Improved hypnotic treatment using chlormethiazole and temazepam.

The effects of a single 384 mg oral dose of chlormethiazole were compared with those of 20 mg of temazepam and placebo in healthy old and young women (mean ages 72.9 and 24.7 years respectively). Both drugs were effective hypnotics and had no detectable pharmacological action the next morning. Even four hours after administration performance of a simple psychomotor test was not impaired and sway (measured by an ataxiameter) was not increased in either age group. Pharmacokinetic studies showed that chlormethiazole was rapidly absorbed, distributed, and eliminated by both groups, so that minimal plasma concentrations existed 11 hours after administration. Temazepam, however, was less quickly absorbed and distributed, especially in the young group, and substantial amounts remained in the plasma 11 hours after administration. No unwanted effects occurred after temazepam, but 17 of the 20 subjects suffered from nasal irritation after taking chlormethiazole. Thus hangover effects may be avoided in elderly subjects after they have taken hypnotic drugs, and temazepam and chlormethiazole allow sleep to be interrupted safely.     

Hypnotic accumulation and hangover in elderly inpatients: a controlled double-blind study of temazepam and nitrazepam.

The hypnotic and residual sedative effects of the first and seventh of seven regular night-time doses of nitrazepam 5 mg, temazepam 20 mg, and placebo were studied in 58 elderly inpatients. Plasma temazepam and nitrazepam concentrations rose by about 50% and 113% respectively between the mornings of day 1 and day 7. Patients reported sleeping well more often after the first dose of either hypnotic (p less than 0.05), but there was no difference after the seventh dose. Reaction time was unchanged on the morning after the first dose but was significantly prolonged after the seventh dose of both hypnotics (p less than 0.01). The time taken to eliminate the letter E from a page of prose tended to be prolonged after the first dose of both drugs (temazepam v placebo, p less than 0.05; nitrazepam v placebo, not significant) and was further prolonged on the morning after the seventh dose of nitrazepam (nitrazepam v placebo, p less than 0.05). Thus plasma accumulation of the drug was associated with a deterioration in daytime performance. This change in performance did not correlate with age, cerebral blood flow, or plasma concentration, but patients of low intelligence tended to be more severely affected.     

Radioimmunoassay of the antidiarrhoeal loperamide

Production of antibodies against loperamide was induced in rabbits that were repeatedly injected with a loperamide-protein conjugate. By using the antiserum, a sensitive and specific radioimmunoassay procedure for loperamide was developed. The drug could be assayed directly in human plasma in amounts as low as 50 picogram. None of the known metabolites of loperamide interferred with the radioimmunologic determination of loperamide in biological fluids. The disposition of loperamide was studied in man. Following a single oral dose of 4 mg in a tablet formulation, peak plasma levels, corresponding to about 0.75 ng/ml, were reached 4 hours after drug intake and drug plasma concentrations could be measured up to 24 hours after administration.     

Atenolol,sustained-release oxprenolol,and long-acting propranolol in hypertension.

The effect of once-daily atenolol, sustained-release oxprenolol (a new formulation of oxprenolol presented as a compressed tablet in a waxed matrix), and long-acting propranolol (a new formulation presented as spheriods in a capsule) was studied in a double-blind crossover trial in 23 carefully selected hypertensive outpatients. After a run-in period with matching placebo each patient received atenolol (100 mg/day), sustained-release oxprenolol (160 mg/day), long-acting propranolol (160 mg/day), and placebo according to a randomised sequence. After four weeks'' treatment with sustained-release oxprenolol blood pressure in the two to four hours before the next dose was not significantly lower than after placebo. The effectiveness of atenolol and of the new formulation of propranolol in reducing blood pressure was confirmed. These results suggest that the present formulation of sustained-release oxprenolol should be reconsidered.     

