Active Drug Group Research Articles

Change in depression as a precursor of cardiovascular events. SHEP Cooperative Research Group (Systoloc Hypertension in the elderly)

To determine the relationship between increasing depressive symptoms and cardiovascular events or mortality. Cohort analytic study of data from randomized placebo-controlled double-blind clinical trial of antihypertensive therapy. Depressive symptoms were assessed semi-annually with the Center for Epidemiological Studies-Depression (CES-D) scale during an average follow-up of 4.5 years. Ambulatory patients in 16 clinical centers of the Systolic Hypertension in the Elderly Program. Generally healthy men and women aged 60 years or older randomized to active antihypertensive drug therapy or placebo who were 70% white and 53% women and had follow-up CES-D scores and no outcome events during the first 6 months (N=4367). All-cause mortality, fatal or nonfatal stroke, or myocardial infarction. Baseline depressive symptoms were not related to subsequent events; however, an increase in depression was prognostic. Cox proportional hazards regression analyses with the CES-D scale as a time-dependent variable, controlling for multiple covariates, indicated a 25% increased risk of death per 5-unit increase in the CES-D score (relative risk [RR], 1.25;95% confidence interval [CI], 1.15 to 1.36). The RR for stroke or myocardial infarction was 1.18(95%CI,1.08 to 1.30). Increase in CES-D score was an independent predictor in both placebo and active drug groups, and it was strongest as a risk factor for stroke among women (RR,1.29;95%CI,1.07 to 1.34). Among elderly persons, a significant and substantial excess risk of death and stroke or myocardial infarction was associated with an increase in depressive symptoms over time, which may be a marker for subsequent major disease events and warrants the attention of physicians to such mood changes. However, further studies of casual pathways are needed before wide-spread screening for depression in clinical practice is to be recommended.

New approaches to the treatment of patients with acute, nonspecific diarrhea: a comparison of the effects of loperamide and loperamide oxide

The effects of loperamide oxide 1 mg and 2 mg were compared with placebo and with loperamide 2 mg in 261 patients with acute, nonspecific diarrhea. Time to first relief and time to complete relief of diarrhea were statistically significantly shorter in the three active drug groups than in the placebo group. Compared with placebo, neither dosage of loperamide oxide produced a period of posttreatment constipation. Adverse experiences were (nonsignificantly) less frequent for loperamide oxide 1 mg and 2 mg than for either placebo or loperamide 2 mg. These results suggest that loperamide oxide 1 mg is as efficacious as loperamide 2 mg for the treatment of patients with acute, nonspecific diarrhea. Because of its low potential for causing constipating effects and adverse experiences, loperamide oxide 1 mg may be preferred over either loperamide oxide 2 mg or loperamide 2 mg.

A Meta-Analysis of Fluoxetine Outcome in the Treatment of Depression

A meta-analysis was conducted on all the double-blind, placebo-controlled efficacy trials of the antidepressant fluoxetine (Prozac). This drug has become the antidepressant most frequently prescribed by psychiatrists and has been hailed by the media as a "wonder drug." Results produced a relatively modest overall effect size that was no greater than effect sizes obtained by previous meta-analyses of tricyclic antidepressants. This study also examined the possibility that bias may have contaminated study outcome ratings. Because past studies suggest that the greater frequency of side effects in active drug groups unblinds study participants, we examined the relationship between study effect sizes and the percentage of patients reporting side effects. As predicted, both clinician and patient outcome ratings correlated significantly with the percentage of patients experiencing side effects. Questions are raised about the role of side effects in mediating drug outcome results.

MK-801 potentiates the glutathione depletion induced by acetaminophen in rat brain

To investigate the relationship between acetaminophen (APA) and calcium ion (Ca 2+) homeostasis within the glutathione (GSH) oxidation-reduction cycle, male rats were given APA (one buccal injection of 3 g/kg) and/or MK-801 (three intraperitoneal injections each of 0.2 mg/kg), a noncompetitive N-methyl-D-aspartate receptor antagonist. There were injection-vehicle control groups for all active drug groups; an additional control group received no injections (total of seven experimental groups; 134 rats). The brain tissue was examined 8 hours after administration of the drugs to determine the levels of GSH, APA, and protein. APA produced a 25% decrease in GSH that was strongly enhanced by the coadministration of MK-801 (49% decrease). MK-801 alone produced a 32% decrease in brain levels of GSH. This reduction of GSH is probably linked to the interference of Ca 2+ homeostasis and can be considered as a trigger for cell injury in oxidative stress.

