Dysregulation of neurosteroids in obsessive compulsive disorder.

Alterations in hormone concentrations, including adrenocorticotropin, corticotropin releasing hormone, and cortisol have been reported in patients with obsessive compulsive disorder (OCD). Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEA-S, have not been assessed in patients with OCD. We report 24-h serum DHEA, DHEA-S, and cortisol concentrations in a young man with OCD and 15 healthy young men. Circadian patterns of DHEA and cortisol were markedly different in the subject with OCD than in the control subjects. DHEA and DHEA-S concentrations were substantially higher in the OCD subject than in the control subjects. In contrast, cortisol concentrations were similar in the OCD subject and the control subjects. Future clinical studies are needed to evaluate the significance of DHEA and DHEA-S in OCD.

Endogenous concentrations of DHEA and DHEA-S decrease with remission of depression in older adults.

BACKGROUND: Clinical studies of endogenous concentrations of dehydroepiandrosterone (DHEA) and its sulfated conjugate DHEA-S in depression are limited. This study was designed to evaluate the influence of successful pharmacological treatment of late-life depression on concentrations of DHEA, DHEA-S and cortisol. METHODS: We determined endogenous concentrations of DHEA, DHEA-S and cortisol in elderly control subjects (n = 16) and in elderly depressed patients who remitted (n = 44) or failed to remit (n = 16) with pharmacological treatment. Depressed patients were treated for 12 weeks with either nortriptyline or paroxetine. RESULTS: In remitters, DHEA and DHEA-S concentrations were lower at week 12 than at week 0 (p =.002 and p =.0001, respectively). In the nonremitters and control subjects, neither DHEA nor DHEA-S concentrations changed. Decreases in hormone concentrations were associated with improvement in mood and functioning in depressed patients. Although cortisol concentrations decreased in remitters and nonremitters, the change was not significant. CONCLUSIONS: Our data suggest that the decrease in DHEA and DHEA-S in remitters is related to remission of depression rather than to a direct drug effect on steroids, as nonremitters had no change in hormone concentrations.

Dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol concentrations in intensive care unit patients.

STUDY OBJECTIVE: This purpose of this study was to determine whether severity of illness, as defined by the intensive care unit (ICU) admission APACHE II (updated Acute Physiology and Chronic Health Evaluation) score, is correlated with early morning cortisol, dehydroepiandrosterone (DHEA), and/or dehydroepiandrosterone-sulfate (DHEA-S) concentrations. DESIGN: Early morning concentrations of DHEA, DHEA-S, and cortisol were determined within 24 hrs of admission and compared with admission APACHE II scores. SETTING: Medical (MICU), neurologic (NICU), and surgical (SICU) intensive care units of the University of Pittsburgh Medical Center. PATIENTS: A total of 191 men and women ranging in age from 16 to 93 yrs. All had been admitted to an ICU. MEASUREMENTS AND MAIN RESULTS: Statistically significant correlations between APACHE II scores and cortisol were observed for women in the MICU and SICU (r = .68, p = .0001; r = .35 p = .017, respectively) and for men in the NICU (r = .55, p = .003) and the SICU (r = .29, p = .036). The correlations between APACHE II scores and DHEA concentration data were statistically significant for women in the MICU (r = .37, p = .047) and SICU (r = .43, p = .002), as was the correlation between APACHE II and DHEA-S concentrations among women in the SICU (r = .38, p = .008). Although not statistically significant, a similar relationship was observed in the smaller group of NICU women (r = .40, p = .099). Each correlation was essentially unchanged when adjusted for age. CONCLUSION: These data show a positive correlation between APACHE II and cortisol concentrations in all groups except the MICU men. Also evident is the positive correlation between APACHE II scores and DHEA and DHEA-S concentrations in women, but not in men.

Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple-dose administration in healthy older adults.

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA-S) after single- and multiple-dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA-S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA-S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5- to 6-fold in both men and women, and DHEA-S concentrations increased 5-fold in men and 21-fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.

Clonazepam and sertraline: absence of drug interaction in a multiple-dose study.

