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L Ereshefsky

Publications and source records attributed to L Ereshefsky.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1996

Pharmacokinetics and drug interactions: update for new antipsychotics.

Advances in our understanding of schizophrenia have led to a new generation of antipsychotic agents. These medications not only demonstrate reduced extrapyramidal symptoms but also possess pharmacologic profiles that can be especially advantageous in treating the negative symptoms of schizophrenia. The pharmacokinetics of many of the newer agents are compared and contrasted with typical neuroleptics. Changes in the pharmacokinetics and dosage of the newer agents are also reviewed. A particular emphasis is placed on the metabolism of the newer agents and their potential for drug-drug pharmacokinetic interactions. Clozapine, the archetypal atypical agent, has a complex pharmacokinetic profile with extremely large interpatient variability and many well-documented drug-drug interactions. Thus, clozapine presents special challenges in dose optimization and requires vigilant clinical monitoring for cardiovascular, neurologic, and hematologic adverse effects. Olanzapine demonstrates a very low potential for drug-drug interactions; it requires extremely high inhibitory concentrations at cytrochrome P450 (CYP) systems, typically 30-fold above the usual concentrations observed at steady-state oral high-dose therapy. The metabolic pathways of olanzapine include N-glucuronidation, reducing its overall sensitivity to drugs that might induce or inhibit its own metabolism via CYP or flavin-containing monooxygenase (FMO) systems. Plasma olanzapine concentrations at steady state typically demonstrate only a fourfold to fivefold variability among patients at a standard dose of medications. Sertindole and risperidone demonstrate polymorphic metabolism characteristics mirroring the CYP 2D6 phenotype. The inhibitory potentials of sertindole at CYP 2D6 and CYP 3A are modest and not likely to be of clinical significance. However, in those patients taking CYP 2D6 inhibitors or in those who are genotypic poor metabolizers, concentrations achieved by sertindole and its metabolites might result in moderate inhibition of CYP 3A.

Antipsychotic Agents↗
PubMed1995

Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6.

The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine display the following rank order of in vitro potency against the cytochrome P450 (CYP) isoenzyme CYP2D6 as measured by their inhibition sparteine and/or dextromethorphan metabolism: paroxetine > fluoxetine identical to norfluoxetine > or = sertraline > or = fluvoxamine > venlafaxine. On this basis, paroxetine would appear to have the greatest and fluvoxamine and venlafaxine the least potential for drug interactions with CYP2D6-dependent drugs. In vivo, inhibitory potency is affected by the plasma concentration of the free (unbound) drug, a potentially important consideration since many CYP2D6-metabolised drugs exhibit nonlinear (saturable) kinetics, and by the presence of metabolites, which might accumulate and interact with the CYP system. Under steady-state conditions, paroxetine and fluoxetine are approximately clinically equipotent inhibitors of CYP2D6 in vivo (as determined through their effects on desipramine metabolism); sertraline, in contrast, shows lower steady-state plasma concentrations than fluoxetine and, hence, a less pronounced inhibition of CYP2D6. Of the drugs that are metabolised by CYP2D6, secondary amine tricyclic antidepressants, antipsychotics (e.g. phenothiazines, and risperidone), codeine, some antiarrhythmics (e.g. flecainide) and beta-blockers form the focus of clinical attention with regard to their potential interactions with the SSRIs. Coadministration of desipramine and fluoxetine (20 mg/day) at steady-state produced an approximately 4-fold elevation in peak plasma desipramine concentrations, while the long half-life of the active metabolite norfluoxetine was responsible for a significant and long lasting (approximately 3 weeks) elevation of plasma desipramine concentrations after discontinuation of fluoxetine. Similarly, coadministration of desipramine with paroxetine produced an approximately 3-fold increase in plasma desipramine concentration. In contrast, coadministration of desipramine and sertraline (50 mg/day) for 4 weeks resulted in a considerably more modest (approximately 30%) elevation in plasma desipramine concentrations. Coadministration of fluoxetine (60 mg/day, as a loading dose) [equivalent to serum concentrations obtained with 20 mg/day at steady-state] with imipramine or desipramine resulted in approximately 3- to 4-fold increases in plasma area under the curve (AUC) values for both imipramine and desipramine (illustrating a significant drug interaction potential at multiple isoenzymes). Consistent with its minimal in vitro effect on CYP2D6, fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine (approximately 3- to 4-fold increase in AUC) through inhibition of CYP3A3/4, CYP1A2, and CYP2C19. Thus, the extent of the in vivo interaction between the SSRIs and tricyclic antidepressants mirrors to a large extent their in vitro inhibitory potencies against CYP2D6 and other isoenzyme systems, especially if one takes into account pharmacokinetic factors.

