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Biomedical subjects

K K Midha

Publications and source records attributed to K K Midha.

At least 109 records · Page 6Linked to original sources
PubMed1990

Defining treatment refractoriness in schizophrenia.

Addressing the need for research on the nature of refractoriness to antipsychotic drug therapy exhibited by a substantial minority of schizophrenic patients, Philip R.A. May and Sven Jonas Dencker instigated an international study group to discuss this problem, beginning with the International Congress of Neuropsychopharmacology in Göteborg, Sweden, in 1980. The study group subsequently met in Haar, Federal Republic of Germany, in 1985; in Banff, Canada, in 1986; and again in Telfs, Austria, in 1988. The study group set three objectives: (1) to clarify the concept of treatment resistance or refractoriness; (2) to suggest criteria for defining or rating the degree of treatment refractoriness; and (3) to explore the role of psychosocial and drug therapies in increasing the responsiveness of the treatment refractory patient. This position article represents a distillation of the study group's efforts to define treatment refractoriness in schizophrenia.

Activities of Daily Living↗
PubMed1990

Therapeutic monitoring of steady-state plasma levels of the N4'-oxide metabolite of fluphenazine in chronically treated schizophrenic patients determined by a specific and sensitive radioimmunoassay.

Highly specific and sensitive antisera for fluphenazine-N4'-oxide (FLUNO) were obtained from New Zealand white rabbits immunized with a bovine serum albumin conjugate of 7-(3-carboxypropionyl)propchlorperazine-N4'-oxide. One of the antisera was used to develop a radioimmunoassay (RIA) procedure that enabled for the first time the determination of steady-state plasma levels of FLUNO, an active metabolite, in patients treated with oral or intramuscular (i.m.) fluphenazine (FLU). This method has sufficient sensitivity to quantitate accurately 20 pg of FLUNO in 200 microliters of plasma extract with a coefficient of variation of less than 8%. The antiserum had negligible cross-reactivity (less than 2%) with FLU and its major metabolites such as FLU sulfoxide, 7-hydroxy-FLU, and N-deshydroxyethyl-FLU. To confirm that the developed RIA procedure specifically quantitated FLUNO, FLUNO was selectively reduced to FLU by sodium dithionite in plasma samples from patients. A good correlation (r2 = 0.9646) was observed between the total FLU level and the sum of FLU and FLU equivalent to FLUNO determined separately in the same plasma. The steady-state plasma concentrations of FLUNO in patients receiving a daily oral dose of 5 to 20 mg of FLU dihydrochloride ranged from 13 to 378% of that of FLU, whereas this value ranged from 10 to 214% in plasma samples from patients treated with a biweekly intramuscular (i.m.) dose of 5 mg of FLU decanoate.

Administration, Oral↗
PubMed1990

The metabolism of chlorpromazine N-oxide in man and dog.

1. The metabolism of chlorpromazine N-oxide was studied in female dogs and adult male humans after a single oral dose. 2. There was extensive metabolism in both species in that between four and seven metabolites were separately identified in urine and faeces. Apart from chlorpromazine N-oxide, chlorpromazine N,S-dioxide was the only isolated metabolite which retained the N-oxide group. The other identified metabolites were chlorpromazine and its 7-hydroxy, sulphoxide, N-desmethyl, 7-hydroxy-N-desmethyl and N-desmethylsulphoxide derivatives. 3. With dog samples, metabolites were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis. With human samples, metabolites were directly subjected to h.p.l.c.-mass spectrometric determination. With all metabolites their structures were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic samples. 4. The metabolites identified in urine and faeces were for the most part the same in both species, with the exceptions that chlorpromazine N-oxide was identified in the faeces of dog only and 7-hydroxy-N-desmethylchlorpromazine was identified in the urine of man only. 5. The observation of N-oxide compounds in the excreta of both man and dog contrasted with that for the previously studied rat, where no such compounds were detected.

Animals↗
PubMed1990

Fluphenazine plasma levels and clinical response.

We monitored fluphenazine plasma levels in 39 schizophrenic patients who participated in a 2-year double-blind comparison of 5 mg and 25 mg of fluphenazine decanoate (FD) administered every 14 days. We investigated the relationship between log-transformed plasma levels at 3, 6, and 9 months and subsequent psychotic exacerbations with logistic regression and survival analysis. Using logistic regression, the relationship was nonsignificant at 3 months (chi-square = .21, df = 1, p = .65), but significant at 6 months (chi-square = 4.38, df = 1, p = .04) and 9 months (chi-square = 8.98, df = 1, p = .003). Using survival analysis with fluphenazine levels as a covariate (Cox models), we also found significant relationships between the fluphenazine plasma level and the risk of exacerbations at 6 months (chi-square = 3.77, df = 1, p = .052) and 9 months (chi-square = 12.21, df = 1, p = .0005), but not at three months (chi-square = 0.87, df = 1, p = .65). These findings suggest that the measurement of fluphenazine plasma levels may be helpful in decision-making about the dosage of FD.