Thirteen subjects (seven men, six women) completed a placebo-controlled, randomized, double-blind, crossover study to determine whether an interaction occurs between clonazepam and sertraline. Ten days of once-daily doses of either clonazepam 1 mg and placebo (CZ + PL) or clonazepam 1 mg and sertraline 100 mg (CZ + SR) were administered; there was an 11-day washout period. Sertraline did not significantly affect the pharmacokinetics of clonazepam (p > 0.13). Clonazepam apparent oral clearance, volume of distribution, and half-life were 3.9 +/- 0.2 L/hr, 233 +/-11 L, and 40.5 +/- 0.3 hours, respectively. The kinetics of the inactive metabolite 7-aminoclonazepam were marginally affected by sertraline, with a 21% decrease in the elimination half-life (p = 0.03) relative to CZ + PL and no significant difference between treatments in area under the curve or metabolite ratio. Card sorting (CS), digit-symbol substitution test (DSST), nurse-rated sedation scale (NRSS), and self-rated sedation scores were assessed four times daily on days -1 (PL + PL), 1, 4, 7, and 10. There were no differences between treatments in area under the effect curve or maximum observed effect for CS, DSST, or NRSS. Maximum impairment on all assessment days was low, with a less than 10% change from the drug-free values for CS and DSST. Despite higher clonazepam concentrations, predose (time 0) psychomotor and sedation scores did not differ among days -1, 1, 4, 7, and 10 or between treatments. These results in healthy volunteers indicate that sertraline does not affect the pharmacokinetics or pharmacodynamics of clonazepam.

Alprazolam increases dehydroepiandrosterone concentrations.

The gamma-aminobutyric acid (GABA) agonist alprazolam is known to decrease adrenocorticotropic hormone and cortisol concentrations. Dehydroepiandrosterone (DHEA) is secreted synchronously with cortisol by the adrenal glands and demonstrates diurnal variation. The major objective of this study was to determine whether alprazolam affects concentrations of DHEA and DHEA-S, the sulfated metabolite. In vitro studies have demonstrated that DHEA-S, and perhaps DHEA, have GABA antagonistic activity. Another objective was to determine whether DHEA-S and/or DHEA concentrations are related to psychomotor impairment after alprazolam. Thirty-eight healthy volunteers (25 young men, aged 22-35, and 13 elderly men, aged 65-75) received a single intravenous dose of alprazolam 2 mg/2 min (part 1). Fifteen young and 13 elderly men responded to alprazolam and agreed to participate in part 2 of the study, which was a crossover of placebo and alprazolam infusion to plateau for 9 hours. Plasma samples at 0, 1, 4, and 7 hours were assayed for steroid concentrations. Alprazolam produced (1) significant increases in DHEA concentrations at 7 hours in both young and elderly men; (2) significant decreases in cortisol concentrations; and (3) no change in DHEA-S concentrations. The relationship between psychomotor decrement and DHEA concentrations at 7 hours after alprazolam 2 mg/2 min was described by a u-shaped curve (p < 0.0047). Both the linear and quadratic components of the equations for the tests were significant (p < 0.002). These results suggest that alprazolam modulates peripheral concentrations of DHEA and that DHEA and/or DHEA-S may have an in vivo role in modulating GABA receptor-mediated responses.

DHEA and DHEA-S: a review.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA-S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA-S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA-S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA-S concentrations, as well as concentrations of DHEA and DHEA-S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA-S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.

Simplified procedure for measurement of serum dehydroepiandrosterone and its sulfate with gas chromatography-ion trap mass spectrometry and selected reaction monitoring.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that have recently been widely publicized as potential treatments for many disorders. This paper describes a gas chromatographic-ion trap mass spectrophotometric assay with selected reaction monitoring for measurement of DHEA and DHEAS levels. The hormones and internal standard (5-androsten-3beta-ol-16-one methyl ester) are extracted from serum with Oasis solid-phase extraction tubes. The extracted steroids are dissolved in methanol and injected into a Finnigan GCQ ion trap mass spectrometer. In the selected reaction mode, both DHEA and DHEAS can be identified and quantified in a single injection. No derivatization or expensive deuterated internal standards are required.

Correlates and prevalence of benzodiazepine use in community-dwelling elderly.

