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Biomedical subjects

J W Hubbard

Publications and source records attributed to J W Hubbard.

At least 37 records · Page 2Linked to original sources
PubMed1997

alpha-Adrenergic activity and cardiovascular effects of besipirdine HCl (HP 749) and metabolite P7480 in vitro and in the conscious rat and dog.

Besipirdine displays potent adrenergic activity in a variety of pharmacological and behavioral tests. Based on this property, we evaluated the effects of besipirdine and its N-despropyl metabolite N-despropyl-besipirdine (P7480) on cardiovascular function in rats and dogs. Besipirdine and P7480 bind alpha-2 adrenoceptors (K(I): 380 and 10 nM, respectively) and facilitate the stimulated release of [3H]norepinephrine from rat cortical slices due to presynaptic autoreceptor blockade. In rat aorta rings and the pithed rat, P7480, but not besipirdine, also behaved as a postsynaptic alpha-1 adrenoceptor agonist. In conscious rats, besipirdine (2-10 mg/kg, p.o.) and P7480 (3-10 mg/kg, p.o.) produced dose-related increases in mean arterial pressure. Inhibition of hepatic cytochrome P-450 enzyme activity blocked the pressor effect of besipirdine, but not of P7480; therefore, P7480 mediated besipirdine's pressor effect. The bradycardia after either agent was unaffected. In conscious dogs, besipirdine (0.1-2 mg/kg, p.o.) also produced dose-related hypertension and bradycardia. The hypertension, but not the bradycardia, were sensitive to prazosin (3 mg/kg, p.o.), but not hexamethonium (10 mg/kg, p.o.). Muscarinic and beta-adrenergic receptor blockade studies in anesthetized dogs demonstrated the bradycardia to be due to withdrawal of cardiac sympathetic tone. These findings suggest that besipirdine's peripheral hypertensive effect is primarily mediated by the pressor metabolite P7480, although facilitated norepinephrine release may contribute. Besipirdine's bradycardic action appears to be centrally mediated, because both compounds lacked direct negative chronotropic activity on spontaneously beating guinea pig atria in vitro.

Adrenergic Agents↗
PubMed1996

Application of electrospray mass spectrometry in the identification of intact glucuronide and suplate conjugates of clozapine in rat.

1. The phase II metabolites in the bile, urine and faeces of rat dosed with clozapine were investigated by means of electrospray mass spectrometry (ESMS) in both positive and negative ion modes. 2. When operated at a cone voltage of 45 V, this soft ionization technique permitted the detection of quasi molecular ions of both sulphate and glucuronide conjugates of hydroxylated phase I metabolites of clozapine. With the cone voltage set at 90 V, however, the ESMS also contained highly diagnostic ions resulting from the loss of 80 Daltons (sulphur trioxide) or 176 Daltons (the glucuronide moiety) from sulphates and O-glucuronides respectively. 3. A sufficient quantity of one metabolite was isolated from rat bile to permit further analysis by 1H-nmr. This metabolite, which was also found in rat urine, was proved to be 7-O-glucuronyl-7-hydroxyclozapine. The analogous sulphate metabolite was also identified in bile by ESMS. 4. Correspondingly glucuronide and sulphate conjugates of a hydroxylated N-desmethyl clozapine were similarly detected in rat bile. There was insufficient material to permit analysis by 1H-NMR, but it appears likely that conjugation was also at the 7-position of N-desmethylclozapine. 5. Finally, the sulphate conjugate of a hydroxy dechlorinated derivative of clozapine was identified by ESMS in both urine and bile. By analogy with a previous report of a similar metabolite in man, the metabolite was tentatively identified as 8-hydroxy-8-deschloroclozapine.

Animals↗
PubMed1995

The pharmacokinetics and cardiovascular pharmacodynamics of HP 749 (besipirdine HCl) and metabolite P86-7480 in the conscious monkey.

