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Vural Ozdemir

Publications and source records attributed to Vural Ozdemir.

11 recordsLinked to original sources
PubMed2007

Second-generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia: an observational pharmacoepidemiology study from 1988 to 2002.

Patients with schizophrenia are at increased risk for cardiovascular disease as a consequence of lifestyle habits, impaired access to health care, and, increasingly, due to metabolic side effects ostensibly attributed to second-generation antipsychotics (SGAs). There is little evidence, however, on the extent and temporal patterns of SGA-associated metabolic side effects. We longitudinally examined the differential prevalence rates of obesity, diabetes mellitus, and diabetic ketoacidosis among inpatients with schizophrenia compared with control inpatients without schizophrenia. The data were derived from the National Inpatient Sample, the largest all-payer inpatient care database in the United States consisting of 5 to 8 million inpatient hospital stays per year sampled to approximate a 20% sample of community hospitals from 1988 to 2002. Overlaid on these observations was the market penetration data for SGAs. In 1988, the net difference from controls in obesity prevalence among inpatients with schizophrenia was +4.7%; by 2002, this difference had widened to +14.7%. Similarly, a significant increase in net prevalence of diabetes mellitus and diabetic ketoacidosis was observed from 1988 to 2002 among schizophrenic inpatients. In conclusion, after the introduction of SGAs, patients with schizophrenia in the United States have experienced a striking net increase in the prevalence of obesity and diabetes mellitus. This is likely to significantly add to an already elevated risk for cardiovascular disease in this population. Further investigations are urgently required so that health policy can be appropriately amended for preventive measures.

Adult↗
PubMed2006

Effect of CYP2D6 genetic polymorphism on the population pharmacokinetics of tipifarnib.

OBJECTIVE: Evaluate the effect of CYP2D6 genotype on the pharmacokinetics of tipifarnib. METHODS: A total of 268 subjects included in six clinical trials were treated orally with tablet formulation of tipifarnib, as a single dose or as multiple b.i.d. doses (range 50-600 mg), and/or intravenously following 1, 2, and 24 h infusions. A total of 2,575 tipifarnib concentrations were fitted to an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of CYP2D6 genotype was explored as a covariate for tipifarnib systemic clearance and absolute bioavailability. Likelihood ratio test was used to compare these parameters in homozygous extensive metabolizers (EM) (N=152), heterozygous EM (N=97), or poor metabolizers (PM) (N=19). Computer simulations were undertaken to explore the CYP2D6 genotype effect on the tipifarnib pharmacokinetics. RESULTS: The ratio of tipifarnib systemic clearance for the heterozygous EM and the PM subjects, relative to the homozygous EM group, were 0.95 (95%CI 0.87-1.03) and 0.96 (95%CI 0.82-1.11), respectively (chi2=2.376, df=2, P=0.305). The ratio of tipifarnib absolute bioavailability for the heterozygous EM and the PM, relative to the homozygous EM, were 1.06 (95%CI 0.83-1.30) and 0.95 (95%CI 0.55-1.34), respectively (chi2=1.398, df=2, P=0.497). CONCLUSIONS: These results indicate that CYP2D6 genetic polymorphism does not appreciably influence the pharmacokinetics of tipifarnib. Hence, concomitant administration of potent CYP2D6 inhibitors is anticipated to have little or no significant impact on the systemic exposure to tipifarnib.

Administration, Oral↗
PubMed2006

Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines.

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20-50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines--chlorpromazine, fluphenazine and haloperidol--belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualize therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library--one that enlists the 'essential biomarkers' required for optimal pharmacotherapy--may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.

Antipsychotic Agents↗
PubMed2006

Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness?

