Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects

The relationships between alprazolam and metabolite concentrations and CNS effects were determined in a double-blind placebo controlled four-way crossover trial in 16 normal male volunteers. Active drug treatments consisted of 4-day regimens of 4 mg alprazolam PO daily as 2 mg bid., 1 mg qid, and 0.25 mg each hour. On days 1 and 4, the kinetics, sedative and psychomotor effects were evaluated. Plasma concentrations of the 4- and α-hydroxy metabolites of alprazolam were less than 10% of unchanged alprazolam levels on both days. Accumulation of these metabolites and alprazolam was dependent on alprazolam half-life (11.6 h). Acute and chronic tolerance to the sedative and psychomotor effects was observed with all active drug treatments. All alprazolam treatments resulted in significantly greater sedation than placebo on days 1 and 4. However, on day 4, sedation was 16–36% less than observed on day 1, despite plasma concentrations 1.4–2.76 times the day 1 concentrations. Sedation from alprazolam was reduced in each successive study phase, suggesting a tolerance which was sustained during the 10-day washout between phases. By day 4, psychomotor performance was not different from placebo, indicating more complete development of tolerance than occurred for the sedative effect. Sedation and psychomotor impairment on day 1 were greatest with 2 mg alprazolam bid. During the initiation of therapy, the patient will likely experience less sedation and psychomotor impairment with smaller, more frequent doses. Since tolerance develops to these effects, the advantage of more frequent dosing regimen dissipates by the 4th day.     

Effects of alprazolam and diazepam on the daytime sleepiness of non-anxious subjects

Eighteen non-anxious volunteers underwent sleep recordings and daytime tests of sleepiness, performance, and mood while receiving, either alprazolam 0.5 mg b.i.d. or diazepam 5 mg b.i.d. for 7 consecutive days. Recordings and tests were done before treatment and on the 1st and 7th days of treatment. Nocturnal sleep changes were similar for both groups; there were no statistically significant changes in mood. However, levels of daytime sleepiness differed. Alprazolam subjects showed more daytime sedation than diazepam subjects on treatment day 1, but showed a significant decreased in Day 1–7 daytime sedation. Although diazepam subjects were less sedated at the onset, they showed no tolerance to this effect; thus by treatment day 7, the two groups did not differ in levels of daytime sleepiness. Results suggested that tolerance to alprazolam's sedative effects (which develops during the 1st week of treatment) may be separable from tolerance to its antianxiety effects (which develops after at least 4 weeks). As daytime sedation is common and potentially dangerous with most anxiolytics, selective tolerance to this side effect is highly desirable.     

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.     

Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing

Previous studies have suggested that elderly men eliminate alprazolam more slowly than young adults. This study in the elderly was designed to determine whether a change in pharmacokinetics influences the response to alprazolam during multiple dose regimens. In addition, the study was designed to determine alprazolam pharmacokinetics and the degree to which its hydroxymetabolites accumulate, the degree of psychomotor impairment, and whether tolerance to impairment and sedation develops during three different multiple dose regimens. Twenty-six subjects completed this study. The subjects were randomized into one of three treatment groups: 0.25 mg q8h, 0.5 mg q8h, and 2 mg q12h. Subjects remained in the clinic for 8 days (day — 2-day 5). Day 0 was used as a drug free testing day to establish baseline scores for sedation, digit symbol substitution (DSS), card sorting (CS) tasks, and two computer tests. Subjects received the drug according to schedule on days 1 through 4, with day 5 as the washout day. Blood samples were assayed for alprazolam, alpha-hydroxyalprazolam and 4-hydroxyalprazolam. Alpha-hydroxyalprazolam concentrations were below assay detection limits in all subjects in the 0.25 and 0.5 mg q8h groups and 2.6 ng/ml in the 2 mg q12h group. When detectable, 4-hydroxyalprazolam concentrations were <10% of the corresponding alprazolam concentration. Mean alprazolam oral clearance values in the three treatment groups ranged between 0.54 and 0.62 ml/min/kg and half-lives were in excess of 21 h. Degree of sedation and impairment was dose related. Sedation and impairment was not higher on day 4 despite concentrations 2–3 times as great as on day 1, indicating development of tolerance. Subjects were not, however, back to baseline level of performance on day 4.     

Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects

The interaction of clomipramine and moclobemide with alcohol was compared in a double blind parallel groups study in 24 healthy volunteers. Moclobemide was given at the highest recommended therapeutic dose (200 mg t.i.d.) and clomipramine in a subtherapeutic dose (25 mg b.i.d.) because of its poor tolerance in healthy subjects. Psychometric evaluations were performed during a placebo run-in phase; after a 5-day treatment period; assessments were made before, and again 1 h and 4 h after alcohol ingestion. Alcohol doses were pre-determined for each subject in order to produce a blood alcohol concentration of 0.6 g/l 1 h after alcohol intake and this individual alcohol dose was given on test days. The day before alcohol intake tests for autonomic functions were made to assess the anticholinergic effects of the drugs. Alcohol significantly increased body sway, decreased critical flicker fusion frequency, prolonged choice reaction time, impaired copying skills, impaired memory and increased the subjective feelings of satisfaction and tension. Drugs increased the effect of alcohol on body sway and this was essentially due to clomipramine. Clomipramine both without and with alcohol increased body sway, prolonged choice reaction time more than did moclobemide. Clomipramine seemed to diminish alcohol-induced memory impairment in one of the memory tests used. Subjects taking clomipramine had significantly more adverse effects after alcohol ingestion than did subjects of the moclobemide group. In contrast to moclobemide, clomipramine produced a moderate but significant drop in standing systolic blood pressure and a clear inhibition of salivary excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine

We have assesed the pharmacokinetic and pharmacodynamic interaction between fluvoxamine, a serotonin reuptake inhibitor, and alprazolam, a triazolobenzodiazepine.Healthy men took fluvoxamine maleate daily for 10 days (50 mg on days 1–3, 100 mg on days 4–10) (n=20), 1 mg of alprazolam four times daily for four days (days 7–10 of the study period) (n=20), or a combination of the two (n=20), according to a parallel study design. Alprazolam and fluvoxamine concentrations were measured in serial plasma samples by HPLC and gas chromatography respectively, and psychomotor performance and memory were assessed on days 1, 7, and 10.Fluvoxamine increased plasma alprazolam concentrations by 100%. The mean apparent half-life of alprazolam was increased from 20 h to 34 h after fluvoxamine co-administration.The increased plasma concentrations of alprazolam resulted in significantly greater reductions in psychomotor performance evident on day 10. Mean fluvoxamine plasma concentrations were about 25% lower in those who took the combination than in those who took only fluvoxamine; this was more likely due to heterogeneity between the treatment groups than to an effect of alprazolam.The dosage of alprazolam should be reduced during co-administration with fluvoxamine.     

Clomipramine, a better reference drug for panic/agoraphobia. II. Psychomotor and cognitive effects

The present reference drugs for the treatment of panic disorder and agoraphobia are imipramine and alprazolam. The latter decreases performance and cognitive functioning. No study of such functions in panic/agoraphobia is available. Fifty four out-patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia (PAG), taking part in a parallel groups controlled trial of imipramine (mean dose ±SEM 114±9 mg), clomipramine (50±4 mg) and propanteline (active placebo) over 8 weeks, were studied. A test battery of psychomotor and memory tests was administered at baseline, and after 1, 4 and 8 weeks of treatment. Their results were compared (at baseline and at the end of the trial) with those of a control group of 57 normal untreated subjects. There was no difference between treatments, and no drug effect on any test at any time. No consistent difference between patients and controls was detected. Given its apparently higher potency, and the absence of deleterious effects on cognitive measures known to be affected by benzodiazepines, we conclude that clomipramine is better than imipramine or alprazolam as a reference drug for panic/agoraphobia.     

Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance

Objective There is evidence of more widespread use and abuse of benzodiazepines (BZPs) among elderly women. However, factors underlying this observation are poorly understood but could be related to more intense withdrawal reactions, which are a major risk factor for continued BZP use. We previously reported elevations in interdose morning plasma cortisol levels in healthy elderly individuals after chronic treatment with alprazolam, possibly consistent with increased hypothalamic–pituitary–adrenal (HPA) axis activity and drug withdrawal. In this study, we examined sex-related differences in this population. Method Twenty-five cognitively intact healthy elderly (13 women and 12 men) participated in a parallel, double-blind, placebo-controlled study that included a group that received acute and chronic (3 weeks) treatment with alprazolam (0.5 mg b.i.d.). Results Elderly women, but not men, experienced significant elevations in interdose morning plasma cortisol levels over 3 weeks of chronic treatment with alprazolam (0.5 mg b.i.d.) compared to placebo. In addition, higher morning plasma cortisol levels were significantly associated with better cognitive performance but not with higher plasma drug levels or greater degree of tolerance development to an acute alprazolam challenge. Conclusion Elderly females experienced a greater interdose activation of the HPA axis during treatment with therapeutic doses of alprazolam than men, which could be related to drug withdrawal.     

