Search PubMed⌕ Search

Biomedical subjects

K K Midha

Publications and source records attributed to K K Midha.

At least 145 records · Page 8Linked to original sources
PubMed1987

A new radioimmunoassay of thioridazine and its comparison with a high performance liquid chromatographic method and another radioimmunoassay.

A new radioimmunoassay (RIA) procedure for the determination of thioridazine in plasma is described. Antiserum was produced in rabbits immunized with N-(2-carboxyethyl)desmethylthioridazine-protein conjugate. The developed RIA procedure can measure as low as 80 pg of thioridazine in a 200-microliter human plasma sample with a coefficient of variation of less than 5%. This RIA procedure was compared with previously reported RIA and high performance liquid chromatographic (HPLC) methods by determining plasma concentrations of thioridazine in samples from human volunteers over 72 h after administration of single 50-mg oral doses of thioridazine hydrochloride. There was a good correlation between the assay values (n = 55) determined by the new RIA and HPLC methods (r2 = 0.916), and the slope of the regression line was not significantly different from 1.0 (p greater than 0.60, 95% confidence limits 0.981 +/- 0.081 when RIA values were plotted on the y axis, and HPLC values on the x axis; p greater than 0.10, 95% confidence limits 0.934 +/- 0.080 when HPLC values were plotted on the y axis and RIA values on the x axis). Also, the plot of the differences between these two assay values against the average of the assay values showed that the differences were independent of the concentration range studied. Similar favorable statistical comparisons were obtained when the assay values (n = 44) determined for thioridazine by the two RIA procedures were compared with one another.

Analysis of Variance↗
PubMed1987

Development of a radioimmunoassay procedure for mesoridazine and its comparison with a high-performance liquid chromatographic method.

A radioimmunoassay (RIA) procedure for mesoridazine was developed using an antiserum raised in rabbits immunized with N-(2-carboxyethyl) desmethylmesoridazine-porcine thyroglobulin conjugate. The RIA procedure enabled the quantitation of 40 pg of mesoridazine in a 200-microliters human plasma sample with a coefficient of variation of less than 5%. Except for N-desmethylmesoridazine, the antiserum showed no marked cross-reaction with any of the other available potential cross-reactants. Furthermore, statistically indistinguishable results were obtained for the determination of mesoridazine in the presence or absence of a fivefold excess of thioridazine or sulforidazine. This RIA procedure was compared with a high-performance liquid chromatographic (HPLC) method by determining concentrations of mesoridazine in plasma samples from human volunteers over 72 h after administration of single 50-mg oral doses of thioridazine hydrochloride. Good correlation existed between the assay values (n = 55) determined by the RIA and HPLC methods (r2 = 0.940), but the slope of the regression line was significantly different from 1.0 (p less than 0.05, when RIA values were plotted on the gamma axis and HPLC values were plotted on the chi axis; p less than 0.001, when HPLC values were plotted on the gamma axis and RIA values were plotted on the chi axis). The plot of the differences between these two assay values against the average of the assay values showed, however, that the differences were independent of the concentration range studied. Moreover, statistically favorable comparisons were obtained for area under the plasma level/time curve to 48 h (AUC0(48)), Cmax, and Tmax calculated from the data obtained by the two methods.

Animals↗
PubMed1987

Stereoselective disposition of methylphenidate in children with attention-deficit disorder.

Six boys with attention-deficit disorder were given single doses (5 or 10 mg) of dl-threo-methylphenidate (Ritalin, Ciba-Geigy, Basel, Switzerland). Plasma samples through 8 hr were analyzed by capillary column gas chromatography with electron capture detection. Enantiomers were separated and measured as heptafluorobutyryl-1-prolyl derivatives. The method was sensitive to 0.1 ng of enantiomer per ml of plasma. The plasma levels of d-methylphenidate were at least 5-fold greater than those of the l-enantiomer in the profiles of all six children. Mean areas under the plasma level-time curves were 24.48 +/- 7.62 ng/hr/ml for d-methylphenidate and 3.77 +/- 1.04 ng/hr/ml for l-methylphenidate. There was appreciable intersubject variation in plasma level maxima and times to maximal plasma levels of each enantiomer.

Adolescent↗
PubMed1987

Therapeutic monitoring of chlorpromazine. IV: Comparison of a new high-performance liquid chromatographic method with radioimmunoassays for parent drug and some of its major metabolites.