The effect of dose and route of oestradiol benzoate administration on plasma concentrations of oestradiol and FSH in long-term ovariectomised heifers

Oestradiol (E(2)) suppresses FSH and affects follicle wave dynamics in cattle. However, neither the optimum dose of ODB required to suppress FSH nor the effect of route of ODB administration on blood concentrations of E(2) are known; hence, the aim of this experiment was to answer these questions. Ovariectomised heifers received Progesterone Releasing Intravaginal Device (PRID) for 7 days, and 4 days later heifers received one of eight ODB treatments at second PRID insertion as follows; (1) 0.0 mg (Control; n=3), (2) 0.5 mg (n=4), (3) 1.0 mg (n=4), (4) 2.5 mg (n=6), (5) 5.0 mg (n=4), (6) 10. 0 mg (n=4), (7) 5.0 mg (n=4), and (8) 10.0 mg (n=5). For treatments 2-6 inclusive, ODB was administered intramuscularly in oil, while for treatments 7 and 8, the ODB in powder form was administered topically in the vagina by gelatine capsule attached to the PRID. Blood samples were collected every 6 h for the first 48 h, every 12 h for the next 48 h, and twice daily for a further 6 days. The interval from ODB administration to peak E(2) concentration was similar (P0.05) for treatments 2-6 where ODB was administered intramuscularly (mean 13.4+/-1.24 h), and was longer (P<0.05) for the intravaginal capsule treatments (mean 25.5+/-2.84 h). Plasma concentrations of E(2) increased with increasing intramuscular dose of ODB injected, (plasma E(2)=-0.237+16.109 (dose)-0.74 (dose)(2), R(2)=0.75; P<0.05). Peak plasma concentrations of E(2) following the 5- and 10-mg capsules were similar to each other and to those following the 0.5-mg injection (P0.05), but were lower than concentrations obtained following injection of 1.0-5.0 mg (P<0.05). Across all treatments, both the maximum percentage decline in FSH and the interval to FSH nadir were related to the peak plasma concentrations of E(2) (maximum % decline in FSH=11.17+1.564 (peak E(2))-0.009 (peak E(2))(2), R(2)=0.75; P<0.01), (hours to FSH nadir=10.628+1.486(hours to peak E(2))-0.0282(hours to peak E(2))(2), R(2)=0.22; P<0.05). Concentrations of FSH increased as E(2) declined from its peak value, irrespective of maximum value achieved. It was concluded that the intramuscular administration of ODB in oil to ovariectomised heifers given a PRID results in higher plasma concentrations of E(2) and causes a greater reduction in FSH than administration topically by intravaginal gelatine capsule. E(2) transiently suppresses FSH in ovariectomised heifers, and the magnitude of the suppression is dose-dependent; however FSH concentrations begin to increase 1-2 days after ODB administration while concentrations of E(2) were declining but still high.     

Ethanol/cocaine interaction: cocaine and cocaethylene plasma concentrations and their relationship to subjective and cardiovascular effects.

To investigate the pharmacologic effects of the interaction between ethanol and cocaine, eleven male, paid volunteers familiar with the use of both ethanol and cocaine were tested in a dose-response, placebo-controlled, single-blind, randomly-assigned, cross-over design. Ethanol (0.85 g/kg) or placebo was administered in divided doses over a thirty minute period. Fifteen minutes after the termination of ethanol ingestion, cocaine HCl (1.25 and 1.9 mg/kg) or placebo (lidocaine and mannitol) was given by nasal insufflation (snorting). Cocaine and cocaethylene plasma concentrations, blood ethanol levels, subjective ratings of drug effects, and cardiovascular parameters were measured. Statistical analysis of the results indicate that: 1) cocaine administration did not alter blood ethanol concentrations nor the ratings of ethanol intoxication; 2) ethanol caused a significant increase in cocaine plasma concentrations, ratings of cocaine "high", and heart rate; 3) acute tolerance to the subjective and heart rate effects of cocaine was observed; 4) when combined with cocaine, ethanol led to the slow formation of cocaethylene in amounts much lower than those of its parent compound; and 5) the appearance of cocaethylene in plasma did not alter cocaine's subjective and cardiovascular effects.     

Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

Effects of Sibutramine on Resting Metabolic Rate and Weight Loss in Overweight Women

Sibutramine, a monoamine re-uptake inhibitor, has recently been approved by the Food and Drug Administration as a weight loss agent. Sibutramine lowers body-weight in rodents by reducing energy intake and increasing energy expenditure. Sibutramine facilitates weight loss in human subjects, but it is not clear whether it acts on energy intake, energy expenditure, or both. The present study was a randomized clinical trial designed to assess the effects of sibutramine (at 10 or 30 mg/day) on body weight and resting metabolic rate (RMR). Forty-four overweight women were randomized to 1) placebo (n=15); 2) sibutramine at 10 mg/day (n=15) or, 3) sibutramine at 30 mg/day (n=14). All subjects were instructed to consume a 1200 kcal/day diet for 8 weeks while receiving drug or placebo. RMR was assessed by indirect calorimetry at baseline, at 3 hours after the first dose of drug (or placebo), and at the end of the 8-week weight-loss period. Sibutramine reduced body weight-relative to placebo, but there was no difference between weight loss on the two sibutramine doses. No significant differences in RMR between sibutramine and placebo were seen, either 3-hour post dose or after the 8-week weight-loss period. After the weight loss period, all groups were taken off medication and kept weight stable for another 4 weeks. RMR was measured again and was not different among groups. That there was no change in RMR when sibutramine was stopped further suggests that the drug does not directly affect RMR. In summary, while sibutramine was shown to be an effective weightloss agent over 8 weeks, we found no evidence that it increased RMR.     

Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial

Objective: To determine the effects of temazepam on the quality of sleep and on oxygen saturation during sleep in subjects at high altitude. Design: Randomised, blinded, crossover, placebo controlled trial. Setting: Base camp at Mount Everest (altitude 5300 m). Subjects: 11 members of British Mount Everest Medical Expedition recently arrived at base camp. Intervention: Participants were randomly allocated to receive either temazepam 10 mg or placebo on their first night at base camp and the other treatment on the second night. Main outcome measures: Quality of sleep (assessed subjectively), mean arterial oxygen saturation value, and changes in saturation values (as measure of periodic breathing) while participants taking temazepam or placebo. Results: All participants noted subjective improvements in sleep. Mean saturation value remained unchanged when temazepam was compared with placebo (74.65% v 75.70%, P=0.5437). There were fewer changes in oxygen saturation when participants took temazepam and when measured as decreases >4% below the mean value of saturation each hour (P=0.0036, paired Student’s t test (two tailed)). Conclusions: Participants taking temazepam at 5300 m showed no significant drop in mean oxygen saturation values during sleep. Both the number and severity of changes in saturation during sleep decreased and the quality of sleep improved. This may be a result of a reduction in the number of awakenings and might lead to greater respiratory stability and fewer episodes of periodic breathing. This has the effect of improving the quality of sleep and reducing the number of periods of desaturation during sleep

Key messages

• Poor sleep at high altitude is common and may be due to a combination of physiological and physical factors
• Frequent arousals, periodic breathing, and episodes of oxygen desaturation lead to poor sleep and daytime symptoms of drowsiness and reduced performance
• In this study 10 mg temazepam improved subjective reports of the quality of sleep and reduced episodes of arterial desaturation, with no significant effect on mean oxygen saturation during sleep

     

Effect of oral nalmefene, an opiate-receptor antagonist, on meal-stimulated gastric acid secretion and serum gastrin concentration in man

We evaluated whether nalmefene, an orally administered opiate-receptor antagonist, would inhibit gastric acid secretion in response to a meal in healthy humans. On separate days either 50 mg nalmefene or a placebo tablet was administered by mouth 90 min before a blenderized steak meal was infused into the stomach through a nasogastric tube. Compared to placebo, nalmefene inhibited meal-stimulated acid secretion in each of 6 subjects studied (P less than 0.05). During the second and third hours after the meal, nalmefene inhibited mean acid secretion by 16%. Nalmefene also resulted in significantly higher meal-stimulated serum gastrin concentrations than placebo (P less than 0.05) even though intragastric pH was kept constant at 5.0 in both experiments. These studies indicate that an orally administered opiate-receptor antagonist can inhibit gastric acid secretion in response to a meal in humans, yet increase meal-stimulated serum gastrin concentrations.     