Tolerance,cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps

Previous research has found that drugs with affinity for (benzodiazepine) sites differ in their abilities to produce tolerance and dependence. The present study therefore investigated the effects of ligands of (BZ) sites in rats that had been rendered tolerant to a benzodiazepine. Two experiments were carried out in separate groups of rats. Behavioral changes induced by chronic infusion of triazolam (3 mg/kg/day, SC, for 14 days) via osmotic pumps were studied in animals trained on a fixed ratio 10 schedule of food presentation. Control animals were implanted with pumps containing the vehicle. Test drugs were administered IP using cumulative dosing. In one experiment triazolam decreased response rates on days 1, 2 and 3 after implantation of the pumps and tolerance developed to this depressant effect. In the other experiment, vehicle and triazolam treated rats differed in their responding during chronic infusion but differences were not statistically significant on any particular day. Flumazenil (3.0–30 mg/kg) greatly decreased rates of responding on day 11 in triazolam treated rats. This effect may represent a precipitated withdrawal syndrome. However, no withdrawal effects on operant performance were observed upon pump removal. Chronic infusion of triazolam did not affect the sensitivity of rats to alpidem on day 11 (10–100 mg/kg) whereas it abolished the stimulant effect of bretazenil (0.1–1.0 mg/kg). Chronic triazolam treatment produced tolerance to the depressant effects of triazolam (1.0–3.0 mg/kg), lorazepam (0.3–3.0 mg/kg) and zopiclone (10 mg/kg) but no tolerance to those of CL 218,872 (3.0–30 mg/kg) and zolpidem (0.3–3.0 mg/kg) when tested 3–14 days after pump removal. Differences between compounds highlighted with this model are in agreement with previous observations that these agents possess different pharmacological profiles and different potentials to induce tolerance and dependence.     

Acute effects of the anxiolytics suriclone and alprazolam on cognitive information processing utilizing topographic mapping of event-related brain potentials (P300) in healthy subjects

In a double-blind, placebo-controlled, cross-over study, acute effects of suriclone — a cyclopyrrolone derivative — were investigated by means of topographic mapping of event-related potentials (ERPs). Fifteen normal volunteers, aged 22–35 years, received randomized, oral single doses of placebo, 0.1 mg, 0.2 mg and 0.4 mg suriclone and 1 mg alprazolam as a reference compound. ERPs were investigated in an auditory oddball paradigm before and 3 h after intake of each drug. In addition to 17 EEG leads, vertical and horizontal electro-oculograms (EOGs) were recorded. After EOG minimization and artifact identification, the peak latencies of the spatial average were determined by an automatic procedure. Compared to placebo, no significant effects of the low and middle doses of suriclone on N1 amplitude were observed; the highest dosage reduced N1 amplitude, as did 1 mg alprazolam to an even greater extent. While no consistent effects on P2 amplitude were observed after suriclone, alprazolam reduced P2 amplitude. P300 amplitude was reduced only after the highest dosage of suriclone, but much more so after alprazolam. P300 latency was not affected significantly by suriclone, but a marked prolongation of P300 latency was observed after 1 mg alprazolam. Concerning N1 and P2 effects, alprazolam, but not suriclone, may have an inhibitory influence on stimulus-induced cortical arousal. Concerning P300 effects, the used doses of suriclone were superior to 1 mg alprazolam, which seemed to have reduced cognitive information processing capacity and prolonged stimulus evaluation time. Self-rated well-being (adjective checklist) showed subtle beneficial effects after 0.1 mg and 0.2 mg, but marked sedative effects after both 0.4 mg suriclone and 1 mg alprazolam.     

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration

Six fasting male subjects (20–32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam wre as follows: volume of distribution (V _d) 0.72 and 0.84 l/kg; elimination half-life (t _1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in V _d, t _1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.     

Interdose elevation in plasma cortisol during chronic treatment with alprazolam but not lorazepam in the elderly.

Benzodiazepines (BZPs) have been shown to reduce hypothalamic-pituitary-adrenal (HPA) axis activity acutely in normal humans. In contrast, the effects of chronic BZP treatment on the HPA axis have not been well studied, especially in the geriatric population. This study examined the acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol in 68 subjects (60-83 years) who received 0.25 or 0.50 mg b.i.d. alprazolam, or 0.50 or 1.0 mg b.i.d. lorazepam, or placebo orally according to a randomized, double-blind, placebo-controlled parallel design. Memory assessment and blood samples for plasma cortisol were obtained prior to the morning dose on days 0, 7, 14, and 21, and at 1, 2.5, and 5 h postdrug on days 0 and 21. Assessments of anxiety and depression were carried out at days 0, 7, 14, and 21 before drug administration. Plasma cortisol was affected compared to placebo only by the 0.5 mg alprazolam dose. During the first and the last day of treatment, there was a significant drop in cortisol at 2.5 h after alprazolam compared to placebo. The predose cortisol levels increased significantly during chronic alprazolam treatment, and correlations were found between these cortisol changes and changes in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose HPA axis activation in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment.     