A new high-performance liquid chromatographic (HPLC) procedure for the simultaneous determination of chlorpromazine and its six metabolites, namely, 7-hydroxy-chlorpromazine, N-monodesmethyl-chlorpromazine, 7-hydroxy-N-monodesmethyl-chlorpromazine, chlorpromazine-sulfoxide, chlorpromazine N-oxide, and N-monodesmethyl-chlorpromazine-sulfoxide, in plasma was developed and compared with four radioimmunoassay (RIA) procedures that measured separately chlorpromazine, 7-hydroxy-chlorpromazine, chlorpromazine-sulfoxide, and chlorpromazine N-oxide. The results of this study for the determination of plasma levels in four healthy volunteers given a 100-mg single oral dose of chlorpromazine hydrochloride demonstrated that in some cases, strong correlations could be found between the plasma levels determined by the HPLC and RIA procedures, whereas in other cases, there was a lack of strong correlation. The discrepancies observed were not only due to nonspecificity of the immunoassay procedures employed, but also to a lack of rigorous specificity of the HPLC procedure in plasma samples from dosed humans. These findings clearly indicate that even a chemical method of analysis, such as HPLC, has its limitations in its application to multianalyte analysis, as is the case with drugs like chlorpromazine.

Chlorpromazine↗
PubMed1986

Development of enantioselective gas chromatographic quantitation assay for dl-threo-methylphenidate in biological fluids.

An enantioselective gas chromatographic quantitation assay was developed for the enantiomers of dl-threo-methylphenidate in plasma and urine. dl-threo-Methylphenidate and the internal standard were acylated with N-heptafluorobutyryl-1-prolylchloride under Schotten-Baumann conditions prior to gas chromatographic separation on achiral mixed stationary phases. The derivatives were detected by means of a nitrogen-phosphorus detector. Linear and reproducible calibration curves were obtained over the concentration ranges 0.43-43.25 and 2.16-216.25 ng/ml enantiomer in plasma or urine, respectively. This enantioselective gas chromatographic quantitation assay was applied in a single oral dose disposition study of dl-threo-methylphenidate in a healthy adult volunteer. Stereoselective differences were observed in the plasma concentration-time profiles and cumulative urinary excretion profiles following oral doses of 20 and 40 mg of dl-threo-methylphenidate hydrochloride. Only d-threo-methylphenidate was detectable in plasma after 4 h.

Adult↗
PubMed1986

Fluphenazine plasma levels in patients receiving low and conventional doses of fluphenazine decanoate.

Plasma fluphenazine concentrations (FLU) were measured in 45 patients with schizophrenic disorders who participated in a double-blind comparison of 5 and 25 mg fluphenazine decanoate (FD). The rise in plasma level of FLU 24 h after a "test dose" was significantly correlated with steady state FLU concentration at 12 weeks (for 5 mg patients, r = 0.45, P = 0.04; for 25 mg, r = 0.78, P = 0.005). Patients who had low FLU at baseline required nearly 6 months to reach a steady state when they received 25 mg. Patients who received 5 mg and had low FLU at baseline continued to demonstrate relatively low plasma levels for the entire 1st year. Although the mean FLU at 6 months was lower for patients who relapsed during the subsequent 18 months (0.57 ng/ml for relapsers vs 1.01 ng/ml for nonrelapsers), this difference was not statistically significant. When plasma levels from both dosage groups were combined, FLU at 12 weeks correlated significantly with factor scores for akinesia (r = 0.52, P = 0.002) and BPRS cluster scores for retardation (r = 0.52, P = 0.002). These results indicate that the measurement of fluphenazine plasma levels may be useful in determining when patients treated with FD are receiving drug doses which are likely to cause discomforting side effects.

Adult↗
PubMed1986

Chiral pharmacology and its consequences for therapeutic monitoring.

The individual enantiomers of chiral drugs may have profound differences in their pharmacologic and toxicologic properties. Their metabolism and pharmacokinetics may also differ markedly, and the presence of one enantiomer may inhibit the metabolism of the other. Stereospecificity is required in analytical methods, whether these be chromatography or radioimmunoassay.

Chromatography↗
PubMed1986

Doxylamine metabolism in rat and monkey.

Metabolites of doxylamine obtained with rat-liver homogenate in vitro and from urine of Wistar rats and squirrel monkeys in vivo were examined. The metabolites were separated by g.l.c., h.p.l.c. and t.l.c., and tentatively identified through interpretation of their mass-spectrometric behaviour. N-Desmethyldoxylamine was identified in vitro while both N-desmethyl and N,N-didesmethyldoxylamine were detected in rat and monkey urine. The N-acetyl conjugates of N-desmethyl and N,N-didesmethyldoxylamine were tentatively identified both in rat urine and in vitro. Only the N-acetyl conjugate of N,N-didesmethyldoxylamine was detected in monkey urine. In addition, nine other metabolites were tentatively identified in rat urine: N,N-dimethyl-2-[1-(?-hydroxyphenyl)-1-(2-pyridyl)ethoxy]ethanamine; N-methyl-2-[1-(?-hydroxyphenyl)-1-(2-pyridyl)ethoxy]ethanamine; 1-phenyl-1-(2-pyridyl)ethanol; 1-(?-hydroxyphenyl)-1-(2-pyridyl)ethanol; 1-phenyl-1-(2-pyridyl)ethane; 1-(?-hydroxyphenyl)-1-(2-pyridyl)ethane; 2-phenyl-2-(2-pyridyl)ethanol; N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)-2-hydroxyethoxy]ethanamine; doxylamine pyridine N-oxide. The excretion of doxylamine aliphatic N-oxide in rat urine was confirmed by comparison with the authentic synthetic compound.

