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Urinary urge incontinence: randomised crossover trials of penthienate versus placebo and propantheline.

OBJECTIVE: To compare the efficacy of penthienate with that of propantheline and placebo for treatment of primary idiopathic detrusor instability. DESIGN: Two prospective, randomised, crossover trials (double-blind for penthienate versus placebo and non-blinded for penthienate versus propantheline). SETTING: Urology Clinic of Prince Henry Hospital, Sydney, NSW (an outpatient clinic of a tertiary referral hospital), in 1993-1994. PARTICIPANTS: Neurologically intact patients with urodynamically proven detrusor instability, urgency and urge incontinence, but no stress incontinence (20 participated in the penthienate/placebo trial and 23 in the penthienate/propanthelin trial). OUTCOME MEASURES: Cystometrography results before and after treatment; frequency and volumes of urine voided in weeks 1 and 4 of treatment; and patient scores for degree of continence, side effects, efficacy and acceptability of treatment. INTERVENTIONS: Penthienate (5 mg), propantheline (15 mg) or placebo (all three times a day) for 4 weeks. RESULTS: Penthienate produced significantly greater improvements than placebo in frequency (daytime, P = 0.002; and night-time, P = 0.02), incontinence scores (P = 0.002) and amplitude of unstable detrusor contractions, when present (P = 0.01), and significantly increased diurnal and nocturnal bladder capacity, both on cystometrography (P = 0.003) and by voiding-diary records (P < 0.001). It also increased residual urine volume over the baseline level, but not significantly. Side effects, especially dry mouth, were common with penthienate, and one patient developed urinary retention. Penthienate was significantly better than propantheline in improving cystometric capacity (P = 0.03), and reducing the amplitude of unstable detrusor contractions (P = 0.01), and was perceived as more effective by patients for frequency, nocturia and incontinence. CONCLUSIONS: Penthienate (5 mg three times a day) was objectively and subjectively significantly better than both placebo and propantheline (15 mg three times a day) for treatment of primary idiopathic detrusor instability.

Adult↗

Use of isosorbide dinitrate for the symptomatic treatment of patients with Chagas' disease achalasia. A double-blind, crossover trial.

1. A randomized, double-blind, placebo-controlled trial was carried out to determine the efficacy of isosorbide dinitrate (ISD) on dysphagia in patients with Chagasic achalasia. 2. Twenty-three patients with Chagas' disease and dysphagia entered the study and 20 (87%) completed the two 7-day treatment periods. Subjects were given either 5 mg ISD (12 patients) or placebo (11 patients) by the sublingual route for the first 7 days. On the 8th day, patients crossed over and began another 7-day period during which they received the opposite, identical-appearing tablets. 3. Scores attributed by uninformed investigators for the frequency and severity of dysphagia were significantly lower (P less than 0.05) following ISD treatment than after the placebo period or for the pretreatment condition. A significantly higher degree of improvement of dysphagia was experienced by the patients during ISD treatment than during the placebo period. Fourteen patients experienced meal-related headaches during ISD, but not placebo treatment. The extent of improvement in general well-being due to ISD was the same when the drug was given in the first or second test period. 4. Our results indicate that ISD, 5 mg by the sublingual route, is effective in alleviating dysphagia in patients with Chagasic achalasia but its usefulness is limited by the high rate of headache as a side effect.

Adolescent↗

Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes.

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process.

Blood Glucose↗

Triggering effect of physical and mental stress on spontaneous ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators.

