Cold cardioplegia and the K+ channel modulator aprikalim (RP 52891): improved cardioprotection in isolated ischemic rabbit hearts.

Cellular potassium extrusion is now considered a natural protective mechanism following myocardial ischemia, and newly synthetized molecules mimicking cellular extrusion of K+ (potassium channel activators) appear promising for cardioprotection, although the underlying mechanisms for their beneficial effects have not been fully characterized. Indeed, the cardioprotective efficacy of K+ channel activators at low temperature or in the presence of the high K+ content of standard cardioplegic solution has never been addressed. Therefore the cardioprotective interaction of the thioformamide K+ channel activator aprikalim (RP 52891) and high K+ content, cold cardioplegia was studied in isolated ischemic rabbit hearts. Isolated hearts were perfused according to the Langendorff procedure at a constant pressure (85 cmH2O; 1 cmH2O = 98.1 Pa); systolic and diastolic left ventricular pressures, coronary flow, and heart rate were monitored throughout the study. Cardiac temperature was monitored through a thermocouple microprobe positioned in the left ventricular free wall. Global ischemia was carried out by completely shutting off the perfusate flow for 90 min, and reperfusion was monitored for 30 min. Several groups of isolated hearts (n = 6 per group) were treated before ischemia with either cold cardioplegia (St-Thomas' Hospital cardioplegic solution, 4 degrees C), aprikalim (10 microM), or glibenclamide (1 microM) alone, or with one of the following combinations: cold cardioplegia + aprikalim, cold cardioplegia + glibenclamide, or cold cardioplegia + both aprikalim and glibenclamide. A 10 microM infusion of aprikalim significantly increased coronary flow (33 to 63 mL/min, +90%) without negative chronotropic or inotropic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of deep vein thrombosis after major knee surgery--a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo.

Consecutive patients undergoing knee arthroplasty or tibial osteotomy at four participating hospitals received either enoxaparin, 30 mg subcutaneously every 12 h (n = 66) or an identical-appearing placebo (n = 65). All study medications started the morning after the operation and were continued up to a maximum of 14 days. Patients underwent surveillance with 125I-fibrinogen leg scanning and impedance plethysmography. Bilateral contrast venography was performed routinely at Day 14 or at time of discharge, if sooner. Deep vein thrombosis was detected by venography in 35 of 54 patients (65%) in the placebo group and in 8 of 41 patients in the enoxaparin group (19%), a risk reduction of 71%, P less than 0.0001. For the entire study group, deep vein thrombosis was detected by either venography of non-invasive tests in 37 of 64 patients (58%) in the placebo group and in 11 of 65 patients (17%) in the enoxaparin group, a risk reduction of 71%, P less than 0.0001. Proximal vein thrombosis was found in 19% of the placebo patients and in none of the enoxaparin patients, a risk reduction of 100%, P less than 0.001. Bleeding complications occurred in 5 of 65 patients (8%) in the placebo group and in 4 of 66 patients (6%) in the enoxaparin group, P = 0.71. There were no differences in the amount of blood loss, minimum hemoglobin levels and number of units of packed red cells given between the two treatment groups. We conclude that a fixed dose regimen of enoxaparin, started post-operatively, is an effective and safe regimen for reducing the frequency of deep vein thrombosis after major knee surgery.

Electromagnetic treatment of shoulder periarthritis: a randomized controlled trial of the efficiency and tolerance of magnetotherapy.

The potential benefit of magnetotherapy was investigated in 47 consecutive outpatients with periarthritis of the shoulder. Using a controlled triple-blind study design, one group of patients received hot pack applications and passive manual stretching and pulley exercises; the other group received the same therapy plus magnetotherapy. Treatment was administered three times a week. For a maximum of three months, a standardized treatment protocol was used. There was no significant improvement in pain reduction or in range of motion with electromagnetic field therapy. After 12 weeks of therapy, the patients who received magnetotherapy showed mean pain scores of 1.5 (+/- .61 SD) at rest, 2.2 (+/- .76 SD) on movement, and 1.9 (+/- .94 SD), on lying, compared to scores for the control group of 1.4 (+/- .65 SD), 2.2 (+/- .7 SD), and 1.9 (+/- .95 SD), respectively. Linear pain scale scores improved from 71 to 21 for both groups. At 12 weeks the gain in range of motion was mean 109 degrees +/- 46.8 in patients receiving electromagnetic field therapy, compared to 122 degrees +/- 33.4 for the controls (not significant). At entry, the functional handicap score was 53.5 for both groups. At 12 weeks, it was 24 for the magnetotherapy group and 17 for the control group (difference not significant). In conclusion, this study showed no benefit from magnetotherapy in the pain score, range of motion, or improvement of functional status in patients with periarthritis of the shoulder.

Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal.

Zopiclone (7.5 mg), a cyclopyrrolone derivative with a 6.5 h half-life, and flurazepam (30 mg) were compared to placebo in a randomized double-blind study involving 36 adult patients suffering from insomnia. All previous psychotropic drugs were discontinued 1 week prior to the study. During 4 weeks, 12 patients received zopiclone, 12 flurazepam and the others placebo. Thereafter, all patients received single-blind placebo for 3 nights. Rapidity of sleep onset, sleep duration, frequency of nocturnal awakenings, psychomotor coordination and side-effects were assessed daily with a questionnaire and a symptom checklist. The results of the study suggest that zopiclone 7.5 mg was at least as potent as flurazepam 30 mg in inducing and maintaining sleep. Both drugs maintained their efficacy during the 4 weeks of treatment. However, the two drugs differed in that flurazepam impaired psychomotor coordination whereas zopiclone did not demonstrate daytime protracted effects on psychomotor performance. Upon discontinuation of drug treatment, score values of the different sleep parameters under study returned to the baseline values. Side-effects were mild and consistent with earlier studies.

A comparison of the efficacy, safety and withdrawal effects of zopiclone and triazolam in the treatment of insomnia.

A double-blind study comparing zopiclone and triazolam, in 48 healthy, chronic insomniacs, was undertaken in two centers to compare the hypnotic and withdrawal effects of both compounds. Comparable doses of 7.5 mg zopiclone and 0.25 mg triazolam were given at bedtime for 21 nights after a 3 day wash-out period, followed by 4 placebo nights of withdrawal monitoring. During the investigation, a 17 item post-sleep questionnaire was completed daily, the Clinical Global Impression (CGI) scale weekly, and the Hamilton Anxiety Scale (HAM-A) at baseline and at the end of the study. Withdrawal effects were evaluated with a withdrawal symptom checklist and the CGI (withdrawal). Results indicated that both compounds improved sleep and were equally effective. However, a larger number of triazolam subjects withdrew from the study because of ineffectiveness or adverse side-effects. A greater number of zopiclone subjects experienced a transient modification of taste which disappeared with discontinuation of therapy. Significant deterioration in nearly all sleep parameters were noted after the first withdrawal night of triazolam; much fewer modifications of sleep parameters were observed following the discontinuation of zopiclone.

Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomniacs.

Most studies with zopiclone, a cyclopyrrolone derivative with a short elimination half life (5 h) have compared its hypnotic activity with that of long elimination half life molecules. In this double-blind study in geriatric patients, drugs were administered during 3 weeks and the therapeutic effects of zopiclone at optimal dosage (5 or 7.5 mg) were compared to those of triazolam (0.125 or 0.25 mg). After a 3 day single-blind washout period, placebo responders were excluded and 48 patients were thereafter treated with either placebo (Tétreault et al., 1965), zopiclone or triazolam (Pegram et al., 1980). The initial dosage was increased when indicated at the end of the first week and kept constant thereafter. At the end of the third week of double-blind treatment, a 4 day single-blind placebo washout was performed to assess drug withdrawal effects. Results confirmed the safety and efficacy of both drugs over placebo during active administration. Hypnotic activity was maximal at 7.5 mg of zopiclone and 0.25 mg of triazolam. Drug efficacy was found constant over the 3 week administration both for triazolam and zopiclone. During withdrawal, no true rebound effect was demonstrated but the active drugs were significantly worse than placebo during the first day for sleep onset duration, sleep soundness and quality of sleep. With triazolam some effects persisted up to the third day of withdrawal.

Effects of adjunctive treatment of periodontitis with tetracycline and spiramycin.

The present study was undertaken to compare the efficacy of two antibiotics, spiramycin and tetracycline, with a placebo when used adjunctively with scaling and root planing in the treatment of advanced adult chronic periodontitis. This was a double-blind, parallel, randomized trial with one factor (drug) at three levels. Ninety-six patients (mean age 46 +/- 1) were randomly assigned into one of three groups. All groups were scaled and root planed with each respective group receiving either spiramycin, tetracycline, or a placebo for 2 weeks. Two sites with probing depth of at least 7 mm were evaluated and the following clinical parameters were measured at baseline, 2, 8, 12, and 24 weeks: plaque index, bleeding on probing, crevicular fluid, probing depth, and change in the attachment level. The changes in the subgingival bacteria were monitored also using a differential staining technique. Seventy-nine patients completed the study. At the end of 24 weeks, although all three groups had shown clinical improvement when compared to the baseline data, there were no significant intergroup differences in any of the clinical parameters measured. While the proportion of spirochetes were significantly decreased (P less than 0.05) at 2- and 8-week intervals in both tetracycline and spiramycin groups (26% to 0.04% and 28% to 0.04%, respectively), compared to the placebo group (30% to 7%), only in the spiramycin group was the proportion of spirochetes significantly lower than the placebo group at the 24-week interval (3% and 11%, respectively). At week 24, the proportion of spirochetes in the tetracycline group had rebounded to 7%, which was not significantly different from the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Zopiclone in insomniac shiftworkers. Evaluation of its hypnotic properties and its effects on mood and work performance.

