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L Ereshefsky

Publications and source records attributed to L Ereshefsky.

At least 19 recordsLinked to original sources
PubMed2001

Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine.

Administration, Oral↗
PubMed2001

Branded versus generic clozapine: bioavailability comparison and interchangeability issues.

Clozapine has been the treatment of choice for patients with refractory schizophrenia. Generic clozapine has recently become available, because of a waiver of the usual criteria for establishing bioequivalence. However, there are biopharmaceutical, bioavailability, and clinical concerns related to the generic formulation raised by both clinicians and academic researchers. We conducted a prospective, randomized, crossover study to evaluate steady-state pharmacokinetics, pharmacodynamics, and tolerability of generic clozapine (Zenith Goldline Pharmaceuticals) versus Clozaril (Novartis Pharmaceuticals) in schizophrenic patients. A preliminary report of the pertinent bioavailability results is presented here. Despite comparable mean plasma concentration-time curves, significant differences were found in the primary pharmacokinetic parameters of the 2 formulations in almost 40% of patients. Such intraindividual differences raise the issue of average bioequivalence versus individual bioequivalence and the implication for interchangeability of different clozapine formulations. The decision to switch a patient from branded to generic clozapine should be made on an individual basis with special emphasis on clinical outcome, and patients should be monitored closely during the transition.

Adult↗
PubMed2000

Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: focus on venlafaxine.

Improving outcomes for patients with depression involves selecting the best possible drug therapy. Considerations relevant to drug product selection include: 1) pharmacokinetic issues such as half-life and time to steady-state, and protein binding; 2) pharmacodynamic drug-drug interactions; and 3) drug metabolism-related drug interactions. A comparison of selected antidepressants with an emphasis on venlafaxine's similarities and differences is presented. Based on these parameters, selecting an antidepressant medication, such as venlafaxine, that has a low potential for drug interactions at the Cytochrome P450 (CYP) enzyme system, and is easy to monitor and dose, facilitate successful treatment of patients. Venlafaxine has been evaluated in clinical studies that demonstrate low to negligible drug interaction potential at CYP2D6, CYP1A2, CYP2C19, and CYP3A4. Its short half-life and time to steady-state, when coupled with the extended release characteristics of the preferred dosage formulation allow for once daily dosing and rapid attainment of therapeutic effects. The CYP3A4 system is involved in both first-pass metabolism and systemic clearance of medications. Drug interactions at this isoenzyme have proven to be of high clinical relevance ranging from cardiovascular toxicity and death with commonly used drugs such as cisapride, to subtherapeutic levels of cyclosporine or protease inhibitors leading to transplant rejection or HIV relapse. Reasons for the under detection and reporting of drug interaction mediated adverse events include healthcare system structure, the poor return to follow up of non-adherent patients, the need for greater education and training of clinicians to recognize drug-related adverse events, and the reluctance of patients to spontaneously communicate about the unpleasant effects of their medication.

Aged↗
PubMed2000

CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations.

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; chi 2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.

Chromatography, High Pressure Liquid↗
PubMed1999

CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline.

The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.

Adult↗
PubMed1999

Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic.

Recent advances in our understanding of schizophrenia along with neuroscience insights into antipsychotic medication mechanisms of action have led to a renaissance in new drug development, including an expanded therapeutic spectrum encompassing more of the symptoms encountered in schizophrenia. Atypical antipsychotics, or new generation therapies, also demonstrate greater selectivity for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern armamentarium of drugs spans a wide range of pharmacologies, and it is more accurate to envision shades of gray rather than a black-and-white description for typical versus atypical properties of medications. As our paradigms for antipsychotic efficacy have shifted, a reexploration of the "older" neuroleptics is warranted to determine if they possess pharmacologic attributes that might have been overlooked during the era of high-dose neuroleptic therapy. Loxapine appears to be in the center of this spectrum, somewhere between haloperidol and risperidone. Dosing implications for drugs with a more even serotonin-2A (5-HT2A) receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine might have a window of partial atypicality at doses < or = 50 mg/day. These lower doses might have potential as both monotherapy in responsive patients with persistent psychotic disorders and as an adjunctive treatment in partially responding patients on concurrent atypical antipsychotic treatments. The pharmacologic properties of loxapine within its usable dosage range are quite complex and are the net sum of the parent's plus metabolites' contributions (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic effects include alpha-adrenergic blockade, inhibition of the noradrenergic transporter protein (reuptake inhibition), and antimuscarinic effects. Drug interactions and cigarette smoking might alter the parent-to-metabolite concentration ratios, affecting the relative atypicality of this antipsychotic therapy. Moreover, with the intramuscular formulation, which does not undergo first-pass metabolism, the parent compound of loxapine, i.e., not its metabolites, is predominantly detected in the plasma of patients, reducing the likelihood for EPS during emergency interventions in patients with positive symptoms. Further study is warranted to determine loxapine's place in our treatment of schizophrenia.

Antipsychotic Agents↗
PubMed1997

Venlafaxine.

Explore the source record for details and available documents.

Antidepressive Agents, Second-Generation↗
PubMed1996

Drug-drug interactions involving antidepressants: focus on venlafaxine.