Adult↗
PubMed1989

Enantioselective gas chromatographic assays with electron-capture detection for methoxyphenamine and its three primary metabolites in human urine.

Sensitive and enantioselective gas chromatographic assays have been developed and applied to the quantitation in human urine of the enantiomers of methoxyphenamine and its three primary oxidative metabolites, namely, N-desmethylmethoxyphenamine, O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine. The separation of the various analytes was achieved through the combined use of high-resolution gas chromatography coupled with electron-capture detection and employing a capillary OV-225 column. The formation of diastereometric derivatives involved the chiral acylating reagent N-heptafluorobutyryl-L-prolyl chloride. The assays for methoxyphenamine and O-desmethylmethoxyphenamine were linear over the range 0.25-2.0 micrograms/ml for each analytes' enantiomers, while in the case of the enantiomers for N-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine linearity was shown over the ranges 0.094-0.75 and 0.188-1.5 micrograms/ml, respectively. The mean coefficients of variation in all cases were less than 4%.

Amphetamines↗
PubMed1989

Comparative bioavailability of a new commercial tablet formulation and two lots of a reference formulation of haloperidol.

The bioavailability of a new tablet formulation (5 mg) of haloperidol was estimated relative to two lots of a reference product. Twenty-eight healthy male volunteers completed all three phases in that they received the test (T) and the two reference formulations (R1 and R2) in a balanced three-way crossover design. Using a sensitive HPLC method, plasma concentrations of haloperidol and reduced haloperidol were monitored over a period of 96 h following administration of each formulation. Haloperidol was measurable in the plasma of all the volunteers, whereas reduced haloperidol was measurable in only 6 out of 28 volunteers following each administration. Therefore, the assessment of bioequivalence in this study is based on haloperidol data only. The maximum plasma concentration (Cmax), time to Cmax (tmax), and area under the curve up to the last measurable concentration (AUCot) or infinity (AUCo infinity) were compared by analyses of variance and found not to be significantly different across the formulations. The relative bioavailability based on T:R1 or T:R2 ratios of AUCo infinity, AUCot, and Cmax was, in each case, within the acceptable range of 100 +/- 20%. Also, the relative bioavailability of R1 compared with R2 was within 100 +/- 20% in terms of the above bioavailability parameters. Except for tmax, all other pharmacokinetic parameters showed wide intersubject variation.

Adolescent↗
PubMed1989

Single dose kinetics of thioridazine and its two psychoactive metabolites in healthy humans: a dose proportionality study.

Dose proportionality in some pharmacokinetic parameters for thioridazine and its two active metabolites (mesoridazine and sulforidazine) was investigated in 11 healthy human subjects following oral administration of three single doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by an interval of two weeks. Also, after a further two weeks, another 100-mg dose of thioridazine (divided as 5 mg every 0.5 h) was administered to all the volunteers to investigate the effect of a slow rate of dosage input on the pharmacokinetic parameters of this drug. An HPLC method was used to measure concentrations of thioridazine, mesoridazine, and sulforidazine in plasma samples collected up to 72 h following each dose. Dose proportionality for the three single doses of thioridazine was observed for all three analytes in the area under the plasma concentration versus time curves (AUC infinity 0 or AUCt0) and the maximum plasma concentration (Cmax) in that the relationships between the dose and these parameters were each describable by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose. This suggests nonlinear trends in the elimination kinetics at high doses of thioridazine. When a 100-mg divided oral dose of thioridazine was administered, no statistically significant differences between single and divided doses were observed in the mean AUC infinity 0 or AUCt0 for thioridazine or sulforidazine. A significant decrease in the mean AUC infinity 0 or AUCt0 was observed for mesoridazine after the administration of the divided dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit-hyperactivity disorder.

It has been shown previously that immediate-release dl-threo-methylphenidate (Ritalin) undergoes stereoselective disposition in human adults as well as in children with attention deficit-hyperactivity disorder. Although the sustained-release formulation of dl-threo-methylphenidate (Ritalin-SR) has been demonstrated to be effective in sustaining the attention of the children with attention deficit-hyperactivity disorder, there are no data on plasma levels of methylphenidate after administration of the sustained-release formulation. The purpose of this present investigation was twofold: (1) to determine whether the levels of methylphenidate were sustained for over a time period of 8 h, and (2) to examine enantioselective aspects of the pharmacokinetics following the ingestion of the sustained-release formulation. Six children with attention deficit-hyperactivity disorder were given 20 mg of sustained-release dl-threo methylphenidate. Plasma samples were harvested for a period up to 12 h following ingestion of the drug. The levels of both the enantiomers were sustained for a period of 8 h (the plasma levels of d-methylphenidate were 8- to 10-fold higher than those of the l-enantiomer in the profiles of all six children). Mean areas under the plasma level time curves were 132.78 +/- 92.47 ng.h/mL for d-methylphenidate and 12.73 +/- 7.37 ng.h/mL for l-methylphenidate. The values of oral clearance and apparent volume of distribution calculated for l-enantiomer were higher than the corresponding values for the d-antipode.

