Melatonin, temazepam and placebo in hospitalised older patients with sleeping problems (MATCH): a study protocol of randomised controlled trial.

INTRODUCTION: Hospitalised older patients frequently suffer from inadequate sleep, which can lead to patient distress and delayed recovery from acute illness or surgical procedure. Currently, no evidence-based treatments exist for sleeping problems in hospitalised older patients. Benzodiazepines, such as temazepam, are regularly prescribed by physicians, although they have serious side effects; for older patients in particular. Melatonin is proposed as a safe alternative for sleeping problems in hospitalised older patients, but the efficacy of melatonin is unclear in this population. Therefore, the aim of this study is to investigate the effects of melatonin and temazepam compared with placebo on sleep quality among hospitalised older patients with sleeping problems. METHODS AND ANALYSIS: This study is a multicentre, randomised, placebo-controlled trial. A total of 663 patients will be randomised in a 1:1:1 fashion to receive either melatonin (n=221), temazepam (n=221) or placebo (n=221). The study population consists of hospitalised patients aged 60 years and older, with new or aggravated sleeping problems for which an intervention is needed. The primary outcome is sleep quality measured with the Leeds Sleep Evaluation Questionnaire (LSEQ). Secondary outcomes include sleep parameters measured with actigraphy and medication-related adverse effects. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of the Academic Medical Centre Amsterdam, (No 2015_302). Study findings will be disseminated through presentations at professional and scientific conferences and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6908; Pre-results.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

GABAA receptor positive allosteric modulators (GABAA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABAA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABAA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABAA receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABAA receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABAA receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine.

Randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people.

Current pharmacological treatments for insomnia include benzodiazepine and non-benzodiazepine hypnotics targeting γ-aminobutyric acid (GABA)A receptors, as well as agonists of the melatonin receptors MT1 and MT2. Melatonin, temazepam and zolpidem are thought to exert their effect through different mechanisms of action, but whether this leads to differential effects on electroencephalogram (EEG) power spectra during sleep in middle-aged people is currently not known. To establish whether the effects of prolonged-release melatonin (2 mg) on the nocturnal sleep EEG are different to those of temazepam (20 mg) and zolpidem (10 mg). Sixteen healthy men and women aged 55-64 years participated in a double-blind, placebo-controlled, four-way cross-over trial. Nocturnal sleep was assessed with polysomnography and spectral analysis of the EEG. The effects of single oral doses of prolonged-release melatonin, temazepam and zolpidem on EEG slow-wave activity (SWA, 0.75-4.5 Hz) and other frequencies during nocturnal non-rapid eye movement (NREM) sleep were compared. In an entire night analysis prolonged-release melatonin did not affect SWA, whereas temazepam and zolpidem significantly reduced SWA compared with placebo. Temazepam significantly reduced SWA compared with prolonged-release melatonin. Prolonged-release melatonin only reduced SWA during the first third of the night compared with placebo. These data show that the effects of prolonged-release melatonin on the nocturnal sleep EEG are minor and are different from those of temazepam and zolpidem; this is likely due to the different mechanisms of action of the medications.

Oxazepam and temazepam attenuate paroxetine-induced elevation of serotonin levels in guinea-pig hippocampus.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are used as a first-line treatment in depression. However, many depressed patients are also treated with benzodiazepines to alleviate increased anxiety and sleep disturbances normally associated with depression. Since benzodiazepines inhibit 5-HT neuronal firing activity, they might attenuate SSRI-induced increase in extracellular 5-HT levels. This study aimed to assess, using in-vivo microdialysis, the effects of the benzodiazepines oxazepam or temazepan on the SSRI paroxetine-induced 5-HT increase in the hippocampus of freely moving guinea-pigs. It was found that the acute systemic administration of paroxetine increased extracellular 5-HT levels. Pre-administration of oxazepam or temazepam significantly diminished the paroxetine-induced elevation of extracellular 5-HT levels (from 350% to 200% of baseline). It was concluded that benzodiazepines attenuate the ability of SSRIs to elevate hippocampal 5-HT levels. Thus, co-administration of benzodiazepines might affect the therapeutic efficacy of SSRI treatment.

Effects of organic solvents on the time-dependent inhibition of CYP3A4 by diazepam.

