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J W Hubbard

Publications and source records attributed to J W Hubbard.

At least 91 records · Page 5Linked to original sources
PubMed1988

The pharmacokinetic properties of yohimbine in the conscious rat.

We used high performance liquid chromatography with fluorescence detection to measure the concentration of yohimbine in serum and brain of conscious Sprague-Dawley rats at various times after the i.v. injection of 1 mg/kg of yohimbine. The serum concentration-time profile of yohimbine was biphasic with a rapid distribution phase (t1/2 alpha = 0.048 h) followed by a very slow elimination phase t1/2 beta = 16.3 h). The clearance of yohimbine was 11 ml/h.kg-1, and the volume of distribution was 259 ml/kg. Increasing doses (0.3, 1 and 3 mg/kg, i.v.) of yohimbine produced non-linear increases in serum yohimbine concentration. Yohimbine entered the brain rapidly (5,000 ng/g at 5 min after 1 mg/kg, i.v.) and disappeared from brain with a t1/2 beta of 7.7 h. In contrast to serum yohimbine concentration, increasing doses of yohimbine (0.3, 1 and 3 mg/kg) produced linear increases in brain yohimbine concentration, a phenomenon which is consistent with concentration-dependent binding of yohimbine to plasma proteins. The rapid entry of yohimbine into the brain, the slow rate of elimination of yohimbine from serum and brain and the linear relationship of brain yohimbine concentration as a function of dose should be taken into consideration whenever yohimbine is to be used as a probe of alpha 2-adrenoceptor function in vivo.

Animals↗
PubMed1988

Radioimmunoassay for fluphenazine sulfoxide in human plasma.

Antisera to fluphenazine sulfoxide were raised in New Zealand white rabbits to an immunogen synthesized by covalent linkage of bovine serum albumin to 10-[[3-[4-(4-carboxybutyl)-1-piperazinyl] propyl]]-2-trifluoromethyl-10H-phenothiazine 5-sulfoxide. With use of an antiserum, a radioimmunoassay for fluphenazine sulfoxide was developed that is able to quantitate 0.156 ng ml-1 using only a 200 microliter plasma sample with a coefficient of variation less than 5%. The antiserum had negligible cross-reactivities to fluphenazine (less than 1%) and its important metabolites, such as fluphenazine N4'-oxide (1%), 7-hydroxyfluphenazine (less than 1%), and N4'-deshydroxy-ethylfluphenazine (1%). The cross-reactivities with structurally similar phenothiazine 5-sulfoxides, such as those of trifluoperazine, prochlorperazine, perphenazine, and N4'-deshydroxyethylfluphenazine, were considerable, such that the antiserum can be used to develop a quantitative radioimmunoassay for any of these compounds. The reported radioimmunoassay was found to be suitable and adequate to quantitate fluphenazine sulfoxide in the plasma of patients treated with oral or intramuscular fluphenazine.

Fluphenazine↗
PubMed1988

Changes in plasma catecholamines and plasma renin activity during hypotension in conscious rats with lesions of the nucleus tractus solitarii.

The purpose of the present study was to examine the effects of lesions of the nucleus tractus solitarii on the reflex control of sympathetic activity and renin release in the conscious rat. Two doses of the arteriolar vasodilator hydralazine (0.3 and 1 mg/kg, i.v.) were used to activate reflexively the sympathetic nervous system in nucleus tractus solitarii lesion and control rats. Administration of 1 mg/kg of hydralazine to the control rats caused mean arterial pressure to fall from 120 +/- 2 mm Hg to 84 +/- 2 mm Hg and elicited an 11.2-fold increase in plasma renin activity and a 2.7-fold increase in plasma norepinephrine concentration. Administration of 0.3 mg/kg of hydralazine caused the arterial pressure of the lesion group to fall from 118 +/- 3 mm Hg to a comparable value of 85 +/- 4 mmg Hg, but plasma renin activity and plasma norepinephrine concentration did not rise significantly. However, administration of 1 mg/kg of hydralazine to the lesion group caused arterial pressure to fall from 128 +/- 6 mm Hg to 64 +/- 2 mm Hg, in association with a 12.4-fold increase in plasma renin activity and a 1.6-fold elevation in plasma norepinephrine concentration. Atenolol, a beta 1-adrenoceptor antagonist, blocked 70% of the rise in plasma renin activity caused by 1 mg/kg of hydralazine in both groups of rats. In addition, prior renal denervation also markedly attenuated the rise in plasma renin activity caused by hydralazine in the lesion group. Finally, electrical stimulation of the vagus nerves, which caused a large vasodepressor response in the control group, failed to lower the arterial pressure of the lesion group. Based on these observations, we conclude that in the conscious rat (1) nucleus tractus solitarii lesions eliminate the arterial baroreflexes as well as the cardiopulmonary baroreflex, and (2) severe hypotension induces sympathetically mediated renin release in the apparent absence of arterial and cardiopulmonary baroreflex function.

