Pulmonary infiltrations induced by tolfenamic acid.
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Acute Disease↗
Biomedical subjects
K Aranko
Publications and source records attributed to K Aranko.
Anxiogenic effects in benzodiazepine withdrawal are linked to the development of tolerance.
Rats were tested in the elevated plus-maze test of anxiety after a probe injection of chlordiazepoxide (CDP 5 mg/kg) following short-term (5 days) or long-term (20 days) pretreatment with 5 or 20 mg/kg/day. After short-term pretreatment with either dose, the probe dose had anxiolytic effects (it increased the % number of entries, and % of time spent, on the open arms). After long-term pretreatment with either dose of CDP there was tolerance to these effects. When the rats were tested 24 hours after their last dose of CDP, there was no indication of spontaneous withdrawal responses in the rats from the short-term pretreatment groups, but the rats in the long-term pretreatment groups showed increased anxiety (decreases in the % number of entries, and the % of time spent, on the open arms, compared with controls). These results support suggestions that the development of tolerance and the incidence of withdrawal anxiety may both be manifestations of the underlying changes occurring during drug dependence.
Animals↗
Interaction of diazepam or lorazepam with alcohol. Psychomotor effects and bioassayed serum levels after single and repeated doses.
Nine healthy volunteers in a double-blind, cross-over trial received diazepam (DZ) 10 mg, lorazepam (LZ) 2.5 mg, or placebo (P). Serum benzodiazepine (BZ) was bioassayed (radioreceptor method) and psychomotor tests were carried out on Day 1 (before and 1 h after the first dose) and on Day 4 (before and after the fifth dose). In each session alcohol 1 g/kg was administered 1.5 h after drug intake and the measurements were repeated twice. Serum BZ concentrations, expressed as DZ equivalents (microgram/l), ranged from 390 to 440 and from 990 to 1240 measured 2 h 45 min after the first doses of DZ and LZ, respectively. On Day 1 BZ alone impaired psychomotor skills. LZ affected performance more in objective tests, but DZ was subjectively rated as causing more drowsiness. After the intake of alcohol, all groups showed impairment in various tests. The rank order was LZ + alcohol greater than DZ + alcohol greater than P + alcohol. Residual BZ activity on Day 4, measured 18 h after the fourth dose, averaged 290 and 450 micrograms/l after DZ and LZ, respectively. At the same time slight residual exophoria was found after both BZs. Tolerance to BZs on Day 4 was unambiguous only when drug effects were related to the bioassayed serum levels. The combined action of BZs and alcohol was similar on Days 1 and 4. However, a tendency to an increased drug-alcohol interaction during advanced treatment with DZ was seen in the body sway test.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Benzodiazepines, but not antidepressants or neuroleptics, induce dose-dependent development of tolerance to lorazepam in psychiatric patients.
Psychomotor effects of oral lorazepam 3 mg were studied in psychiatric patients stratified into four groups: 1) a group of six patients with no previous use of psychotrophic drugs (NoD), 2) a group of 12 patients treated with antidepressants and/or neuroleptics (PsyD), 3) a group of 10 patients treated with low doses of benzodiazepines (BZs) (lowBZ), and 4) a group of nine patients treated with high doses of BZs (high BZ). Similar objective psychomotor tests and subjective assessments were administered under single-blind conditions to all treatment groups at baseline, after intake of placebo, and after intake of 3 mg lorazepam. Both lorazepam (CGC) and total BZs (bioassay) in serum were assayed. The results demonstrate that treatment with BZs induce dose-dependent development of tolerance to psychomotor effects of lorazepam. Antidepressants and neuroleptics failed to induce cross-tolerance to lorazepam. The rise in serum lorazepam concentrations after lorazepam intake was similar (about 28 micrograms/l) in all treatment groups, suggesting a functional, not dispositional, tolerance. However, the initial learning effect in psychomotor performance was poorer among BZ users than among others.
Administration, Oral↗
Psychomotor effects of alprazolam and diazepam during acute and subacute treatment, and during the follow-up phase.