HP 749 was absorbed slowly in the conscious monkey after single oral doses (10, 20, and 40 mg/kg), with gradual metabolism to the N-despropyl metabolite, P86-7480. The tmax was 2 to 4 hours after dosing, with nonlinear increases in Cmax and the AUC0-4th for HP 749. The calculated elimination half life (t1/2) after oral administration was 7.4 +/- 2.1 hours; however, absorption appeared to influence the terminal phase because the t1/2 after intravenous administration of 10 mg/kg was 1.5 hours. Plasma concentration of HP 749 2 minutes after intravenous bolus was 26.08 micrograms/mL. The HP 749 was rapidly distributed (t1/2 alpha = 0.064 +/- 0.033 hours) after intravenous administration, and displayed a VZ of 2.6 +/- 0.85 L/kg. The CL of HP 749 was 20.8 +/- 6.9 mL/min/kg, whereas renal clearance (CLR) of unchanged drug was only 0.13 +/- 0.04 mL/min/kg. Thus, only about 1% of the administered dose was excreted unchanged by the kidney. The P86-7480 also was rapidly distributed and eliminated after an intravenous bolus, but was less extensively distributed than HP 749. HP 749 administered either as an intravenous bolus or orally caused a significant pressor effect soon after dosing. A significant tachycardia resulted from intravenous administration, but not after oral administration of the drug. An intravenous bolus of P86-7480 (0.1 mg/kg) resulted in an immediate increase in MAP and decreased heart rate. The duration of these cardiovascular events was significantly shorter after intravenous administration of P86-7480 than with intravenous or oral administration of the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic.

Iloperidone (HP 873) is a D2 and 5-HT2 receptor-antagonist that is under development as a potential atypical antipsychotic agent. Two studies on iloperidone evaluated its safety and tolerability, made a preliminary pharmacokinetic assessment of single 3- and 5-mg doses, and determined the effect of food on its tolerability and pharmacokinetics in healthy volunteers after single 3-mg doses. Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3- or 5-mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5 mg (from 2.2 to 5.2 ng/mL for Cmax, and 16 to 50 ng/mL.h for AUC). Iloperidone was eliminated slowly, with a mean t1/2 of 13.5 to 14.0 hours. Coadministration with food did not significantly affect AUC, tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadministration of food reduced the incidence and severity of these events.

Adolescent↗
PubMed1995

A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia.

Following a 2-week placebo lead-in, schizophrenic patients were randomly assigned to fluoxetine 20 mg/day or placebo added to depot neuroleptic for a 6-week, double blind trial. All patients had received a stable dose of depot neuroleptic for at least 6 months and did not meet criteria for depression. Serum samples were obtained at baseline and at weeks 4 and 6. Scores on the negative symptom subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower at week 6, controlling for baseline scores, in patients receiving fluoxetine (n = 20) compared to patients receiving placebo (n = 21). Measures of psychosis, depression, global functioning and extrapyramidal symptoms (EPS) did not differ between groups at week 6. Fluoxetine administration was associated with a mean 65% increase in serum fluphenazine concentrations in 15 patients and a mean 20% increase in serum haloperidol concentrations in three patients. The change in negative symptoms at week 6 did not correlate with serum concentrations of fluoxetine or norfluoxetine, but did inversely correlate with S-norfluoxetine, an active stereoisomer of fluoxetine. For these chronically ill patients, fluoxetine significantly improved negative symptoms and did not worsen EPS, despite causing substantial elevation in serum concentrations of neuroleptics.

Double-Blind Method↗
PubMed1994

Decomposition of clozapine N-oxide in the qualitative and quantitative analysis of clozapine and its metabolites.

Pooled plasma from healthy volunteers was spiked with pure, synthetic clozapine or clozapine N-oxide and then made alkaline with either sodium hydroxide or sodium carbonate. The alkalized samples were allowed to stand at room temperature for various time intervals before extraction with organic solvent and then analyzed by high-performance liquid chromatography. It was found that clozapine N-oxide was reduced to clozapine in plasma made alkaline with sodium hydroxide, but such reduction was negligible in the plasma made alkaline with sodium carbonate. The amount of clozapine produced from clozapine N-oxide depended upon both the strength of the alkali added to the plasma and the duration of exposure of the plasma proteins plus clozapine N-oxide to the alkali. The reduction appears to take place through reducing equivalents generated by the action of strong alkali on plasma proteins. The thermal lability of clozapine N-oxide during gas chromatography-mass spectrometric analysis was also investigated. It was found that clozapine N-oxide was quantitatively decomposed to clozapine during gas chromatography-mass spectrometric analysis.

Chemistry Techniques, Analytical↗
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↗
PubMed1993

Logarithmic transformation in bioequivalence: application with two formulations of perphenazine.

