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Circadian periods of single suprachiasmatic neurons in rats.

Neuronal activity of a single neuron was monitored continuously for more than 5 days by means of a multi-electrode dish in dispersed cell culture of the rat suprachiasmatic nucleus (SCN). Sixty-seven out of 88 neurons showed a robust circadian rhythm in firing rate. The mean circadian period was 24.2 h, which was almost identical to that of the locomotor activity rhythm in 114 weanling rats blinded on the day of birth. However, the circadian period in individual SCN neurons was scattered from 20.0 to 28.3 h (SD, 1.4 h), while the period of activity rhythm clustered from 24.0 to 24.8 h (SD, 0.2 h). It is concluded that a large number of SCN neurons contain the circadian oscillator, the period of which is more variable than the circadian period of the SCN as a whole. It is suggested that the circadian rhythms in individual SCN neurons are capable of synchronizing to each other and are integrated to constitute a multiple oscillator system(s) within the SCN.

Animals↗

The cognitive, subjective, and physical effects of a ginkgo biloba/panax ginseng combination in healthy volunteers with neurasthenic complaints.

We evaluated the effects of a Ginkgo biloba/ginseng combination on cognitive function in this 90-day, double-blind, placebo-controlled, parallel-group study. Sixty-four healthy volunteers (aged 40 to 65 years), selected on the basis of fulfilling the ICD-10 F48.0 criteria for neurasthenia, were assigned randomly to four equal dosing groups, receiving 80, 160, or 320 mg of the combination b.i.d. or placebo. Assessments were performed on the day before dosing, and again at Days 1, 30, and 90 at 1 hour after the morning dose and 1 hour after the afternoon dose. The assessments included the Cognitive Drug Research (CDR) computerized assessment system, the Vienna Determination Unit, cycle ergometry, and various questionnaires. The treatments were well tolerated by all volunteers. On Day 90 at 1 hour post morning dosing, dose-related improvements were seen on the CDR tests, the 320 mg dose being significantly superior to placebo. These effects, however, were reversed 1 hour after the afternoon dose, possibly suggesting that a longer inter-dosing interval would be preferable. The 80-mg dose produced a significant benefit on the ergometry assessment of heart rate at maximum load. There were also several supporting changes from other assessments, including an advantage of 320 mg over placebo on the global score from the Symptom Checklist-90-revised (SCL-90-R) at Day 90.

Adult↗

Transition from estrogen therapy to raloxifene in postmenopausal women: effects on treatment satisfaction and the endometrium-a pilot study.

OBJECTIVE: To compare the effects of transferring from low-dose, transdermal estrogen to raloxifene with a phase of alternate-day raloxifene therapy with or without low-dose transdermal estrogen on patient satisfaction, endometrial changes, and overall safety in healthy, postmenopausal women previously administered hormone therapy. DESIGN: Healthy postmenopausal women were randomized to one of two treatment groups: raloxifene + low-dose, transdermal estrogen (RLX+E) and raloxifene + placebo (RLX+P). The study consisted of four equal phases of 8 weeks each: Phase I (low-dose, transdermal estrogen, 25 microg/day), phase II (double-blind, alternate-day raloxifene 60 mg + low-dose, transdermal estrogen or placebo patch), phase III (alternate-day RLX 60 mg + placebo patch), and phase IV (raloxifene 60 mg/day + placebo patch). Primary endpoints included patient satisfaction, endometrial changes, overall safety, and quality of life. RESULTS: Sixty women were randomized in this study. Baseline characteristics were similar between the two treatment groups. For the primary analysis (phase II to phase IV, inclusive), there were no significant differences between the therapy sequences for patient satisfaction, endometrial thickness, or quality of life. In the therapy comparison phase (phase II), mean change in patient satisfaction score was 3.2 mm (SD = 16.2) for RLX+E and -17.1 mm (SD = 38.7) for RLX+P (P = 0.003), whereas mean change in endometrial thickness was 0.8 mm (SD = 2.7) for RLX+E and -0.9 mm (SD = 1.5) for RLX+P (P = 0.021). The RLX+P group showed a significantly greater increase in vasomotor events, with a mean score change of 1.7 (SD = 1.9) compared with a mean score change of 0.2 (SD = 1.8) in the RLX+E group (P = 0.005). There were no statistically significant differences between the two therapy groups in the reporting of treatment-emergent adverse events. CONCLUSION: Gradual conversion to raloxifene from low-dose estrogen, with a progression from 60 mg every alternate day to 60 mg/day, is a viable option in potentially symptomatic, postmenopausal women.