The effects of organic solvents, acetonitrile, dimethyl sulfoxide (DMSO), and methanol, which are used to dissolve lipophilic test compounds and cytochrome P450 (P450) substrates, and carried into pre-incubation at 1% (v/v), on time-dependent inhibition of CYP3A4 by diazepam, were evaluated using human liver microsomes (HLM) and recombinant human P450 expressed microsomes (rCYPs). The inactivation kinetics of CYP3A4 by diazepam dissolved in acetonitrile and methanol were almost equal with k(inact)/K(I) values, 0.095 and 0.15 min(-1) mM(-1) for HLM and 1.1 and 1.4 min(-1) mM(-1) for rCYP3A4, respectively. In contrast, the inactivation by diazepam dissolved in 1% DMSO significantly decreased and the kinetic parameter could not be calculated. The formation rate of nordiazepam and temazepam metabolized from diazepam dissolved in DMSO were approximately half of those using substrate dissolved in acetonitrile and methanol in both HLM and rCYP3A4. Dixon plots revealed that the metabolism of diazepam in rCYP3A4 were inhibited by DMSO in a competitive or mixed-type manner with K(i) (inhibition constant) values of 6 and 24 mM for nordiazepam and temazepam, respectively. In conclusion, the time-dependent inhibition of CYP3A4 by diazepam was attenuated by DMSO, while acetonitrile and methanol had no effect. The metabolite formation profile under the conditions tested suggested that DMSO competitively inhibit the formation of the reactive metabolites of diazepam by CYP3A4. The effect of organic solvents should be taken into consideration when evaluating the in vitro time-dependent inhibition of new chemical entities.

Highway driving in the elderly the morning after bedtime use of hypnotics: a comparison between temazepam 20 mg, zopiclone 7.5 mg, and placebo.

A major problem related to hypnotic drug use is residual sedation the morning after bedtime administration. This constitutes a particular safety hazard for patients who have to drive a car the next morning. Information on the severity of residual effects is mainly derived from studies conducted with young healthy volunteers. However, most users of hypnotics are older people who may be more sensitive to drug effects. The aim of this study was to evaluate the residual effects the morning after evening doses of temazepam 20 mg and zopiclone 7.5 mg on driving performance in healthy elderly drivers. Eighteen healthy elderly drivers (10 females and 8 males; mean age, 64.3 years) participated in a double-blind, 3-way crossover study. Treatments were single oral doses of temazepam 20 mg, zopiclone 7.5 mg, and placebo administered at bedtime. Subjects performed a standardized highway driving test between 10 and 11 hours after hypnotic intake. Before and after the driving test, cognitive performance was assessed. Driving performance did not differ between temazepam and placebo but was significantly impaired after zopiclone 7.5 mg (P < 0.002). The results of the laboratory tests were in line with the effects on driving of both hypnotics. Temazepam 20 mg is unlikely to impair driving 10 hours or more after bedtime administration in healthy elderly aged 75 years or younger. Zopiclone 7.5 mg moderately impairs driving in the elderly at least until 11 hours after administration. The magnitude of impairing effects in the elderly was comparable with those found previously in younger volunteers.

Catatonia and CPK elevation in neurosyphilis: role of plural pharmacodynamic mechanisms.

OBJECTIVES: To report catatonia in neurosyphilis with elevated creatine phosphokinase (CPK) and to understand the pharmacodynamics of catatonia. EXPERIMENTAL DESIGN: Case Report. PRINCIPAL OBSERVATIONS: We encountered catatonia in a man with neurosyphilis after increasing aripiprazole and valproate (drugs reported to improve catatonia) and reducing doxycycline and temazepam dosages, consistent with identified dopamine D2, serotonin 5HT2, and 5HT1a (aripiprazole), GABA-B (valproate), glutamatergic NMDA (aripiprazole, valproate, doxycycline), and GABA-A (aripiprazole, temazepam) mechanisms of catatonia. CPK was markedly elevated despite the absence of neuroleptic malignant syndrome (NMS) and responded to lorazepam, as did the catatonia. CONCLUSIONS: This appears to be the first case report of catatonia without NMS associated with each of the following: neurosyphilis, aripiprazole, and temazepam withdrawal. This case further adds to the emerging literature of catatonia arising with valproate and atypical antipsychotic co-administration, and of non-NMS catatonia associated with CPK elevations. Plural simultaneously - operant pharmacodynamic mechanisms may explain catatonia of unclear etiology and reconcile a seemingly contradictory literature (e.g., the capacity of certain drugs (e.g., aripiprazole, valproate) to either relieve or precipitate catatonia depending on their pharmacological contexts). Besides reduced D2, 5HT2, and GABA-A and increased 5HT1a, GABA-B, and NMDA receptor stimulation appreciated in the clinical literature, stimulation of adenosine, muscarinic, and H1 histamine receptors may also have promoted catatonia in this case and others, whereas the alpha-2 agonist clonidine has alleviated it. Multiple drugs in this regimen and our current reliance on mechanisms determined primarily in preclinical studies now indicate the need for clinical studies to determine the relative importance of each mechanism in human patients.