Fifty adult insomniac shiftworkers (47 males and 3 females) between the ages of 22 and 55 participated in this two-week, double-blind comparative study of the hypnotic properties and effects on mood and work performance of zopiclone 7.5 mg and placebo. All subjects took inactive medication on the first night of the study and then received either zopiclone or placebo for the following 13 nights according to randomization. Pre-study variables included a demographic profile, medical history, physical examination, laboratory data, profile of insomnia and work shift pattern description. A sleep questionnaire along with mood and work performance questionnaires were filled out on Days 1, 2, 4, 9 and 12 of the study; on Days 7 and 14, adverse events were recorded. After the first placebo night, subjects assigned to receive zopiclone showed significantly improved sleep induction; from the second night on, a distinct pharmacological effect over placebo was observed and maintained since statistically significant increases in quantitative sleep induction and sleep soundness (qualitative and quantitative) were noted during the course of zopiclone treatment. Active hypnotic treatment did not interfere with morning awakening and functioning, nor did it affect mood or work performance. Zopiclone treatment produced significantly more taste disturbance and drowsiness. In summary, zopiclone was shown to be an effective, fast-acting hypnotic which maintained its efficacy over a two-week period in our sample of insomniac shiftworkers and did not produce mood changes or influence work performance.

Comparison of spiramycin and tetracycline used adjunctively in the treatment of advanced chronic periodontitis.

This study was designed to compare both clinical and microbiological changes during the treatment of advanced periodontal disease with mechanical debridement, with or without the adjunctive use of either spiramycin or tetracycline. The study, which included 96 patients with advanced periodontitis, was performed as a controlled double-blind parallel randomized trial. All patients received thorough scaling and root planing as well as adjunctive placebo or spiramycin or tetracycline. Probing depth measurements, attachment level changes, plaque level, gingival crevicular fluid, bleeding on probing and microbiological evaluation were carried out at baseline, 2-, 8-, 12- and 24-week visits. Seventy-nine patients (24 placebo, 27 tetracycline and 28 spiramycin) completed the study. At 24 weeks there were no intergroup differences in the improvement of any of the clinical parameters. Spiramycin was the only antibiotic which produced a significantly greater decrease in the proportion of spirochaetes than the placebo group at the 24-week visit. It was concluded that mechanical debridement alone was sufficient in decreasing the subgingival bacteria to a level which would result in the return to periodontal health. The study was not long enough to determine whether or not the difference in spirochaete level was an indication that the spiramycin group would have maintained the benefits of treatment for a longer time.

A sleep laboratory evaluation of the long-term efficacy of zopiclone.

Six patients between the ages of 25 and 59, with chronic, primary insomnia received the new, non-benzodiazepine, hypnotic zopiclone continuously for 17 weeks after a drug free interval of 12 nights. To qualify for the study, sleep efficiency, determined by a sleep study on two, consecutive, placebo-controlled nights, had to be less than 75%. Patients evaluated their sleep by questionnaire and had sleep studies completed throughout active treatment. Zopiclone (7.5 mg) increased sleep efficiency by decreasing sleep latency, wakefulness after sleep onset and increasing total sleep time. Sleep architecture was minimally affected by zopiclone treatment; no significant changes in delta or REM sleep were observed. The commonest side effect was a bitter or metallic taste. No significant changes in biological functioning were noted throughout the study period. These findings indicate that zopiclone is a safe and effective hypnotic medication which maintains its effectiveness with protracted use.

Respiratory center output following zopiclone or diazepam administration in patients with pulmonary disease.

Mouth occlusion pressure at 0.1 s (P0.1) and minute ventilation (VE) were measured at rest and during progressive hypercapnia in 32 patients. Under double-blind conditions and according to a 2 x 2 Latin-square design, half the patients received one oral dose of diazepam and its placebo. Using the same design, the other half received zopiclone and its placebo. Normocapnic and moderately hypoxemic patients between the ages of 21 and 69 with moderate to severe chronic obstructive pulmonary disease were included in the study. Diazepam produced a statistically significant decrease (p less than 0.05) over its placebo in delta P0.1/delta PETCO2 values following CO2 rebreathing. Zopiclone did not influence either delta P0.1/delta PETCO2 or delta VE/delta PETCO2, but produced a significant increase in respiratory frequency. However, no statistically significant differences were observed between the two active treatments.