Administration, Cutaneous↗

[Psychopathologic and psychophysiologic follow-up of inpatient depressed patients with standardized treatment with clomipramine and oxaprotiline].

The aim of this study was to show psychopathological and especially psychophysiological data of depressed inpatients which were collected during a 28-day double-blind study with 68 depressed inpatients given clomipramine 150 mgr/die) or maprotiline/oxaprotiline 150 mgr/die). Using Hamilton-Depression-Scale, Self-depression-scale (SDS by Zung), Beschwerdeliste (BL) and Befindlichkeitsskala (Bf-S) by v. Zerssen an impressive reduction of depression scores was observed in all rating scales with some superiority of clomipramine. But at the end of the study at treatment day 28 both groups - clomipramine and maprotiline/oxaprotilin - had similar results. During treatment each patient was part of a weekly habituation experiment using electrodermal activity in an orientation reaction as measure. Contrary to other studies (Lader 1975 or Heimann 1976, 1980) there was no difference in the course of psychophysiological data (EDA) between both treatment groups or between depressive agitation and psychomotor retardation. There was also no relationship between reactivity in EDA at study begin and treatment results.

Adult↗

The effect of short-term (21-day) orlistat treatment on the physiologic balance of six selected macrominerals and microminerals in obese adolescents.

OBJECTIVES: Orlistat is a gastrointestinal lipase inhibitor used to reduce dietary fat absorption and could be used to treat overweight and obesity in adolescents. The primary objective was to assess whether orlistat has an effect on the physiologic balance of three macrominerals (calcium, phosphorus and magnesium) and three microminerals (iron, zinc and copper). METHODS: This was a 21-day, double-blind, randomized, parallel-group, placebo-controlled mineral balance study conducted in adolescent obese volunteers (BMI >or=85th percentile, adjusted for age and gender). Subjects were maintained on a hypocaloric diet with a normal daily mineral content in both treatment groups and received oral treatment with orlistat 120 mg (n = 16) or placebo (n = 16) three times daily for 21 days. Following a 14-day equilibration period, balances for calcium, phosphorus, magnesium, iron, copper and zinc were measured for days 15-21. Serum and urine electrolytes were also measured at baseline and at the end of treatment. RESULTS: On average, orlistat inhibited dietary fat absorption by approximately 27%. This degree of dietary fat inhibition caused no significant changes in mineral balance between orlistat and placebo groups. In addition, serum and urine electrolytes (sodium and potassium) as well as urinary creatinine excretion were not affected by orlistat treatment. Orlistat was well tolerated; adverse events occurred mainly in the gastrointestinal tract and were of mild or moderate intensities. CONCLUSIONS: Administration of orlistat had no significant effect on the balance of six selected minerals in adolescent obese patients.

Adolescent↗

Modification of the thermogenic effect of acutely inhaled salbutamol by chronic inhalation in normal subjects.

BACKGROUND: Acute inhalation of clinical doses of salbutamol in normal volunteers increases resting metabolic rate by up to 20% above control values. This study was designed to see if chronic treatment with salbutamol causes a sustained increase in metabolic rate and whether it modifies the acute thermogenic response to the drug. METHODS: The effects of chronic inhaled salbutamol on resting oxygen consumption (VO2) and carbon dioxide output (VCO2) were studied in seven normal subjects (age 20-47 years, weight 52-105 kg, five men). An open canopy method of indirect calorimetry was used to measure VO2, VCO2, and respiratory quotient (RQ). Subjects inhaled two puffs of salbutamol or placebo four times a day in a double blind manner. Measurements of resting VO2 and VCO2 after 10 days of salbutamol were compared with the values after 10 days of placebo and with those taken at the start of the study. At the end of each treatment period subjects inhaled eight puffs (800 micrograms) of salbutamol and the acute effects on VO2, VCO2 and RQ were monitored for one hour. RESULTS: Resting VO2, VCO2, and RQ were not significantly different at the end of the salbutamol and placebo periods but the acute response to eight puffs of salbutamol was abolished by regular inhalation. The mean VO2 integrated over one hour after 800 micrograms salbutamol given acutely was different (241.3 and 210.7 ml/kg/h in the placebo and salbutamol groups respectively). Differences were not significant between placebo and salbutamol groups for changes in VCO2, heart rate, blood pressure, and RQ after acute inhalation. CONCLUSION: Regular treatment with inhaled salbutamol (800 micrograms/day) does not cause a sustained increase in resting metabolic rate but prevents the increase in VO2 that occurs after acute inhalations in normal subjects.

Administration, Inhalation↗

Rapid and sustained efficacy of mizolastine 10 mg once daily in seasonal allergic rhinitis.