OBJECTIVE: To describe the prevalence of benzodiazepine use, sociodemographic and physical health factors associated with use, dosages taken, and directions for use among individuals aged 65 years and older. DESIGN: Cross-sectional analysis of baseline data from the community-based, prospective observational Cardiovascular Health Study. PATIENTS/PARTICIPANTS: Medicare eligibility lists from four U.S. communities were used to recruit a representative sample of 5,201 community-dwelling elderly, of which 5,181 participants met all study criteria. MEASUREMENTS AND MAIN RESULTS: Among participants, 511 (9.9%) were taking at least one benzodiazepine, primarily anxiolytics (73%). Benzodiazepines were often prescribed to be taken pro re nata (PRN "as needed"), and 36.5% of prescriptions with instructions to be taken regularly were taken at a dose lower than prescribed. Reported over-the-counter (OTC) sleep aid medication use was 39.2% in benzodiazepine users and 3.3% in nonusers. In a multivariate logistic model, the significant independent correlates of benzodiazepine use were being white (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.0, 3.4), female (OR 1.7; CI 1.4, 2.2), and living in Forsyth County, North Carolina, or Washington County, Maryland, compared with living in Sacramento County, California, or Allegheny County, Pennsylvania (OR 2.3; CI 1.4, 2.2); having coronary heart disease (OR 1.6; CI 1.2, 2.1), health status reported as poor or fair (OR 1.8; CI 1.4, 2.3), self-reported diagnosis of nervous or emotional disorder (OR 6.7; CI 5.1, 8.7), and reporting use of an OTC sleep aid medication (OR 18.7; CI 14.1, 24.7). CONCLUSIONS: One in 10 participants reported taking a benzodiazepine, most frequently an anxiolytic, often at a lower dose than prescribed and usually PRN. The high prevalence of OTC sleep aid medication and benzodiazepine use may place the patient at increased risk of psychomotor impairment. Physicians should assess OTC sleep aid medication use when prescribing benzodiazepines.

Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same time course?

The purpose of this study was to determine whether short-term tolerance develops to GABA-agonist-induced changes in saccadic eye movements (SEMs), and whether the time course for GABA-agonist induced onset and offset of impairment is similar for SEMs and for psychomotor function. An additional goal was to determine whether there are differences in sensitivity between SEMs and psychomotor function. Six healthy volunteers participated in this balanced double-blind, three-way crossover, single-dose study of placebo and two different dosage forms of the GABA-agonist alprazolam: a rapidly absorbed oral 1.5-mg compressed tablet (CT) and a 3.0-mg sustained release (SR) tablet. Treatments were separated by a 7-day washout period. Peak concentrations did not differ between CT and SR treatments, although area under the concentration-time curve (AUC) of alprazolam was greater after administration of SR than after CT, because plateau concentrations were attained after SR. Both SEM and psychomotor tests showed time-dependent responses consistent with the development of tolerance. SEMs discriminated the differences in rate of drug input of the CT and SR formulations, with impairment evident at low concentrations during absorption. SEM impairment also persisted longer than did psychomotor impairment. Peak saccade velocity is a more sensitive indicator of pharmacologic effects mediated by the GABA-benzodiazepine receptor complex than are psychomotor responses. This is probably the result of the very high GABA dependency of SEMs, along with their limited sensitivity to motivation.

Alprazolam in young and elderly men: sensitivity and tolerance to psychomotor, sedative and memory effects.

This study was designed to determine whether age influences sensitivity to alprazolam and/or rate of acute tolerance development to the effects of alprazolam. Three treatments were each separated by 4 weeks. Twenty-five young (ages 22-35) and 13 elderly (ages 65-75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially for 12 hr. Clearance was lower (P = .05) and elimination t[1/2] was longer (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maximum impairment was greater in the elderly for all assessments. Mean EC50 values differed between the elderly (25.3 and 25.0 ng/ml) and the young (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitution, respectively (P < .001). Bolus treatment data were used to individualize doses for the crossover of placebo and alprazolam; infusions were designed to maintain a plateau alprazolam concentration between 1 and 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Median t[1/2] for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increases sensitivity to effects of alprazolam through a mechanism other than pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensity of initial effect as a determinant of rate of tolerance development.

Adverse effects of risperidone on eye movement activity: a comparison of risperidone and haloperidol in antipsychotic-naive schizophrenic patients.

