SUMMARYIn a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two weeks of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n=14), polysomnography (n=22), actigraphy (n=13), sleep log (n=22), and subjective sleep quality (n=25). Mean dim light melatonin onset (DLMO) (±SD), before treatment, occurred at 23.17 hours (±138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.

AimTo compare the pharmacokinetics/pharmacodynamics, antibiotic resistance and clinical efficacy of continuous (CA) vs. intermittent administration (IA) of cefotaxime in patients with obstructive pulmonary disease and respiratory infections. MethodsA randomized controlled prospective nonblinded study was per formed in 93 consecutive hospitalized patients requiring antibiotics for acute exacerbations of chronic obstructive pulmonary disease. Forty-seven patients received 2 g of cefotaxime intravenously over 24 h plus a loading dose of 1 g, and 46 patients were given the drug intermittently (1 g three times daily). ResultsSimilar pathogens were identified in both groups, being mostly Haemophilus influenzae (51%), Streptococcus pneumoniae (21%) and Moraxella catharralis (18%). Mean minimal inhibitory concentration (MIC) values were also similar before and after treatment in both groups. Clinical cure was achieved in 37/40 (93%) (CA) vs. 40/43 (93%) (IA) of patients ( P = 0.93). In microbiologically evaluable patients, criteria such as 70% of treatment time with antibiotic concentrations ≥ MIC (CA 100% vs. IA 60% of patients) and/or ≥ 5 × MIC (CA 100% vs. IA 55% of patients) were significantly better following continuous administration ( P < 0.01). Samples with suboptimal antibiotic concentrations were found in 0% of CA vs. 65% of IA patients ( P < 0.01). ConclusionsAlthough clinical cure rates were comparable, continuous cefota xime administration led to significantly greater proportions of concentrations > MIC and > 5 × MIC compared with intermittent dosing. Continuous administration of cefota xime at a lower dose [2 g (CA) vs. 3 g (CI)] is equally effective pharmacodynamically and microbiologically, may be more cost-effective and offers at least the same clinical efficacy. Based on these observations, we recommend continuous administration of cefotaxime as the preferred mode of administration. Continuous vs. intermittent cefotaxime infusion in COPDBr J Clin Pharmacol 63 :1 101

In 20 patients with pure menstrual migraine either Estraderm TTS 50 patches (E) or placebo (P) patches were applied during three successive menstrual cycles, randomly allocated to the treatment sequences E-P-E or P-E-P. Clinical neurophysiological tests, contingent negative variation (CNV) and exteroceptive temporalis muscle suppression test (ETST) were performed before treatment. The predictive value of these tests regarding the efficacy of Estraderm TTS was studied. Neither the number, duration and severity of the migraine attacks, nor the consumption of analgesics and ergotamine differed significantly during Estraderm TTS and placebo treatment. The ETST was consistent with migraine in 35% (95% confidence interval 15.4 to 59.2) of the patients. The CNV in 55% (31.5 to 76.9), and both tests in 25% (8.7 to 49.1%). Regarding the prediction of the Estraderm TTS effect on the migraine attacks, the specificity of the ETST, CNV and the combination of ETST with CNV, calculated for the first two cycles, was respectively 81.8% (48.2 to 97.7), 45.5% (16.8 to 76.6) and 80% (28.4 to 99.5). For the last two cycles these values were respectively 75% (42.8 to 94.5), 50.0% (21.1 to 87.9) and 71.4% (29.0 to 96.3). The sensitivity of the tests was respectively 62.5% (24.5 to 91.5), 62.5% (24.5 to 91.5) and 66.7% (22.3 to 95.7) in the first 2 cycles. In the last 2 cycles 50.0% (15.1 to 84.3), 62.5% (24.5 to 91.5) and 60% (14.7 to 94.7). This study did not demonstrate an effectiveness of Estraderm TTS in perimenstrual migraine, except for the subgroup of perimenstrual migraine patients in whom the ETST test results were consistent with migraine.

Exogenous melatonin, which can be used to treat certain circadian rhythm disorders, maximally advances delayed rhythms when administered 5 hours before the endogenous melatonin starts to increase. The time of the start of the endogenously melatonin is defined as Dim Light Melatonin Onset (DLMO). The DLMO concentration has been defined in serum to be 10 pg/ml. Because of the greater practicability of frequent saliva sampling over blood sampling, we have validated radioimmunoassay (RIA) measurements of melatonin in saliva in patients diagnosed as suffering from a typical circadian rhythm disorder: Delayed Sleep Phase Syndrome (DSPS). Based on these results we have defined the equivalent salivary DLMO concentration to be 4 pg/ml.

The occurrence of headache and its change after treatment with melatonin 5 mg were studied in 30 patients with delayed sleep phase syndrome. The medication was taken 5 hours before the endogenous nocturnal plasma melatonin concentration had reached 10 pg/mL. Three women (aged 14, 14, and 23 years) suffered from chronic tension-type headache. Their headache disappeared within 2 weeks after the start of treatment with melatonin. One 54-year-old man suffered from disabling migraine attacks without aura, twice a week. After starting melatonin treatment, only three migraine attacks were reported in 12 months. Ever since his 40s, a 60-year-old man complained of cluster headache episodes lasting about 2 months, twice a year. In the year since starting melatonin treatment, only one 5-day cluster episode occurred. Nocturnal melatonin secretion in the patients with delayed sleep phase syndrome and headache did not differ significantly from that in the patients with the sleep disorder but without headache. Melatonin may be helpful in patients with headache who are suffering from delayed sleep phase syndrome. Its effectiveness may be due to modification of vascular and nociceptive systems or to its chronobiological action which adjusts the patient's biological clock to his/her life-style.