The behavioural effects of lorazepam are poorly related to its concentration in the brain

The brain and plasma pharmacokinetics of lorazepam were investigated in rats that had received 5 once daily injections of 0.5 or 1.0 mg/kg of the compound. The sedative effects of the drug were also assessed using a holeboard test. Thirty minutes after the final injection of 1.0 mg/kg lorazepam animals showed a similar degree of sedation to animals tested 90 min after their final injection of 0.5 mg/kg, despite having brain concentrations of lorazepam that were 3 times higher. Four hours after 0.5 mg/kg lorazepam, when the concentration of lorazepam in the brain was very low, animals' head-dipping and locomotor activity scores were still only 60% of the controls' scores. It is concluded that brain concentrations of lorazepam are of little use in predicting the behavioural effects of the compound.     

Changes in serum testosterone and estradiol concentrations following acute androstenedione ingestion in young women.

The effect of androstenedione intake on serum hormone concentrations in women is equivocal. Therefore, we examined the hormonal response to androstenedione intake in healthy young (22.1 +/- 0.4 y) women for 4 hours. On day 3 of the follicular phase, subjects ingested placebo, 100, or 300 mg androstenedione in a random, double-blind, cross-over manner. Blood samples were collected before and every 30 min for 240 min after intake. Serum androstenedione concentrations (means +/- SE) increased above basal (6.2 +/- 0.8 nmol/l) from 60-240 min for both 100 mg (22.6 +/- 1.0 nmol/l at 240 min) and 300 mg (28.1 +/- 1.3 nmol/l at 210 min). Androstenedione intake increased serum total testosterone concentrations above basal (1.2 +/- 0.2 nmol/l) from 120-240 min (5.5 +/- 0.9 nmol/l at 210 min) with 100 mg and from 60-240 with 300 mg (10.2 +/- 1.6 nmol/l at 210 min). Androstenedione intake also increased serum estradiol concentrations (basal 191 +/- 24 pmol/l) at 150 min with 100 mg (237 +/- 35 pmol/l) and from 150-240 min with 300 mg (reaching 260 +/- 32 pmol/l at 240 min). These data indicate that, in contrast to men, androstenedione intake in women increases serum testosterone concentrations.     

Plasma Concentrations of Digoxin after Oral Administration in the Fasting and Postprandial State

After the oral administration of 0·5 mg of digoxin in tablet form to fasting subjects peak plasma levels were reached in 30 to 60 minutes. Levels then fell to reach a plateau at six to eight hours. When the same dose was given after food the peak plasma concentrations were significantly lower, but the concentrations reached in samples obtained from two to eight hours after the dose did not differ appreciably from corresponding samples obtained in the fasting experiments.In a four-week cross-over study of 21 patients on maintenance therapy, digoxin taken regularly in the fasting state produced plasma concentrations similar to those obtained when the drug was taken after meals.The rapid appearance of digoxin in the blood suggests that the oral route of administration is adequate for most patients who require rapid digitalization, and the timing of maintenance dosage in relation to meals is unimportant.     

A Randomized Controlled Trial on the Effect of Tapentadol and Morphine on Conditioned Pain Modulation in Healthy Volunteers

Background

Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids.

Methods and Results

On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate release tablet) or placebo. At both time points, CPM was detectable after treatment with placebo and tapentadol (peak pain ratings reduced by 20-30% after application of the conditioning stimulus) but not after morphine. Compared to placebo morphine displayed significantly less CPM: mean treatment difference 18.2% (95% CI 3.4 to 32.9%) at 60-90 min after drug intake and 19.5% (95% CI 5.7 to 33.2%) at 120-150 min after drug intake (p = 0.001). No difference in CPM between placebo and tapentadol was detected: mean treatment difference 1.5% (95% CI -11.6 to 14.6%) at 60-90 min after drug intake and 1.5% (95% CI -16.0 to 18.9%) at 120-150 min after drug intake (p = 0.60).

Conclusions

Our data show that in volunteers morphine affects CPM, while tapentadol was without effect despite identical experimental conditions. These data confirm that tapentadol’s main mechanism of action is distinct from that of morphine and likely related to the effect of adrenergic stimulation on descending controls.

