Biomedical subjects

S R Marder

Publications and source records attributed to S R Marder.

At least 73 records · Page 4Linked to original sources

PubMed1994

Radioimmunoassay for 7-hydroxy metabolite of fluphenazine and its application to plasma level monitoring in schizophrenic patients treated long term with oral and depot fluphenazine.

Immunization of New Zealand white rabbits with a bovine serum albumin conjugate of 7-hydroxy-N-carboxyethyl-N-deshydroxyethylfluphenazine produced highly specific antisera for 7-hydroxyfluphenazine (7-OHFLU). A radioimmunoassay (RIA) was developed using antisera from one of the rabbits that enabled for the first time the determination of plasma levels of 7-OHFLU, an active metabolite of fluphenazine (FLU), in patients treated with oral FLU dihydrochloride or i.m. FLU decanoate. The assay method provided sufficient sensitivity to determine accurately 20 pg of 7-OHFLU in 200 microliters (0.1 ng/ml) of plasma with a coefficient of variation of < 10%. The antiserum used in the RIA for 7-OHFLU demonstrated negligible cross-reactivity with FLU and its metabolites such as FLU sulfoxide, N-deshydroxyethylFLU, FLU N4'-oxide, N-deshydroxyethyl-7-OHFLU, and 7-O-glucuronide of FLU and also with other antipsychotic agents and commonly coadministered drugs. The 7-OHFLU was present in measurable amounts in all plasma samples obtained at 4-week intervals from patients receiving a daily oral dose of 5 (n = 10), 10 (n = 13), or 20 (n = 14) mg of FLU dihydrochloride. Large interindividual variations in the plasma level of FLU and 7-OHFLU were noted and the mean plasma levels ratios of 7-OHFLU/FLU at these doses were 2.07 +/- 1.08, 2.07 +/- 1.13, and 2.02 +/- 0.82, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

The role of dosage and plasma levels in neuroleptic relapse prevention.

Recent research has focused on strategies for optimizing the long-term treatment of schizophrenia by decreasing relapse rates at the same time that antipsychotic drug side effects are minimized. Studies have suggested that substantially lowering the dose by as much as 80% can result in fewer side effects, less anxiety and depression, and improved compliance. However, dosage reduction can also lead to increases in the vulnerability to mild exacerbation of psychosis. A recent study from our laboratory indicates that supplementing low dose depot antipsychotic medications with oral supplementation at the time of prodromal symptoms may improve the safety of low doses. For patients who are treated with fluphenazine decanoate, monitoring plasma fluphenazine levels may also help to minimize relapse rates.

Antipsychotic Agents↗

PubMed1994

Optimal drug and behavior therapy for treatment-refractory schizophrenic patients.

Thirteen treatment-refractory schizophrenic patients (10 men and three women) who were receiving more than 50 mg/day of haloperidol and who had been hospitalized for more than 1 year successfully tolerated a mean dose reduction of 63% with consequent improvement in psychopathology and side effects. The addition of intensive behavior therapy to the optimal dose of haloperidol yielded further improvements in functional behavior, such as self-care and social interaction.

Adult↗

PubMed1994

Risperidone in the treatment of schizophrenia.

OBJECTIVE: The purpose of this study was to investigate the safety and efficacy of risperidone in the treatment of schizophrenic patients and determine its optimal dose. METHOD: This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States. Patients were randomly assigned to 8 weeks' treatment with placebo, one of four doses of risperidone (2, 6, 10, or 16 mg), or 20 mg of haloperidol daily. RESULTS: Clinical improvement (20% reduction in total scores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% of the patients receiving 2 mg of risperidone, 57% receiving 6 mg, 40% receiving 10 mg, and 51% receiving 16 mg; and by 30% receiving haloperidol and 22% receiving placebo. Statistically significant differences in clinical improvement were found between 6 and 16 mg of risperidone versus placebo and versus haloperidol. Positive symptom scores were significantly lower after 6, 10, and 16 mg of risperidone and 20 mg of haloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 16 mg of risperidone. The incidence of extra-pyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 16 mg of risperidone or 20 mg of haloperidol than placebo. The results indicate that the optimal daily dose of risperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 16 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo. CONCLUSIONS: Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia.