Animals↗
PubMed1986

Development and application of a specific radioimmunoassay for trifluoperazine N4'-oxide to a kinetic study in humans.

A hapten derivative of prochlorperazine N4'-oxide, 7-(3-carboxy-propionyl)-prochlorperazine N4'-oxide, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with this conjugate generated antibodies which were utilized to develop a radioimmunoassay (RIA) for the quantitation of trifluoperazine N4'-oxide (TFPNO). This assay enabled for the first time the quantitation of TFPNO in plasma, and 20 pg can be measured in a 200-microliter plasma sample with a coefficient of variation less than 5%. Statistically, indistinguishable results were obtained by the assay procedure with or without the selective extraction of TFPNO, and also in the presence or absence of an excess of trifluoperazine (TFP) and other major metabolites, such as trifluoperazine sulfoxide and 7-hydroxytrifluoperazine. This RIA and a previously reported RIA for TFP were used to directly determine plasma concentrations of TFP and TFPNO after administration of a single 5-mg p.o. dose of TFP to six healthy male volunteers. The mean +/- S.D. for the peak concentration, time to peak concentration, area under the curve from 0 to 72 hr and the elimination T1/2 for the terminal portion of the plasma concentration vs. time curve for TFPNO were found to be 3.7 +/- 0.7 ng/ml, 3.2 +/- 0.4 hr, 51.1 +/- 9.8 ng X hr/ml and 26.9 +/- 14.0 hr, respectively, whereas the corresponding values for TFP were found to be 2.7 +/- 0.7, 3.1 +/- 0.8, 42.2 +/- 6.9 and 21.9 +/- 6.5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Therapeutic monitoring of chlorpromazine. III: Minimal interconversion between chlorpromazine and metabolites in human blood.

Chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), and chlorpromazine N-oxide (CPZNO) were each incubated (37 degrees C), for various timed intervals up to 60 min, with pooled human whole blood. Plasma and red blood cells were then separated and analyzed by a high performance liquid chromatographic method that avoids the use of alkaline extraction procedures. It was found that CPZ, CPZSO, and CPZNO were remarkably stable in whole blood under physiological conditions. CPZ was converted into CPZSO to a small extent (1%). Reports of 15-50% conversion of CPZ into CPZSO are largely due to artifacts, which result when red blood cell materials come into contact with alkali. CPZNO was recovered (85%) unchanged from the plasma. A small portion (1%) of the CPZNO was reduced to CPZ in the red blood cells. Thus, on the basis of these in vitro data, blood does not appear to be an important tissue for the metabolism of CPZ, CPZSO, or CPZNO.

Biotransformation↗
PubMed1985

Radioimmunoassay for the 7-hydroxy metabolite of trifluoperazine and its application to a kinetic study in human volunteers.

A hapten derivative of the 7-hydroxy metabolite of trifluoperazine, 7-hydroxy-10-[[3-[4-(2-carboxyethyl)-1-piperazinyl]propyl]]-2 -tri-fluromethyl-10H-phenothiazine, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand white rabbits with this drug-protein conjugate resulted in the production of antisera, one of which was subsequently utilized in the development of an RIA procedure. The described RIA for the first time enables the quantitation of the 7-hydroxy metabolite of trifluoperazine in human plasma after oral administration of single and therapeutic doses of trifluoperazine, in which 20 pg of the nonconjugated 7-hydroxy metabolite in 200 microL of plasma can be measured with a CV of less than 3% in B/Bo readings. Similar results were obtained by this assay procedure with or without the selective extraction of the 7-hydroxy metabolite and in the presence or absence of a large excess of trifluoperazine and other suspected major metabolites, such as the sulfoxide and N4'-oxide metabolites. This RIA procedure, together with a previously developed RIA for trifluoperazine, was used to directly determine plasma concentrations of trifluoperazine and its 7-hydroxy metabolite after administration of a single 5-mg oral dose of trifluoperazine to six healthy male volunteers. The mean +/- SD for the peak concentration (Cmax), the time to Cmax, the area under the curve from 0 to 24 h and, the apparent terminal elimination half-life for the 7-hydroxy metabolite were found to be 0.86 +/- 0.2 ng/mL, 6.2 +/- 1.6 h, 11.1 +/- 4.9 ng . h/mL, and 10.6 +/- 5.7 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Metabolism of methoxyphenamine in extensive and poor metabolizers of debrisoquin.