Trial Registration

Netherlands Trial Register NTR2716     

Pharmacokinetic study of 11-Keto beta-Boswellic acid.

INTRODUCTION: Boswellia serrata has been used in traditional medicine for treatment of inflammatory diseases since antiquity. However human kinetic studies are lacking for this. Hence to better elucidate its effects in humans and determine its optimal dosing, this study was planned. MATERIAL AND METHODS: Twelve healthy adult men volunteers were given capsule Wok Vel containing 333 mg of Boswellia Serrata Extract, orally, after a seven days washout period. Venous blood samples were drawn through indwelling canula from each volunteer prior to drug administration and at 30, 60, 120, 150, 180, 210, 240, 300, 360, 480, 600, 720, 840 minutes after drug administration. Plasma obtained after centrifuge was analyzed to measure concentration of 11-Keto beta-Boswellic Acid (KBA) by HPLC. Various kinetic parameters were then calculated from the plasma concentrations. RESULTS: The results are expressed as mean +/- Standard Error of Mean. The peak plasma levels (2.72 x 10(-3) +/- 0.18 micromoles/ml) of BSE were reached at 4.5 +/- 0.55 h. The concentration declined with a mean elimination half life of 5.97 +/- 0.95 h. The apparent volume of distribution averaged 142.87 +/- 22.78 L and the plasma clearance was 296.10 +/- 24.09 ml/min. The AUC(0-infinity) was 27.33 x 10(-3) +/- 1.99 micromoles/ml h. CONCLUSION: Elimination half life of nearly six hours suggests that the drug needs to be given orally at the interval of six hours. The plasma concentration will attain the steady state after approximately 30 hours. BSE is a safe drug and well tolerated on oral administration. No adverse effects were seen with this drug when administered as single dose in 333 mg.     

Tablet Levothyroxine (L-T4) Malabsorption Induced by Proton Pump Inhibitor; A Problem that was Solved by Switching to L-T4 in Soft Gel Capsule

ObjectiveTo report a patient in whom the impaired absorption of tablet levothyroxine (L-T4) due to a proton pump inhibitor (PPI) use was corrected by switching the patient to the soft gel capsule.MethodsA woman with Hashimoto’s thyroiditis-associated hypothyroidism (serum thyroid-stimulating hormone [TSH] 6.8-9.6 mU/L) had been treated with tablet L-T4 (100 μg/day). Because she used to take pantoprazole just before L-T4 in the morning, TSH failed to normalize (4.4-6.5 mU/L). Thus, the daily dose had been progressively increased to 125 and 150 μg/day, with serum TSH levels of 2.4 and 0.6 mU/L, respectively.ResultsWhile maintaining pantoprazole, we switched the tablet L-T4 (150 g/day) to a soft gel capsule (125 μg/ day; Tirosint® capsule, IBSA, Lugano, Switzerland) and after 2 months, to 100 μg/day. Serum TSH was lower than under the equivalent regimens with the tablet: 0.5 versus 2.4 mU/L (125 μg/day) and 2.4 versus 4.4 to 6.5 mU/L (100 μg/day). Upon switching back to the tablet (100 μg/day), serum TSH increased to 3.2 and 4.7 mU/L and then dropped to 2.7-3.0 mU/L when the dose was increased to 125 μg/day. We also acutely evaluated the intestinal absorption of L-T4 by administering 600 μg LT4 as a tablet or soft gel capsule while maintaining pantoprazole. Pharmacokinetic indices showed better and faster absorption for the soft gel capsule versus tablet (area under the curve [AUC]_0-4h = 16,240 vs. 10,960 nmol/L × 4 hours, maximum absorption [C_max] = 108 vs. 73 nmol/L, and time of maximum absorption [T_max] = 120 minutes vs. 180 minutes).ConclusionConfirming in vitro studies conducted by other authors, the soft gel capsule L-T4 is negligibly affected by changes in gastric pH compared to tablet L-T4. (Endocr Pract. 2014;20:e38-e41)     

New non-steroidal aromatase inhibitors: focus on R76713

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).     

