The effect of temazepam on melatonin secretion and light sensitivity

Seven healthy male volunteers had their light sensitivity (melatonin suppression) and melatonin phase measured before and after treatment with temazepam (20 mg) for 7 days. Temazepam did not alter the circadian phase of melatonin secretion (the Dim Light Melatonin Onset, the timing of the peak of secretion), the total melatonin secretion nor the sensitivity of melatonin secretion to suppression by full spectrum light. This is an important negative finding which suggests that the short half-life benzodiazepine hypnotic temazepam does not confound tests of light sensitivity or melatonin phase.     

Melatonin sensitivity to dim white light in affective disorders.

Both dim and bright light has been shown to suppress the nocturnal secretion of the pineal hormone melatonin. Early reports suggests that an abnormal response to light occurs in patients with bipolar affective disorder, where as patients with major depressive disorder respond similarly to controls. It has been suggested that this abnormal sensitivity of the melatonin response to light could be a trait marker of bipolar affective disorder. However reports lack consistency. Hence, we investigated the melatonin suppression by dim light (200 lux) in patients with bipolar affective disorder, seasonal affective disorder and major depressive disorder. Results suggest that a supersensitive melatonin suppression to light in bipolar affective disorder (p < .005), and seasonal affective disorder (p < .05), whereas patients with major depressive disorder display similar suppression to controls. The supersensitivity may be a mechanism where by phase-delayed rhythms, are resynchronised to a new circadian position. Conversely, an abnormality may exist in the pathway from the retina to the suprachiamatic nucleus.     

Melatonin sensitivity to dim white light in different seasons

It is well known that the pineal hormone melatonin is suppressed by light. The melatonin suppression by dim light has also been suggested as a possible trait marker of bipolar disorder. However, there is large inter individual differences in the light responses. It is possible that methodological factors may contribute to the variable responses observed. Most studies in the past have been conducted in different seasons under different lighting conditions. It is possible the external lighting conditions may affect the melatonin suppression to dim light. Hence we examined the melatonin suppression by dim light in (1) a large group of subjects randomly tested once in one of the four seasons (part one) and (2) small group of subjects tested in all seasons (part two). Subjects were placed in a dark room from 2100 h to 0230 h. Light exposure was between midnight and 0100 h in a sitting position. Blood samples were collected at regular intervals for measurement of plasma melatonin. No statistically significant seasonal differences in the percentage suppression of melatonin were found in both parts of the study (p>0·5). The study suggests that seasonal changes in external lighting do not affect the melatonin suppression by dim light in healthy controls. Copyright © 1999 John Wiley & Sons, Ltd.     

Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers.

Sensitivity of the pineal hormone melatonin to bright light at night has been proposed as a putative marker of bipolar affective disorder. Patients with bipolar disorder have a super-sensitive melatonin response to light. No studies have investigated whether super-sensitivity is due to agents used to treat the illness or is associated with the disorder per se. We investigated the effect of valproate on this phenomenon. Melatonin sensitivity to light was determined on two nights in 12 healthy volunteers (5M, 7F). Between testing nights participants received 200 mg of valproate b.d. for 5 days. Valproate significantly decreased the sensitivity of melatonin to light. On the other hand, valproate had no effect on overall melatonin secretion or dim light melatonin onset. The ability of valproate to decrease the sensitivity of melatonin to light may relate to its therapeutic effect in bipolar disorder--an ability to lengthen circadian period similar to that of lithium.     

The effect of clonidine and bright light on plasma melatonin

We studied the effect of the α₂-adrenoceptor agonist, clonidine, and bright artificial light (>2500 lux) on the nocturnal increase in plasma melatonin in normal subjects. Clonidine (1.5 μg/kg, intravenously) was without effect on plasma melatonin concentration. In contrast, bright light treatment abolished the increase in night-time melatonin. Bright light is a simple and effective means of altering melatonin secretion in humans.     

Subsensitive melatonin suppression by dim white light: possible biological marker of panic disorder

Light is involved in providing entrainment of circadian rhythms and the suppression of the pineal hormone melatonin. In patients with affective disorders, there have been indications of circadian as well as seasonal variation in illness, which may be reflected in melatonin production. Varying sensitivity to light has been noted within healthy individuals as well as in some patients with affective disorders. Recent evidence suggests that patients with panic disorder may have an altered and phase-delayed melatonin rhythm. The present study examined the nocturnal plasma melatonin rhythm in patients with panic disorder, and also examined their melatonin sensitivity to dim light. The melatonin rhythm was examined in 6 patients with panic disorder and 8 controls. The melatonin sensitivity to dim white light (200 lx) was examined in 8 patients with panic disorder and 63 controls and was compared to that of a group of 7 patients with other anxiety disorders. Patients with panic disorder demonstrated a trend towards higher and delayed peak melatonin levels compared to controls. Patients with panic disorder also had a subsensitive melatonin suppression by dim white light, compared to controls and patients with other anxiety disorders (p<0.005). The phase-delayed circadian rhythm observed in patients with panic disorder may be secondary to the subsensitivity of the melatonin response to light. It is hypothesized that the subsensitivity may be due to abnormal neurotransmitter/receptor systems involved in regulation of melatonin suppression and circadian rhythmicity, and may lead to phase- delayed circadian rhythms. The melatonin subsensitivity to light may be used as a biological marker of panic disorder.     

Effect of digoxin on the sensitivity to flickering light.