BACKGROUND: Physical and mental stress as well as sexual activity are potential triggering factors of acute coronary events and sudden cardiac death. HYPOTHESIS: These factors may also trigger recurrence of spontaneous ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators (ICDs). METHODS: We performed a case-crossover study in 43 consecutive patients with 95 symptomatic, ICD-documented tachyarrhythmic events and calculated the relative risk of tachyarrhythmia recurrence during physical and mental stress. Physical and mental activity was graded on a 4-step intensity scale, and stress was defined as physical exertion or mental stress with an intensity grade > or = II during or up to 1 h before arrhythmia recurrence. Relative risk was determined taking into account the habitual weekly stress frequency of each patient. RESULTS: Physical stress was present in 26% (n = 25), mental stress in 24% (n = 23), and sexual activity in 2% (n = 2) of analyzed events. The weekly habitual stress frequency was 8 +/- 8 (median 7) for physical stress, 6 +/- 6 (median 4) for mental stress, and 0.5 +/- 0.5 (median 0.25) for sexual activity. Thus, relative risk of arrhythmia recurrence during the presence of stress was 7.5 for physical activity (95% confidence interval [CI] 5.2-11.1), 9.5 (CI 6.3-14.5) for mental activity, and 7.5 (CI 2.3-24.8) for sexual activity. CONCLUSIONS: Physical and mental stress as well as sexual activity are factors that significantly increase relative risk of spontaneous recurrence of sustained ventricular tachyarrhythmias in patients with ICDs. Consideration of this stress-related relative risk increase may contribute to avoidance of harmful shock delivery in ICD recipients.

Aged↗

Effects of remoxipride on measures of psychological performance in healthy volunteers.

The acute psychomotor effects after oral doses of 30, 60 and 120 mg remoxipride, a new selective D2 receptor blocker, and placebo were investigated in a double-blind crossover study in 11 healthy male volunteers. Two out of the first three subjects given 120 mg remoxipride experienced marked akathisia, and therefore no subsequent subjects were given this dose. There were no other clearly drug-related adverse effects reported below 120 mg, although restlessness was reported at 60 mg. Remoxipride was associated with increases in error scores on a continuous attention task and on auditory vigilance, and with a reduction in critical flicker frequency, suggesting a decrease in arousal level. There were no significant changes in psychomotor measures such as choice reaction time, decision making time, or body sway. Subjective assessments using visual analogue scales showed a slight dose-related increase in drowsiness, while the calm-excited scale showed a small change in the excited direction with 30 mg only. The peak effects were at 4-6 h after drug intake, which was later than expected from previous pharmacokinetic data. These results indicate that remoxipride may have a slight depressant effect in the dose-range used. The pattern of changes is consistent with current theories on the role of dopamine in attention and arousal, and with the effects of other neuroleptics. It differs, however, from tranquilisers such as the benzodiazepines, which show a more global pattern of effects.

Adult↗

Prone positioning in infant gastroesophageal reflux: is elevation of the head worth the trouble?

To determine whether head-elevated prone positioning is better than flat prone positioning for infants with gastroesophageal reflux, we studied 100 babies less than 6 months of age who were being examined for reflux with an intraluminal esophageal pH probe while the babies were in each of the two positions, with the use of a crossover design protocol. During both a 2-hour postprandial period and a fasting period, pH probe measurements in each position included (1) minutes with pH less than 4, (2) number of episodes with pH less than 4, (3) mean duration of such episodes, (4) number of such episodes longer than 5 minutes, and (5) the duration of the longest episode. Significant reductions with head elevation were found for only two of these 10 values: the frequency of reflux episodes postprandially (7.5 +/- 0.7 vs 5.9 +/- 0.5 episodes per 2 hours; p less than 0.05) and the frequency of episodes longer than 5 minutes postprandially (1.4 +/- 0.1 vs 1.2 +/- 0.1 episodes per 2 hours; p less than 0.005). There was no significant reduction in the total duration of postprandial reflux nor in any measure of reflux during the fasting period. The 90 infants in whom an abnormal degree of gastroesophageal reflux was documented had no significant differences between flat prone and head-elevated prone position for any of the 10 pH probe measurements. Head-elevated prone positioning is probably not worth the extra effort required to maintain it.

Esophagus↗

Effect of an oral bulking agent and a rectal laxative administered alone or in combination for the treatment of constipation.