TOPICAL TREATMENT OF ACUTE SPRAINS

SUMMARY In a randomised, placebo‐controlled, double‐blind study with parallel group comparison, the efficacy and tolerability of topical treatment with a mucopolysaccharide polysulphate/salicylic acid cream was investigated in 156 patients with acute sprains of the knee or ankle joint. There was a more rapid reduction in pain on movement (the main parameter) in the active drug group compared with the placebo group. On day 9 after randomisation the difference was highly significant. There were no adverse events in the active drug group.

Effects of Terodiline on Urinary Incontinence among Older Non‐Institutionalized Women

To determine the effectiveness of terodiline, a drug with calcium antagonist and anticholinergic properties, on the frequency of incontinence in older non-institutionalized women. Randomized, placebo-controlled, parallel-group, double-blind trial. Twelve outpatient clinics across the United States affiliated with programs in either geriatrics, gynecology, or urology. Ninety-eight women, age 60 or older, with symptoms of urge incontinence and self-reported frequency of incontinence four or more times per week and involuntary bladder contractions on dual-channel water cystometry. Self-reported urinary frequency, urgency, number of incontinence episodes, and number of heavily soaked pads. Eighty-one women, average age 71, completed the trial, 40 in the active drug group, 41 in the placebo group. Incontinence frequency and the number of heavily soaked pads were reduced in the active drug group by 64% and 55%, respectively, and by 21% (P = 0.002) and 9% (P = 0.04) in the placebo group. No patients dropped out due to adverse effects. An intention-to-treat analysis of all 98 patients yielded the same conclusion. Terodiline is highly effective in reducing incontinence in older, noninstitutionalized women with urge incontinence. Because of its potential association with polymorphic ventricular tachycardia (torsades de pointes), terodiline must undergo further testing to define its safety before it can be recommended for clinical use in the incontinent geriatric population.

Low-dose amitriptyline as an adjunct to opioids for postoperative orthopedic pain: A placebo-controlled trial

Tricyclic antidepressants (TCAs) have been found to be useful in the management of a variety of chronic pain conditions, although there is little published regarding the potential efficacy of this class of drug as an adjunct for the control of acute postoperative pain and related symptoms. Twenty-eight patients undergoing total hip or knee arthroplasty completed a randomized, placebo-controlled, double-blinded trial of 50 mg of amitriptyline p.O. HS on postoperative days 1, 2 and 3 while using patient-controlled morphine or meperidine analgesia (PCA). Visual analog (VAS) and numerical verbal (NVS) pain ratings, sedation scores, sleep quantity/quality scores, and sense of well-being scores were assessed twice daily on each of the days succeeding amitriptyline/placebo use. Hourly opioid use was recorded and transcribed from the memory of the PCA devices in use. Mean scores in the amitriptyline group for pain NVS were greater ( P < 0.05) (higher score = greater pain) on day 1 and greater on day 2 for the pain VAS. Mean scores for sense of well-being were greater ( P < 0.05) (higher score = better sense of well-being) for the placebo group on days 1 and 2. On days 2 and 3, sleep scale variable mean scores were worse in the placebo group ( P < 0.025). There were no other statistically significant differences between the control and active drug groups for any of the outcome variables measured. We conclude that amitriptyline at the dose prescribed is no different than placebo in altering the majority of postoperative symptom variables studied in the sample study population but caused no significant adverse effects. There does not appear to be an opioid-sparing effect nor an improvement in general well-being. Although this specific drug (or other TCAs) may be indicated for symptom management in selected postoperative patients, the results of this study do not support general use as a co-analgesic.