Adolescent↗

PubMed1994

Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia.

This review covers some recent work on: 1. The effects of route of administration on the pharmacokinetics of fluphenazine and some of its metabolites; 2. The clinical pharmacokinetics of fluphenazine in acute patients medicated with oral fluphenazine; 3. The clinical pharmacokinetics of haloperidol in acute patients medicated with oral haloperidol; 4. The clinical pharmacokinetics of fluphenazine in the maintenance of individuals with chronic schizophrenia with fluphenazine decanoate; 5. A systematic dose reduction study in maintenance treatment refractory patients with oral haloperidol. A study in which plasma levels of fluphenazine and fluphenazine sulfoxide were measured in a group of DSM-III-R patients with schizophrenia before and after switching from oral fluphenazine to depot fluphenazine, decanoate revealed much higher levels of fluphenazine sulfoxide with oral medication compared with those found with depot fluphenazine. These data illustrate the effect of "first pass" metabolism after oral fluphenazine. Thus in a group of 33 patients randomly assigned to receive 5 mg, 10 mg or 25 mg oral fluphenazine daily, steady state plasma fluphenazine levels at each dose were significantly lower that those of fluphenazine sulfoxide or 7-hydroxy-fluphenazine, although there were no significant differences between the levels of fluphenazine and fluphenazine N4-oxide. On the other hand, plasma levels of the parent drug were significantly higher than those of any metabolite in a corresponding group of patients at steady state on depot medication. These observations underscore the importance of route dependent differences in the pharmacokinetics of fluphenazine which can lead to problems when switching patients from oral to depot neuroleptics. The concept of "disabling side-effects" is an important development in understanding relationships between plasma levels of neuroleptic drugs and clinical response in patients with schizophrenia. Risk-benefit analysis shows clearly that evaluation of relationships between plasma levels and clinical response must take into account the consequences of side-effects which the patient feels have a negating effect on therapy. Emerging data on putative therapeutic plasma level ranges in maintenance therapy are potentially important and may be particularly useful in the maintenance of patients on low dose therapy. It is noteworthy that in a carefully executed dose reduction study in treatment resistant patients under medication with haloperidol, the mean lowest effective dose (8.7 ng/mL) lay within the optimal therapeutic range (5 ng/mL to 12 ng/mL) found in acutely psychotic patients. The study showed that gradual dose reduction of neuroleptic was possible in chronic treatment resistant patients with schizophrenia who were originally thought by ward staff to require high doses of neuroleptic.(ABSTRACT TRUNCATED AT 400 WORDS)

Antipsychotic Agents↗

PubMed1994

In vivo MR evaluation of age-related increases in brain iron.

PURPOSE: To assess the validity of an MR method of evaluating tissue iron. METHODS: The difference between the transverse relaxation rate (R2) measured with a high-field MR instrument and the R2 measured with a lower field instrument defines a measure termed the field-dependent R2 increase (FDRI). Previous in vivo and in vitro studies indicated that FDRI is a specific measure of tissue iron stores (ferritin). T2 relaxation times were obtained using two clinical MR instruments operating at 0.5 T and 1.5 T. T2 relaxation times were measured in the frontal white matter, caudate nucleus, putamen, and globus pallidus of 20 healthy adult male volunteers with an age range of 20 to 81 years. R2 was calculated as the reciprocal of T2 relaxation time. These in vivo MR results were correlated with previously published postmortem data on age-related increases of nonheme iron levels. RESULTS: The FDRI was very highly correlated with published brain iron levels for the four regions examined. In the age range examined, robust and highly significant age-related increases in FDRI were observed in the caudate and putamen. The correlations of age and FDRI in the globus pallidus and white matter were significantly lower and did not have statistical significance. CONCLUSIONS: The data provide additional evidence that FDRI is a specific measure of tissue iron stores. The data also show that age-related increases in tissue iron stores can be quantified in vivo despite significant age-related processes that oppose the increase in R2 caused by iron. These results are relevant to the investigation of neurodegenerative processes in which iron may catalyze toxic free-radical reactions.