This 28-day, double-blind, randomized study in 256 patients compared the efficacy and safety of mizolastine 10 mg daily with placebo in patients with seasonal allergic rhinoconjunctivitis. All four nasal symptoms (itch, rhinorrhoea, sneezing, obstruction) and three ocular symptoms (itch, tears, redness) were rated by investigators using both a 0-3 and a 0-9 rating scale. Compared with the placebo group total, nasal and ocular scores were all significantly lower in the mizolastine-treated patients at day 14 of the study (P = 0.0002-0.0009, using the 0-9 scale) and relief was maintained throughout the 4-week study duration. Patient diary total scores showed that mizolastine was effective from the first day of treatment. The 0-9 scale appears to be more sensitive than the 0-3 scale for rating symptoms of seasonal allergic rhinitis.

Adult↗

Effect of aminophylline on plasma [K+] and hypoxic ventilatory response during mild exercise in men.

To examine the role of endogenous adenosine on the hypoxic ventilatory response (HVR) enhanced during exercise, we measured HVR at rest and during mild exercise (12.5 W) in nine healthy men in a supine position after pretreatment with aminophylline (5 mg/kg), an adenosine receptor blocker, or dipyridamole (0.6 mg/kg), an adenosine uptake blocker, by using a 3-day double-blind placebo-controlled design. Although HVR was enhanced during exercise on all occasions, HVR with aminophylline [0.42 +/- 0.07 (SE) l.min-1.%fall-1 of arterial O2 saturation] was significantly lower than that with placebo (0.64 +/- 0.13 l.min-1.%fall-1) or dipyridamole (0.64 +/- 0.08 l.min-1.%fall-1) during exercise (P < 0.05 for both) at similar end-tidal PCO2 on the 3 days but not at rest. We then examined the changes in plasma K+ concentration ([K+]) and catecholamines, the other possible endogenous potentiators of the carotid body activity. The exercise- and hypoxia-induced increases in plasma [K+] were significantly lower with aminophylline (0.23 +/- 0.09 meq/l) than with the placebo (0.51 +/- 0.10 meq/l) or dypyridamole (0.58 +/- 0.13 meq/l) (P < 0.05 for both). We therefore conclude that aminophylline attenuates the enhancement of HVR during mild exercise and that this might be due to its attenuating effect on exercise- and hypoxia-associated increases in plasma [K+] rather than due to its antagonizing effect on endogenous adenosine.

Adolescent↗

Longitudinal chronobiologic blood pressure monitoring for assessing the need and timing of antihypertensive treatment.

To examine the need for antihypertensive therapy and its timing, a 46 year-old woman with a 10-year history of "mild to moderate hypertension," treated for that span with 50 mg of hydrochlorothiazide per day, usually taken before retiring, carried out a study in a series of stages. Throughout the first 8 stages, she monitored her blood pressure and heart rate at 15-minute intervals around the clock for 70 consecutive days. In the first two stages, her medication was continued for a total of 10 days, of which the last 7 days constituted a double-blind study start. For the next 25 days, she was placed on a placebo once in the evening. For the ensuing week, she received three tablets per day (in the morning, noon and evening), with all three being placebo. Thereafter, for consecutive 7-day spans, she was placed on treatment, only in the morning, only at noon or only in the evening, with placebo at other times. The desirability of one vs. another treatment was assessed by a comparison of slopes fitted to the daily MESORs; on that basis, the morning or noon treatment appeared to be possibly superior to the evening treatment. Eventually the patient was taken off medication; 5 months later her sphygmochrons, based on two-to-six day monitoring, were acceptable by current standards. The slope of MESORs may be a useful endpoint to assess the need for medication, to optimize its timing or to establish the likelihood that medication is not needed. This approach should, however, be based on several (rather than a single) double-blind alternation of drug and placebo treatments for spans that are the longer the smaller the extent of apparent blood pressure elevation. Thus, in the case of apparent mild MESOR-hypertension, the blood pressure MESOR changes following the change in medication should be assessed during spans longer than one week. In the particular case studied, it seems possible that the patient had taken medication for 10 years, perhaps without justification. In cases of very mild blood pressure elevation, it seems desirable, by self-measurement or preferably automatic measurement, to take the patient off medication for spans measured in weeks or preferably months rather than days, in order to rule in or rule out the need for treatment, on the basis of repeated blood pressure profiles, to be compared eventually with reference standards from peers at low familial and personal risk of developing high blood pressure.

Antihypertensive Agents↗

Early versus late replacement of autotransfused blood in elective spinal surgery. A prospective randomized study.