Attenuation of sleep propensity, core hypothermia, and peripheral heat loss after temazepam tolerance

If changes in thermoregulation mediate sleepiness induced by sedative/hypnotics, then a reduction in the soporific efficacy (tolerance) of these agents may be accompanied by a concomitant reduction in their thermoregulatory effects. We compared the thermoregulatory and soporific effects of acute temazepam (30 mg at 1400) in 11 young male subjects before and immediately after 7 consecutive days of temazepam (30 mg). Subjects lay supine (0800-2030), while foot (T(ft)) and rectal (T(c)) temperatures were recorded. Sleep onset latency (SOL) was measured hourly using 20-min multiple sleep latency tests. Relative to placebo, temazepam significantly reduced both T(c) and SOL (-0.31 degrees C and 14.1 min) while increasing T(ft) (3.39 degrees C). A significant tolerance developed after the week of temazepam, with a mean reduction in soporific efficacy of 4.0 +/- 0.8 min. This was accompanied by a concomitant attenuation in both T(c) (-0.16 degrees C) and T(ft) (1.44 degrees C). Furthermore, SOL was temporally related to T(ft) and the maximum rate of decline in T(c) before and after tolerance. Together, these results indicate that the thermoregulatory system may be functionally involved in the regulation of sleepiness.     

Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised,double blind,multicentre study. European Multicentre Study Group for Cabergoline in Lactation Inhibition.

OBJECTIVE--To compare the efficacy and safety of a single dose of 1 mg of cabergoline with that of bromocriptine 2.5 mg twice daily for 14 days in the inhibition of puerperal lactation. DESIGN--Prospective, randomised, double blind, parallel group, multicentre study. SETTING--University of hospital departments of obstetrics and gynaecology in different European countries. SUBJECTS--272 puerperal women not wishing to lactate (136 randomised to each drug). INTERVENTIONS--Women randomised to cabergoline received two 0.5 mg tablets of cabergoline and one placebo tablet within 27 hours after delivery and then placebo twice daily for 14 days. Those randomised to bromocriptine received 2.5 mg of bromocriptine and two placebo tablets within 27 hours and then 2.5 mg of bromocriptine twice daily for 14 days. MAIN OUTCOME MEASURES--Success of treatment (complete or partial) according to milk secretion, breast engorgement, and breast pain; rebound symptomatology; serum prolactin concentrations; and number of adverse events. RESULTS--Complete success was achieved in 106 of 136 women randomised to cabergoline and in 94 of 136 randomised to bromocriptine and partial success in 21 and 33 women respectively. Rebound breast symptomatology occurred respectively in five and 23 women with complete success up to day 15 (p less than 0.0001). Serum prolactin concentrations dropped considerably with both drugs from day 2 to day 15; a prolactin secretion rebound effect was observed in women treated with bromocriptine. cabergoline and 36 receiving bromocriptine (p = 0.054), occurring most during the first treatment day. CONCLUSION--A single 1 mg dose of cabergoline is at least as effective as bromocriptine 2.5 mg twice daily for 14 days in preventing puerperal lactation. Because of the considerably lower rate of rebound breast activity and adverse events and the simpler administration schedule cabergoline should be the drug of choice for lactation inhibition.     

Plasma levels of glibenclamide in diabetic patients during its routine clinical administration determined by a specific radioimmunoassay

Plasma concentration of glibenclamide in routine clinical practice was determined by a specific radioimmunoassay. In diabetic patients treated with glibenclamide for a month or longer, the drug level in fasting morning plasma was variable but the mean level paralleled the daily dose. After oral administration of 2.5 mg in healthy and diabetic subjects, the drug level reached peaks in 1.5 hours and declined to the half of the peak level in next 2-3 hours. The plasma glibenclamide profile after oral dose did not differ significantly in patients with secondary failure to the drug. Comparison of a single-dose and divided-dose schedules of 5 mg glibenclamide revealed that plasma drug level increased each time after administration. Plasma glucose and insulin concentrations did not differ significantly at most times of the day but there was a tendency that increment of plasma glucose after meal was suppressed by a dose taken immediately before a meal. The relationship of blood level of glibenclamide to clinical effectiveness may be rather indirect and needs to be elucidated.