Adult↗

PubMed1993

An investigation of the interrelationships between linear and nonlinear polarizabilities and bond-length alternation in conjugated organic molecules.

A computational method was devised to explore the relationship of charge separation, geometry, molecular dipole moment (mu), polarizability (alpha), and hyperpolariz-abilities (beta, gamma) in conjugated organic molecules. We show that bond-length alternation (the average difference in length between single and double bonds in the molecule) is a key structurally observable parameter that can be correlated with hyperpolarizabilities and is thus relevant to the optimization of molecules and materials. By using this method, the relationship of bond-length alternation, mu, alpha, beta, and gamma for linear conjugated molecules is illustrated, and those molecules with maximized alpha, beta, and gamma are described.

Journal Article↗

PubMed1993

Determination of risperidone in plasma by high-performance liquid chromatography with electrochemical detection: application to therapeutic drug monitoring in schizophrenic patients.

A highly sensitive high-performance liquid chromatography method with electrochemical detection for the determination of risperidone in plasma has been developed. Remoxipride is used as an internal standard. A simple one-step extraction with 25% methylene dichloride in pentane is used to isolate the drug from the plasma. This is followed by high-performance liquid chromatography analysis on a cyano column with electrochemical detection. Under the experimental conditions described here, commonly coadministered drugs and other antipsychotic drugs did not interfere with the analysis of either risperidone or the internal standard. Also, the available two metabolites of risperidone did not interfere in the assay. This method has sufficient sensitivity to quantitate risperidone accurately at 0.1 ng/mL, when 1 mL of plasma was used for the analysis, with a coefficient of variation of < 9%. This method has been successfully used in the determination of plasma levels of risperidone in schizophrenic patients treated with 4-, 6-, and 8-mg oral doses per day.

Antipsychotic Agents↗

PubMed1993

Field dependent transverse relaxation rate increase may be a specific measure of tissue iron stores.

The degree to which MRI magnet field strength affects measured transverse relaxation rates (R2) defines a measure termed the field dependent R2 increase (FDRI). We report here the results of in vivo and in vitro experiments that were conducted to evaluate whether FDRI is a potentially useful measure of tissue iron stores. T2 relaxation times were obtained using two clinical MRI instruments operating at 0.5 and 1.5 Tesla, and relaxation rates (R2) were calculated as the reciprocal of T2. The in vivo experiment measured R2 in human brain frontal white matter, caudate nucleus, putamen, and globus pallidus. The FDRI was very highly correlated with published brain iron levels for the four regions examined. The in vitro experiment measured R2 in agarose gel-based phantoms containing physiologic forms and amounts proteins involved in iron storage and transport (ferritin, apoferritin, transferrin, and apotransferrin). Significant field dependence was observed only for the ferritin phantoms. The differences in the R2 values obtained at the two field strengths were striking, and were proportional to the ferritin levels of the phantoms. These studies suggest that FDRI may be a specific measure of tissue ferritin. The quantitative significance of the results to imaging and possible applications to the clinical investigation of pathologic states are discussed.

Adult↗

PubMed1993

Reliability of in vivo volume measures of hippocampus and other brain structures using MRI.

Volume reductions of the hippocampus are associated with Alzheimer's disease, schizophrenia, and epilepsy. We used clinically available MRI methods (2D acquisition; inversion recovery and calculated T2 images; 3 mm contiguous slices) that optimize image contrast, quality, and resolution and standardized positioning protocols to maximize the in vivo accuracy (test-retest reliability) of brain volume measurements in volunteers who were scanned two or three times. Volunteers were scanned in the same MRI instrument (intrascanner reliability) as well as in two different instruments (interscanner reliability). A single rater obtained brain volume measures of seven contiguous slices centered on the anterior commissure. The in vivo intrascanner reliability for measures of anterior hippocampus and ventricular volumes was very good, with reliability coefficients [intraclass r (rxx)] ranging between .855 and .997, and a median coefficient of variation (CV) of 6.4%. Reliability was good for amygdala (rxx of .740 and .764) and for total frontal and temporal lobe volumes and white matter volume measures (rxx ranging between .640 and .823, median coefficient of variation was 3.2%). Overall, interscanner reliability was also good. We discuss the implications of our results relative to the possible clinical utility of hippocampal quantification and the feasibility of prospective studies aimed at quantifying progressive neurodegeneration.