Animals↗
PubMed1993

A loading-dose strategy for converting from oral to depot haloperidol.

OBJECTIVE: The author's aim was to evaluate the safety and efficacy of a loading-dose regimen for initiating use of a depot medication, haloperidol decanoate, with patients who had been maintained on oral haloperidol. Patients were given a loading dose of about 20 times their oral maintenance dose in divided injections during the first two weeks of conversion to depot medication. The dose of haloperidol decanoate was gradually reduced, dropping to about ten times the oral dose in the third and fourth months. No supplemental oral medication was used. METHODS: Haloperidol decanoate was initiated using the loading-dose regimen in 16 chronically ill patients. Lower initial doses of haloperidol decanoate were used in two other groups of patients, one that received supplemental oral haloperidol and one that did not. Plasma levels of haloperidol, severity of illness, and side effects were monitored from baseline to 56 days after the beginning of depot therapy. RESULTS: Patients who received the loading-dose regimen showed statistically significant clinical improvement and reduced side effects over baseline by the 28th day. The second group of patients also maintained therapeutic response but improved no further. The third group relapsed during the first month and were returned to a regimen of oral haloperidol by the second month. CONCLUSIONS: A loading-dose regimen for initiating treatment with haloperidol decanoate is safe and effective and can be useful in a clinical setting.

Administration, Oral↗
PubMed1993

Pharmacological profile of risperidone.

The pharmacodynamics and pharmacokinetics of risperidone, an important atypical antipsychotic drug with potent serotonin-5-HT2 and dopamine-D2 receptor blocking effects, are presented. The pharmacology of atypical versus typical antipsychotic drugs is discussed in the contest of a pathophysiological conceptualization for schizophrenia which incorporates a parkinsonian model with an important role for serotonin and excitatory amino acid neurotransmission. In the normal therapeutic dose range, risperidone displays dose-linear pharmacokinetics in humans and reaches steady-state within 24 hours. Risperidone metabolism yields a active metabolite, 9-OH-risperidone, that has a similar pharmacological profile to the patient compound and therefore contributes to the clinical efficacy of the drug.

Antipsychotic Agents↗
PubMed1991

Ethnic comparison of haloperidol and reduced haloperidol plasma levels: Taiwan Chinese versus American non-Chinese.

Steady-state haloperidol (HAL) and reduced HAL (RHAL) plasma levels were measured in Chinese and non-Chinese schizophrenic patients. The patients (n = 38) were matched according to age (+/- 1 yr) and by HAL dose. In general, Chinese patients had higher mean plasma HAL levels and lower RHAL/HAL ratios compared to non-Chinese patients (23.6 +/- 14.9 ng/ml versus 17.1 +/- 10.1 ng/ml, p less than 0.05; 0.52 +/- 0.44 versus 0.82 +/- 0.62, p less than 0.05). Six groups were formed according to HAL dose (number per group): 10 mg/day (6); 20 (11); 30 (11); 40 (4); 50 (3); and 60 (3). No significant differences were found in age, weight and dose/weight. In each dose group, HAL plasma levels were generally higher in the Chinese patients than in the non-Chinese patients, though significance was only detected in the 30 mg group (26.1 +/- 7.0 ng/ml versus 18.5 +/- 5.1 ng/ml, p = 0.035) and a slight trend in the 40 mg group (36.0 +/- 15.0 ng/ml versus 23.5 +/- 10.4 ng/ml, p = 0.074). RHAL/HAL ratios were generally lower in the Chinese patients than in the non-Chinese patients, with a strong trend toward the significance level in the 20 mg and 30 mg groups (0.22 +/- 0.13 versus 0.58 +/- 0.57, p = 0.066 and 0.43 +/- 0.26 versus 0.71 +/- 0.34, p = 0.062). This study further suggests the possibility of different metabolic rates between Chinese and non-Chinese patients. Possible differences in the enzyme systems which relate to the metabolism of HAL and RHAL between Chinese and non-Chinese populations are discussed.

Adult↗
PubMed1991

Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables.

Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.

Administration, Oral↗
PubMed1990

Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients.

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.

Adult↗
PubMed1990

Pathophysiologic basis for schizophrenia and the efficacy of antipsychotics.