Psychomotor effects of alprazolam (AZ) and diazepam (DZ) were compared in a controlled double-blind and cross-over trial in 24 student volunteers, who received, three times daily, placebo for the first 4 days, then an active drug (AZ) 0.25 mg or DZ 5 mg) for 7 days, and again placebo for 3 days. After a 3 week wash-out period the procedure was repeated with the comparative drug. Objective and subjective measurements were made on day 3 (placebo), on days 4 and 10 (active drug) and on days 11, 12 and 13 (follow-up placebo). Baseline levels were measured in the morning, a capsule was taken, and the tests were repeated 2 hours and 8 hours later. Blood samples were taken in the afternoon of day 10 for the bioassay of serum benzodiazepine concentrations. Single doses of both AZ 0.25 mg and DZ 5 mg showed similar degree of impairment in several objective tests. At the end of the 7-day maintenance DZ (15 mg daily) proved significantly more sedative and impaired more psychomotor performance than AZ (0.75 mg daily) did. Improvement of the complex test performances (a learning effect) was counteracted by DZ more than by AZ. No actual development of tolerance was demonstrated after either drug. During the follow-up placebo phase, DZ showed more objective residual effects than AZ. The Maddox wing test (exophoria) showed a significant DZ effect to be still present on the third post-treatment day. However, during the follow-up period subjects reported subjectively more sedation and clumsiness after AZ than after DZ, but this was not associated with impairment of objective skills.
Adolescent↗
Task-dependent development of cross-tolerance to psychomotor effects of lorazepam in man.
Development of cross-tolerance between lorazepam and four other benzodiazepines (BZ) was studied in two trials by measuring objective psychomotor performance and by subjective assessments. In trial I, nitrazepam 10 mg (NZ), temazepam 20 mg (TZ) or placebo were administered to 14 healthy students for 10 consecutive nights. After each pretreatment, psychomotor impairment by the challenge dose of lorazepam 3 mg (LZ) was measured. In trial II, responses to LZ after pretreatment with diazepam 5 mg (DZ) (8 subjects) or alprazolam 0.25 mg (AZ) (10 subjects), both t.i.d., were compared to LZ responses measured after one-month wash-out period. In trial I no cross-tolerance between BZs was found in objective tests, and LZ induced exophoria was even increased. However, the subjects rated LZ to cause less drowsiness after pretreatment with NZ in a situation where the manifestation of cross-tolerance was facilitated by ingestion of caffeine. In trial II a clear but task-dependent development of tolerance to the challenge dose of LZ was documented. One-week pretreatment with DZ reduced subjects responses to LZ. The total serum BZ activity bioassayed by radioreceptor method after intake of LZ was significantly (P less than 0.05) higher after pretreatment with DZ than in the end of wash-out period. Thus a functional cross-tolerance was documented on complex tasks after the subjects have been continuously working under DZ burden.
Adult↗
Objective and subjective assessment of hangover during subacute administration of temazepam and nitrazepam to healthy subjects.
Fourteen, healthy students volunteered for a double-blind, cross-over trial of temazepam 20 mg (soft gelatine capsule), nitrazepam 10 mg (uncoated tablet) and placebo in matched formulations, single doses of each being given for 10 nights with a three-week wash-out period between each treatment. Residual drug effects were measured objectively (psychomotor skills) and subjectively (visual analogue scales) in the morning and afternoon of Days 0 (before the first tablet), 1 and 10. The subjects also recorded various events during each treatment period. Serum benzodiazepine concentrations were bioassayed in blood samples taken after the last assessment. Both benzodiazepines shortened sleep latency during the first few nights, and nitrazepam prolonged the duration of sleep. The residual effect of drowsiness was noted during the nitrazepam period, whilst temazepam proved less sedating. The 'morning after' effect was a subjective observation and not an objective measurement. The learning effect interfered with the complex objective assessments, and simple measurement of exophoria with the Maddox wing test provided the clearest objective evidence of drug effects. On Day 10 residual concentrations of nitrazepam were detectable in the serum whereas the level of temazepam was found to be low or negligible. It is concluded, that temazepam 20 mg in a soft gelatine capsule is a suitable hypnotic for subjects whose daily work requires constant alertness.