Risperidone is a novel and clinically effective atypical antipsychotic medication with a unique biochemical profile. To contrast the neurophysiological effects of this new medication with those of a typical antipsychotic medication, we performed quantitative measurements of saccadic eye movements in a series of antipsychotic-naive schizophrenic patients treated with either risperidone or haloperidol. Patients were tested before and after 1 month of treatment, and a matched group of healthy subjects was tested twice over a similar time interval. Risperidone, but not haloperidol, was associated with prolonged latency and decreased peak velocity and accuracy of saccadic eye movements that was detectable 4 weeks after treatment initiation. The adverse effects of risperidone may be due to the lack of development of acute tolerance to its powerful serotonergic (5-HT2A) antagonism, which could be responsible for the disruption of brainstem physiology in regions controlling saccadic eye movements.

Progesterone: does it affect response to drug?

This article presents an overview of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex (GBRC) and its in vitro modulation by THP, a metabolite of progesterone, as well as the results of a single-dose study of progesterone and triazolam in 16 post-menopausal women. The study results indicate that a 300 mg oral dose of progesterone administered 2.5 hours prior to a challenge dose of triazolam significantly increases sensitivity to triazolam: concentration values required for 50 percent of maximum effect (EC50) decreased by 20 to 32 percent after pre-treatment with progesterone. These data support the In vitro findings that THP enhances binding of benzodiazepines to the GBRC. The full clinical implications of these data, including extensions to other steroids, need to be explored.

Oral administration of micronized progesterone: a review and more experience.

Historically, oral progesterone has been regarded clinically ineffective because of its poor absorption and rapid clearance. Recent evidence suggests that an oral micronized form of natural progesterone is readily absorbed, produces luteal phase serum concentrations, provokes an end-organ response, and has no detrimental effect on the lipoprotein profile. Thus it is considered by many to be an attractive alternative to synthetic progestin. We evaluated the effects of a single oral dose of micronized progesterone 300 mg in eight healthy postmenopausal women. The maximum serum concentration ranged from 15.72-625.98 ng/ml. The extent of absorption increased with increasing age. The reviewed literature and our data indicate considerable intersubject variability in the extent of progesterone absorbed after administration of oral micronized progesterone.

Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment.

One hundred two healthy men were evaluated in one of three studies conducted to evaluate the coadministration of nefazodone, 200 mg twice daily, and three benzodiazepines: triazolam, 0.25 mg; alprazolam, 1 mg twice daily; or lorazepam, 2 mg twice daily. In the first study, psychomotor performance, memory, and sedation were assessed at 0, 0.5, 1.5, 2.5, and 9 hours after single doses of triazolam alone and again after 7 days of nefazodone. Data from 6 of 12 subjects in this study were evaluable because of a dosing error in the other 6 subjects. In the subsequent two parallel design studies, groups of 12 volunteers received 7 days of either placebo; nefazodone, 200 mg; alprazolam, 1 mg twice daily; or alprazolam plus nefazodone or, in the second study, either placebo; nefazodone; lorazepam, 2 mg twice daily; or lorazepam plus nefazodone; the studies were identical, double-dummy, double-blind designs. Psychomotor performance, memory, and sedation were assessed at 0, 1, 3, and 8 hours after the 8 a.m. dose on days 1, 3, 5, and 7 of the studies. In all studies, blood samples were also obtained at testing times so that effect/concentration comparisons could be made and so full pharmacokinetic analyses could be done for separate studies. Nefazodone had no effect on psychomotor performance, memory, or sedation relative to placebo in any study. The mean maximum observed effect (MaxOE) on psychomotor performance and sedation were increased when triazolam was given after 7 days of nefazodone (p < 0.05); also, triazolam concentration was 60% higher at this time. Alprazolam and lorazepam impaired performance on day 1 (mean MaxOE, 34 and 30%, respectively) relative to placebo and nefazodone. By day 7 of alprazolam or lorazepam, psychomotor impairment decreased, indicating the development of tolerance. Alprazolam plus nefazodone increased psychomotor impairment (MaxOE, approximately 50%) and sedation relative to alprazolam alone on days 3, 5, and 7 (p < 0.05). Higher alprazolam concentrations explained the increased impairment in the alprazolam plus nefazodone treatment group; however, it is also possible that there was a delay in the development of tolerance. There were no differences in psychomotor impairment, memory, sedation, or lorazepam concentration detected between the lorazepam alone and lorazepam plus nefazodone treatments. This is consistent with the absence of a pharmacokinetic interaction between nefazodone and lorazepam. These results indicate that if the coadministration of a benzodiazepine is required in patients receiving nefazodone therapy, clinically significant interactions would be less likely with those eliminated by conjugative metabolism such as lorazepam. In cases where a benzodiazepine eliminated by oxidative metabolism is required, a reduction in initial dosage and careful clinical evaluation for signs of psychomotor impairment may be appropriate.