Transdermal Clonidine Reduced Some Withdrawal Symptoms but Did not Increase Smoking Cessation

Clonidine may be useful in controlling tobacco withdrawal and in facilitating smoking cessation. This study was developed to test the efficacy of transdermal clonidine in promoting smoking cessation. We conducted a five-center, double-blind, placebo-controlled, randomized controlled trial of transdermal clonidine in conjunction with a minimal behavioral intervention for smoking cessation. The intervention was based on the American Lung Association's Freedom From Smoking program. Self report of not smoking was validated with exhaled air carbon monoxide of less than 8 ppm and salivary cotinine of less than 20 ng/mL. Transdermal clonidine therapy began 1 week before the target quit date: 0.1 mg/24 h for the first 4 days increasing to 0.2 mg/24 h for the next 3 days, if the lower dose was tolerated. The highest tolerated dose was then continued for 6 weeks after target quit day. Withdrawal symptoms were measured daily for the first 7 days after target quit day. A total of 213 patients were enrolled (106 active drug and 107 placebo). During the study, 15.5% of patients had drug therapy discontinued due to adverse effects, 24.5% (26/106) taking active drug vs 8.4% (9/107) receiving placebo. There was a significant reduction in anxiety score from 3.0 to 2.4 (placebo vs active) and irritability score from 2.2 to 1.7 (placebo vs active) during the first week after cessation. There was no reduction in other withdrawal symptoms. The overall 12-week abstinence rate was 33.0% (35/106) in the active drug group vs 34.5% (37/107) in the placebo group (not significant). This study demonstrated some reduction in early withdrawal symptoms with the use of a clonidine transdermal patch, but no increase in cessation rate, 6 weeks after medication had been discontinued.

Predictors of response to monoamine oxidase inhibitors: Do they exist?

Multiple regression analysis was conducted on potential response predictors in a double-blind study of monoamine oxidase inhibitors (MAOI) and placebo treatment in 130 depressed outpatients. Positive main effects were found for sex (female), lack of prior hospitalization, presence of precipitating events. A negative main effect was found for concurrent physical illness. Treatment x predictor effects were found for distinct quality and non-reactivity. Non-reactivity was associated with positive outcome in the active drug group, but with negative outcome in the placebo group [corrected]. Distinct quality demonstrated a more complex effect, its presence being associated with decreased improvement in the treatment group and greater improvement in the control group. No atypical depressive symptoms predicted MAOI response, and we were unable to characterize a specifically responsive MAOI syndrome.

Nonlinear Modeling of Serial Immunologic Data: A Case Study

Abstract This article concerns the analysis of serial immunologic data from a clinical trial of immunosuppressive chemotherapy in the treatment of multiple sclerosis. The goal of the analysis is to relate levels of drug dose to levels of an immunologic outcome variable. I propose a new, nonlinear model for the analysis of such data. The model assumes that the mean function is the solution of an ordinary differential equation in time, parameters of which are related to the dose via a regression function. The defining differential equation is that which gives rise to the generalized logistic function, a flexible form that includes a number of popular growth models. We fit the model, which accounts for random effects and time series autocorrelation, by maximum likelihood. Results suggest strong treatment effects in two active-drug groups and a small but significant effect in a placebo group. These findings agree well with previously reported analyses of clinical outcomes from the trial. An empirical comparison suggests that nonlinear models of this kind can fit better than linear models of comparable complexity.

Nonlinear Modeling of Serial Immunologic Data: A Case Study

Abstract This article concerns the analysis of serial immunologic data from a clinical trial of immunosuppressive chemotherapy in the treatment of multiple sclerosis. The goal of the analysis is to relate levels of drug dose to levels of an immunologic outcome variable. I propose a new, nonlinear model for the analysis of such data. The model assumes that the mean function is the solution of an ordinary differential equation in time, parameters of which are related to the dose via a regression function. The defining differential equation is that which gives rise to the generalized logistic function, a flexible form that includes a number of popular growth models. We fit the model, which accounts for random effects and time series autocorrelation, by maximum likelihood. Results suggest strong treatment effects in two active-drug groups and a small but significant effect in a placebo group. These findings agree well with previously reported analyses of clinical outcomes from the trial. An empirical comparison suggests that nonlinear models of this kind can fit better than linear models of comparable complexity.

