Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers

Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design.No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST.These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.Presented in part at the Nineteenth Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, NV, November 4–8, 1990     

The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design, subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10 mg parenteral (IV) adinazolam mesylate, (3) 30 mg IV NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and NDMAD concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After IV administration of adinazolam, Asians manifested significantly higher C_max, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after IV NDMAD Asians had significantly higher NDMAD C_max and AUC than Caucasians and African-Americans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher C_max, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of C_max, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups. Received: 19 June 1996/Final version: 17 September 1996     

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.     

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adinazolam pharmacokinetics and behavioral effects following administration of 20–60 mg oral doses of its mesylate salt in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam were studied in 15 normal, healthy, non-obse volunteers. Placebo capsules and capsules containing 20, 40, and 60 mg adinazolam mesylate were administered as single oral doses in a randomized, 4-way crossover design. Plasma concentrations of adinazolam and mono-N-desmethyladinazolam (NDMAD) were determined by HPLC. Psychomotor performance and memory tests were performed and the degree of sedation assessed at designated times following drug administration. Adinazolam and NDMAD pharmacokinetics were linear throughout the dosage range studied. The ratio of NDMAD to adinazolam area under the curve was approximately 4:1. Dose-related decrements in psychomotor performance and memory were observed up to 8h after dosing (P<0.025 in all cases). Psychomotor performance decrements correlated more closely with NDMAD plasma concentrations than with adinazolam concentrations. These results suggest that NDMAD is responsible for a significant degree of the sedative and psychomotor effects observed after the administration of adinazolam.     

The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD) were evaluated in twelve healthy non-smokers (NS) and twelve smokers (S, ? 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained-release tablets in an open-label, parallel-group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8±25.8 versus 48.2±14.01 h^?1) or peak adinazolam plasma concentrations (C_max) (93.3±31.8 versus 90.4±18.0 ng ml^?1) between groups. NDMAD AUC (2541.457 versus 2798±447 ng h ml^?1) and C_max (173±30.3 versus 175±26.9 ng ml^?1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non-smokers (8.7±0.7 versus 10.7±2.71 h^?1; p<0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol-digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam after oral and intravenous dosing in healthy young and elderly volunteers.

The pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam were studied in 18 young subjects, from 21 to 36 years of age, and 18 elderly subjects, ranging in age from 65 to 76 years. Nine men and 9 women per age group were studied in a randomized three-way crossover design. Single doses of one 30-mg adinazolam mesylate sustained release tablet, one 30-mg immediate release tablet, and 15 mg of intravenous adinazolam mesylate were administered. Plasma adinazolam and N-desmethyladinazolam were determined by high-performance liquid chromatography, and psychomotor performance tests, including digit-symbol substitution and two card-sorting tasks, were performed. An effect index, defined as the maximal performance decrement divided by N-desmethyladinazolam maximum plasma concentration was calculated as a measure of sensitivity to these effects. Adinazolam oral and systemic clearances were reduced approximately 30% and 25%, respectively, in elderly volunteers. Adinazolam half-life was prolonged approximately 40% in the elderly after oral dosing. N-Desmethyladinazolam plasma concentrations and half-life were increased approximately 40% in elderly volunteers. Psychomotor performance decrements were observed following all treatments; decrements were lowest following sustained release tablets and intravenous adinazolam. Maximal performance decrements in elderly subjects were approximately twice those observed in young subjects. No significant influence of age on the effect index for digit-symbol substitution was evident. Effect indices for card-sorting tests were significantly higher in the elderly. Lower clearances of adinazolam and N-desmethyladinazolam are observed in elderly volunteers, and increased N-desmethyladinazolam levels contribute to increased psychomotor performance decrements in elderly subjects. Results also suggest that elderly subjects may be more sensitive to certain cognitive effects of N-desmethyladinazolam.     

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects

Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P=0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P=0.031), and the difference in maximum category recall decrement was marginally significant (P=0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.     

