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Biomedical subjects

M W Jann

Publications and source records attributed to M W Jann.

At least 73 records · Page 4Linked to original sources
PubMed1991

Ethnic comparison of haloperidol and reduced haloperidol plasma levels: Taiwan Chinese versus American non-Chinese.

Steady-state haloperidol (HAL) and reduced HAL (RHAL) plasma levels were measured in Chinese and non-Chinese schizophrenic patients. The patients (n = 38) were matched according to age (+/- 1 yr) and by HAL dose. In general, Chinese patients had higher mean plasma HAL levels and lower RHAL/HAL ratios compared to non-Chinese patients (23.6 +/- 14.9 ng/ml versus 17.1 +/- 10.1 ng/ml, p less than 0.05; 0.52 +/- 0.44 versus 0.82 +/- 0.62, p less than 0.05). Six groups were formed according to HAL dose (number per group): 10 mg/day (6); 20 (11); 30 (11); 40 (4); 50 (3); and 60 (3). No significant differences were found in age, weight and dose/weight. In each dose group, HAL plasma levels were generally higher in the Chinese patients than in the non-Chinese patients, though significance was only detected in the 30 mg group (26.1 +/- 7.0 ng/ml versus 18.5 +/- 5.1 ng/ml, p = 0.035) and a slight trend in the 40 mg group (36.0 +/- 15.0 ng/ml versus 23.5 +/- 10.4 ng/ml, p = 0.074). RHAL/HAL ratios were generally lower in the Chinese patients than in the non-Chinese patients, with a strong trend toward the significance level in the 20 mg and 30 mg groups (0.22 +/- 0.13 versus 0.58 +/- 0.57, p = 0.066 and 0.43 +/- 0.26 versus 0.71 +/- 0.34, p = 0.062). This study further suggests the possibility of different metabolic rates between Chinese and non-Chinese patients. Possible differences in the enzyme systems which relate to the metabolism of HAL and RHAL between Chinese and non-Chinese populations are discussed.

Adult↗
PubMed1991

Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables.

Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.

Administration, Oral↗
PubMed1991

Interconversions between haloperidol and reduced haloperidol in schizophrenic patients and guinea pigs: a steady-state study.

Plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were measured in 8 schizophrenic patients, neuroleptic-free for at least 4 weeks, after repeated oral administrations of 10 mg HAL and RHAL. Each agent was given for 10 days with a 2-week washout period between the two compounds. HAL and RHAL were interconverted in all subjects. Plasma RHAL/HAL ratios at steady state during HAL treatment were significantly greater than the HAL/RHAL ratios after repeated reduced HAL administration (0.51 +/- 0.12 vs. 0.16 +/- 0.04 SD, p less than 0.0005). This result suggests that the interconversions between HAL and RHAL are apparently not equivalent in humans. A negative correlation was found between RHAL/HAL ratios after HAL administrations and HAL/RHAL ratios after RHAL administrations (r = -0.82, p less than 0.05). Repeated injections of HAL or RHAL at low (0.1 mg/kg) or high (1.0 mg/kg) doses were conducted in guinea pigs. Drug concentrations in striatum and plasma were measured. Both RHAL/HAL ratios after HAL injections and HAL/RHAL ratios after RHAL injections were dose- and time-dependent. High doses and repeated injections produced greater RHAL/HAL ratios after HAL and smaller HAL/RHAL ratios after RHAL than those observed with low doses and single injections, respectively. Compared with the results obtained from schizophrenic patients, the conversion from HAL to RHAL in guinea pigs was greater than that in humans, but the back conversions appeared to be similar between the guinea pigs and humans. Based upon the dose-dependent increase in RHAL/HAL ratios, a hypothesis of the therapeutic window effect for HAL treatment is proposed.

Adult↗
PubMed1990

Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients.