Adult↗

PubMed1993

Preliminary associations between motor procedural learning, basal ganglia T2 relaxation times, and tardive dyskinesia in schizophrenia.

The hypothesis that the caudate nucleus is involved in the pathophysiology of tardive dyskinesia (TD) in schizophrenia was investigated by examining motor procedural learning on the pursuit rotor task and basal ganglia T2 relaxation times (T2) determined using magnetic resonance imaging (MRI). Increased severity of TD was associated with shortened caudate T2 and decreased motor learning. Motor-learning scores of schizophrenic patients with and without TD did not differ significantly from those of normal control subjects, but motor learning in the schizophrenic patients correlated with caudate T2. The results suggest that a corticocaudate system subserves motor procedural learning and provide converging evidence from neuropsychological and MRI measures suggesting caudate involvement in TD.

Adult↗

PubMed1993

Psychopharmacologic treatment of schizophrenia.

Antipsychotic (neuroleptic) medications continue to be a critical component in the treatment of schizophrenia. Despite numerous advances in brain imaging, genetics, and neurochemistry, the pharmacologic agents routinely used to treat schizophrenia have not changed markedly over the last 30 years. The introduction of clozapine, however, represents an important step in drug development and has stimulated renewed activity in this area. In addition, its novel effects have had a heuristic value in efforts to better understand neuropharmacologic mechanisms. While we await further advances in treatment development, we are benefiting from clinical research focusing on improving our ability to use available pharmacotherapy in the most effective and least toxic manner. Recent studies reemphasize the potential value of using the minimum effective dosage for acute treatment (e.g., 10-15 mg/day of oral haloperidol) and provide needed data on the benefits and risks of long-term dosage reduction strategies (i.e., continuous low-dose or targeted/intermittent treatment).

Antipsychotic Agents↗

PubMed1993

Clinical perspectives of some neuroleptics through development and application of their assays.

Attempts to investigate relationships between plasma levels of neuroleptics and therapeutic outcome in schizophrenic patients have been hampered due to such factors as the chemical nature of these drugs, their metabolism, and the very heterogeneous nature of the disease states. Two clinical studies are described that investigate the relationship between plasma levels of fluphenazine (FLU) and its metabolites and therapeutic outcome in schizophrenic patients. In the first of these studies the levels of FLU and fluphenazine sulfoxide (FLUSO) in schizophrenics receiving either 5 or 25 mg of fluphenazine decanoate (FLUD) intramuscularly every 2 weeks were monitored. Patients given 25 mg of FLUD required 3 months to reach plasma level steady state. The results suggest that such patients, when being switched from the oral to the depot formulation of FLU, should continue to receive oral supplementation during the 1st 3 months after conversion. The relationship between log-transformed plasma levels at 26 and 38 weeks with subsequent psychotic exacerbation was investigated with the use of logistic regression and survival analysis. Both demonstrated significant relationships between FLU plasma levels and a risk of psychotic exacerbation at 26 and 38 weeks. The possibility of any correlations between neurological side effects and plasma concentrations were also investigated, with statistically significant correlations between FLU levels and akinesia found at 2 and 26 weeks. In the second of these studies the levels of FLU, FLUSO, 7-hydroxyfluphenazine (7-OHFLU), and fluphenazine N4'(-)-oxide (FLUNO) in schizophrenics receiving 5, 10, or 20 mg of oral fluphenazine dihydrochloride daily for 4 weeks were monitored. The relationships between log-transformed plasma levels, disabling side effects, and global improvement were examined by logistic regression for the 4-week period. The study showed a significant correlation between increases in both plasma levels and disabling side effects such that at a plasma level of 2.7 ng/ml, approximately 90% of acutely ill patients experienced disabling side effects. Conversely, the study also showed that at a plasma level of 0.67 ng/ml, 48% of patients experienced improvement without the development of disabling side effects. When relationships between metabolite levels, disabling side effects, and global improvement were examined by logistic regression, a stronger correlation between disabling side effects and FLUNO levels than between side effects and FLU levels was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Antipsychotic Agents↗

PubMed1993

Patients' perceptions of family emotional climate and outcome in schizophrenia.