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.     

Double-blind comparison of alprazolam and adinazolam for panic and phobic disorders

Subjects primarily suffering from DSM-III panic disorders (agoraphobia with panic attacks, 13 subjects; panic disorder, one subject) were tested with two drug treatments after a baseline was established using single-blind placebo capsules three times daily for 1 week. Double-blind, 4-week crossover treatments were given with alprazolam, 0.5-6.0 mg/day, and adinazolam mesylate, 10-120 mg/day. Mean final doses in mg/day were 3.1 for alprazolam and 95.5 for adinazolam mesylate. Both were broadly effective in comparison with the baseline condition. Measures included self-rated symptoms and global impressions, physician-rated global impressions, and two forms of challenges, agoraphobic and noradrenergic. The two active drugs were highly similar in overall efficacy across the sample, but alprazolam was favored globally in six subjects, and adinazolam was favored globally in another six subjects. Only two subjects obtained maximal improvement ratings without side effects with both drugs. No diagnostic or demographic factor correlated with the differential in responses to the two active treatments. No clinically significant laboratory abnormalities occurred with either drug.     

Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.     

Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam.

Alprazolam, adinazolam, and clonazepam share the typical pharmacological effects of benzodiazepines yet are diverse in their pharmacokinetic properties. Alprazolam has an average terminal elimination half-life of 12 hours, whereas adinazolam generates a metabolite responsible for its benzodiazepine effects whose half-life is less than 3 hours. Clonazepam shows a much slower elimination with a half-life of 20 to 80 hours. The rate of decline of plasma benzodiazepine concentration may be an important factor in determining the number of daily doses necessary to maintain optimal anti-panic effects and to minimize rebound anxiety and withdrawal effects. Clonazepam, which has a longer half-life, would be expected to have some advantages over the other drugs. The limited data available do not provide evidence for any substantial advantages of one benzodiazepine over another. The potential disadvantage of the rapid elimination half-life of adinazolam and its metabolite may be offset by formulation in a sustained release capsule. When discontinuing therapy abruptly, a benzodiazepine with a longer half-life may be advantageous; however, when pharmacotherapy is discontinued gradually, the importance of half-life is diminished. Studies of the pharmacodynamics of drug-receptor interactions suggest new approaches to minimizing the adverse effects of discontinuing benzodiazepine therapy. Preliminary data relating plasma alprazolam concentrations to anxiolytic and adverse effects are presented.     

Extent and Variability of the First-Pass Elimination of Adinazolam Mesylate in Healthy Male Volunteers

The pharmacokinetics of adinazolam and N-desmethyladinazolam (NDMAD) were studied in 14 healthy male volunteers who received 15 mg adinazolam mesylate orally as a solution and 5 mg adinazolam mesylate intravenously in a crossover design. Two weeks prior to the crossover study, each subject received 5 mg/kg indocyanine green (ICG) as an intravenous bolus injection to estimate liver blood flow. The absolute bioavailability (F), calculated as the dose-corrected ratio of oral to iv adinazolam area under the curve (AUC) values, was found to be 39%. NDMAD AUC values were similar following oral and iv administration, and adinazolam mean absorption time was approximately 0.77 hr. Thus, adinazolam is completely and rapidly absorbed after oral administration in man; the incomplete bioavailability is due to first-pass metabolism. Mean liver blood flow, adinazolam systemic clearance, blood/plasma ratio, and extraction ratio were 1189 ml/min, 498 ml/min, 0.70, and 0.57, respectively. The extraction ratio agrees with that calculated as 1-F (0.62), suggesting that the liver is primarily responsible for first-pass metabolism of adinazolam. The unbound fraction of adinazolam in plasma was 0.31 (range, 0.25–0.36); adinazolam free intrinsic clearance (a reflection of metabolic capacity) was 4285 ml/min (range, 2168–6312 ml/min). These results suggest that the majority of the variability in adinazolam plasma concentrations following oral administration is due to the variability in the metabolic capacity of the liver for adinazolam, rather than variability in plasma protein binding.     

Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam

The pharmacokinetics and pharmacodynamics of the benzodiazepine alprazolam (1 mg, administered orally) were compared between eight patients with panic disorder and eight age- and sex-matched healthy volunteers. Subjects received orally administered placebo and alprazolam in a randomized, double-blind, single-dose crossover study. The elimination half-life, time of maximum plasma concentration, maximum concentration, volume of distribution, and clearance of alprazolam were similar for both groups. For each cohort, alprazolam treatment (vs. placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and impaired cognitive performance on the digit-symbol substitution test. For the panic disorder group only, there was a significant increase in the subjective rating of"contented" and a reduction in the rating of "easily irritated." For the healthy volunteer group, alprazolam produced increases in ratings of "fatigued" and "slowed thinking," but also increases in ratings of "relaxed." In each group, alprazolam significantly increased the electroencephalographic (EEG) measure of relative beta amplitude (range, 13-30 Hz) compared with placebo. Concentration-EEG response curves fit a sigmoid E(max) model, and there was greater sensitivity to EEG effects, as measured by a 28% reduction in the EC50 value, in the panic disorder group compared with healthy control subjects. After alprazolam treatment, there was increased sensitivity to EEG and mood effects and fewer aversive effects in the panic disorder group compared with healthy subjects. There were no differences in the pharmacodynamic measures of sedation and cognition or differences in pharmacokinetics between the two groups.     

Effect of chronic administration of alprazolam and adinazolam on clonidine- or apomorphine-induced aggression in laboratory rodents

The activity of chronic (3 weeks) treatment with the triazolobenzodiazepines, alprazolam and adinazolam, on clonidine- and apomorphine-induced aggression were studied. Adinazolam, like desipramine, potentiated aggression induced by clonidine while diazepam and alprazolam completely abolished it. In the apomorphine-induced aggression, adinazolam suppressed both aggressivity and stereotypy, while diazepam slightly potentiated it. Alprazolam did not modify the effect of aggression induced by apomorphine. On the whole, while adinazolam seemed to develop an activity closer to that of a classical antidepressant like desipramine, alprazolam appeared to be more similar to the benzodiazepines on clonidine-induced aggression in mice. Compared to desipramine and diazepam, adinazolam left these two effects induced by apomorphine almost unchanged. The experiments performed showed differences between the profiles of action of the two triazolobenzodiazepines studied.     

Diffusion in HPMC Gels. II. Prediction of Drug Release Rates from Hydrophilic Matrix Extended-Release Dosage Forms

Purpose. A mathematical model is described for the prediction of the relative change in drug release rate as a function of formulation composition for HPMC-based extended-release (ER) tablets of adinazolam mesylate and alprazolam. Methods. The model is based on the equation derived by Higuchi for the diffusional release of soluble drugs from polymeric matrices and on our recent measurements of the concentration dependency of adinazolam diffusivity in dilute HPMC gels and solutions. The assumptions made in applying the model include (i) that diffusion is the sole mechanism of drug release (i.e. swelling kinetics are ignored), and (ii) that the surface area-to-volume ratio and concentrations of adinazolam, lactose and HPMC in the gel layer are proportional to that of the dry tablet. Results. Reasonable correlations were obtained between the experimental drug release rate ratios and the predicted drug release rate ratios for ER adinazolam mesylate (R² = 0.82) and low-dose (0.5 mg) ER alprazolam tablets (R² = 0.87). The predictive power for a 6-fold higher dose of ER alprazolam tablets was not as good (R² = 0.52). Conclusions. These results are consistent with previous knowledge of the release mechanisms of these formulations. ER adinazolam mesylate and ER alprazolam 0.5 mg exhibit primarily a diffusion controlled release mechanism, while ER alprazolam 3 mg deviates from pure diffusional release. The limitations of the model are discussed and point to the need for continued study of the swelling kinetics of matrix ER systems.     