Coadministration of nefazodone and benzodiazepines: II. A pharmacokinetic interaction study with triazolam.

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and triazolam after a single dose of triazolam and multiple doses of nefazodone in a randomized, double-blind, placebo-controlled study in healthy male volunteers. The metabolism of triazolam is dependent on cytochrome P450 3A4, and because nefazodone has been shown in vitro to be an inhibitor of this isoenzyme, this study was conducted to assess the potential for an interaction between the two drugs. Twelve subjects were assigned to one of two groups and received an oral dose of either placebo or 0.25 mg of triazolam on days 1 and 2. Nefazodone (200 mg) was administered twice daily from the evening of day 2 to the morning of day 9. Subjects received either 0.25 mg of triazolam or placebo with the nefazodone dose on the mornings of days 8 and 9. Serial blood samples were collected on the mornings of days 1, 2, 8, and 9 for the analysis of triazolam by a validated gas chromatography/electron capture detection method and on days 8 and 9 for the analysis of nefazodone and its metabolites, hydroxynefazodone (HO-nefazodone) and m-chlorophenylpiperazine (mCPP), by a validated high-performance liquid chromatography/ultraviolet method. Noncompartmental pharmacokinetic analysis showed that there was no effect of triazolam on the pharmacokinetics of nefazodone, HO-nefazodone, or mCPP after the coadministration of triazolam and nefazodone. There was a significant effect of 200 mg of nefazodone twice daily on the pharmacokinetics of triazolam. Mean triazolam peak concentration values increased (p = 0.003) from 2.33 to 3.88 ng/ml when triazolam was administered alone and in combination with nefazodone, respectively. Corresponding mean triazolam area under the curve values increased (p < 0.001) from 8.14 to 31.74 ng.h/ml. The plasma protein binding of triazolam was approximately 85% when triazolam was given alone and when given concurrently with nefazodone. The increase in triazolam concentrations in plasma appears to be attributable to the inhibition of cytochrome P450 3A4 metabolism by nefazodone. If triazolam is coadministered with nefazodone, a reduction in the triazolam dosage is recommended; no dosage adjustment is required for nefazodone.

Effect of neuroactive steroids on [3H]flumazenil binding to the GABAA receptor complex in vitro.

Modulation of benzodiazepine receptor ligand binding to the GABAA receptor complex by the neuroactive steroids 3 alpha-hydroxy-dihydroprogesterone (3 alpha-OH-DHP) and 3 alpha-hydroxycorticosterone (3 alpha- THDOC) was assessed in an in vitro binding assay with the benzodiazepine antagonist [3H]flumazenil using rat cortical membranes. Neuroactive steroids, pentobarbital, GABA and bicuculline did not significantly affect flumazenil binding. However, the addition of neuroactive steroids significantly decreased the Ki of benzodiazepine agonists, including alprazolam, diazepam and clonazepam, indicating an increase in agonist affinity. Only the addition of 3 beta-OH-DHP, an inactive stereoisomer had no effect on the Ki of these agonists. The binding of the benzodiazepine inverse agonist FG 7142 was not significantly affected by these steroids, but the addition of GABA significantly increased the Ki of FG 7142 indicating a decrease in inverse agonist affinity. High concentrations of GABA or bicuculline were able to occlude the 3 alpha-THDOC mediated decrease in alprasolam Ki, indicating a GABA dependent mechanism of binding enhancement. An advantage of using [3H]flumazenil is that neither the Ki nor the Bmax change in the presence of allosteric site modulators, permitting the simple and direct assessment of alterations in benzodiazepine ligand affinity for the GABAA receptor complex by neuroactive steroids.

Triazolam pharmacokinetics after intravenous, oral, and sublingual administration.