Current concepts of schizophrenia and its treatment are discussed. Schizophrenia entails negative symptoms, such as behavioral and cognitive deficits, attributed to loss of normal functions, and positive, or florid, symptoms that originate from the disturbed function of the remainder of the brain. Schizophrenia type I has positive symptoms predominating, and schizophrenia type II has negative symptoms predominating. Many atypical antipsychotics are now in Phase II and Phase III development; the prototype, clozapine, is now available. These agents challenge traditional views about drug treatment in schizophrenia. Schizophrenia may be explained by a persistent impairment in one or more neurotransmitter or neuromodulatory regulatory mechanisms, resulting in unstable or erratic neurotransmission. A more complex conceptualization of the role of the dopaminergic system makes it possible to understand the lack of biochemical tolerance to the therapeutic effects of antipsychotics, the varied time to onset of effects and prevalence of extrapyramidal symptoms, and the differences in efficacy within and among patients. Drug selection on the basis of patient-specific biological markers and neuropsychological function might expedite treatment responses. Drug therapy should augment homeostatic mechanisms and restore appropriate dopaminergic responses to physiological stimuli. Atypical antipsychotics may act by stabilizing presynaptic activity at a new set point, activating prefrontal dopaminergic systems and inhibiting mesolimbic systems, or exerting pharmacologic or functional effects on other neurotransmitter and neuropeptidergic systems. The traditional view that schizophrenia is simply a manifestation of dopaminergic overactivity is inadequate. New investigative techniques and the study of atypical antipsychotics suggest that a dysregulation hypothesis may be more consistent with the complexities of schizophrenia.

Antipsychotic Agents↗
PubMed1990

Cocaine abuse and its treatment.

Widespread use and abuse of cocaine have increased the frequency with which health professionals must manage acute and chronic intoxication and the complications stemming from drug ingestion. Acute intoxication from catecholamine excess progresses through three stages, affecting the cardiovascular, respiratory, and central nervous systems. Management is to support or return these systems to normal with sedation, beta blockade, and antiarrhythmics. Casual cocaine use is no longer considered benign, and numerous related medical complications are now recognized. Dopaminergic systems are the principal sites of reward and participate in abstinence symptomatology, putatively through depletion of dopamine and changes in receptor sensitivity and responsiveness. Long-term treatment approaches have focused on psychologic strategies of behavior modification and supportive psychotherapy. Pharmacotherapy with desipramine, amantadine, and bromocriptine was shown in preliminary studies to minimize the symptoms of cocaine withdrawal when used adjunctively with psychotherapy. The response to treatment may depend on the patient's premorbid psychiatric status.

Animals↗
PubMed1990

Kinetics and clinical evaluation of haloperidol decanoate loading dose regimen.

We have evaluated the efficacy and safety of different dosing regimens of haloperidol decanoate (HLD). Eighteen patients were evaluated as part of our ongoing Therapeutic Drug Monitoring Program. Diagnoses were chronic schizophrenia (n = 12), bipolar with psychosis (n = 3), and others (n = 3). Patients were assessed prior to each HLD dose using the Clinical Global Impressions (CGI) rating scale. The total monthly HLD dose for our population was calculated based on a target conversion ratio of 20 times the previously administered oral haloperidol dose given in divided doses of 100 mg to 150 mg every 3 to 7 days until the full amount was administered. This HLD dosing pattern was repeated during the second month, but at a lower dose to compensate for drug accumulation. Despite this loading dose paradigm, significantly greater haloperidol plasma concentrations were present during oral haloperidol than during the first month of HLD therapy. This regimen achieves therapeutically equivalent plasma concentrations (Cps) more rapidly following conversion from oral haloperidol than standard dosing procedures. A series of cases and pharmacokinetic simulations are used to illustrate the therapeutic relationship of dosing to plasma concentrations.

Adult↗
PubMed1989

Haloperidol and reduced haloperidol plasma levels in Chinese vs. non-Chinese psychiatric patients.

Haloperidol and reduced haloperidol plasma concentrations were measured in age-matched Chinese and non-Chinese patients (n = 32). Steady-state plasma concentrations were obtained 10-12 hours after the bedtime dose. Haloperidol and reduced haloperidol concentrations were measured by liquid chromatography and radioimmunoassay. Haloperidol plasma concentrations did not significantly differ between the populations, but reduced haloperidol levels were 3 times greater in non-Chinese patients than in Chinese patients. The incidence of extrapyramidal side effects was higher in Chinese patients (18 vs. 10), while non-Chinese patients with extrapyramidal symptoms had higher reduced haloperidol plasma levels. Logistic regression analysis revealed that ethnicity and reduced haloperidol/haloperidol ratios were important variables in predicting extrapyramidal symptoms. These results suggest that the metabolism and disposition of haloperidol and reduced haloperidol could differ among ethnic populations.