Activity Cycles↗
The contribution of the active metabolites to the tolerance developing to diazepam in man: relationship to bioassayed serum benzodiazepine levels.
Seven healthy students cooperated in this study. They underwent four experimental periods at one-month intervals, each period comprising a single-dose test with diazepam (D) 15 mg, oxazepam (OX) 45 mg, nordiazepam (ND) 15 mg or placebo (given double-blind in randomized order) on day 1, followed by maintenance with respective drug for 7 days, and a retest with D 15 mg on day 8. Thus, psychomotor responses to D 15 mg were measured after one-week treatment with D 5 mg, OX 15 mg, ND 5 mg, or placebo, all taken twice daily. Serum samples were taken at each session day before and 2.5 hr after the drug intake for bioassay of serum benzodiazepine (BZ) levels against commensurable diazepam standard. On day 1, a single dose of OX 45 mg resulted in fourfold concentrations of serum BZ levels in comparison with the results of the doses D 15 mg and ND 15 mg. Psychomotor skills were also most impaired by oxazepam. ND 15 mg was less effective than D 15 mg, irrespective of the same serum BZ levels. One-week of treatment with D and OX seemed to diminish most responses to D, despite increased BZ effects on these functions. Pretreatment with ND reduced the subjective sedative effects of D. Our results support the view that the rate of development of tolerance to BZs is task-dependent. Tolerance developed mostly to the complex tests subject to learning while Maddox wing test (reflecting the degree of muscle relaxation) was resistant. ND, the main metabolite of D, plays little part in the tolerance that developed to D.
Adult↗
Development of tolerance and cross-tolerance to the psychomotor actions of lorazepam and diazepam in man.
1 Development of tolerance and cross-tolerance to lorazepam and diazepam in man was assessed in a double-blind and cross-over trial where eight pretrained healthy students volunteered for four 1 week treatment periods started at 1 month intervals. 2 In each period acute psychomotor responses to oral lorazepam 3 mg and diazepam 15 mg were recorded on day 1, as well as on day 8 after 1 week's treatment twice daily with diazepam 5 mg, lorazepam 1 mg, and placebo. At each session several objective psychomotor tests and subjective assessments were done before the drug intake and 1, 2.5, and 4 h after it. 3 In general, the effects of lorazepam were stronger and of longer duration than those of diazepam at the doses used. When comparing the single-dose responses on days 1 and 8, tolerance to lorazepam effects and some cross-tolerance developed on several functions measured. Tolerance but not cross-tolerance developed on choice reaction errors whereas the opposite was found on flicker fusion. No definite tolerance was found on subjective effects. 4 The results tally with an assumption that tolerance to benzodiazepine actions develops at different rates on various parameters measured.
Adult↗
Effects of alcohol on buspirone and lorazepam actions.
Psychomotor and psychologic effects of single doses of buspirone (10 and 20 mg) and lorazepam (2.5 mg) alone or combined with alcohol (1 gm/kg) were investigated in 12 healthy young men (crossover study). Lorazepam alone impaired psychomotor skills (tracking, body balance, extraocular muscle balance, and flicker recognition), the effects being maximal at 180 min. This impairment was not subjectively perceived by the subjects. Neither dose of buspirone alone impaired objective measurements, although buspirone, especially in the 20-mg dose, was felt to cause drowsiness, weakness, and faintness. Lorazepam, but not buspirone, interacted with alcohol.
Adult↗
Acute effects of buspirone and alcohol on psychomotor skills.
Acute psychomotor and psychological effects of oral buspirone (10 and 20 mg) with and without alcohol (1 g/kg) were studied in a double-blind crossover trial in 12 young males. Treatments were administered at 1-week intervals in balanced order. Buspirone failed to impair objective performance but caused drowsiness and fatigue. The reference drug lorazepam (2.5 mg) impaired skills objectively, with less subjective impairment. Lorazepam, but not buspirone, interacted with alcohol.
Adult↗
Bioavailability of two clodronate formulations.
Sodium clodronate is effective in the management of osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastasis. Clinical and biochemical data underpin a licensed total daily dose of 1600-3200 mg.
Administration, Oral↗