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C L DeVane

Publications and source records attributed to C L DeVane.

At least 19 recordsLinked to original sources
PubMed2001

A high-performance liquid chromatography assay with ultraviolet detection for olanzapine in human plasma and urine.

Olanzapine is a commonly used atypical antipsychotic medication for which therapeutic drug monitoring has been proposed as clinically useful. A sensitive method was developed for the determination of olanzapine concentrations in plasma and urine by high-performance liquid chromatography with low-wavelength ultraviolet absorption detection (214 nm). A single-step liquid-liquid extraction procedure using heptane-iso-amyl alcohol (97.5:2.5 v/v) was employed to recover olanzapine and the internal standard (a 2-ethylated olanzapine derivative) from the biological matrices which were adjusted to pH 10 with 1 M carbonate buffer. Detector response was linear from 1-5000 ng (r2>0.98). The limit of detection of the assay (signal:noise=3:1) and the lower limit of quantitation were 0.75 ng and 1 ng/ml of olanzapine, respectively. Interday variation for olanzapine 50 ng/ml in plasma and urine was 5.2% and 7.1% (n=5), respectively, and 9.5 and 12.3% at 1 ng/ml (n=5). Intraday variation for olanzapine 50 ng/ml in plasma and urine was 8.1% and 9.6% (n=15), respectively, and 14.2 and 17.1% at 1 ng/ml (n=15). The recoveries of olanzapine (50 ng/ml) and the internal standard were 83 +/- 6 and 92 +/- 6% in plasma, respectively, and 79 +/- 7 and 89 +/- 7% in urine, respectively. Accuracy was 96% and 93% at 50 and 1 ng/ml, respectively. The applicability of the assay was demonstrated by determining plasma concentrations of olanzapine in a healthy male volunteer for 48 h following a single oral dose of 5 mg olanzapine. This method is suitable for studying olanzapine disposition in single or multiple-dose pharmacokinetic studies.

Antipsychotic Agents↗
PubMed2001

A single dose of methadone inhibits cytochrome P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio.

AIMS: To examine the effect of a single oral dose of methadone on cytochrome P450 (CYP) 3A activity using the urinary 6beta-hydroxycortisol to cortisol ratio (UCR) as a marker of CYP3A activity. METHODS: A single oral dose (0.2 mg kg-1) of rac-methadone was administered to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected for 96 h following dosing. The UCR and the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in plasma and urine. All quantifications were performed by validated high performance liquid chromatography assays. RESULTS: In all volunteers a significant decline of the UCR from immediately predose values was observed at the 4-8 and 8-12 h collection periods (P < 0.05, 95% CI for the differences: 0.4,16 and 0.6,16, respectively) with a return to immediately predose values after 2-3 days, suggesting methadone was an inhibitor of CYP3A. The UCR was found to be significantly correlated with the amount of EDDP excreted in the urine and with the area under the plasma concentration vs time profile for total (R + S) methadone, supporting in vitro data that CYP3A is primarily responsible for EDDP formation and has a significant influence on methadone disposition. CONCLUSIONS: Methadone appears to be a CYP3A inhibitor in vivo following a single oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.

Analysis of Variance↗
PubMed2001

Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate.

BACKGROUND: The pharmacokinetics and dynamics of methadone are characterized by high interindividual variability. This study aimed to examine a number of factors that may contribute to this variability. METHODS: Eight healthy drug-free women were administered 0.2 mg/kg of R,S-methadone orally. The concentrations of methadone's enantiomers in plasma and urine were monitored for 96 hours. Vital signs, blood biochemical parameters, and pupillary diameter were monitored frequently during this period. Cytochrome P450 3A (CYP3A) activity and alpha1-acid glycoprotein (alpha1-AGP) concentrations and phenotypes were determined. Pharmacokinetic and pharmacodynamic modeling was used to assess the influence of the above-mentioned covariables on methadone enantiomer disposition and actions. RESULTS: The pharmacokinetic profile of the active enantiomer of methadone, R -methadone, showed a relatively normal distribution with 38% to 90% of the interindividual variability in modeled pharmacokinetic parameters being explained by their individual variability in CYP3A activity, the cumulative amount of the main CYP3A4 metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, excreted in the urine, the fraction unbound in plasma, and the alpha1-AGP orosomucoid 2 (ORM2) variant plasma concentration. S-Methadone showed an idiosyncratic distribution with largely unpredictable pharmacokinetics. Pupillary constriction response was highly variable between individuals. CONCLUSIONS: The disposition of the active enantiomer, R -methadone, can be predicted in part by CYP3A activity and protein binding to alpha1-AGP (ORM2), whereas S-methadone disposition is not well explained by the factors examined in this study. Central nervous system effects were difficult to interpret on the basis of plasma R-methadone pharmacokinetics.