Animals↗
PubMed1988

Hypotensive effects of lesions of the rostral ventrolateral medulla in rats are anesthetic-dependent.

These studies were designed to determine if the hypotensive effects of bilateral electrolytic lesions of the rostral ventrolateral medulla are dependent on the type of anesthetic agent used. The lesions caused an immediate fall in mean arterial pressure (MAP) in rats anesthetized with urethane, alpha-chloralose or sodium pentobarbital. At 30 min after placement of the lesions, severe hypotension (MAP = 54 +/- 5 mm Hg) persisted in the rats anesthetized with urethane. However, 30 min after placement of the lesions, the MAP of rats anesthetized with alpha-chloralose or sodium pentobarbital was 87 +/- 9 mm Hg and 99 +/- 10 mm Hg, respectively. Subsequent transection of the cervical spinal cord produced a much greater decrease in MAP in rats anesthetized with alpha-chloralose and sodium pentobarbital as compared to rats anesthetized with urethane. Heart rate was significantly lower after placement of the lesions in all 3 groups. We conclude that the magnitude of the hypotensive effect caused by placement of lesions in the rostral ventrolateral medulla is anesthetic-dependent and that the rostral ventrolateral medulla is not the only area of the central nervous system capable of maintaining vasomotor tone.

Anesthetics↗
PubMed1988

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

A new analytical method has been developed for the simultaneous quantitation of haloperidol and reduced haloperidol in plasma. The method is based on high performance liquid chromatography (HPLC) with coulometric detection. The extraction and sample clean up procedures are simple and rapid to execute, yet yield chromatograms virtually free of interference from endogenous plasma constituents, such that the extraordinary sensitivity of the coulometric detector can be exploited fully. The detection limits for haloperidol and reduced haloperidol are 20 pg/ml plasma, and the limits of quantitation are 50 pg/ml for both drug and metabolite. Standard curves were linear down to 50 pg/ml with coefficients of variation of less than 7.0% at the limits of quantitation. The method was applied to the study of the plasma levels of haloperidol and reduced haloperidol in two healthy subjects. It was possible to monitor the plasma levels of haloperidol for at least 96 h (4 days) after the administration of a 5-mg oral dose of haloperidol. It was also possible to monitor reduced haloperidol levels over 96 h in one subject, although the metabolite was not detectable in the plasma of the other at any stage.

Chromatography, High Pressure Liquid↗
PubMed1988

S-oxidation of thioridazine to psychoactive metabolites: an oral dose-proportionality study in healthy volunteers.

Thioridazine has two major active metabolites, which are formed from S-oxidation of its 2-methylthio group; the sulphoxide, mesoridazine, and the sulphone, sulforidazine. Dose proportionality of the three compounds was investigated for the first time in 11 males after administration of three single oral doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by two weeks. Based on the plasma concentrations of the three analytes over 72 h following each dose, large intersubject variabilities in such parameters as AUCot and Cmax were observed for each of the three compounds. The relationships between dose and parameters such as AUCot and Cmax for each analyte were described 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, suggesting non-linearity in the elimination of thioridazine at high dose.

Adult↗
PubMed1987

Parabrachial lesions increase plasma norepinephrine concentration, plasma renin activity and enhance baroreflex sensitivity in the conscious rat.

Electrolytic lesions of the parabrachial nucleus (PBN) caused significant increases in basal plasma renin activity (+433%) and basal plasma norepinephrine concentration (+98%) in conscious rats. Plasma epinephrine concentration, mean arterial pressure, heart rate, hematocrit, plasma osmolality and plasma sodium and potassium concentrations were not significantly affected by the lesions. Atenolol reduced the elevated plasma renin activity in the lesion group to a value similar to that of a control group (sham lesions or lesions in areas adjacent to the PBN). Captopril significantly lowered mean arterial pressure in the lesion group, but it had no effect on arterial pressure in the control group. Lesions of the PBN also increased the baroreflex-mediated bradycardia evoked by an abrupt elevation of arterial pressure. We propose that the PBN tonically inhibits sympathetic activity, sympathetically mediated renin release and baroreflex sensitivity.

Animals↗
PubMed1987

Radioimmunoassay for the N-oxide metabolite of chlorpromazine in human plasma and its application to a pharmacokinetic study in healthy humans.

Antibodies specific to chlorpromazine N-oxide (CPZNO) were produced in rabbits immunized with a hapten-bovine serum albumin conjugate, which was prepared by linking the 7-position of the phenothiazine ring of the metabolite to the protein via a 4-carbon bridge. An extraction radioimmunoassay (RIA) was developed using this antiserum and shown to have adequate sensitivity and specificity for determination of plasma concentrations of CPZNO in the presence of chlorpromazine (CPZ) and its major metabolites. It was used together with the previously developed RIAs for CPZ, chlorpromazine sulfoxide (CPZSO), and 7-hydroxychlorpromazine (7-OHCPZ) to study the pharmacokinetics of CPZ and these metabolites in five healthy volunteers after they received a single 50-mg oral dose of CPZ. It is interesting to note that peak plasma concentrations of CPZNO were considerably higher than CPZ, and the apparent elimination half-lives of this metabolite were shorter than those of CPZ.