Acute and chronic antianginal efficacy of continuous twenty-four-hour application of transdermal nitroglycerin

To resolve the controversies surrounding the antianginal use of chronic, continuous 24-hour transdermal nitroglycerin therapy, a double-blind, placebo-controlled, randomized, parallel-group study was designed. Eligible patients had chronic angina pectoris with symptom-limited, reproducible treadmill tests and were responsive to sublingual nitroglycerin (n = 562). Patients were randomly assigned to placebo or 1 of 7 doses of active treatment (15, 30, 45, 60, 75, 90 and 105 mg/24 hours). In the active drug groups, treatment was initiated with 15 mg/24 hours during the first week of double-blind dosing with subsequent weekly increases until the assigned dose was reached, after which the dose was held constant. Treadmill tests were performed 0, 4 and 24 hours after the initial double-blind patches were applied, after each titration step and after 8 weeks. At the end of double-blind therapy, a sublingual nitroglycerin exercise challenge was repeated. Exercise tolerance in patients using the active patch increased 34 seconds (p < 0.05) over patients taking placebo 4 hours after the initial application of double-blind therapy, but there was no statistically significant difference in exercise time between placebo and active drug groups by 24 hours after the first application or for the remaining 8 weeks of the trial. Increasing the dose did not overcome the loss of effect. A partial attenuation of the response to a sublingual nitroglycerin challenge seen on exercise tolerance testing also occurred, with patients who received the highest dose showing the greatest attenuation. There were no differences in angina frequency among the groups, although in a post hoc analysis, patients with >7 attacks per week had a reduction in anginal frequency of 6 to 7 attacks per week with active treatment versus 2 attacks per week with placebo. The study showed that (1) tolerance to the exercise effects of continuous transdermal nitroglycerin develops within 24 hours after application; and (2) increasing the dose does not overcome this tolerance. The observation that symptomatic improvement may occur in the absence of increases in exercise tolerance seems deserving of further study.

Effect of buspirone on cigarette withdrawal symptoms and short-term abstinence rates in a smokers clinic

This paper reports on a double blind trial of the effect of buspirone, 15 mg per day, on cigarette withdrawal symptoms and ability of smokers to maintain abstinence during treatment. A total of 61 smokers were randomly assigned to active or placebo conditions. They were maintained on their drug for 2 weeks prior to attempting abstinence and then for a further 4 weeks of abstinence. Subjects attended weekly group sessions of a psychological treatment programme. There was no evidence that the side effects in the active drug group were worse than those in the placebo group. Although there was no significant difference between active and placebo conditions on withdrawal symptoms, smokers in the active drug condition were more than twice as likely to maintain abstinence for the duration of the study than those in the placebo condition (47% versus 16%, chi square = 5.3, P less than 0.025). The results provide preliminary evidence for short-term efficacy of buspirone as an aid to smoking cessation at a low dose. They also provide evidence of a dissociation between withdrawal symptoms and successful abstinence.

Clinical and humoral effects of beta-blockade with ICI 118,551 in the general neurotic syndrome

Fifty-six patients satisfying the diagnostic criteria for the general neurotic syndrome, a mixed anxiety-depressive disorder, were randomly allocated to treatment with a selective β( 2)-blocking drug, ICI 118,551, in a dose of 50 mg tds, or placebo for 4 weeks after a 2-week placebo run-in period. Ratings of anxiety using the Hamilton anxiety rating scale and patient self-assessments in 46 evaluable patients showed no significant difference in the outcome of active drug and placebo groups, and also no significant improvement over time during the study. This unusual finding supports the impression of the general neurotic syndrome as a severe form of neurotic disorder which shows little evidence of placebo response. Diastolic blood pressure was increased and heart rate reduced after 2 weeks on ICI 118,551, and plasma levels of noradrenaline and adrenaline showed no evidence of an expected decrease with active drug; on the contrary the data showed some evidence of increased catecholamine levels. The results suggest that selective β-blockade has little part to play in the treatment of anxiety and that on repeated dosage the effects of selective blockade are attenuated or reversed.