The use of autologous blood is a well established and extremely popular technique to decrease the necessity for homologous transfusions and the attendant risks of hepatitis, HIV, and HTLV--I/II infections. The most beneficial timing for autologous reinfusion of predonated blood remains unknown. The present study was undertaken to determine the optimal timing of autologous blood reinfusion in elective spinal surgery. Fifty-seven patients were prospectively individually randomly allocated into early versus delayed reinfusion groups prior to undergoing elective spinal surgery by a single surgeon. Three surgical subgroups were entered into the study: anterior/posterior (A/P) spinal fusion patients, posterior thoracolumbar scoliosis fusion patients (PSF), and degenerative posterior lumbar fusion patients (LF). Randomization was successful in that three was no significant difference in male to female ratio, age, preoperative hemoglobin, or number of units predonated between the early and delayed reinfusion groups. Likewise, there was no significant difference in the details of the operative procedure when compared as a group for the early versus delayed reinfusion groups. A significant increase in the postoperative day #1, 2 and 3 hemoglobin was seen in the early reinfusion group, while there was no significant difference seen in the postoperative day #7 hemoglobin between the early versus delayed reinfusion group. There was no effect of surgical grouping on these significant comparisons. Earlier patient mobilization was also seen in the early reinfusion groups for the A/P and PSF groups. There was no difference in patients' subjective evaluation of satisfaction and discomfort between the early or delayed reinfusion groups as determined by blinded interview on days 1, 3, 5, and 7 postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

A comparison of costs and effectiveness of the BACTEC NR-730 system and a conventional method of blood culture.

Results and costs of the first six months experience with BACTEC NR-730 were compared with a series of blood cultures performed by the conventional method previously used. The newer technology detected the growth of 14.1% of significant isolates on the day of receipt of the specimens. The previous method lacked blind subcultures on the day of receipt and therefore detected growth only after overnight incubation. No direct comparison of the sensitivities of the methods was possible, but the percentages of cultures yielding significant isolates were similar for the two methods. With the new method, technicians needed less time for daily screening of blood cultures, fewer subcultures were required and less contamination was observed. The method used to calculate the directly-related variable costs of the two methods is set out. In the particular situation reported, workload and labor costs were such that introduction of BACTEC NR-730 resulted in a saving on variable costs.

Bacteria, Aerobic↗

Efficacy and tolerability of the renin inhibitor Ro 42-5892 in patients with hypertension.

The efficacy of multiple oral administration of the renin inhibitor Ro 42-5892 [(S)-alpha-](t-butylsulfonyl)-methyl]hydrocinnamamido]-N-[1S , 2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imi dazole-4- propionamide] was studied. Forty-nine patients with moderate essential hypertension were randomly assigned to three groups that entered an 8-day double-blind oral treatment period: daily administration of placebo (group A), 300 mg Ro 42-5892 (group B), or 600 mg Ro 42-5892 (group C). Four hours after the last oral drug intake, placebo was administered intravenously to subjects in group A and 100 mg Ro 42-5892 was administered intravenously to subjects in groups B and C. Sitting systolic and diastolic blood pressures were measured on days 1 and 8 with a blood pressure device. On day 1, systolic blood pressure maximally decreased by 13.3 +/- 9.3, 20.2 +/- 11.2, and 24.1 +/- 11.3 mm Hg in groups A, B, and C, respectively (mean +/- SD; p < 0.01 for group A versus group C). Diastolic blood pressure maximally decreased 9.4 +/- 5.7, 13.9 +/- 8.7, and 11.8 +/- 5.7 mm Hg (difference not significant). On day 8, systolic blood pressure maximally decreased 19.5 +/- 16.5, 26.5 +/- 17.4, and 30.5 +/- 18.4 mm Hg and diastolic blood pressure maximally decreased 14.8 +/- 5.0, 16.2 +/- 9.0, and 17.9 +/- 12.7 mm Hg (difference not significant) compared with pretreatment values. Intravenous drug administration did not further reduce blood pressure, suggesting that the mode of action and not the low bioavailability was the limiting factor for the low efficacy.

Administration, Oral↗

Effects of diuretic therapy on the development of tolerance to nitroglycerin and exercise capacity in patients with chronic stable angina.

BACKGROUND: Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect. METHODS AND RESULTS: Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371 +/- 26 versus 288 +/- 16 seconds, diuretic versus placebo, P < .01). Similar results were obtained during both acute and sustained nitroglycerin therapy. CONCLUSIONS: The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.

Administration, Cutaneous↗

Adrenal suppression with high-potency corticosteroid ointment formulations in normal subjects.

