgroups
No full textOBJECTIVE: To verify the presence of different age at onset (AAO) subgroups of patients in a sample of patients with migraine without aura (MWA) and compare clinical correlates among them.
BACKGROUND: MWA is a long-lasting disease whose prognosis has not yet been fully investigated. Patients may present complete remission, partial clinical remission, persistence and progression (migraine attack frequency and disability may increase over time leading to chronic migraine). Limited evidence exists regarding the identification of risk factors or predictors which might influence migraine prognosis. AAO has been proven a useful tool in the investigation of the clinical, biological, and genetic characteristics able to influence the prognosis of a number of neuropsychiatric disorders. AAO distribution was studied using mixture analysis, a statistical approach that breaks down the empirical AAO distribution observed into a mixture of normal components.
METHODS: A sample of 334 outpatients affected by MWA, recruited in a clinical genetic study at our Headache Center from 2004 to 2008, was enrolled for this study. Diagnosis was made according to International Headache Society criteria 2004. AAO distribution in patients was studied using mixture analysis. Chi-square test was used to compare clinical correlates among identified subgroups. Logistic regression was performed in order to correct for effect of possible confounders.
RESULTS: Mixture analysis broke up the observed distribution of AAO into 3 normal theoretical distributions. Informational criteria clearly showed a better 3-component model rather than the 2-component one. An early-onset (≤ 7 years of age), an intermediate-onset (≥ 8 and ≤ 22), and a late-onset group (≥ 23) were identified. Comparison of clinical correlates among subgroups by means of chi-square test showed a statistically significant result for migraine frequency (χ(2) = 7.41, P = .02). Considering the frequency of migraine attacks as a main outcome, the regression model showed a higher AAO is associated with low frequency (odds ratio =0.95; P= .02).
CONCLUSIONS: The significant association between AAO and attack frequency found in our study supports the hypothesis that AAO could act as a predictor factor able to influence prognosis. AAO could represent a phenotype suitable for identifying MWA susceptibility genes
Migraine and Tumor Necrosis Factor gene polymorphism: an association study in a sardinian sample
No full textAssociation study between the phenotype migraine without aura-panic disorder and dopaminergic receptor genes
No full textClinical and epidemiological evidence suggests that migraine often co-occurs with psychopathological conditions. Several longitudinal and population-based studies have suggested that migraine and panic disorder might share a common predisposition. An abnormal dopaminergic function has been hypothesized to be involved as etiological factor in panic disorder as well as in migraine. Epidemiological and molecular data suggest the role of genetic factors in the pathogenesis of both migraine and panic attack disorder. We assessed the presence of panic disorder in 100 probands suffering from migraine without aura and the present study was designed to analyse the possible association of the migraine-panic phenotype with dopaminergic genes. In our sample, 17 out of 100 migraineurs were affected by panic disorder and were thus considered for the genetic association study. The allele frequencies of DRD1, DRD3, DRD5, DRD2 in probands did not differ from that of parental non-transmitted chromosomes. This result does not seem to support, in our limited sample, a common pathological basis, with regard to the dopaminergic system, between migraine and panic. Should migraine and panic disorder share some common mechanisms, these could be sought in neuro-chemical systems other than the dopaminergic one
Clozapine toxicity due to a multiple drug interaction: a case report
No full textIntroduction: We report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine-antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice. Case presentation: A 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days. Conclusions: Clozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine-antifungals and clozapine-contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity
Migraine and tumour necrosis factor gene polymorphism. An association study in a Sardinian sample
No full textTo assess the possibility of an association between TNF gene polymorphisms and migraine without aura, a case-control study was performed in a Sardinian sample. Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development. Several studies suggest that tumour necrosis factors (TNF) (TNF-alpha and lymphotoxin-alpha or TNF-ss) may be involved in the pathophysiology of migraine. The TNF-alpha and TNF-ss genes are located on chromosome 6p21.3 in the human leukocyte antigene (HLA) class III region. We evaluated 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls. The polymorphisms G308A of the TNF- alpha gene, and G252A of TNF-beta gene were determined by NcoI restriction fragment length polymorphism analysis. We found a statistically significant difference in allele (p = 0.018; OR = 1.46 95 % CI: 1.066 to 2.023) and genotype (trend chi2 = 5.46, df = 1, p = 0.019) frequencies of TNF-beta gene, between cases and controls. Allele and genotype frequencies of TNF-alpha polymorphism did not differ significantly between the two groups. These data suggest that subjects with the TNFB2 allele have a low risk of developing migraine without aura and/or that the polymorphism of the TNF-beta gene is in linkage disequilibrium with other migraine responsible genes in the HLA region
Interstitial lung disease induced by fluoxetine: Systematic review of literature and analysis of Vigiaccess, Eudravigilance and a national pharmacovigilance database.
No full textWe investigated a pulmonary adverse drug reaction possibly induced by fluoxetine, the Interstitial Lung Disease, by performing a systematic review of published case reports on this subject, a review of the World Health Organization VigiAccess database, of the European EudraVigilance database and of a national Pharmacovigilance database (Italian Pharmacovigilance Network). The research found a total of seven cases linking fluoxetine to Interstitial Lung Disease in the literature. 36 cases of interstitial lung disease related to fluoxetine were retrieved from the VigiAccess database (updated to July 2016), and 36 reports were found in EudraVigilance database (updated to June 2016). In the Italian Pharmacovigilance database (updated to August 2016), we found only one case of Interstitial Lung Disease, codified as "pulmonary disease". Our investigation shows that fluoxetine might be considered as a possible cause of Interstitial Lung Disease. In particular, although here we do not discuss the assessment of benefits and harms of fluoxetine, since this antidepressant is widely used, our review suggests that fluoxetine-induced Interstitial Lung Disease should be considered in patients with dyspnea, associated or not with dry cough, who are treated with this drug. An early withdrawn of fluoxetine could be useful to obtain a complete remission of this adverse drug reaction and special attention should be particularly devoted to long-term therapy, and to female and elderly patients. Although the spontaneous reporting system is affected by important limitations, drug post- marketing surveillance represents an important tool to evaluate the real world effectiveness and safety of drugs
Association study between clinical response to rizatriptan and some candidate genes
No full textThe aim of this study was to test genetic differences in the clinical response to rizatriptan in patients affected by migraine without aura. These genetic differences could be explained by various genes, the HTR1B, encoding the 5-HT(1) receptor subtype, MAOA gene that encodes the monoamino-oxidase, the main metabolic enzyme of this triptan, SLC6A4 (gene encoding the serotonin transporter) and DRD(2) (gene encoding the D(2) receptor), both involved in the pathogenesis of migraine. Fifty unrelated patients affected by migraine without aura (IHS) were included. Patients were divided into two groups (responders and non-responders) according to clinical response. Thirty-one out of fifty patients responded to rizatriptan. A significant difference among the two groups was observed in both allele (p=0.02) and genotype distribution (p=0.03) of DRD2/NcoI. The significant association with the DRD2/NcoI polymorphism in responders suggested that the DRD2/NcoI C allele may be considered a susceptibility factor heralding a good response to rizatriptan
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