Integration of genomic data from pharmacokinetic pathways and drug targets is an emerging trend in bioinformatics, but is there a clear separation of pharmacokinetic pathways and drug targets? Should we also consider the potential interactions of endogenous substrates of drug-metabolizing enzymes with receptors and other molecular drug targets as we combine pharmacogenomic datasets? We discuss these overarching questions through a specific pharmacogenomic case study of the cytochrome P450 (CYP)2D6, serotonin and dopamine triad. Importantly, CYP2D6 may contribute to the regeneration of serotonin from 5-methoxytryptamine by virtue of its catalytic function as a 5-methoxyindolethylamine O-demethylase. Furthermore, serotonergic neurons provide a regulatory feedback on dopaminergic neurotransmission. Hence, we hypothesize that independent of its role as a pharmacokinetic gene, CYP2D6 may nuance the regulation of serotonergic and dopaminergic neurophysiology. Additionally, we reflect upon the contribution of hyperspecialization in biomedicine to the present disconnect between research on pharmacokinetics and drug targets, and the potential for remedying this important gap through informed dialogue among clinical pharmacologists, human geneticists, bioethicists and applied social scientists.

5-Methoxytryptamine↗
PubMed2005

Low-dose fluvoxamine as an adjunct to reduce olanzapine therapeutic dose requirements: a prospective dose-adjusted drug interaction strategy.

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

Benzodiazepines↗
PubMed2004

Pharmacogenomic-guided rational therapeutic drug monitoring: conceptual framework and application platforms for atypical antipsychotics.

Atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine and ziprasidone offer many advantages over conventional neuroleptics. These agents reduce negative symptoms of schizophrenia, are effective in treatment refractory cases, and have a markedly lower incidence of extrapyramidal symptoms and tardive dyskinesia. However, there is considerable patient-to-patient variability in therapeutic dose requirements of atypical antipsychotics and the propensity for side effects. Hence, the initial excitement since the introduction of atypical antipsychotics in late 1980s is now shifting towards a focus on individualization of pharmacotherapy and elucidation of the mechanistic basis of interindividual variability in drug response with use of pharmacokinetic and pharmacodynamic biomarkers. Pharmacogenomics, introduced in late 1990s, is the study of variability in drug response using information from the entire genome of a given individual patient. Both pharmacogenomics and conventional therapeutic drug monitoring (TDM) share the similar goal of improving pharmacotherapy through better explanation of individual variability in drug response. Hence, pharmacogenomic biomarkers offer a unique opportunity to complement and expand the scope of traditional TDM in clinical psychopharmacology. Importantly, pharmacogenomics enables the investigation of factors distal to drug exposure in the plasma compartment (e.g. drug targets at the biophase), thereby providing a more complete portrayal of sources of variability in psychotropic drug response. We discuss (1). the definitions for biomarkers and surrogate endpoints in the context of pharmacogenomics, (2). genetic variations in isozyme-specific atypical antipsychotic metabolism in vivo, (3). selected examples of pharmacogenomic variability in pertinent drug targets and, (4). the anticipated roadmap from implementation of pharmacogenomics to changes in healthcare and therapeutic policy. In addition, a conceptual framework that outlines the theoretical advantages of pharmacogenomics-guided TDM is presented using recent clinical applications as precedence.

Antipsychotic Agents↗
PubMed2003

Fasidotril Eli Lilly.

Lilly is developing fasidotril, a diester prodrug of the active metabolite fasidotrilat, for the potential treatment of hypertension and congestive heart failure (CHF). Phase II trials to investigate the potential of fasidotril for the treatment of hypertension and CHF had commenced by the late 1990s, and were ongoing in July 2003 in the US and Europe.

Alanine↗
PubMed2002

Psychiatric pharmacogenetics: personalizing psychostimulant therapy in attention-deficit/hyperactivity disorder.

There is a substantial amount of variation in response and adverse drug reactions to psychostimulant therapy in attention-deficit/hyperactivity disorder (ADHD). Psychiatric pharmacogenetics is a rapidly developing field, which can be applied to identify genetic predictors of this variability in outcome to psychostimulant medications. This article will briefly review ADHD and its pharmacotherapy. This will be followed by an overview of the pharmacokinetics and pharmacodynamics of methylphenidate, the most commonly used psychostimulant in the US. Then the field of psychiatric pharmacogenetics will be introduced and its methodology will be described. This will be followed by a discussion about how pharmacogenetics can be applied to children afflicted with ADHD. The future of psychiatric pharmacogenetics will then be presented with an emphasis being placed on developing prospects that will ensure the continued advancement of this field.

Attention Deficit Disorder with Hyperactivity↗
PubMed2002

Aripiprazole (Otsuka Pharmaceutical Co).

Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484].

Animals↗