Specific effects of benzodiazepines and tricyclic antidepressants in panic disorder: comparisons of clomipramine with alprazolam SR and adinazolam SR

In order to compare the efficacy and safety of tricyclic antidepressants and benzodiazepines in panic disorder, with or without agoraphobia, two studies were carried out comparing clomipramine with alprazolam sustained release (SR) or with adinazolam SR. Two hundred and fifty‐seven patients received alprazolam SR (2–6 mg/day given in two divided daily doses) or clomipramine (50–150 mg/day given in two divided daily doses) for 12 weeks in a single‐blind, randomised, multicentre study and 347 patients received adinazolam SR (30–90 mg/day given in two divided daily doses) or clomipramine (50–150 mg/day given in two divided daily doses) for 24 weeks in a double‐blind, randomised, multicentre study. Both benzodiazepines showed an earlier onset of therapeutic efficacy than clomipramine. At the end of the treatment periods, however, clomipramine was equally as effective as alprazolam SR and more effective than adinazolam SR. Withdrawal problems were also somewhat less common with clomipramine than with alprazolam SR and adinazolam SR. Both benzodiazepines were clearly better tolerated than clomipramine. The rate of premature withdrawal was also notably higher with clomipramine than with alprazolam SR. In conclusion, the benzodiazepines alprazolam and adinazolam SR are better tolerated than the tricyclic antidepressant clomipramine in the treatment of panic disorder, but have no advantages in terms of efficacy. Copyright © 1999 John Wiley & Sons, Ltd.     

N-desmethyladinazolam pharmacokinetics and behavioral effects following administration of 10–50 mg oral doses in healthy volunteers

Results of previous studies suggest that N-desmethyladinazolam, the major metabolite of adinazolam in man, contributes substantially to psychomotor effects and sedation observed following adinazolam administration. Therefore, the pharmacokinetics and pharmacodynamics of N-desmethyladinazolam were explored following administration of single oral doses of placebo and solutions containing 10, 30, and 50 mg N-desmethyladinazolam mesylate in a double-blind, randomized, four-way crossover design to 15 healthy male volunteers. Plasma concentrations of N-desmethyladinazolam were determined by HPLC. Psychomotor performance tests (digit symbol substitution and card sorting by fours and suits), memory tests and sedation scoring were also performed following drug administration. N-desmethyladinazolam pharmacokinetics were dose independent over this range. Doserelated performance effects were observed at 1, 2, and 6 h after dosing. Memory was likewise affected at 2 h. Psychomotor performance decrements correlated with log N-desmethyladinazolam plasma concentrations. Analysis of the relationship between percentage decrements in digit-symbol substitution and plasma N-desmethyladinazolam using the Hill equation revealed a EC₅₀ of 325 ng/ml. These results establish the relationship between N-desmethyladinazolam plasma concentrations and performance effects; these data will be helpful in assessing the contribution of N-desmethyladinazolam to clinical effects observed after adinazolam administration.     

Kinetic Characterization and Identification of the Enzymes Responsible for the Hepatic Biotransformation of Adinazolam and N-Desmethyladinazolam in Man

The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10–1000 μm . The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lympho-blastoid cells, and by the use of CYP isoform-selective chemical inhibitors. Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, K_m, at which the reaction velocities were 50% of the maximum were 92 and 259 μm , respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (K_m 498 μm ). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (K_m 39 μm ) and CYP 3A4 (K_m 83 μm ); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0·15 μm and the inhibition constant, K_i, was < 0·04 μm in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1·96 μm . The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 μm ) and sulphaphenazole, α-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (K_m 220 μm , Hill number A 1·21), CYP 2C19 (K_m 187 μm , Hill number A 1·29) and CYP 2C9 (K_m 1068 μm ). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0·14 μm ) and formation of U (IC50 < 0·1 μm ) whereas omeprazole and sulphaphenazole had no effect on reaction rates. These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.