Adult↗
PubMed1989

Clozapine: an atypical antipsychotic agent.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed. Clozapine is a dibenzazepine compound chemically similar to loxapine but with a distinct pharmacologic profile. Unlike currently available medications, clozapine has a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity. It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors. Clozapine given orally is nearly completely absorbed and readily metabolized. Urinary excretion is the major route of metabolite elimination. Clozapine has been used to treat schizophrenia, nonschizophrenic psychotic states, depression, neuroses, and behavioral disorders. Double-blind comparative studies have shown clozapine to be superior to haloperidol, chlorpromazine, and placebo in treating the symptoms of schizophrenia, as measured with validated psychiatric rating scales. Adverse effects include orthostatic hypotension, tachycardia, benign hyperthermia, hypertension, seizures, and sedation. Many of these effects are transient. Because of the risk of agranulocytosis, a comprehensive case-management system has been developed. In treating acute psychosis, the optimum dosage of clozapine is 300-450 mg/day given orally in divided doses. The high cost of clozapine may be offset by improved patient response and reduced hospital costs. Clozapine may be superior to other agents in the treatment of refractory schizophrenia and is associated with a negligible incidence of extrapyramidal symptoms.

Antipsychotic Agents↗
PubMed1988

Clinical outcome and adverse effect profile associated with concurrent administration of alprazolam and imipramine.

Clinical outcome and adverse effects associated with concurrent alprazolam and imipramine administration were studied in 29 patients with major depressive disorder who completed a 6-week trial in which they served as their own controls. Alprazolam was added on Day 8 in gradually escalating, then gradually tapering dosages while imipramine dosages remained unchanged. Significant decreases were observed in scores on the Hamilton Rating Scales for Depression and Anxiety at all later evaluation days with Day 8 as baseline. The mean total Symptom and Side Effects score decreased significantly from Day 8 to Day 22 when alprazolam doses were 1 mg q.i.d. For most side effects, total number of reports remained constant or decreased from Day 1 to later evaluation days. Standing diastolic blood pressures were significantly lower on Day 22 than on Day 1. No significant relationship was found between any rating scale score and plasma concentration data.

Adult↗
PubMed1988

Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine--new data and review.

The selection of a starting dose for an antidepressant, and subsequent clinical titration to an appropriate therapeutic dosage, should be based on pharmacokinetic and pharmacodynamic principles. In the past decade, therapeutic monitoring of antidepressant drugs and use of pharmacokinetic principles have been shown to be an improvement over the dose-response approach. Endogenous (e.g., genetic metabolic phenotype, hepatic blood flow, and protein binding) and exogenous factors (e.g., smoking, dietary habits, concurrent medications) are capable of influencing physiological and pharmacokinetic variables in patients, accounting for the marked interindividual differences in the clearance rates of cyclic antidepressants. Interpatient variability for steady-state concentrations in plasma (Cpss) greater than 20-fold are observed at a fixed dose of imipramine (r2 = 0.525, df = 346, t = 19.541, P less than 0.0001) or doxepin (r2 = 0.506, df = 128, t = 11.403, P less than 0.0001). Analysis of doxepin in plasma vs estimated in oral clearance for 61 patients demonstrates a significant decline in oral clearance as a function of Cpss. At doses approaching the upper range recommended for the treatment of depression, Cpss appear to approach, in at least a few individuals, the maximum metabolic capacity of the patient (Vmax), leading to greater-than-expected increases in concentrations for a given dosage increment. Significant alterations in oral clearance are observed when medications are administered concomitantly. A greater-than-threefold difference in mean oral doxepin clearance rates is observed between two groups of patients receiving additional medications that are either inducers or inhibitors (P less than 0.0001, df = 32, t = 6.687). Pharmacokinetic principles defining and explaining the determinants of oral clearance can provide the clinician with a greater insight into the reasons for therapeutic failure and toxicity.

Aged↗
PubMed1987

An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction.

The use of observational data, collected during the routine clinical care of patients, has been advocated as a means to obtain clinically relevant information regarding the pharmacokinetic parameters of drugs. However, the validity of this approach and its proper role in new drug development is unclear. This study was performed to evaluate the ability of three approaches to estimate population pharmacokinetic parameters: the traditional approach, mixed-effect modeling, and a simple pharmacokinetic screen. The evaluation was performed with data collected during a multicenter, open-label study evaluating the efficacy, safety, and pharmacokinetics of imipramine and alprazolam in combination. The traditional pharmacokinetic study demonstrated a 20% decrease in the clearance of imipramine in the presence of 4 mg/day alprazolam. Mixed-effect modeling extends these findings by suggesting that the interaction is dependent on the simultaneous concentration of alprazolam, a finding that was not possible under the study design typically used for traditional pharmacokinetic studies. Although the simple screen suggests the presence of the drug-drug interaction, limited information regarding pharmacokinetic parameters is available and those parameters that can be estimated are biased.

Adult↗