Haloperidol disposition has been associated with reversible metabolism: it is reversibly reduced to its metabolite, reduced haloperidol, which has less pharmacologic activity than the parent compound. To characterize the interconversion process, six healthy male schizophrenics were administered a single dose of 10 mg haloperidol or reduced haloperidol in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the clearances of haloperidol and reduced haloperidol are 1.15 +/- 0.32 l/h/kg and 0.76 +/- 54 l/h/kg, respectively. These clearances are similar to that obtained by the usual mammillary model analysis. With a single 10 mg dose administration of either drug, about 23% of the biotransformation of haloperidol involves the reduction pathway. Back conversion from the reduced metabolite to the parent drug through oxidation contributes even less to the total biotransformation of reduced haloperidol. This action of interconversion or saturation under chronic drug administration is unknown. Reversible metabolism of haloperidol could partially account for the wide therapeutic range for haloperidol as reported in the literature.

Adult↗
PubMed1989

Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients.

Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.

Adult↗
PubMed1989

Clinical implications of increased antipsychotic plasma concentrations upon anticonvulsant cessation.

Plasma antipsychotic concentrations were measured in five patients when their anticonvulsant medications were discontinued. Plasma antipsychotic concentrations increased by two- to five-fold at 4 weeks after cessation. All patients demonstrated either moderate or marked improvement as antipsychotic plasma concentrations increased. Four patients experienced extrapyramidal side effects within 30 days of anticonvulsant discontinuation. Careful monitoring of clinical symptoms, adverse effects, and plasma antipsychotic concentrations is recommended.

Adult↗
PubMed1989

Haloperidol and reduced haloperidol plasma levels in Chinese vs. non-Chinese psychiatric patients.

Haloperidol and reduced haloperidol plasma concentrations were measured in age-matched Chinese and non-Chinese patients (n = 32). Steady-state plasma concentrations were obtained 10-12 hours after the bedtime dose. Haloperidol and reduced haloperidol concentrations were measured by liquid chromatography and radioimmunoassay. Haloperidol plasma concentrations did not significantly differ between the populations, but reduced haloperidol levels were 3 times greater in non-Chinese patients than in Chinese patients. The incidence of extrapyramidal side effects was higher in Chinese patients (18 vs. 10), while non-Chinese patients with extrapyramidal symptoms had higher reduced haloperidol plasma levels. Logistic regression analysis revealed that ethnicity and reduced haloperidol/haloperidol ratios were important variables in predicting extrapyramidal symptoms. These results suggest that the metabolism and disposition of haloperidol and reduced haloperidol could differ among ethnic populations.

Adult↗
PubMed1989

Pharmacokinetics of haloperidol.

Haloperidol has been used extensively for the treatment of psychotic disorders, and it has been suggested that the monitoring of plasma haloperidol concentration is clinically useful. Different assay methodologies have been used in research and clinical practice to examine the relationship between response and plasma concentration of the drug. Chemical assays such as high pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC) have good precision and sensitivity; radioimmunoassay (RIA) is generally more sensitive, but less precise and specific. Radioreceptor assay quantifies dopaminereceptor blocking activity but does not provide results comparable with those of HPLC, GLC and RIA. Large doses of haloperidol can safely be given intravenously and intramuscularly for rapid neuroleptisation; the bioavailability of this agent administered orally ranges from 60 to 65%. However, there is large interindividual, but not intraindividual, variability in plasma haloperidol concentrations and most pharmacokinetic parameters. This interindividual variability could be partially explained by the reversible oxidation/reduction metabolic pathway of haloperidol: it is metabolised via reduction to reduced haloperidol, which is biologically inactive. Different extents of enterohepatic recycling, and ethnic differences in metabolism, could also account for the observed variability in haloperidol disposition. Although not conclusive from different clinical studies, it appears that a plasma haloperidol concentration range of 4 micrograms/L to an upper limit of 20 to 25 micrograms/L produces therapeutic response. The role of reduced haloperidol in determining clinical response is not clear, although in some studies a high reduced haloperidol/haloperidol concentration ratio has been suggested to be associated with therapeutic failure. Measurements of red blood cell or cerebrospinal fluid haloperidol concentration have also been proposed as determinants of therapeutic response, but results from different studies are inconsistent, and do not seem to provide a significant advantage over plasma concentration monitoring. Physiological parameters such as prolactin and homovanillic acid levels have been evaluated, with the latter showing some promise that warrants further investigation. Haloperidol decanoate can be characterised by a flip-flop pharmacokinetic model because its absorption rate constant is slower than the elimination rate constant. Its plasma concentration peaks on day 7 after intramuscular injection. The elimination half-life is about 3 weeks, and the time to steady-state is about 3 months.