Adolescent↗
PubMed1989

Pharmacokinetics of long-acting injectable neuroleptic drugs: clinical implications.

The authors review the literature regarding the pharmacokinetics of long-acting injectable neuroleptic drugs (LINS). There are important differences between LINS and oral neuroleptics that affect their pharmacokinetics. By avoiding first pass metabolism in gut and liver, LINS result in lower circulating concentrations of metabolites than are found after oral administration. In addition, LINS take more time to reach a stable steady state than their oral counterparts. The clinical significance of these pharmacokinetic properties is discussed. The authors recommend that when patients are being changed from oral neuroleptics to LINS, that this conversion be done gradually over several months.

Antipsychotic Agents↗
PubMed1989

Interconversion between haloperidol and reduced haloperidol in healthy volunteers.

The interconversion between haloperidol (HAL) and reduced haloperidol (RHAL) was examined following their separate administration in low (5 mg) single oral doses to 15 young healthy male volunteers in a crossover design. Using an ultrasensitive HPLC method plasma concentrations of HAL and RHAL were monitored over a period of one week following each administration. Except in one case, both the analytes were found in the plasma of all the volunteers following each administration, thereby indicating interconversion of the two compounds. Comparison of the AUC(0-t) ratios of RHAL/HAL and HAL/RHAL following administration of HAL and RHAL, respectively, revealed that the interconversion favours the reduction of HAL to RHAL. The disposition of HAL following administration of RHAL appears to be limited by its rate of formation and the disposition of RHAL following administration of HAL, on the other hand, is much slower than that of the parent compound.

Adult↗
PubMed1989

Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol.

Single oral doses (5 mg) of haloperidol were administered to 36 healthy men (26 black, 10 white) of whom 28 (22 black, 6 white) completed the study. Plasma samples harvested over 96 hours were analyzed for haloperidol and reduced haloperidol by means of a new high performance liquid chromatographic method. Reduced haloperidol was detectable in the plasma of only six of the 28 subjects (five blacks, one white). In these individuals reduced haloperidol plasma concentrations were generally much lower than those of the parent drug. This finding in the present single-dose study is in contrast to literature reports that have described levels of reduced haloperidol higher than those of the parent drug in some patients chronically mediated with haloperidol. There was wide intersubject variation in area under the plasma concentration versus time curve and apparent oral clearance values for haloperidol. The distributions of these pharmacokinetic parameters about their respective means were each leptokurtotic and skewed toward higher values. In each case the geometric mean gave a better estimate of central tendency than the arithmetic mean. Wide intersubject variation prevented the detection of significant differences in these pharmacokinetic parameters between black and white subjects or between smokers and nonsmokers.

Adolescent↗
PubMed1989

Adverse effects of fenfluramine in treatment refractory schizophrenia.

Fenfluramine was administered to eight severely ill schizophrenic patients as an adjunct to neuroleptic drugs in a double-blind, multiple baseline design. A significant adverse effect of fenfluramine on psychopathology was detected through nurses' ratings, target symptom scales, the Brief Psychiatric Rating Scale, and time-sampled behavioral observations. Clinical deterioration was correlated with fenfluramine-induced reductions in blood serotonin levels and persisted beyond the point of discontinuation of fenfluramine.

Adult↗
PubMed1989

An ultrasensitive method for the measurement of fluphenazine in plasma by high-performance liquid chromatography with coulometric detection.

A new sensitive analytical method is described for the quantitation of fluphenazine in 1 ml plasma samples after low oral doses of this antipsychotic agent. The drug is isolated by a simple one step extraction technique and analyzed by high-performance liquid chromatography (HPLC) with coulometric detection. The limit of detection for fluphenazine was 10 pg/ml of plasma and standard curves from 25 to 1,000 pg/ml were linear with an overall coefficient of variation (CV) of less than 5%. The lowest quantifiable concentration of 25 pg/ml could be determined with a CV of 4.7%. The sensitivity of the HPLC assay was such that plasma concentrations of fluphenazine could be followed for 2 days following administration of a single 10 mg oral dose of fluphenazine dihydrochloride to healthy volunteers. Known metabolites of fluphenazine did not interfere in the assay as they eluted with retention times different from that of fluphenazine.

Adult↗
PubMed1989

Selective in vivo inhibition by quinidine of methoxyphenamine oxidation in rat models of human debrisoquine polymorphism.