Thirty-nine chronic schizophrenic male out-patients and their relatives were interviewed separately to assess their perceptions of their current relationships. Two simple 5-point rating scales predicted the risk of psychotic exacerbation during a one-year follow-up: patients' perceptions of the relatives' attitudes towards them, and patients' own attitudes towards the relatives. Survival analysis of data in a 2 x 2 factorial--combining degree of contact with the key relatives and the patients' perceptions of their relatives--found that patients in frequent contact with a positively perceived relative had significantly better survival rates without psychotic exacerbation. Patients' perceptions of their relatives may help identify patients at risk of exacerbation of their illness.

Adolescent↗

PubMed1993

Systematic dosage reduction in treatment-resistant schizophrenic patients.

Thirteen treatment-resistant, chronically institutionalized schizophrenic patients on high-dose neuroleptic (the equivalent of at least 50 mg of haloperidol (HPL) daily) were transferred to a special research ward for a trial of systematic dosage reduction. In these 13 patients, it was possible to reduce the dose of HPL from 63.1 mg/day (SD +/- 12.5, range = 50-80 mg/day) to 23.1 mg/day (SD +/- 16.3, range = 0-65 mg/day) over a mean period of 32 weeks (SD +/- 9.6, range = 15-46 weeks). Their total Brief Psychiatric Rating Scale (BPRS) scores were improved (p = .04), they definitely experienced fewer extrapyramidal side effects (p = .01), and 6 of the patients showed global improvement. On several behavioral rating scales there was, if anything, an improvement in negativistic behavior. The substantial dosage reduction was paralleled by a comparable drop in plasma levels. HPL plasma levels at baseline were 38.8 ng/mL (SD +/- 17.8, range = 21.5-69.5 ng/mL) and at the lowest effective dose were 12.4 ng/mL (SD +/- 10.3, range = 0-43.4 ng/mL).

Adult↗

PubMed1993

Metabolism of phenothiazine and butyrophenone antipsychotic drugs. A review of some recent research findings and clinical implications.

Whereas some metabolites of antipsychotic drugs are psychoactive and contribute to clinical improvement, recent studies have provided evidence that certain metabolites contribute to side-effects which can be disabling enough to negate clinical improvement as regards the psychosis. The route of administration of the drug can determine the amount of metabolite produced in the body and affect how the patient feels in response to the treatment.

Animals↗

PubMed1993

Dose response of prophylactic antipsychotics.

A review of the literature concerning the use of oral and depot antipsychotic medication has high-lighted some important considerations in the treatment of chronic schizophrenic patients. All patients not treated with any form of antipsychotic drug will relapse within 3 years. These relapses will be more clinically significant and will occur at greater frequency than in patients who receive medication on a regular basis. Careful consideration should be given to each patient when choosing between oral or depot medication and inpatient or outpatient therapy. In addition, the clinician should consider the dosage schedule of each medication and balance this against the probability of extrapyramidal side effects and noncompliance. One option for the prevention of relapse without an increase in adverse side effects is the administration of depot haloperidol. For all therapeutic options, medication should be given on a regular basis, since intermittent dosing strategies do not work, and psychosocial rehabilitation should be initiated.

Administration, Oral↗

PubMed1993

Schizophrenia.

The pharmacologic treatment of the schizophrenic patient has remained substantively unchanged during the last 35 years. It is evident that as our knowledge of neuropharmacology has grown--the notion of schizophrenia being merely caused by a hyperdopaminergic state may be too simplistic. Multiple neurotransmitter systems may be involved in the manifestations of this illness. Conventional neuroleptics--the mainstay of antipsychotic treatment--have proved to be only partially effective and their untoward side effects have led to notorious patient noncompliance and iatrogenic morbidity. The demonstration that clozapine possesses both increased efficacy and reduced neurotoxicity, however, has forever altered the conventional wisdom that held all antipsychotics to be equally efficacious and uniformly neurotoxic. The pharmacologic legacy of clozapine promises to provide clinicians with biologic therapies that are at once safe, effective, and easy to administer.

Antipsychotic Agents↗