Administration, Oral↗
PubMed2001

A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates.

Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.

Adult↗
PubMed2001

An evaluation of risperidone drug interactions.

Risperidone, an atypical antipsychotic drug, is widely used in the treatment of psychoses associated with schizophrenia, Alzheimer's disease, and other psychiatric disorders. Polypharmacology is a necessary condition for the optimal treatment of many patients with comorbid psychiatric and medical illness. One concern raised by the widespread use of multiple concurrent pharmacotherapies is the potential for drug-drug interactions to adversely affect patient outcome. Accordingly, the biomedical literature was reviewed for reports of drug interactions involving risperidone, and the clinical significance of each report was evaluated. Additionally, the potential for risperidone to participate in drug interactions was evaluated by considering the drug's pharmacokinetic properties. Controlled studies and case reports indicate that risperidone has a low potential for metabolic drug interactions. Drugs that inhibit cytochrome P450 (CYP) 2D6 or induce or inhibit CYP3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions seems to be minimal. Adherence to a few guidelines for the design of dosage regimens should limit the effect of drug-drug interactions on patient status and contribute to optimal pharmacotherapy with risperidone.

Anticonvulsants↗
PubMed2001

Drug glucuronidation in clinical psychopharmacology.

Glucuronidation is a phase II metabolic process and one of the most common pathways in the formation of hydrophilic drug metabolites. At least 33 families of uridine diphosphate-glucuronosyltransferases have been identified in vitro, and specific nomenclature similar to that used to classify the cytochrome (CYP) P450 system has been established. The UGT1 and UGT2 subfamilies represent the most important of these enzymes in human drug metabolism. Factors affecting glucuronidation include the following: cigarette smoking, obesity, age, and gender. In addition, several drugs have been found in vitro to be substrates, inhibitors, or inducers of UGT enzymes. Induction or inhibition of both UGT and CYP isoforms may occur simultaneously. Some important drug interactions involving glucuronidation have been documented and others can be postulated. This review summarizes the relevant literature pertaining to drug glucuronidation and its implications for clinical psychopharmacology.

Adolescent↗
PubMed2001

Intranasal sumatriptan in post-ECT headache: results of an open-label trial.

BACKGROUND: Significant headaches occur in up to 45% of patients receiving electroconvulsive therapy (ECT) as a result of treatment. Headaches may at times be severe and affect patient compliance with this treatment modality. The 5-HT(1B/1D) receptor agonist sumatriptan has been reported to be effective for post-ECT headache in several case reports. The aim of the present open-label study was to assess the efficacy and tolerability of intranasal sumatriptan for post-ECT headache. METHOD: Patients undergoing ECT who experienced moderate-to-severe post-ECT headache were enrolled in the study. Patients were asked to rate their headache severity and describe headache characteristics using a standard headache diary. Headaches rated as severe or moderate were treated with 20 mg of intranasal sumatriptan. Additional headache ratings were recorded at 0.25, 0.5, 1.0, 1.5, and 2 hours after sumatriptan administration and compared with baseline values. RESULTS: Eight female patients (ages 34-45 years old) participated in the trial and experienced a total of 13 post-ECT headaches, which were treated with intranasal sumatriptan. Of the headaches treated, six (46.2%) were described as severe and seven (53.8%) were characterized as moderate in severity. Twelve (92.3%) of the treated headaches responded by the 2 hour posttreatment time point and 11 (84.6%) had responded within 1 hour. Comparisons made at the 1- and 2-hour time point revealed a statistically significant improvement from baseline (p = 0.002). Of the 12 headaches that responded, 6 (50%) were reported as no pain and 5 (38.5%) were reported as only mild pain at 1 hour following treatment. At the 2-hour assessment, an additional headache, which had previously not responded, was rated at mild resulting in six (50%) headaches with complete resolution of pain and six (50%) with a decrease in pain symptoms from moderate or severe to mild. Overall, sumatriptan treatment was well tolerated, and no significant adverse effects or changes in vital signs were recorded. In no case was a second dose of sumatriptan given. The most common complaint was the taste of the medication (n = 4), which was not treatment limiting. No patient withdrew from the study due to an adverse event. CONCLUSION: Intranasal sumatriptan spray may be an effective, well-tolerated, and prompt treatment for patients experiencing moderate-to-severe post-ECT headache. Preventing post-ECT headache may contribute to patient compliance with the ECT treatment modality. Additionally, the known pharmacologic effects of sumatriptan and the generally positive results found in the present study suggest that ECT-induced headache is vascular in origin. Further placebo-controlled, double-blind studies are needed to confirm our open-label results.