1 The sensitivity to flickering light at various light frequencies (DeLange curve) was determined in 20 controls and 45 patients receiving maintenance doses of digoxin. 2 Flicker thresholds (mean percentage of maximal light modulation +/- s.d.; F 30 Hz) were 7.6 +/- 1.7 in controls and 9.4 +/- 1.7 in patients with optimal plasma digoxin levels (0.5-1.9 ng/ml), but they rose to 15.5 +/- 1.9 at subtoxic levels (2.0-3.0 ng/ml), and to 21.8 +/- 2.6 at toxic levels (above 3.0 ng/ml). 3 Flicker sensitivity was inversely correlated with plasma digoxin levels and returned to baseline values when the administration of digoxin was interrupted. 4 The DeLange curve seems to be a valuable tool to measure the toxic effects of digitalis on the visual system.     

The effect of age on the sensitivity of pre- and postsynaptic alpha-adrenoceptors to agonists and antagonists in the rat

Summary Age-related changes in presynaptic alpha-2 and postsynaptic alpha-1 adrenoceptors have been determined using the rat isolated vas deferens and the thoracic aorta, respectively. The IC₅₀ values of clonidine, B-HT 933 and UK 14,304 for inhibition of the electrically evoked contractions of the vas deferens were significantly higher in 50 week old rats when compared with rats of 5 weeks. Similarly, EC₅₀ values for the contraction of the thoracic aorta by noradenaline, methoxamine and phenylephrine were significantly increased in 50 week old rats compared with 5 week old rats. No age-related changes in the potency of the selective alpha-2 adrenoceptor antagonists yohimbine and Wy 26392 were detected in the vas deferens. Similarly, there were no age-related changes in the alpha-1 adrenoceptor antagonist potency of indoramin or prazosin on the aorta.The results of the present study suggest that the potency of both alpha-1 and alpha-2 adrenoceptor agonists, as measured by their respective EC and IC₅₀ values decreases with increasing age.     

The effect of pretreatment with 6-hydroxydopamine on the norepinephrine concentration and sensitivity of the rat vas deferens.

Injection of 6-hydroxydopamine via the dorsal vein of the penis results in a marked depletion of the endogenous norepinephrine of the vas deferens. Seven days after pretreatment with 6-hydroxydopamine there is a shift to the left and increase in maxima of the dose-response curves for norepinephrine and methoxamine. The results indicate that pretreatment with 6-hydroxydopamine produces denervation of the vas deferens and that the in vitro tissue exhibits both prejunctional and postjunctional supersensitivity.     

Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers

Sensitivity of the pineal hormone melatonin to bright light at night has been posited as a putative marker of affective disorders. Research demonstrates melatonin supersensitivity to light in bipolar disorder, however the role that lithium carbonate plays in this response is unclear. This study assessed the effect of lithium on nocturnal melatonin secretion and sensitivity to light in healthy adults. Ten participants, tested on two nights, had blood samples drawn between 20:00 and 02:30 hours. On testing nights participants were exposed to 200 lux of light between 24:00 and 01:00 hours. Participants took 250 mg of lithium daily for 5 d between testing nights. The results indicated that lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis. This finding has implications on the true magnitude of the melatonin light response in people with bipolar disorder and may elucidate possible mechanisms of action of lithium.     

The effect of the acute and chronic administration of melatonin on the relearning of rats in a Y maze and their sensitivity to haloperidol

After acute (10 mg/kg) and chronic (1 mg/kg, 10 days) administration melatonin facilitated parameters of rats relearning in the Y-maze. A simultaneous shortening of latency avoidance reaction was observed. Haloperidol (0.1 mg/kg) against the background of chronic melatonin administration more strongly optimized the animals' relearning. The hormonal action is supposed to depend on its sedative properties.     

The effect of melatonin on normal sleep

We examined the effect of 1-mg and 5-mg oral dosages of melatonin on the electroencephalogram-recorded sleep of ten normal subjects in a randomized, double-blind design. Although high dosages of melatonin have previously been reported to be a sedative and to have behavioral effects, we could not find any change in onset or duration of sleep, or any effect on mood or alertness the following day using these low dosages. An increase in rapid eye movement (REM) latency was noted at the 5-mg dose, but no other parameter of REM sleep was changed.     

Increased sensitivity to nitrazepam in old age.

The effects of a single 10 mg oral dose of nitrazepam were compared with those of a placebo in healthy young and old people. Both the young and the elderly slept better on three successive nights after nitrazepam but they felt less awake at 12 and 36 hours (P less than 0-01). Elderly people made significantly more mistakes in a psychomotor test than did the young, despite similar plasma concentrations of nitrazepam and half lives in the two groups. This difference in response to psychomotor testing is probably explained by an increased sensitivity of the ageing brain to the action of nitrazepam.     

The effect of age on the pharmacokinetics of ifosfamide.

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.     

The effect of age on the pharmacokinetics of pentisomide.

The effects of age on the pharmacokinetics of pentisomide (CM7857), an orally effective antiarrhythmic agent, were studied in two groups of volunteers. Sixteen young volunteers (mean age 26.4 years) and 10 elderly volunteers (mean age 67.8 years) received a single 200 mg oral dose of pentisomide. Mean AUC was larger and terminal elimination half-life longer in the elderly subjects, due to a decrease in total plasma clearance of pentisomide in the elderly. This decrease was due to a reduction in renal clearance of the drug which was paralleled by a significantly lower creatinine clearance in the elderly subjects. Dosage reduction, or a reduced frequency of dosing of pentisomide would be necessary in the elderly or those with impaired renal function.