The interactions of ethanol with single and repeated doses of suriclone and diazepam on physiological and psychomotor functions in normal subjects

Summary The effects of diazepam (5 mg t.i.d.), suriclone (0.2 and 0.4 mg t.i.d.) and placebo (t.i.d.) were assessed in 12 normal, healthy volunteer subjects after a single dose and after treatment for a period of 8 days. A battery of physiological, psychomotor and subjective tests was administered on days 1 and 8 both before and after drug and after a measured dose of ethanol. The effects of diazepam on the EEG were characteristic of benzodiazepines — a decrease in the slow frequency wave-bands, an increase in fast frequency wave-band and diminished evoked response amplitude. Suriclone had similar effects on fast frequency activity and evoked response amplitude but, in contrast to diazepam, also increased the slow frequency wave-bands after 7 days treatment.Some improvements in performance were seen with suriclone on critical flicker fusion, tapping speed, spiral maze and digit cancellation. In contrast, suriclone impaired performance to a greater extent than diazepam on digit symbol substitution and symbol copying. Body sway was also enhanced by suriclone to a greater extent than diazepam.Subjective ratings for mood and adverse-effects showed few differences between suriclone or diazepam. However, suriclone caused greater gastro-intestinal disturbances than diazepam, especially after ethanol, and subjects rated themselves as more antagonistic and more irritable on suriclone. Ratings for calmness suggested that in contrast to diazepam, suriclone had no anxiolytic effect.Several of the parameters tested showed a build up of effect with diazepam over the treatment period which was not seen with suriclone. It is suggested that this difference may be due to differences in elimination rate.There was little evidence of interaction with ethanol with any of the treatments, most effects being simply additive.The profile of effects of suriclone was similar to that of diazepam but with some differences. The effects of suriclone were usually dose-related, the 0.4 mg dose having equivalent or greater effects than diazepam.     

Development and retention of tolerance to the sedative effects of chlordiazepoxide: Role of apparatus cues

Groups of rats were pretreated for 5 days with chlordiazepoxide (5 to 50 mg/kg) or with control water injections. On the sixth day the rats were given a test dose of chlordiazepoxide (10 mg/kg), or water. The rats that had received 5 days of pretreatment with chlordiazepoxide were significantly less sedated by the test dose than were those given chlordiazepoxide for the first time, i.e. they had developed tolerance. There were no significant differences between the two pretreatment groups in the extent of tolerance. A second experiment examined the effects of associating drug injections with apparatus cues. This had no effect on the development of tolerance, but had a significant effect on its retention: rats pretreated and replaced in their home cages showed complete recovery from tolerance after two drug-free days, whereas those placed in the apparatus after each day's injection retained some tolerance even after two drug-free weeks.     

Setting New Standards for the Pharmacological Treatment of Panic Disorder

Three drugs are currently licensed for the treatment of panic disorder: the benzodiazepine, alprazolam; the tricyclic antidepressant, clomipramine; and, most recently, the selective serotonin reuptake inhibitor, paroxetine. Alprazolam and clomipramine are effective in the treatment of panic disorder, but are less than ideal agents due to their tolerability profiles. An extensive clinical trial programme has been undertaken to investigate the efficacy and tolerability of paroxetine treatment in panic disorder. This article reviews the clinical evidence for the short- and long-term efficacy and tolerability of paroxetine in panic disorder, and its effect on relapse prevention and on quality of life. The results from the short-term studies indicate that paroxetine is effective in treating panic disorder (with or without agoraphobia) either alone or in combination with cognitive-behavioural therapy. The minimum effective dose is 40 mg daily. Paroxetine was equally as effective as clomipramine in reducing the frequency of panic attacks but produced an earlier improvement in symptomatology. Continued treatment with paroxetine over periods of up to 9 months provided evidence that paroxetine maintained its anti-panic effect and prevented relapse. Paroxetine was well-tolerated during both the short- and long-term studies at doses of up to 60 mg per day. © 1997 John Wiley & Sons, Ltd.     

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0–8.0 mg/kg) or chlordiazepoxide (CDP; 4.0–32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0–8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0–16.0 mg/kg) produced increases in response rates. Finally, the effects of cumulative doses of morphine did not differ significantly from the effects of noncumulative doses of the drug.     