Administration, Intranasal↗
PubMed2001

Substance P: a new era, a new role.

Substance P has been extensively studied and is considered the prototypic neuropeptide of the more than 50 known neuroactive molecules. The understanding of substance P has evolved beyond the original concept as the pain transmitter of the dorsal horn. Animal and genetic research, recent developments of nonpeptide substance P antagonists, and important changes in the understanding of neurotransmission have each contributed to the current understanding of substance P After 7 decades, the physiologic role of substance P is known as a modulator of nociception, involved in signaling the intensity of noxious or aversive stimuli. Genetic studies in mice and development of substance P antagonists provide more recent results that support the redefinition of the central role of substance P Evidence suggests that this neuropeptide is an integral part of central nervous system pathways involved in psychologic stress.

Animals↗
PubMed2001

Clinical pharmacokinetics of quetiapine: an atypical antipsychotic.

Quetiapine is a dibenzothiazepine derivative that has been evaluated for management of patients with the manifestations of psychotic disorders. In pharmacokinetic studies in humans, quetiapine was rapidly absorbed after oral administration, with median time to reach maximum observed plasma concentration ranging from 1 to 2 hours. The absolute bioavailability is unknown, but the relative bioavailability from orally administered tablets compared with a solution was nearly complete. Food has minimal effects on quetiapine absorption. The drug is approximately 83% bound to serum proteins. Single and multiple dose studies have demonstrated linear pharmacokinetics in the clinical dose range (up to 375mg twice daily). The drug is eliminated with a mean terminal half-life of approximately 7 hours. The primary route of elimination is through hepatic metabolism. In vitro studies show that quetiapine is predominantly metabolised by cytochrome P450 (CYP) 3A4. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% in faeces. Quetiapine accounted for less than 1% of the excreted radioactivity. 11 metabolites formed through hepatic oxidation have been identified. Two were found to be pharmacologically active, but they circulate in plasma at 2 to 12% of the concentration of quetiapine and are unlikely to contribute substantially to the pharmacological effects of the drug. The pharmacokinetics of quetiapine do not appear to be altered by cigarette smoking. Oral clearance declines with age, and was reduced in 2 of 8 patients with hepatic dysfunction but not in patients with renal impairment. Quetiapine has no effect on the in vitro activity of CYP1A2, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations. The lack of effect of quetiapine on hepatic oxidation was confirmed in vivo by the lack of effect of quetiapine on antipyrine disposition. Quetiapine had no effect on serum lithium concentration. Phenytoin and thioridazine increase the clearance of quetiapine, and ketoconazole decreases clearance. No clinically significant effects of cimetidine, haloperidol, risperidone or imipramine on the pharmacokinetics of quetiapine were noted. Quetiapine dosage adjustment, therefore, may be necessary when coadministered with phenytoin, thioridazine or other potent CYP3A4 inducers or inhibitors. The relationship between the therapeutic effects and the plasma concentrations of quetiapine has been investigated in a multicentre clinical trial. There was no statistically significant association between trough plasma quetiapine concentration and clinical response as measured by traditional assessments of psychotic symptom severity. Subsequent clinical studies of the plasma concentration versus effect relationships for quetiapine may help to further define guidelines for dosage regimen design.

Adolescent↗
PubMed2001

An explanation of the second-dose effect in pharmacokinetics and its meaning for clinical psychopharmacology.