Usefulness of temazepam and zaleplon to induce afternoon sleep.

UNLABELLED: Insufficient daytime sleep may result in reduction of effectiveness and safety during overnight military missions. The usefulness of temazepam and zaleplon to optimize afternoon sleep and their effects on performance and alertness during a subsequent night shift were studied. METHOD: In a randomized double-blind within-subjects design, 11 subjects took 20 mg of temazepam, 10 mg of zaleplon, or placebo before a 5:30-10:00 p.m. sleep period. Sleep length and quality were measured. Subjects were kept awake throughout the night while alertness, cognitive performance, and muscle power were repeatedly measured. RESULTS: Temazepam provided significantly longer and qualitatively better sleep than zaleplon or placebo. During the night, sleepiness increased and muscle power was impaired in all conditions. Better sleep was correlated with less sleepiness during the night. CONCLUSION: Temazepam is useful to optimize a 4.5-hour afternoon sleep before overnight missions. Irrespective of hypnotic treatment, sleepiness and fatigue increased during the night shift.

Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress.

We investigated the influence of a representative classical benzodiazepine on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis activity both under basal conditions and stress. Adult male Wistar rats were intravenously administered with temazepam (0.5, 1, and 3 mg/kg body weight) and plasma concentrations of corticotropin (ACTH) and vasopressin (AVP) were measured in blood samples collected via chronically implanted jugular venous catheters. Simultaneously, the release of AVP within the hypothalamic paraventricular nucleus (PVN) was monitored via microdialysis. Plasma AVP levels remained unaffected by the different treatment conditions. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner. Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release. An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.

Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures.

Uncomfortable working and sleeping environments, high operational tempos, sustained operations, and insufficient staffing make fatigue a growing concern. In aviation, where a single mistake can cost millions of dollars, it is essential to optimize operator alertness. Although behavioral and administrative fatigue countermeasures should comprise the "first line" approach for sustaining aircrew performance, pharmacological fatigue countermeasures are often required. Various components of the U.S. military have authorized the use of specific compounds for this purpose. Hypnotics such as temazepam, zolpidem, or zaleplon can mitigate the fatigue associated with insufficient or disturbed sleep. Alertness-enhancing compounds such as caffeine, modafinil, or dextroamphetamine can temporarily bridge the gap between widely spaced sleep periods. Each of these medications has a role in sustaining the safety and effectiveness of military aircrews. The present paper provides a short overview of these compounds as well as factors to be considered before choosing one or more to help manage fatigue.

Selective effects of clonidine and temazepam on attention and memory.

The present study compared the effects of clonidine and temazepam on performance on a range of tasks aiming to assess the role of central noradrenergic mechanisms in cognitive function. Fifteen healthy volunteers (seven male, eight female), aged 18-25 years, took part in a five-period crossover study in which they received placebo, temazepam (15 and 30 mg) and clonidine (150 and 300 microg) by mouth in counterbalanced order in sessions at least 4 days apart. A test battery was administered before treatment and at 45, 90 and 135 min after the dose. Performance on most tests was significantly impaired in a dose-related fashion, and subjective sedation was recorded for both drugs. The greatest impairments with clonidine were on attention in the presence of distractors. Clonidine did not affect the formation of new long-term memories, in contrast to temazepam, but did impair measures of working memory. Subjective effects, especially feelings of drunkenness and abnormality, were particularly marked with clonidine. These results support the suggestion that central noradrenergic function may be involved in preventing distraction, but do not confirm other reports suggesting that some aspects of performance are improved with clonidine.

Efficacy of temazepam in frequent users: a series of N-of-1 trials.

BACKGROUND: Benzodiazepines are frequently prescribed for sleep disturbances. However, benzodiazepines are associated with side effects, and may be ineffective when used for a prolonged period of time. OBJECTIVES: To investigate for individual patients whether placebo was as effective as temazepam, or whether 10 mg was as effective as 20 mg temazepam, and whether these results influenced their future temazepam use. METHODS: A series of randomized double-blind N-of-1 trials were conducted in general practices in The Netherlands for patients who were using temazepam regularly. Each patient received five pairs of treatments consisting of one week of temazepam (10 or 20 mg) and one week of the control intervention (placebo or 10 mg temazepam). Per pair, the sequence of treatments was randomized. Main outcome measures were: time to fall asleep, and the individual main complaint. RESULTS: Twelve out of 15 patients completed their trial. In three patients there was no difference, in five a large difference, and in four a small difference in favour of temazepam. At follow-up, seven patients had stopped or reduced their temazepam use. CONCLUSION: The results regarding the efficacy of temazepam varied across patients. N-of-1 trials seem to be valuable in patients who are motivated to stop or reduce their temazepam use. They clearly demonstrate the efficacy of temazepam, and may give patients additional confidence to discontinue regular hypnotic use. The value of N-of-1 trials for patients who are less motivated is unclear, as the size of treatment effect does not seem to influence future hypnotic use.

Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam.

INTRODUCTION: Current military operations often require pharmaceutical methods to sustain alertness and facilitate sleep in order to maintain operational readiness. This study was designed to compare the sleep-inducing power of four medications. METHOD: There were 9 men and 14 women, ages 21-53 yr, who were assessed for psychomotor performance before and for 7 h after ingestion of a single dose of placebo, zaleplon 10 mg, zopiclone 7.5 mg, temazepam 15 mg, or time-released melatonin 6 mg. The experimental design was a double-blind crossover with counterbalanced treatment order. Subjects wore polysomnographic electrodes to record total sleep and sleep latency during 4-min periods with eyes closed immediately before and after each psychomotor test sequence. Subjective drowsiness was assessed by questionnaire. RESULTS: There were drug x trials interactions for zaleplon, zopiclone, and temazepam for total sleep, sleep latency, and subjective drowsiness. More sleep, shorter sleep latency, and more drowsiness occurred immediately after psychomotor testing compared to before testing for all medications. Melatonin did not cause any sleep prior to psychomotor testing sessions, but caused sleep and reduced sleep latency after psychomotor test sessions from 1 3/4 h to 4 3/4 h post-ingestion. CONCLUSIONS: The sleep-inducing power of the medications before psychomotor testing was zopiclone > zaleplon > melatonin > temazepam. The corresponding effect after psychomotor testing was zopiclone > melatonin > zaleplon > temazepam.

Effects of after-midnight intake of zolpidem and temazepam on driving ability in women with non-organic insomnia.

BACKGROUND: Occasionally, insomniac patients may take a sleeping pill after midnight. This may have consequences on their ability to drive a car and result in an increased risk of car accidents. METHODS: This double-blind, randomized, placebo-controlled, three-treatment three-period cross-over study investigated the effects of two frequently prescribed hypnotics of different classes in a real life condition on driving performance and psychomotor skills in insomniac women. Single doses of zolpidem 10 mg (Z), temazepam 20 mg (T) or placebo (P) were administered at 2:00 a.m. to 19 women aged 35-60 years in three treatment periods separated by wash-out periods of 3-14 days. After polysomnography at baseline and each treatment night, patients underwent, 5.5 h after drug intake at 7:30 a.m. on the next morning, a STISIM driving simulator test, and a subsequent neuropsychological test (FePsy). RESULTS: Eighteen insomniac women were included in the analysis (mean age 50 years, mean weight 69 kg, mean BMI 25.6 kg/m2). There were no differences between treatments for the primary outcome measure (mean time to collision; baseline: 0.120 s, P: 0.124, T: 0.118, Z: 0.124; P> or =0.12 for all pairwise comparisons). No differences were recorded for speed deviation and reaction time to tasks for the verum treatments, however, lane position deviation was greater after administration of zolpidem in comparison to both placebo and temazepam (P=0.025 and 0.05, respectively). There were no differences between treatments in the FePsy test. Both medications were well tolerated. CONCLUSIONS: 5.5 h after drug administration there were no major differences in psychomotor performances between both zolpidem and temazepam compared to placebo, which indicates the absence of significant residual effects at that time. However, certain patients were more susceptible than others to the drug effects (two patients with high number of collisions). This underlines the necessity to strongly advocate against the late intake of hypnotics if patients intend to drive a car early the next morning.

The interactive effects of alcohol and temazepam on P300 and reaction time.

The present research investigated the separate and interactive effects of the minor tranquilizer, temazepam, and a low dose of alcohol on the amplitude and latency of P300 and on reaction time. Twenty-four participants completed four drug treatments in a repeated measures design. The four drug treatments, organised as a fully repeated 2 x 2 design, included a placebo condition, an alcohol only condition, a temazepam only condition, and an alcohol and temazepam combined condition. Event-related potentials were recorded from midline sites Fz, Cz, and Pz within an oddball paradigm. The results indicated that temazepam, with or without the presence of alcohol, reduced P300 amplitude. Alcohol, on the other hand, with or without the presence of temazepam, affected processing speed and stimulus evaluation as indexed by reaction time and P300 latency. At the low dose levels used in this experiment alcohol and temazepam appear not to interact, which suggests that they affect different aspects of processing in the central nervous system.