Urine and plasma concentrations of methoxyphenamine (MP) and three of its metabolites were determined after a single oral 60.3 mg dose of MP hydrochloride to healthy subjects of known debrisoquin (D) phenotype. Urine was collected from five extensive (EM) and five poor (PM) metabolizers of D for 12 hours and analyzed after treatment with beta-glucuronidase/sulfatase. There were marked interphenotype differences in the total urinary excretion of O-demethylmethoxyphenamine (ODMP) and 5-hydroxymethoxyphenamine (5HMP), as well as in MP/ODMP and MP/5HMP ratios. In contrast, the urinary output of N-demethylmethoxyphenamine (NDMP) or MP/NDMP ratios showed no interphenotype differences. Plasma data from two EMs and two PMs showed that the mean values for maximum concentration t1/2, and total AUC for MP were two-, three-, and sixfold greater, respectively, in PMs than in EMs. The plasma levels of ODMP and 5HMP were higher in EMs than in PMs, whereas the converse was true for NDMP. Thus, O-demethylation and aromatic 5-hydroxylation of MP are defective in PMs of D, resulting in increased MP and NDMP plasma levels. The form of cytochrome P-450 involved in the N-demethylation of MP is different from that responsible for O-demethylation and aromatic 5-hydroxylation.

Adult↗
PubMed1985

Therapeutic monitoring of chlorpromazine I: Pitfalls in plasma analysis.

Pooled plasma from healthy volunteers was spiked with pure, synthetic chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), or chlorpromazine N-oxide (CPZNO), and then made alkaline with either sodium hydroxide or sodium carbonate. The samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvent. It was found that CPZNO was reduced to CPZ in plasma made alkaline with sodium hydroxide, but not in protein-free buffer solution at high pH nor in plasma made alkaline with sodium carbonate. The reaction appears to take place through reducing equivalents generated by the action of sodium hydroxide on plasma proteins. Thus, apparent concentrations of CPZ in plasma from patients were elevated by as much as 343% when sodium hydroxide was used compared with concentrations in aliquots of the same plasma samples alkalinized with sodium carbonate. The amount of CPZ produced from CPZNO depends on the type of extraction procedure employed as well as on the quantity of sodium hydroxide added to the plasma. By contrast, no interconversion between CPZ and CPZSO or CPZNO and CPZSO was observed in plasma alkalinized and extracted under any of the conditions tested.

Chlorpromazine↗
PubMed1985

Therapeutic monitoring of chlorpromazine II: Pitfalls in whole blood analysis.

Pooled whole blood from healthy volunteers was spiked with pure, synthetic chlorpromazine, chlorpromazine sulfoxide, or chlorpromazine N-oxide and then made alkaline with either sodium hydroxide or sodium carbonate. The addition of alkali causes lysis of red cells, the contents of which spill into the plasma. The lysed samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvents and analysis by high performance liquid chromatography. It was found that a portion (10-14%) of the chlorpromazine spike was oxidised to chlorpromazine sulfoxide, whether the blood was made alkaline with sodium hydroxide or sodium carbonate. Chlorpromazine N-oxide added to whole blood was entirely destroyed in the presence of alkali. The chlorpromazine N-oxide was rapidly reduced to chlorpromazine, a portion of which subsequently underwent oxidation to chlorpromazine sulfoxide. We have found that chlorpromazine N-oxide resides almost entirely in the plasma with only a small portion (less than 4%) distributed into the red cells. Hence, it is essential that red cells and plasma be separated before analysis. Chlorpromazine and chlorpromazine N-oxide can then be extracted from plasma by a method that does not lead to reduction of chlorpromazine N-oxide. Alkaline extraction methods must be avoided in the analysis of chlorpromazine in the red cell fraction.

Chlorpromazine↗
PubMed1985

Methoxyphenamine metabolism in rat models of human debrisoquine phenotypes.

The metabolism of the beta 2-adrenoceptor agent methoxyphenamine was investigated in rats of the Lewis and Dark Agouti strains, which are proposed models for human extensive and poor metabolizers of debrisoquine, respectively. Following oral ingestion of 20 mg kg-1 of methoxyphenamine, Dark Agouti excreted, on the average, significantly more methoxyphenamine and less O-demethylmethoxyphenamine and 5-hydroxymethoxyphenamine in 0- to 24-h urine than Lewis. In contrast, the N-demethylation of methoxyphenamine showed no interphenotype differences between the two strains. It is possible that in rats, the form of cytochrome P-450, which controls the 4-hydroxylation of debrisoquine, may also control the O-demethylation and aromatic 5-hydroxylation of methoxyphenamine.

Animals↗