Most psychopharmacologic agents are administered in multiple dosing regimens. Frequently, the relative intensity and/or duration of action of a second dose of medication appear to differ from the initial dose. A theoretical pharmacokinetic basis exists for this phenomenon. When a second (and equal) dose of a drug is given after cessation of the pharmacologic effect of the initial dose, the relative intensity is more pronounced and the duration of action is greater. However, the third and subsequent doses are equal in intensity and duration to the second. This second-dose effect occurs regardless of the half-life of the drug when dosing is repeated in response to the observed effect. For many commonly used drugs, multiple dosing regimens are begun on a fixed dosage interval. When dosing is repeated before the previous dose has been eliminated from the body, the second and subsequent doses produce a greater effect than the initial dose, but the relative increase in intensity of subsequent doses diminishes. Published literature supports the concept of a "second-dose effect" in clinical psychopharmacology. An appreciation of the assumptions and limitations of the second-dose effect provides a better understanding of the observed effects of many psychoactive drugs after repeated administration.

Algorithms↗
PubMed2001

The emerging recognition of herb-drug interactions with a focus on St. John's wort (Hypericum perforatum).

The use of herbal medications and other alternative therapies is accelerating. Survey data clearly indicate that these agents are frequently combined with prescription and over-the-counter medications. The herbal antidepressant St. John's wort (Hypericum perforatum) is one of the most commonly utilized herbal agents. In spite of growing concern and examples of herb-drug interactions, little systematic research has been published or funded in this area. Computerized searches of the biomedical literature were undertaken utilizing MEDLINE, Current Contents, and PsycINFO computer databases (years 1966-December 2000) and by review of bibliographies to identify all pertinent case reports, case series, and formal studies for this review using search terms St. John's wort, hypericum, herb, in vitro, cytochrome P450, and drug interactions. Little in vitro or in vivo data on St John's wort or other herb-drug interactions is available and current in vitro methods for screening conventional medications may have limited applications to herbal agents which generally have numerous constituents of unknown pharmacokinetics and pharmacology. However, available data from clinical studies and case reports suggests that St. John's wort is unlikely to inhibit cytochrome P450 (CYP) 3A4 or 2D6, but is likely an inducer of CYP 3A4 and possibly the P-glycoprotein transporter. Examples of conventional medications which may undergo significant CYP 3A4 induction by St. John's wort include cyclosporine, indinavir, and oral contraceptives. The accumulating evidence of significant drug interactions with St. John's wort should serve as an example to clinicians to be aware of the potential for St. John's wort, and very likely, other herbal products to participate in important herb-drug interactions when used in combination with conventional medications. Concomitant use of herbal agents and conventional medications should generally be discouraged until further information is available. Additional research is urgently needed in this area.

Animals↗
PubMed2001

A primer on caffeine pharmacology and its drug interactions in clinical psychopharmacology.

Caffeine in the form of various beverages and as an additive in numerous drug formulations is the most widely consumed drug in the world. Its psychostimulant properties account for much of its popularity. Caffeine has multiple pharmacological effects that influence normal physiological functioning, and it has been suspected of contributing to morbidity. Drug interactions of caffeine with other psychoactive drugs are described. This review summarizes the pharmacology of caffeine and its drug interactions relevant to the practice of clinical psychopharmacology. The impact of caffeine consumption should be considered in planning and assessing responses to pharmacotherapy for mental illness.

Animals↗
PubMed2001

Charleston Antidepressant Drug Interactions Surveillance Program (CADISP).

A prospective antidepressant drug interaction surveillance program was established and collected data for over 4 years in Charleston, SC (Charleston Antidepressant Drug Interactions Surveillance Program, CADISP). One hundred and seventy patients were enrolled. The plasma concentrations and/or clinical effects of drug combinations were monitored in psychiatric patients who received therapy with a selective serotonin reuptake inhibitor (SSRI) or one of the other newer antidepressants (nefazodone, venlafaxine) when combined with other drugs metabolized by the cytochrome P-450 (CYP) enzyme system. Patient data were evaluated to estimate the occurrence and significance of antidepressant-induced metabolic drug interactions. Plasma drug concentrations in the presence and absence of treatment with an antidepressant served as the primary assessment variable. Contrary to the hypothesis that pharmacokinetic drug-drug interactions occur but go undetected, little evidence was found for occultly occurring drug interactions with newer antidepressants. The presence of commonly predicted drug interactions was documented. These data do not eliminate the need for caution when prescribing antidepressants with the potential for causing metabolic interactions, but do help allay the fear that such interactions are highly prevalent and routinely hazardous.