Neurobehavioural performance effects of daytime melatonin and temazepam administration.

Exogenous melatonin is a potential treatment for circadian disruption and insomnia. Hence, it is important to determine and quantify neurobehavioural performance effects associated with its use. The present study compared neurobehavioural performance following administration of melatonin and the benzodiazepine temazepam, using a within-subjects design. Following a training day, 16 healthy, young subjects (six males, 10 females; mean age +/- SEM, 21.4 +/- 6 years) participated in a 3-day protocol. After sleeping overnight in the laboratory, subjects completed a battery of tests at hourly intervals between 08:00 and 11:00 hours and at two hourly intervals between 13:00 and 17:00 hours. The neurobehavioural performance tasks included: unpredictable tracking, spatial memory, vigilance and logical reasoning. Subjective sleepiness was measured at hourly intervals using a visual analogue scale. At 12:00 h subjects were administered a capsule containing 5 mg melatonin, 10 mg temazepam or placebo, in a randomized, double-blind crossover fashion. A significant drug x time interaction was evident on the unpredictable tracking, spatial memory and vigilance tasks (P < 0.05). Greater changes in performance were evident following temazepam administration than melatonin administration, relative to placebo. Administration of melatonin or temazepam significantly elevated subjective sleepiness levels, relative to placebo (P

Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects.

Elderly insomniacs are often treated pharmacologically with benzodiazepines, antihistamines, or natural products. A double-blind, randomized, crossover, placebo-controlled study was performed to assess the comparative pharmacodynamics of single doses of temazepam (15 and 30 mg), diphenhydramine (50 and 75 mg), and valerian (400 and 800 mg) in 14 healthy elderly volunteers (mean age, 71.6 years; range, 65-89). Assessments were made at 0, 0.5, 1, 2, 3, 4, 6, and 8 hours postdosing with use of validated measures of subjective sedation and mood (visual analogue scales, Tufts University Benzodiazepine scale) and psychomotor performance (manual tracking and digit symbol substitution tests). Temazepam had dose-dependent effects on sedation and psychomotor ability with a distinct time course. Temazepam 30 mg had the most detrimental effect on psychomotor ability (p < 0.001 compared with all other treatments). Temazepam 30 mg and both doses of diphenhydramine elicited significantly greater sedation than placebo (p < 0.05, all), and temazepam had the greatest effect. There was no difference in sedation scores between 50 and 75 mg diphenhydramine. Sedative effects were slightly lesser with 15 mg temazepam and were not significant in comparison with placebo. Psychomotor impairment was evident after administration of 75 mg diphenhydramine in comparison with placebo on the manual tracking test (p < 0.05); this was less than the impairment with 30 mg temazepam (p < 0.001) but similar to that with 15 mg temazepam (NS). No psychomotor impairment was detected with 50 mg diphenhydramine. Valerian was not different from placebo on any measure of psychomotor performance or sedation.

Effects of diazepam and its metabolites on nocturnal melatonin secretion in the rat pineal and Harderian glands. A comparative in vivo and in vitro study.

We investigated the effects of diazepam (DZP) and its three metabolites: nordiazepam (NZP), oxazepam (OZP), and temazepam (TZP) on pineal gland nocturnal melatonin secretion. We looked at the effects of benzodiazepines on pineal gland melatonin secretion both in vitro (using organ perifusion) and in vivo in male Wistar rats sacrificed in the middle of the dark phase. We also examined the effects of these benzodiazepines on in vivo melatonin secretion in the Harderian glands. Neither DZP (10(-5)-10(-6)M) nor its metabolites (10(-4)-10(-5)M) affected melatonin secretion by perifused rat pineal glands in vitro. In contrast, a 10(-4)M suprapharmacological concentration of DZP increased melatonin secretion of perifused pineal glands by 70%. In vivo, a single acute subcutaneous administration of DZP (3 mg/kg body weight) significantly affected pineal melatonin synthesis and plasma melatonin levels, while administration of the metabolites under the same conditions did not. DZP reduced pineal melatonin content (-40%), N-acetyltransferase activity (-70%), and plasma melatonin levels (-40%), but had no affects on pineal hydroxyindole-O-methyltransferase activity. Neither DZP nor its metabolites affected Harderian gland melatonin content. Our results indicate that the in vivo inhibitory effect of DZP on melatonin synthesis is not due to the metabolism of DZP. The results also show that the control of melatonin production in the Harderian glands differ from that observed in the pineal gland.