OBJECTIVES: The aim of the present study was to search for a synergetic action between psyllium and a defecation-inducing drug, Eductyl, for symptom relief in patients suffering from chronic constipation. METHODS: Twenty healthy volunteers and 20 patients complaining of chronic constipation were included in a randomized crossover study. The study was divided into four 2-weeks periods: pre-inclusion and three periods of treatment with psyllium, Eductyl, and Eductyl + psyllium respectively. Colonic transit time was determined at the end of each period of treatment. During each of the four periods, a self-administered questionnaire was used to assess symptoms of constipation. RESULTS: For constipated patients, treatment with Eductyl and Eductyl-psyllium improved clinical symptoms of constipation: increased stool frequency, resulted in fewer hard stools and less sensation of incomplete evacuation and less straining to defecate. The improvement was associated with a decrease in total and segmental colonic transit time. The Eductyl-psyllium combination did not exhibit any synergetic effect. CONCLUSION: Treatment with Eductyl alone is more efficient than with psyllium alone in providing symptom relief. Combination with psyllium is not synergetic.

Administration, Oral↗

Dynamic fluctuations of dipolar semiflexible filaments.

On the basis of the model of a flexible magnetic filament, the characteristics of their thermal fluctuations are considered. The crossover of the time dependence of the mean quadratic displacement from t(3/4) to t(1/2) at the magnetic field increase is found. Two characteristic mechanisms of the magnetization relaxation time distribution--straightening of the thermal undulations and excitation of the bending modes of the free ends under the action of an ac magnetic field--are described. In both cases, the characteristic scaling law omega(-3/4) of the magnetic susceptibility in a high-frequency range is found.

Journal Article↗

Ibuprofen is a useful treatment for primary dysmenorrhoea.

A double-blind crossover placebo-controlled trial over 6 cycles in 38 Australian women has confirmed that ibuprofen is a valuable drug for the treatment of primary spasmodic dysmenorrhoea. This drug was highly effective when given in a dosage of one 400mg tablet at the first sign of pain or bleeding followed by further 400mg tablets every 4 to 6 hours for the duration of expected symptoms. Side-effects were mild and noted with equal low frequency during placebo treatment.

Adolescent↗

Paradoxical effect of sibutramine on autonomic cardiovascular regulation.

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. METHODS AND RESULTS: In 11 healthy subjects (7 men, age 27+/-2 years, body mass index 23.1+/-0.7 kg/m2), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113+/-3 mm Hg with placebo, 121+/-3 mm Hg with sibutramine (P<0.001 versus placebo), and 111+/-2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position. CONCLUSIONS: The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.

Adrenergic beta-Antagonists↗

Endogenous opioids modulate the increase in ventilatory output and dyspnea during severe acute bronchoconstriction.

The aim of this study was to evaluate whether endogenous opioids are involved in the regulation of breathing pattern and respiratory drive during bronchoconstriction induced by methacholine (MCh). We studied six male asymptomatic asthmatics 18 to 35 yr of age. In a preliminary study we determined the concentration of MCh causing a 60% fall in FEV1 (PC60 FEV1). On two subsequent days, we measured breathing pattern, dyspnea sensation (Borg scale), mouth occlusion pressure (P0.1), and FEV1 before and 10 min after an intravenous injection of either naloxone (0.1 mg/kg) or saline according to a randomized double-blind crossover design. A MCh concentration equal to the PC60 FEV1 was then inhaled, and measurements were repeated 5 min later. Neither placebo nor naloxone affected baseline breathing pattern, P0.1, and FEV1. Naloxone pretreatment did not influence airway response to MCh; the mean percent fall in FEV1 was 65.9 +/- 1.3 and 64.7 +/- 1.2% (mean +/- 1 SE) on the placebo day and the naloxone day, respectively. After MCh inhalation no significant changes in VE, VT, and breathing frequency occurred when patients received placebo. However, P0.1 increased from 1.48 +/- 0.17 to 3.43 +/- 0.70 cm H2O (p less than 0.05), and VT/TI fell from 0.66 +/- 0.08 to 0.52 +/- 0.04 L/s (p less than 0.05). Naloxone pretreatment resulted in an increase in breathing frequency (from 18.2 +/- 1.7 to 22.8 +/- 2.6 breaths/min; p less than 0.05) and VT/TI (from 0.58 +/- 0.06 to 0.74 +/- 0.05 L/s; p less than 0.05) after MCh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Nadolol compared to propranolol for treating chronic stable angina pectoris.