1. Lewis and Dark Agouti (DA) rat strains (n = 4), models of human extensive and poor metabolizer phenotypes of debrisoquine/sparteine, respectively, were dosed with methoxyphenamine with and without prior administration of quinidine. Methoxyphenamine and its three metabolites, namely N-desmethylmethoxyphenamine, O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine were quantified in 0-24 h urine. 2. The oxidative metabolic routes of methoxyphenamine which had been previously shown to involve the debrisoquine/sparteine isozyme, namely O-demethylation and aromatic 5-hydroxylation, were both significantly inhibited by quinidine in the two rat strains. 3. The oxidative metabolic route of methoxyphenamine which had been previously shown to not involve the debrisoquine/sparteine isozyme, namely N-demethylation, was not significantly inhibited by quinidine in either rat strain. 4. The Lewis strain pretreated with quinidine resembled the DA strain without such pretreatment in terms of O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine in that the mean percentages of the dose excreted as these two metabolites and the mean O-desmethylmethoxyphenamine/methoxyphenamine and 5-hydroxymethoxyphenamine/methoxyphenamine ratios were similar to one another. 5. Ten days after quinidine administration to the Lewis strain of rat, all parameters of methoxyphenamine and its metabolites returned to normal. 6. A protocol involving substrate administration to Lewis strain rats with and without prior administration of quinidine could be developed as an attractive approach to screen substrates for metabolism in vivo by the debrisoquine/sparteine isozyme. Such an approach obviates interstrain differences.

Amphetamines↗
PubMed1989

Plasma levels of parent drug and metabolites in patients receiving oral and depot fluphenazine.

We evaluated the metabolism of fluphenazine (FLU) in patients treated with either the oral form of FLU or with fluphenazine decanoate (FD). Samples for both patient populations were analyzed using four different radioimmunoassays developed in our laboratories for fluphenazine, fluphenazine sulfoxide (FS), 7-hydroxy fluphenazine (7OHFLU), and fluphenazine N-oxide (FLUNO). In patients receiving oral FLU the levels of FS and 7OHFLU were significantly higher than levels of FLU. In patients receiving FD, the levels of metabolites were significantly lower than FLU levels. This supports the view that drug metabolism is likely to be a more important factor for patients treated with an oral as opposed to a depot phenothiazine neuroleptic.

Delayed-Action Preparations↗
PubMed1989

Intersubject variation in the pharmacokinetics of chlorpromazine in healthy men.

Interpatient variation in response to therapy with antipsychotic drugs is a major problem. This study was designed to assess the extent of variation in disease-free subjects in whom known sources of variance were controlled as much as possible. The subjects were 32 healthy, nonsmoking males of European origin, aged 18-25 years, and weighing no more than +/- 15% from the ideal weight for height. After an overnight fast, each subject ingested 50 mg of chlorpromazine. Plasma samples were harvested over a 24-hour period during which the subjects were on a standardized, caffeine-free diet. Plasma levels of chlorpromazine were measured by gas-liquid chromatography-mass spectrometry. The results showed wide intersubject variation in all pharmacokinetic parameters including maximum concentration, area under the curve, and oral clearance. Furthermore, none of the data were normally distributed. For each pharmacokinetic parameter, the distribution was leptokurtotic and skewed. As a consequence, the geometric means provided better estimates of central tendency than the arithmetic means. It seems that a major proportion of intersubject variation is an inherent problem that cannot be accounted for by differences in race, diet, smoking habits, or concomitant drug ingestion.

Administration, Oral↗
PubMed1988

Enantioselective gas chromatographic assay with electron-capture detection for dl-fenfluramine and dl-norfenfluramine in plasma.

An enantioselective gas chromatographic assay utilising electron-capture detection has been developed for the simultaneous quantitation of enantiomers of fenfluramine and nonfenfluramine in plasma. The assay involves the conversion of the enantiomers of both fenfluramine and norfenfluramine into their corresponding diastereomeric amide derivatives by an acylation reaction with n-heptafluorobutyryl-S-prolyl chloride under Schotten-Baumann conditions prior to gas chromatographic separation on an achiral polar OV-225 capillary column. Linear and reproducible standard curves were obtained over the concentration ranges 4.30-86.3 ng/ml per enantiomer and 1.25-42.25 ng/ml per enantiomer for the enantiomers of fenfluramine and norfenfluramine, respectively. The method was applied to a single-dose pharmacokinetic study in a healthy adult subject. Stereoselective differences were observed in the plasma concentration versus time profiles of the enantiomers of both fenfluramine and norfenfluramine. The area under the plasma concentration versus time curve values obtained for the l-isomers of fenfluramine or norfenfluramine were higher than the values of their corresponding d-antipodes.

Chromatography, Gas↗