This study was designed to evaluate the relative and absolute bioavailability of triazolam, 0.25 mg, after the administration of the marketed oral tablet and a sublingual prototype wafer; an intravenous dose was used as a reference. Twelve men were evaluated in a three-way crossover study; study days were separated by 1 week. A single dose was administered to each subject at approximately 8 a.m.; serial blood samples were obtained for the determination of triazolam concentration. The fraction absorbed relative to intravenous was 20% higher in the sublingual than in the oral treatment (p = 0.0128); the difference between treatments was greatest in the first 2 hours as indicated by the area under the curve from 0 to 2 hours (p < 0.05). The extraction ratio ranged from 0.05 to 0.25, and the predicted availability after oral administration was 86% with a range of 75 to 95%. In contrast, the observed mean absolute availability was 44% (oral) and 53% (sublingual). A potential explanation for this discrepancy between predicted and observed bioavailability is that after oral administration, a fraction of triazolam may be metabolized by cytochrome P450IIIA4 in the gut wall, with a separate fraction subject to first-pass metabolism in the liver. Although this study was not designed to identify sites of triazolam metabolism, the proposed explanation is consistent with the occurrence of P450IIIA4 in the stomach, small intestine, and liver. Doses administered sublingually avoid first-pass metabolism, producing earlier and higher peak concentrations than do doses administered orally.

Time-dependent sensitization to triazolam? An observation in three studies.

Evidence of time-dependent sensitization (TDS) to triazolam was observed in three separate clinical studies. Study 1 was conducted in 12 normal-weight and 12 obese men; an intravenous bolus dose of triazolam, 0.5 mg, was administered on two occasions. Study 2 was a balanced crossover of three 0.25-mg oral doses and one 0.20-mg oral dose of triazolam in 11 men. Study 3 was a balanced crossover of one placebo, one 0.5-mg, and two 0.4-mg oral doses of triazolam. In all three studies, treatments were separated by 6 days and included serial blood sampling for characterization of pharmacokinetics. Psychomotor response was assessed with the Digit Symbol Substitution Test and the Continuous Performance Test (CPT). Sedation was rated by an observer. For each measure, an effect ratio was calculated as the area under the effect curve divided by the area under the triazolam concentration curve; this parameter relates the extent of response relative to drug concentration in plasma. Effect ratios increased progressively by week for CPT; the percentage increase ranged from 31.9% in the study 1 normal subjects (week 1 to week 2; p = 0.08) to 631% in study 2 (week 1 to week 4; p = 0.0013). Similar increases were observed for other responses. Overall, the effect ratio data demonstrate increasing responsiveness per unit of triazolam concentration when triazolam was administered as a single dose at 1-week intervals. This observation was incidental to the original objectives of the studies. However, the data suggest that definitive studies to verify the occurrence of this phenomenon need to be conducted.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men.

This study was designed to determine whether differences in alpha-1 acid glycoprotein and free drug concentrations result in an altered response to triazolam. Twelve normal-weight and 12 obese adult male subjects received intravenous doses of triazolam, 0.5 mg, on two occasions separated by 1 week. There was a small difference in the alpha-1 acid glycoprotein concentrations between groups but no difference in free fraction of triazolam. There was a longer terminal half-life (t1/2 beta) in the obese subjects (3.16 +/- 0.87 vs. 3.83 +/- 1.24, p = 0.0098). Overall, week 1 data revealed no difference in effect between normal and obese subjects. However, response data reveal a pattern of increased sensitivity with the second exposure to triazolam. For example, area under the effect curve (AUEC) on all tests was significantly greater in week 2 for both groups of subjects. For a memory test and sedation from 0 to 12 hours, AUEC/free AUC ratios were significantly greater in week 2 for all subjects. The obese had a higher ratio on week 2 than on week 1 for all psychomotor tests and sedation (0 to 4.5 hours; p < 0.05). The results of modeling psychomotor impairment-concentration data pooled by group for each week continue the pattern: week 1 data are similar between the obese and normal-weight subjects. Although EC50 values are up to 15% lower in week 2 for the normal-weight subjects, EC50 values are as much as 66% lower in week 2 for the obese, where a lower EC50 indicates greater sensitivity. Logistic regression of the recognition data is consistent with these results.(ABSTRACT TRUNCATED AT 250 WORDS)