In this 14-day, double-blind, in-clinic study, 24 healthy male volunteers were assigned at random to one of four treatment groups to compare the effects of a new formulation of 0.05% diflorasone diacetate ointment in a vehicle of propylene glycol (PG) with the effects of ointments of 0.05% fluocinonide, 0.05% clobetasol propionate, or the vehicle for diflorasone diacetate PG. The medication was applied to 75% of each subject's total body surface once a day for six consecutive days. During treatment and four days before and four days after treatment, various indicators of adrenal suppression were measured. A reduction in plasma cortisol levels was seen in several patients in each treatment group during the pretreatment period (days 1-4). Plasma cortisol continued to decrease during treatment and tended to return to pretreatment levels after cessation of therapy. There were no statistically significant differences between treatment groups. The lowering of plasma cortisol values in all groups was attributed to the applied medications as well as to the volunteers' change in daily routine and environment.

Adult↗

Effects of piroxicam-beta-cyclodextrin on the gastrointestinal tract.

Piroxicam-beta-cyclodextrin (PBC), a complex of piroxicam with beta-cyclodextrin, was developed with the aim of improving the hydrosolubility and bioavailability of piroxicam. The complex is more rapidly absorbed, with a consequent reduction in the time of contact of piroxicam with the gastric and duodenal mucosa. It is hoped that the shorter contact time might reduce the local toxicity of piroxicam, but it is also possible that transiently higher local concentrations of the drug might worsen the injury to the gastro-duodenal mucosa. Four studies have been conducted in healthy volunteers in order to investigate the effects of PBC on the gastro-intestinal tract. In 3 of these trials, all of similar design, PBC (containing 20 mg of piroxicam) was compared with piroxicam 20mg and placebo given once daily with assessment of faecal blood loss using the 51Cr-labelled red-cell technique, and endoscopic appearance of gastroduodenal mucosa before and after 28 consecutive days of treatment. One study showed a significant difference in respect of faecal blood loss towards the end of the 4-week study period favouring PBC over piroxicam, while the 2 others showed comparable but non-significant trends in favour of PBC. In a fourth study, 32 non-patient volunteers received either piroxicam 20mg once daily; PBC 20mg equivalence; indomethacin 50mg twice daily; or placebo. The treatment was given double blind for 14 days. Endoscopy was performed and gastric potential differences were measured by neutral observers before and at the end of treatment. There were no significant differences in the endoscopic scores between the active treatment groups. The gastric potential difference showed greater changes with indomethacin and piroxicam than with placebo and PBC.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Comparison of the suppressive effect of astemizole, terfenadine, and hydroxyzine on histamine-induced wheals and flares in humans.

Thirty-two healthy volunteers completed a 14-day, double-blind, noncrossover study comparing the efficacy and adverse effects of astemizole, terfenadine, and hydroxyzine. The subjects received either astemizole (load), 30 mg once daily for 1 week and then 10 mg once daily for 1 week, or astemizole (no load), 10 mg once daily for 2 weeks, or terfenadine, 60 mg twice daily for 2 weeks, or hydroxyzine, 50 mg once daily for 2 weeks. Before and on days 7 and 14 of treatment, five intradermal tests with various amounts of histamine phosphate (range 0.3 to 40 micrograms) were performed. Wheal-and-flare responses were traced, and the areas were computed by use of a graphics tablet. All four H1-receptor antagonist treatment regimens were equally effective in reducing the flare response to histamine. Astemizole (load) and hydroxyzine were significantly more effective than terfenadine and astemizole (no load) in reducing wheal size. The incidence of adverse effects, including sedation, was low overall and lowest in the astemizole (no load) and terfenadine groups, although this difference was not statistically significant.

Adult↗

Double-blind comparison of two regimens in the treatment of nongonococcal urethritis. Seven-day vs 21-day course of triple tetracyclinc (Deteclo).

In a double-blind comparison of two regimens of triple tetracycline (Deteclo, Lederle) in the treatment of nongonococcal urethritis, 68 (88.6%) of 70 patients treated with one tablet twice for 21 days and seen four weeks after starting therapy had satisfactory results. This was significantly better than the findings among the 73 patients treated with one tablet twice daily for seven days and followed for four weeks, among whom only 47 (64.4%) had satisfactory results. Results were also better for the group treated with the 21-day regimen at three months afer the start of treatment. When analysed individually at four and 12 weeks, urethral discharge, urethral Gram-stained smears, and first-glass urine test all gave similar results, which were markedly better than those before treatment. It appears that the longer course of treatment it indicated where any regular partner may not be treated. Slightly fewer patients had satisfactory results among those who admitted consuming alcohol than among those who did not. Chlamydiae-negative patients, treated for seven days, had fewer clinically satisfactory results than other sub-groups.

Chlamydia trachomatis↗