In order to determine the relative efficacy and dose equivalency of propranolol four times a day and nadolol once daily for the treatment of stable angina pectoris, ten patients were studied in a double blind randomized placebo controlled crossover study. Total daily doses of propranolol and nadolol were determined by titrating until an equivalent degree of reduction in the heart rate response to exercise was achieved. At these doses, the treadmill exercise time to 0.1 mV of electrocardiographic ST-segment depression was increased from 248 +/- 75 seconds on placebo to 405 +/- 56 seconds on propranolol (p less than 0.05) and 471 +/- 46 seconds on nadolol (p less than 0.01). Also, the mean frequency of angina decreased from eight attacks per week on placebo to three on propranolol and nadolol (both p less than 0.05). In six of the ten patients, the effective total daily dose of propranolol and nadolol was identical, and the dose ratio for all ten patients was 1.17:1, propranolol to nadolol. However, individual dose titration is recommended when switching from propranolol four times a day to nadolol once daily because of the dosage variability noted in 40 percent of the patients.

Adrenergic beta-Antagonists↗

Antitussive properties of inhaled bronchodilators on induced cough.

We have studied the antitussive effects of two anticholinergic agents, oxitropium bromide (200 micrograms) and ipratropium bromide (80 micrograms), and a combined beta-agonist and anticholinergic preparation containing fenoterol hydrobromide (200 micrograms) and ipratropium bromide (80 micrograms), in 16 normal and ten asthmatic volunteers in a double-blind, randomized, placebo-controlled crossover trial. Cough was induced by inhalation of ultrasonically nebulized distilled water and hypotonic saline solution. All treatments significantly reduced the cough response to inhaled distilled water aerosol when compared with placebo (p less than 0.001). There was no difference between oxitropium bromide and ipratropium bromide (p greater than 0.05), but the combination preparation displayed a greater antitussive effect than either oxitropium bromide (p less than 0.05) or ipratropium bromide (p less than 0.025). Cough frequencies in response to hypotonic 0.18 and 0.32 percent saline aerosol were lower than those obtained with distilled water (p less than 0.005) for all treatments. Asthmatic patients coughed less frequently than normal volunteers in response to all solutions when placebo was given (p less than 0.05), but there is no evidence to suggest that the response to treatment was different in the two groups. Our results suggest that inhaled anticholinergic bronchodilators alone or in combination with beta 2-adrenergic agonists might be effective in the treatment of pathologic cough.

Administration, Inhalation↗

Multiple n = 1 trials in the identification of responders and non-responders to the cognitive effects of Ginkgo biloba.

OBJECTIVE: A pilot study to assess multiple crossover n = 1 trials with verum/placebo discrimination as the outcome measure as a means of identifying responders and non-responders to the acute nootropic effect of Ginkgo biloba (G. biloba) among healthy volunteers. METHOD: Multiple double-blind, placebo-controlled n = 1 trials with 8 treatments in randomized order and separated by minimum washout periods of 7 days. Treatments were acute 120 mg doses of G. biloba extract (GK501) or undistinguishable placebo. The frequency distribution of correct scores for verum-placebo discrimination was compared with the binomial distribution to identify putative responders, who were then tested for consistency of performance over a further 8 treatments. RESULTS: The frequency distribution of scores (n = 11) was bimodal and a discontinuity defined 3 putative responders and 2 putative negative responders for re-test. Two of the putative responders again performed at above chance level and the probability of achieving their scores or better by chance was 0.013 and 0.052. CONCLUSIONS: n = 1 trials with verum/placebo discrimination as outcome are a promising method for exploring response heterogeneity to treatments with a subjective effect. Preliminary evidence suggests that there are responders and non-responders to an acute G. biloba treatment among healthy subjects.

Adult↗

[Effects of modafinil on visual and auditory reaction abilities and subjective fatigue level during 48 h sleep deprivation].