The rationale for using the logarithmic transformation on concentration-dependent pharmacokinetic parameters a priori is presented. This rationale is based on theoretical pharmacokinetic and statistical grounds, but is also applicable to the practice of physicians in dealing with variations of drug treatment within and between patients. The implications of the transformation on data analysis, specifically analysis of variance, and estimation and inference from the analysis as it pertains to bioequivalence decisions are explored. Implementation of the transformation is shown, with an example of two perphenazine formulations in a single-dose crossover study. It is concluded that the transformation has to be accepted on theoretical grounds because sample sizes are too small in bioequivalence studies and too susceptible to extreme values to state with any certainty the actual distribution of pharmacokinetic parameters or their differences within a subject.

Adolescent↗
PubMed1993

Synthesis of the N-oxides of phenothiazine antipsychotic agents.

Chlorpromazine N-oxide, fluphenazine N4'-oxide, prochlorperazine N4'-oxide, sulforidazine N-oxide, and trifluoperazine N4'-oxide were synthesized by oxidation of the designated nitrogen atom in the N-10 side chain of the respective parent drug with 3-chloroperoxybenzoic acid. In the case of trifluoperazine, a stepwise increase in the amount of oxidant yielded the N1',N4'-dioxide and N1',N4',S-trioxide. The N',S-dioxides of chlorpromazine and sulforidazine were obtained by hydrogen peroxide oxidation of the appropriate parent drug.

Antipsychotic Agents↗
PubMed1993

Pharmacokinetics of chlorpromazine and key metabolites.

A study was carried out in 11 healthy young men to investigate the pharmacokinetics of chlorpromazine (CPZ) after a bolus intravenous (i.v.) dose (10 mg) and three single oral doses (25, 50 and 100 mg), with a washout period of two weeks between doses. Plasma levels of CPZ, CPZ N-oxide (CPZNO), CPZ sulfoxide (CPZSO) and both free and conjugated 7-hydroxy-CPZ (7-HOCPZ) were measured by extraction radioimmunoassays. CPZ exhibited multicompartmental pharmacokinetics in most subjects. There was wide between-subject variability in half life (11.05 h), volume of distribution (1215 l), volume of distribution at steady state (642 l) and mean residence time (8.88 h), whereas systemic clearance was somewhat less variable (76.6 l.h-1). All metabolites were present in measurable concentrations in the plasma of 9 of 11 subjects after i.v. CPZ, whereas free 7-HOCPZ was not detected in the other 2 individuals. With the exception of CPZNO, the biological half lives of the primary metabolites were longer than the half life of CPZ. After oral administration, the percentage of CPZ reaching the systemic circulation intact (F%) was very low (4-38%) and dose dependent. Moreover, both within-subject and between-subject variances were very high. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinite time (AUC) showed evidence of nonlinearity, whereas half life did not appear to be dose dependent. These data suggest that the high degree of variability in the pharmacokinetics of CPZ is a result of extensive first pass metabolism rather than variation in half life.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6.

Haloperidol (HAL) is a potent butyrophenone antipsychotic agent which is reversibly metabolized to reduced haloperidol (RHAL). In order to determine if this reversible metabolic pathway is linked to the debrisoquine 4-hydroxylase isozyme of cytochrome P-450 (P450IID6). HAL (5 mg) or RHAL (5 mg) was orally administered to healthy male volunteers in a randomized crossover design both with and without a prior (1 h) oral dose of quinidine (250 mg bisulfate), a potent inhibitor of this isozyme. Thirteen volunteers, 11 extensive metabolizers, 2 poor metabolizers, completed all four phases of the study. Plasma samples harvested over seven days were analysed for HAL and RHAL. An expression for the apparent fractional availability of metabolite from the parent compound given (Fapppm) was derived and was used to determine whether HAL or RHAL is the preferred metabolite, and whether quinidine co-administration alters Fapp for either compound. The AUC (0-t) for both HAL and RHAL were significantly greater following the administration of either compound with quinidine compared with AUC (0-t) values obtained in the absence of quinidine. The maximum plasma concentration (Cmax) of the administered compound was also greater following the administration of quinidine. Quinidine had no effect on the half-lives of the administered compounds. The Fapp for HAL and RHAL were not significantly affected by the administration of quinidine, indicating that the interconversion of HAL and RHAl is not linked to P450IID6. The Fapp of RHAL after administration of HAL was significantly greater than the Fapp of HAL after RHAL administration, indicating that RHAL is the preferred metabolic form. This difference was not affected by quinidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans.