Adult↗
PubMed1987

The sulfoxidation of fluphenazine in schizophrenic patients maintained on fluphenazine decanoate.

Highly sensitive radioimmunoassays were applied to study the sulfoxidation of fluphenazine in 30 schizophrenic patients maintained on either 5 mg or 25 mg fluphenazine decanoate by intramuscular injection every 14 days over a period of 6 months. The presence of the sulfoxide metabolite was detected in all but one of the patients, such that 97% of the 340 plasma samples analysed contained the metabolite. Interpatient variations in plasma levels of fluphenazine, fluphenazine sulfoxide, and in drug to metabolite plasma level ratios were several fold higher than the corresponding intrapatient variations at both dosages. There were statistically significant tendencies for mean plasma fluphenazine levels to rise and mean plasma sulfoxide levels to fall over the 6-month period of study among patients on the high dose, consistent with our previously reported observation that it takes 3-6 months to establish a steady state of fluphenazine with this dosage regimen. By contrast, there were no statistically significant changes in mean plasma levels of either fluphenazine or its sulfoxide in patients on the low dose. Nevertheless, there was a significant rise in fluphenazine to fluphenazine sulfoxide mean plasma level ratios in both dosage groups. It is difficult to assess the significance of the changes in the drug to metabolite ratios with time, since there are no kinetic data on the phase II metabolism (conjugation) of fluphenazine or fluphenazine sulfoxide. This study shows that sulfoxidation is an important major pathway in the metabolism of intramuscularly-administered fluphenazine, and implies that metabolic sites other than gut wall are also involved in the process.

Fluphenazine↗
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

Cardiovascular and neuroendocrine responses to behavioral stress after central or peripheral barodenervation in rats.

The cardiovascular and neuroendocrine responses to acute behavioral stress were evaluated in rats after disruption of the baroreflexes by electrolytic lesions of the nucleus tractus solitarii (NTS) or sinoaortic denervation (SAD). Rats with NTS lesions or SAD showed significantly greater increases in mean arterial pressure (MAP) and plasma norepinephrine (NE) concentrations than control rats during a single 30-min escape-avoidance test. In addition, the increases in MAP and plasma NE concentration of NTS lesion rats were significantly greater than those of SAD rats. However, NTS lesion rats showed no increase in plasma renin activity (PRA), as observed in the other groups. Thus, disruption of the baroreflexes by NTS lesions or SAD augments the arterial pressure and plasma NE responses to stress. Additionally, NTS lesions appeared to eliminate the neurons or fibers of passage participating in the sympathetically mediated increase in PRA.

Animals↗
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

The effects of intracerebroventricular injection of clonidine on conditioned pressor and adrenergic responses in rats.

Studies from this laboratory have shown that the first filial offspring of female spontaneously-hypertensive rats and male Wistar-Kyoto (WKY) normotensive rats develop stress-induced hypertension. The present study sought to examine the effects of intracerebroventricular administration of clonidine (8 micrograms) on cardiovascular and sympathoadrenal responses to aversive classical conditioning in these borderline hypertensive rats (BHR) and in normotensive WKY control rats. Clonidine caused significant reductions in resting arterial pressure, vascular resistance, heart rate and concentrations of epinephrine (E) in plasma for both hypertensive and normotensive rats. Central administration of normal saline to control rats of each strain did not alter basal cardiovascular or sympathoadrenal function. The presentation of a conditioned stimulus (CS) elicited a significant increase in arterial pressure and total peripheral resistance in hypertensive rats treated with saline and clonidine and in normotensive rats treated with saline. In contrast, normotensive rats treated with clonidine showed no increases in arterial pressure or vascular resistance following the onset of the conditioned stimulus. The aversive conditioning session instigated significant increases in the concentrations of norepinephrine (NE) and E in plasma in saline-treated rats. Hypertensive and normotensive rats treated with clonidine-showed a blunted increase in plasma concentrations of NE and E during this period; however, concentrations of E in hypertensive rats increased significantly from the baseline period after injection. These data suggest that an abnormality in central alpha 2-adrenoceptor-mediated inhibition of sympathoadrenal discharge and sympathetic vasomotor tone may predispose the hypertensive rat to develop stress-induced hypertension.

Animals↗
PubMed1986

Plasma norepinephrine concentration reflects pharmacological alteration of sympathetic activity in the conscious cat.

This study provides the first comprehensive set of basal values for hemodynamic variables, plasma norepinephrine (NE) and epinephrine concentrations and plasma renin activity in the conscious cat and demonstrates that changes in plasma NE concentration in the conscious cat accurately reflect the alterations in sympathetic discharge caused by hydralazine, yohimbine, chlorisondamine and clonidine.

Animals↗