Drug preference in normal volunteers: Effects of age and time of day

These experiments assessed the influence of two variables, age of subjects and time of drug administration, on the reinforcing properties of amphetamine and of diazepam in normal volunteers. Three groups of subjects were tested: i) a group of 40–55-year-old subjects (AGE group; N=11) who were tested in the morning, ii) a group of 21–35-year-old subjects (CTL group; N=12) who were also tested in the morning, and iii) a group of 21–35-year-olds who were tested in the late afternoon (AFT group; N=13). All subjects participated in three separate experiments comparing one drug (5 mg d,l-amphetamine, 5 mg diazepam or 10 mg diazepam) to placebo. Each experiment consisted of nine sessions: On the first four sessions subjects sampled two color-coded capsules on alternate sessions and on the following five sessions they chose and ingested the capsule they preferred. Subjective effects of the drugs were monitored using the Profile of Mood States (POMS) and a shortened version of the Addiction Research Center Inventory (ARCI). Subjects in all three groups chose 5 mg diazepam as often as placebo but preferred placebo to 10 mg diazepam. In contrast, they chose amphetamine either as often as or more often than placebo. The subjective effects of diazepam (i.e. sedation) were similar across all three groups, but after amphetamine the AGE group showed greater stimulant effects. In addition, the AFT group showed fewer positive mood effects after amphetamine than the CTL group. The AFT and AGE groups also differed from the CTL group on several measures of mood, independently of drug administration. Despite the modest group differences in subjective effects, it was concluded that neither time of day nor age of subjects substantially affected the reinforcing properties of either drug.     

Effect of nicardipine on insulin secretion,glucose and lipid metabolism in hypertensive,non-insulin dependent diabetics

Summary Certain acute and chronic metabolic effects of nicardipine have been studied in 20 patients with non-insulin dependent diabetes (NIDD). An intravenous glucose tolerance test (i.v. GTT, glucose 0.33 g/kg as a bolus) and the corresponding insulin response were assessed at the end of a 4 week placebo period, after the first dose and on administration for 12 weeks of nicardipine 20 mg t.i.d.The glucose and insulin responses to the i.v. GTT, evaluated as incremental AUCs, did not change significantly (glucose 30.5 mg/dl·90 min on placebo, 33.1 mg/dl·90 min acutely and 31.4 mg/dl·90 min on chronic administration of nicardipine; insulin 2.08 µU/ml·90 min on placebo, 1.87 µU/ml·90 min acutely and 1.93 µU/ml·90 min after chronic nicardipine). Glucose removal rate (KG) following the i.v. GTT was 0.73%/min on placebo 0.75%/min on acute administration and 0.8%. min^–1 with chronic nicardipine.Active treatment produced a significant reduction of blood pressure (from 187/96 mm Hg on placebo to 166/89 mm Hg acutely and 152/83 mm Hg after 12 weeks of nicardipine treatment). It is concluded that the calcium antagonist nicardipine was an effective antihypertensive drug, and that it did not cause deterioration of metabolic control in hypertensive patients with NIDD.     

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.     

The effect of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and newer antidepressant drugs on the activity and level of rat CYP3A.

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, and desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine and sertraline) and novel antidepressant drugs (mirtazapine and nefazodone) on the activity of CYP3A measured as a rate of testosterone 2beta- and 6beta-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for 1 day or 2 weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1) i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in vitro. The investigated antidepressants added to control liver microsomes produced some inhibitory effects on CYP3A activity, which were very weak (most of TADs, K(i)=145-212 microM), modest (clomipramine and sertraline, K(i)=67.5 and 62 microM, respectively) or moderate (nefazodone and fluoxetine, K(i)=42 and 43 microM, respectively). Mirtazapine did not display this kind of properties. One-day exposure of rats to TADs substantially decreased the activity of CYP3A in liver microsomes, which was maintained during chronic treatment. The observed decreases in the enzyme activity were in contrast to the increased CYP3A protein level found after chronic treatment with TADs. On the other hand, sertraline increased the activity of the enzyme after its prolonged administration and its effect correlated positively with the observed elevation in CYP3A protein level. Fluoxetine, mirtazapine and nefazodone did not change the activity of CYP3A in liver microsomes after their administration to rats. Three different mechanisms of the antidepressants-CYP3A interaction are postulated: 1) a direct inhibition of CYP3A by nefazodone, SSRIs and clomipramine, shown in vitro, with the inhibitory effect of nefazodone being the strongest, but weaker than the effects of this drug on human CYP3A4; 2) in vivo inhibition of CYP3A produced by 1 day and maintained during chronic treatment with TADs, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction by sertraline of CYP3A produced only by chronic treatment with the antidepressant, which suggests its influence on the enzyme regulation.