OBJECTIVE: To investigate the effects of modafinil, a new central stimulant, on visual and auditory motion reaction ability and subjective fatigue level during 48 h sleep deprivation (SD). METHOD: Six male healthy young volunteers were exposed to two 48 h periods of continuous wakefulness during the crossover experiment. In one period, three 200 mg doses of modafinil were given and in the other, separated by two weeks, matching placebos were administered. The SD time started from 7:00 of the first day to 7:00 of the third day. Drugs were given at 0:00, 16:00 of the second day and 0:00 of the third day. Variables, including visual and auditory motion reaction time, attention distribution, critical flicker fusion frequency (CFF), Stanford sleepiness scale (SSS) and rating of perceived exertion (RPE), were tested at 21:00 of the first day and 1, 3, 5, 7 h after each drug administration. RESULT: After 2-3 does of modafinil, the CFF level was obviously enhanced while the scores of Stanford sleepiness scale and RPE were markedly reduced. The visual and auditory motion reaction ability, as well as the attention distribution, showed no significant change. CONCLUSION: Modafinil can effectively reduced the subjective fatigue and sleepiness levels during SD.

Adolescent↗

Crossover comparison of nitrendipine with propranolol in patients with essential hypertension.

The antihypertensive effect of nitrendipine (2 X 10 to 2 X 20 mg/day) was compared with that of propranolol (2 X 80 to 2 X 160 mg/day) in a randomized crossover study. Twenty-five patients were treated over two 4-week periods following a placebo period of 2 weeks. Three patients dropped out of the study because of side-effects (two on nitrendipine and one on propranolol). Arterial pressures decreased in a comparable manner from 171/107 mm Hg (measured in a sitting position) to 147/91 mm Hg after 4 weeks on nitrendipine and to 145/93 mm Hg after 4 weeks on propranolol. The frequency of side-effects possibly related to treatment was comparable for both drugs, but decreased with the duration of therapy with nitrendipine only. The antihypertensive effect of nitrendipine, but not of propranolol, correlated positively with age and plasma noradrenaline.

Adult↗

Intermittent compression units for severe post-phlebitic syndrome: a randomized crossover study.

BACKGROUND: Although uncommon, severe post-phlebitic syndrome may be associated with persistent, intractable pain and swelling that interfere with work and leisure activities. This study was performed to determine whether intermittent compression therapy with an extremity pump benefits patients with this condition and, if so, whether the benefit is sustained. METHODS: The study was a randomized crossover trial. Over the period 1990 to 1996, all patients in the clinical thromboembolism program of an Ontario teaching hospital who had a history of deep vein thrombosis and intractable symptoms of post-phlebitic syndrome were recruited into the study. The study involved using an extremity pump twice daily for a total of 2 months (20 minutes per session). The patients were randomly assigned to use either a therapeutic pressure (50 mm Hg) or a placebo pressure (15 mm Hg) for the first month. For the second month, the patients used the other pressure. A questionnaire assessing symptoms and functional status served as the primary outcome measure and was administered at the end of each 1-month period. A symptom score was derived by summing the scores for individual questions. At the end of the 2-month study, patients were asked to indicate their treatment preference and to rate the importance of the difference between the 12 pressures. Treatment was considered successful if the patient preferred the therapeutic pressure and stated that he or she would continue using the extremity pump and that the difference between the therapeutic and placebo pressures was of at least slight importance. All other combinations of responses were considered to represent treatment failure. Patients whose treatment was classified as successful were offered the opportunity to keep the pump and to alter pressure, frequency and duration of pump use to optimize symptom management. In July 1996 the authors contacted all study participants whose treatment had been classified as successful to determine whether they were still using the pump and, if so, whether they were still deriving benefit. RESULTS: In total 15 consecutive patients (12 women and 3 men) were enrolled in the study. The symptom scores were significantly better with the therapeutic pressure (mean 16.5) than with the placebo pressure (mean 14.4) (paired t-test, p = 0.007). The treatment for 12 of the patients (80%, 95% confidence interval 52% to 96%) was considered successful. Of these, 9 patients continued to use the pump beyond the crossover study and to derive benefit. INTERPRETATION: The authors conclude that a trial of pump therapy is worthwhile for patients with severe post-phlebitic syndrome and that a sustained beneficial response can be expected in most such patients.

Adult↗