Drug Interactions↗
PubMed1988

Buspirone: an update on a unique anxiolytic agent.

Buspirone (Buspar) is a azaspirodecanedione anxiolytic agent. Its mechanism of action is extremely complex, but current investigations indicate that its main neuropharmacologic effects are mediated by the 5-HT1A receptors. Other neuroreceptor systems could be involved, as buspirone displays some affinity for DA2 autoreceptors and 5-HT2 receptors. It has been proposed that inhibition of synthesis and release of serotonin result through the combined interactions of neuroreceptors and secondary messenger systems. This action leads to inhibition of the firing rate of 5-HT-containing neurons in the dorsal raphe. From this novel profile, that differs from that of the benzodiazepines, buspirone lacks anticonvulsant and muscle-relaxant properties, and causes only minimal sedation. The drug is rapidly absorbed after oral administration, with a mean bioavailability of 3.9%. After a single oral dose, the mean elimination half-life is 2.1 hours. Buspirone is mainly bound to albumin and alpha 1-acid glycoprotein. It is metabolized to an active metabolite 1-(2-pyrimidinyl) piperazine (1-PP). The mean elimination half-life of 1-PP is 6.1 hours. Buspirone is indicated in the treatment of generalized anxiety disorders. Its efficacy is comparable to the benzodiazepines. Its use in depression and panic disorders requires further investigation. When combined with alcohol or given alone, psychomotor impairment was not detected. Abuse, dependence, and withdrawal symptoms have not been reported. The frequency of adverse effects is low, and the most common effects are headaches, dizziness, nervousness, and lightheadness. Buspirone should be added to drug formularies and could represent a significant addition in psychopharmacology.

Anxiety↗
PubMed1987

Butorphanol as a dental premedication in the mentally retarded.

Seventy institutionalized severely and profoundly retarded patients were administered intramuscular butorphanol, 1.0 to 4.0 mg, for premedication prior to dental procedures. These patients had been refractory to previous combined chloral hydrate and diphenhydramine treatment. Clinical efficacy was categorized according to the extent that adjunctive restraints were required to accomplish the dental procedure. A total of 151 butorphanol trials were recorded. Butorphanol was observed to be clinically effective in 74.8% of the administrations and sedation was observed in 28.2% of the trials. Dosage titration increased efficacy to 85.0%. Contribution of concurrent central nervous system depressant medication to clinical efficacy and dose requirements lacked statistical significance; however, a strong trend (p = 0.068) was found in the medication-free group with higher dosage. Vomiting (2.6%) was the most frequent adverse effect observed. One patient had marked cardiorespiratory depression that was promptly reversed by intravenous naloxone. Two patients experienced mild hypotensive episodes immediately following injection, but they recovered uneventfully. Butorphanol was shown to be a safe and effective agent for dental premedication in this difficult patient population.

Adolescent↗
PubMed1987

Treatment of panic and phobic disorders.