The role of adjunctive Rodogyl therapy in the treatment of advanced periodontal disease. A longitudinal clinical and microbiologic study.

Several studies have indicated that the combination of metronidazole and spiramycin is synergistic against anaerobic bacteria and may be effective against oral infections. The present study sought to determine the efficacy and safety of a commercial preparation of these two antibiotics (Rodogyl) when used adjunctively in the treatment of advanced periodontal disease. In a double-blind parallel randomized trial, 56 patients (mean age = 44 years) with advanced periodontitis (50 of whom completed the study) were assigned to either the Rodogyl or placebo group. Both groups were thoroughly scaled and root planned for approximately 6 hours, with one group receiving Rodogyl for 2 weeks and the other a placebo. No other therapy was received during the study period. Two sites in each patient with probing depths of at least 7 mm were selected for study. Plaque level (P1I), gingival inflammation (GI), probing depth (PD), and attachment level (AL) were measured at baseline, 14 days, 1 month, and then at monthly intervals up to 6 months. Subgingival bacteria were monitored with dark-field microscopy. The development of resistant bacteria, as well as side effects to the medications, was also monitored. The Rodogyl group exhibited a greater gain in AL (0.67 mm) from the 2-month interval until the end of the study. Although this difference was statistically significant (P less than 0.05), it was not necessarily of biologic significance. There was a significantly greater decline in the proportion of spirochetes in the Rodogyl group at the 14-day interval, and this difference remained significant (P less than 0.05) at all study intervals. No difference in the proportion of motile organisms was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind comparison of ketoprofen and placebo in the treatment of sprains and strains.

Sixty patients (42 men and 18 women between the ages of 18 and 37 years) with grade 2 or grade 3 sprains or elongations participated in a seven-day double-blind study. By random determination, they were treated with either 100 mg of ketoprofen or placebo TID. Pain evaluation, vital signs, concomitant medication, and side effects were determined on days 1,3, and 7. Compared with placebo, ketoprofen produced statistically significant reductions (P less than 0.05) in investigator-rated pain at rest (day 3), on palpation (days 1, 3, and 7), on motion (days 1 and 3), and on the subject-rated analog scale (days 1 and 3). It also achieved a greater relief of pain (days 1 and 3) and greater overall efficacy, as expressed by the statistically significant improvements in the total pain scores on motion and on palpation, on the total pain relief score, on the total pain analog score, and on the sum of pain intensity differences for pain at rest, on palpation, and on motion. Tolerance to the seven-day ketoprofen treatment was excellent. Results from the study indicate that ketoprofen is efficacious in relieving pain following sprains and strains.

Double-blind comparison of ketoprofen and mefenamic acid in the treatment of primary dysmenorrhea.

Forty women with moderate to severe primary dysmenorrhea participated in a two-month, double-blind, crossover trial comparing ketoprofen with mefenamic acid. Treatment with ketoprofen provided rapid and marked pain relief similar to that afforded by mefenamic acid. This improvement in symptoms was accompanied by an amelioration of the disability score, which was equivalent for both drugs. There were no differences between the two treatments with respect to duration of menses or amount of menstrual flow. Patients rated both drugs as equally effective and had no preference for one treatment over the other. One patient dropped out because of a mild allergic reaction to ketoprofen. All other side effects were not severe, although slightly more gastrointestinal reactions were observed with ketoprofen. It is concluded that ketoprofen is as safe and effective as mefenamic acid in the treatment of primary dysmenorrhea.

Butriptyline: human pharmacokinetics and comparative bioavailability of conventional and sustained release formulations.

The pharmacokinetics and relative bioavailability of butriptyline from conventional and a sustained release (SR) formulation have been studied in a panel of 14 volunteers. A single oral dose of 75 mg butriptyline hydrochloride was administered and a 2 X 2 latin square design was followed. Pharmacokinetic modelling has shown that the plasma butriptyline concentration/time profile is adequately described by a two-compartment open model; good agreement was obtained for the model-fitted and measured parameters. The SR formulation was shown to possess sustained release characteristics as evidenced by the increase in Tmax for 2.6 to 7.5 h, the decrease in Cmax from 46.5 to 10.3 ng ml-1, and a three-fold increase in 'half-value duration' (HVD). The changes have been achieved without any significant decrease in the relative bioavailability of the SR formulation. The half-life of butriptyline in plasma was about 20 h and was not formulation dependent.