Selection of an antidepressant is influenced by many factors, including the patient's current drug regimen and the drug's potential for drug-drug interactions. Many psychotropic agents are known to be involved in drug-drug interactions because they are metabolized by various cytochrome pigment 450 (CYP) isoenzymes. In vitro testing with human hepatic microsomal preparations and monoclonal antibody techniques has allowed for the identification and investigation of many of these isoenzymes. Also, screening of substrates (both drug and probe) at the level of the various enzymes expressed in the human liver has allowed for the development of models that predict the risk for drug-drug interactions in vivo. Antidepressants are metabolized by and are competitive inhibitors of several isoenzymes: CYP1A2, CYP2D6, CYP3A3/4, CYP2C8/9, CYP2C19, and others. Of these, CYP2D6 has been the most thoroughly investigated and is the most extensively characterized, whereas CYP3A3/4 are more abundant and play a major role in the metabolism of many commonly used drugs. CYP2D6, but not CYP3A3/4, is subject to genetic polymorphism, which has been identified through the administration of a probe drug (sparteine, debrisoquin, or dextromethorphan). This analysis allows for the determination of an individual's "metabolizer status." This article discusses the CYP isoenzyme system in general terms and presents selected in vitro information that has been used to determine the likelihood of in vivo drug-drug interactions with various antidepressants. Of the marketed antidepressants, venlafaxine seems to have one of the most favorable drug-interaction profiles, and data specific to it are highlighted. In vitro and in vivo data indicate that venlafaxine either does not significantly inhibit or weakly inhibits the activity of isoenzymes CYP2C9, CYP2D6, CYP1A2, or CYP3A3/4.

Animals↗
PubMed1996

Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system.

The article focuses on the effects of the serotonin selective reuptake inhibitors (SSRIs) on specific drug metabolizing isoenzymes: CYP2D6, CYP3A3/4, CYP1A2, CYP2C9, and CYP2C19. Both in vitro and in vivo data regarding the inhibition potential of the SSRIs at each of these isoenzyme systems are reviewed. In general, the magnitude of the in vivo interactions between the SSRIs and substrates for these isoenzyme systems mirrors to a large extent their in vitro inhibitory potencies. However, in vitro work is limited owing to pharmacokinetic considerations, the effect of metabolites on the isoenzymes, and the likelihood that several isoenzymes are co-responsible for the metabolism of a substrate.

Antidepressive Agents↗
PubMed1996

A pharmacoeconomic model of outpatient antipsychotic therapy in "revolving door" schizophrenic patients.

BACKGROUND: The discrepancy between supply and demand in health care today requires that psychiatrists and other providers of patient care expand their traditional role from one of patient advocate to one of allocator of care. In this new role, the care provider must consider not only the efficacy and safety of a therapeutic regimen, but also its impact on society in terms of quality of life and cost-effectiveness. METHOD: A variety of pharmacoeconomic analysis methodologies have been used to assess the economic and quality of life consequences of alternate treatment strategies. A clinical decision analysis model that takes into account compliance rates and associated rehospitalization was used to compare the direct treatment costs associated with alternate outpatient neuroleptic strategies for "revolving door" schizophrenic patients. The antipsychotic treatment options considered were traditional oral neuroleptics (e.g., haloperidol), depot neuroleptics (e.g., haloperidol decanoate), and "atypical" oral agents (e.g., risperidone). RESULTS: The results of this decision analysis model (based on a set of reasonable outcome probabilities and costs) suggest that, under five sets of cost and outcome assumptions, switching to the depot route in a patient with a history of relapse and rehospitalization may reduce total direct treatment costs by approximately $650 to $2600/year compared with an atypical agent and approximately $460 to $1150/year compared with a traditional oral neuroleptic. Under a sixth set of assumptions-namely, a compliance rate with atypical oral drug (80%) equal to that with the depot agent and an average wholesale price of the atypical drug 25% lower than current wholesale price-the atypical oral drug treatment option would be approximately $700 less than treatment with a depot agent, and $1860 less than treatment with a traditional neuroleptic. CONCLUSION: The decision analysis model presented here indicates that, under a variety of assumptions, switching a revolving door patient to a depot medication for outpatient maintenance therapy could result in lower total direct treatment costs over the first year. This finding was consistent, although to varying degrees, under differing probability and cost assumptions. The proposed model can be used in other clinical circumstances, such as treatment-refractory patients or those with severe negative symptoms, as well as with other associated outcome probabilities and costs. Application of this model in different clinical scenarios associated with different outcome probabilities and treatment costs, however, may well provide different results.

Administration, Oral↗
PubMed1996

Serotonin-mediated increase in cytosolic [Ca++] in platelets of risperidone-treated schizophrenia patients.

Stimulating the platelet 5HT2 receptor generates the second messenger IP3, and results in an increase in cytosolic [Ca++] ([Ca++]cyt). Platelets from risperidone-treated patients would be expected to respond less effectively, as measured by decreased [Ca++]cyt, after 5HT2 receptor stimulation. We report the data on 6 risperidone-treated patients and 6 normal controls evaluated at our site using the Fura-2 method for determining platelet [Ca++]. Data analysis was performed by unpaired two-tailed Student's t-test. No significant differences between groups were found for ED50 5HT-stimulated [Ca++]cyt (ED50 5HT delta [Ca++]cyt). Significant differences were found for maximal change [Ca++]cyt (Max delta [Ca+2]cyt) between risperidone-treated patients and normal controls (p = .03). These preliminary data suggest that measurement of 5HT-stimulated changes in platelet cytosolic [Ca+2] might be a useful marker for in vivo risperidone inhibition of 5HT2 function.

Adult↗