The clinical features, pathophysiology, and treatment of panic and phobic disorders are reviewed. Evidence from genetic, epidemiological, biological, and pharmacological studies suggests that phobic and panic disorders differ from other psychiatric illnesses. Dysfunction of the autonomic nervous system, causing excessive release of norepinephrine from the locus ceruleus, is implicated in the pathophysiology of these disorders. Overstimulation of the locus ceruleus by yohimbine, sodium lactate, and carbon dioxide can cause feelings of panic and anxiety in both patients with panic disorder and control subjects. Currently, excessive activity of the locus ceruleus is the only comprehensive neuroanatomic and physiological hypothesis for the etiology of panic disorder. Tricyclic antidepressant agents (TCAs), monoamine oxidase inhibitors (MAOIs), anxiolytic agents, and adrenergic agents all have been used to treat phobic and panic disorders. TCAs and the benzodiazepines, particularly alprazolam, are the drugs most commonly chosen for therapy. If these agents are ineffective, an MAOI or combination therapy can be tried. MAOIs are second-line agents for many patients because of toxicity and dietary limitations. Whether they are more effective than other agents requires further study. Panic and phobic disorders and depression have in common many properties of a dysregulated system; an improved understanding of the pathophysiology of panic and phobic disorders should lead to the development of more effective treatment strategies.

Fear↗
PubMed1986

Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance.

Plasma concentrations of haloperidol and its reduced metabolite (reduced haloperidol) were investigated in cigarette smokers (N = 23) and nonsmokers (N = 27). Steady-state plasma concentrations were obtained 12 h post bedtime dose. Haloperidol and reduced haloperidol concentrations were determined by RIA. Reduced haloperidol was separated by selective succinylation and liquid chromatography. Patients were clinically assessed with the Clinical Global Impression Scale (CGIS). Smokers had significantly lower haloperidol and reduced haloperidol plasma concentrations than nonsmokers (P less than 0.01, P less than 0.05). Clearance of haloperidol was significantly greater in smokers compared to nonsmokers (P = 0.0052). CGIS assessments did not show significant differences between smokers and nonsmokers. Plasma concentrations should be carefully monitored when patients either start or stop smoking.

Adult↗
PubMed1986

Bioavailability of psychotropic drugs: historical perspective and pharmacokinetic overview.

The evolution of the federal government's role in the regulation and evaluation of generic psychotropic medications is described. To place many of the methodologic bioequivalence issues for antipsychotic agents into perspective, the pharmacokinetics of these drugs are reviewed. Appropriate methodologies for studying the pharmacokinetics and pharmacodynamics of psychotropic drugs are in early developmental stages. Many of the issues relating to bioequivalence of generic products will not be resolved until a better understanding of these factors is developed.

Biological Availability↗
PubMed1986

Effect of influenza vaccine on serum anticonvulsant concentrations.

Serum concentrations of the anticonvulsants phenytoin, phenobarbital, and carbamazepine were compared before and after patients received influenza vaccine. Serum drug concentrations were measured in patients at a state school for the mentally retarded who were receiving continuous anticonvulsant therapy with only one of the study drugs and taking no other medication regularly. Patients with hepatic or renal disease or other medical problems were excluded. All study patients had steady-state serum concentrations of the anticonvulsants before they were vaccinated with Influenza Virus Vaccine, USP, Types A and B, Whole Virus. Trough serum concentrations of anticonvulsants were measured by enzyme-mediated immunoassay technique immediately before vaccination and on days 7, 14, and 28. Data were excluded for patients who required dosage adjustments because of toxicity or seizures. On day 7, mean serum concentrations of phenytoin (15.16 +/- 5.52 micrograms/mL, n = 8) and phenobarbital (17.25 +/- 6.77 micrograms/mL, n = 27) were significantly higher than at baseline. Mean carbamazepine concentrations on day 7 (6.89 +/- 2.18 micrograms/mL, n = 20) were not significantly greater than baseline; however, there was a significant increase from day 7 to day 14. In patients who are receiving phenytoin, phenobarbital, or other drugs metabolized by the cytochrome P-450 system, serum concentrations of these drugs may increase as a result of influenza vaccination, and dosage adjustments may be necessary.

Adolescent↗