Adolescent↗
PubMed2001

A pharmacokinetic drug-drug interaction study of venlafaxine and indinavir.

Depression is a common occurrence in the human immunodeficiency virus (HIV)-infected population. Complications in treating depressed HIV-infected individuals include the use of multiple medications, additive side effects, and potentially significant drug-drug interactions. Based on the pharmacologic characteristics of venlafaxine and indinavir, we hypothesized that significant pharmacokinetic drug-drug interactions would not occur when these drugs where taken concurrently. Nine healthy adult subjects were given a single 800 mg oral dose of indinavir and serial blood samples were collected for measurement of plasma drug concentrations. Over the next 9 days, venlafaxine was administered at a dosage of 50 mg every 8 hours following a brief titration. A venlafaxine trough plasma concentration and serial concentrations following venlafaxine administration were obtained on day 10. On day 11, venlafaxine and indinavir were administered together and serial blood sampling was repeated. Indinavir had no effect on venlafaxine plasma concentrations but resulted in a 7% decrease in plasma concentrations of O-desmethyl-venlafaxine (ODV)(P = 0.028). This effect is unlikely to be clinically significant. Venlafaxine coadministration resulted in a 28% decrease in the area under the concentration time curve (AUC) of plasma indinavir (P = 0.016) and a 36% decrease in its maximum plasma concentration (Cmax; P = 0.038). As the plasma concentration of protease inhibitors is a critical factor in maintaining efficacy and minimizing the potential for viral resistance, the decrease in both AUC and Cmax of indinavir from coadministration of venlafaxine is of concern. The clinical significance of these results obtained from a small number of healthy volunteers is unknown. Further studies are needed to substantiate or refute this apparent drug-drug interaction. Until such time, venlafaxine should be used cautiously in patients receiving indinavir.

Adult↗
PubMed2000

Effect of St. John's wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers.

The effects of the herb St. John's wort (Hypericum perforatum), a purported antidepressant, on the activity of cytochrome P-450 (CYP) 2D6 and 3A4 was assessed in seven normal volunteers. Probe substrates dextromethorphan (2D6 activity) and alprazolam (3A4 activity) were administered orally with and without the co-administration of St. John's wort. Urinary concentrations of dextromethorphan and dextrorphan were quantified and dextromethorphan metabolic ratios (DMRs) determined. Plasma samples were collected (0-60 hrs) for alprazolam pharmacokinetic analysis sufficient to estimate tmax, Cmax, t 1/2, and AUC. Validated HPLC methods were used to quantify all compounds of interest. No statistically significant differences were found in any estimated pharmacokinetic parameter for alprazolam or DMRs. These results suggest that St. John's wort, when taken at recommended doses for depression, is unlikely to inhibit CYP 2D6 or CYP 3A4 activity.

Adult↗
PubMed2000

Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency.

The clinical course of a 9-year-old diagnosed with attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette's disorder and treated with a combination of methylphenidate, clonidine, and fluoxetine is described. The patient experienced over a 10-month period, signs and symptoms suggestive of metabolic toxicity marked by bouts of gastrointestinal distress, low-grade fever, incoordination, and disorientation. Generalized seizures were observed, and the patient lapsed into status epilepticus followed by cardiac arrest and subsequently expired. At autopsy, blood, brain, and other tissue concentrations of fluoxetine and norfluoxetine were several-fold higher than expected based on literature reports for overdose situations. The medical examiner's report indicated death caused by fluoxetine toxicity. As the child's adoptive parents controlled medication access, they were investigated by social welfare agencies. Further genetic testing of autopsy tissue revealed the presence of a gene defect at the cytochrome P450 CYP2D locus, which results in poor metabolism of fluoxetine. As a result of this and other evidence, the investigation of the adoptive parents was terminated. This is the first report of a fluoxetine-related death in a child with a confirmed genetic polymorphism of the CYP2D6 gene that results in impaired drug metabolism. Issues relevant to child and adolescent psychopharmacology arising from this case are discussed.

Antipruritics↗