A definitive enantioselective pharmacokinetic evaluation of dl-threo-methylphenidate (MPH) was carried out in 11 healthy volunteers, all of whom received, in a randomized crossover design, three oral administrations of MPH: immediate release (IR), slow release (SR), and SR chewed before swallowing (CH). In addition, all subjects received MPH intravenously (IV) on a separate occasion. Both plasma and urine samples were collected for up to 16 hr after each drug administration. Significant enantioselective differences were found in pharmacokinetic parameters such as CL, MRT, Vdss, AUC infinity 0, and t1/2. A profound distortion of the enantiomeric ratio for MPH (d >> 1) was evident in all plasma samples harvested after oral administration. After IV MPH, however, there was no significant distortion in the plasma d/l ratio until 1.5 hr after dosing, whereafter there was a divergence of the plasma levels of the enantiomers. After oral administration of dl-MPH, the absolute bioavailability (F) of d-MPH was 0.23 and that of l-MPH was 0.05. There were no significant differences in renal clearance for d- or l-MPH after oral or IV administration, although the fraction of the dose excreted unchanged in the urine was significantly greater after IV MPH. These data suggest that enantioselective differences in the pharmacokinetics of oral MPH are the result of enantioselectivity in presystemic metabolism rather than in renal excretion, such that l-MPH is preferentially converted into l-ritalinic acid. Finally, it was found that chewing the slow release formulation led to a pharmacokinetic profile very similar to that of MPH-IR, suggesting that MPH-SR should not be prescribed for children who chew tablets.

Administration, Oral↗
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

Effects of an orally active NO-releasing agent, CAS 936, and its active metabolite, 3754, on cardiac and coronary dynamics in normal conscious dogs and after pacing-induced heart failure.

The mechanism of action of nitrates, compounds that have been used classically in the treatment of heart failure, appears to be the stimulation of guanylate cyclase in vascular smooth muscle, perhaps the same physiologic action as endothelium-derived relaxing factor, now thought to be synonymous with nitric oxide (NO). Drugs that release NO either inside cells or in plasma have been developed recently. One such compound, CAS 936, when taken orally, is converted to an active metabolite, 3754. The goal of our studies was to determine the effects of CAS 936 and 3754 on cardiovascular function in conscious dogs before and after the development of pacing-induced heart failure. CAS 936 (10 mg/kg, p.o.) increased large coronary artery diameter 9.1 +/- 1.2% and reduced left ventricular end diastolic pressure (LVEDP) 2.5 +/- 0.5 mm Hg, but had no significant effects on coronary blood flow or vascular resistance. The metabolite 3754 caused dose-related increases in coronary artery diameter, and large reductions in LVEDP. The effect of these compounds on large coronary artery diameter was significantly greater (p < 0.05) than that of nitroglycerin (25 micrograms/kg). After heart failure, both CAS 936 and 3754 caused significant increases in large coronary artery diameter (10%) and a reduction in preload, up to 10 mm Hg, which was even larger than in normal dogs. Thus, these NO-releasing agents are potent selective large-vessel dilators that also reduce preload and maintain this unique vasodilator profile even in the failing heart.

Administration, Oral↗
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

The role of metabolites in a bioequivalence study 1: loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine.

Loxapine is a drug which is used in the treatment of psychotic disorders. The drug is extensively biotransformed in humans to produce a variety of metabolites, some of which have pharmacological activity. Seven-hydroxyloxapine is 4-5 times more active than the parent drug, although its concentrations in plasma are relatively low. Eight-hydroxyloxapine, on the other hand, is inactive, but is present in higher concentrations in plasma than the parent drug. In the present randomized crossover study to evaluate the bioequivalence of two dosage forms containing loxapine, the parent drug and its 7-hydroxy and 8-hydroxy metabolites were monitored for up to 96 hours after the administration of the test or reference formulations. Estimates of average bioavailability (AUC- infinity, AUC0t and Cmax) were obtained by the difference of the least squares means of log test and log reference. A 90% confidence interval for the log difference was derived from the within-subject error. The test of bioequivalence requires the 90% confidence band so calculated to fall entirely within an imposed regulatory interval of 80-125%. The results showed the two formulations to be bioequivalent in terms of the log mean differences and 90% confidence bands calculated for all three analytes. In fact, the within-subject variabilities of the metabolites were relatively low, so that the 90% confidence intervals for ln AUC0 infinity, ln AUC0t and ln Cmax calculated for the metabolites, were narrower that those for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