The administration of folic acid to institutionalized epileptic adults with phenytoin-induced gingival hyperplasia: A double-blind, randomized, placebo-controlled, parallel study

Twenty severely retarded institutionalized epileptic adults with phenytoin-induced gingival hyperplasia were divided into two groups and received a daily 3 mg capsule of either folic acid or lactose for 16 weeks in a randomized, double-blind, parallel study. Serum folate and phenytoin levels were recorded at baseline and on completion of the study. Twelve areas of the gingiva on each patient were graded at 4-week intervals for 16 weeks with respect to the three indexes: hyperplasia, gingival health, and plaque index. There were no significant differences between treatment groups for any of the three indexes over time. The poststudy serum folate levels were three times baseline levels for the active drug group ( p < 0.001) but unchanged in the placebo group. Phenytoin blood levels that began within the therapeutic window (10 to 20 μg/ml) tended to remain within the therapeutic window for both groups, with no reported seizure activity. A single daily oral 3 mg capsule of folic acid did not show efficacy as the sole therapeutic agent in the reduction of phenytoin-induced gingival hyperplasia.

Pharmacologic and Nutritional Treatment of Mild Hypertension: Changes in Cardiovascular Risk Status

To evaluate the 6-month change in cardiovascular (coronary heart disease) risk as a function of diet and drug therapy for mild hypertension. Collaborative randomized, controlled clinical trial to assess the efficacy of alternative regimens in treating mild hypertension. Three university-based tertiary care centers-the Trial of Antihypertensive Interventions and Management (TAIM). Six hundred and ninety-two men and women ages 21 to 65 years with diastolic blood pressure between 90 and 100 mm Hg and weight between 110% and 160% of ideal weight. Patients stratified by clinical center and race were randomized into diet (usual, low sodium-high potassium, weight loss) and drug (placebo, chlorthalidone, and atenolol) groups resulting in nine diet plus drug combinations. The cardiovascular risk at 6-month follow-up was estimated relative to baseline in 692 participants using the Framingham Study model. Due to the blood pressure reduction, cardiovascular risk declined from baseline for all treatment groups (except the usual diet plus chlorthalidone group because of increased cholesterol levels). The relative cardiovascular risk at 6 months compared to baseline ranged from 0.83 in the weight loss plus atenolol subgroup to 1.03 in the usual diet plus chlorthalidone subgroup. The active drug plus weight loss groups showed the lowest relative cardiovascular risk at 6 months. Mild hypertension was generally reduced to desirable levels within 6 months by monotherapy. Evaluating blood pressure changes together with the risk factors indicated a differential effect on overall cardiovascular risk depending on the diet and drug used. Dietary therapy, particularly weight reduction, was important adjunctive treatment in reducing overall cardiovascular risk.

Prevention of acute complications after percutaneous transluminal coronary angioplasty

The prevention of major complications occurring during or early after percutaneous transluminal coronary angioplasty was evaluated in 376 patients in a randomized, double-blind, placebo-controlled multicenter trial. Starting 24 hours before angioplasty, 187 patients received an aspirin-dipyridamole combination and 189 were given placebo. There were no periprocedural deaths. Periprocedural non-fatal myocardial infarction was diagnosed in 34 patients (9.0%). Q wave myocardial infarction occurred in 16 patients: 3 (1.6%) in the aspirindipyridamole group and 13 (6.9%) in the placebo group ( p = 0.0113). Non-Q wave myocardial infarction occurred in 18 patients: 6 (3.2%) in the active drug group and 12 (6.3%) in the placebo group ( p = 0.1538). Emergency myocardial revascularization was performed in 9 patients in each treatment arm. Q wave myocardial infarction occurred following revascularization in 5 patients (55.5%) in the placebo group and in only 2 (22.2%, p = 0.1670) in the aspirindipyridamole group. Thus the incidence of periprocedural Q and non-Q wave myocardial infarction is high in patients not on antiplatelet therapy (13.2%) and is markedly lower in those on the aspirindipyridamole combination (4.8%, p = 0.0044). Short-term antiplatelet therapy before and after angioplasty can be recommended for patients who do not have contraindications to this medication.

Use of Indomethacin Suppositories in the Prophylaxis of Recurrent Ureteral Colic

To determine the effects of indomethacin suppositories in the relief of acute colic and prevention of recurrent colic, we instituted a prospective double-blind, placebo-controlled protocol. Patients were randomized to receive either 50mg. indomethacin or placebo suppositories every 8 hours and all patients received prescriptions for supplemental narcotics to be used on an as needed basis. Relief of colic was assessed by counting the total number of supplemental narcotics used by each patient per 24 hours during the study period, which was defined as until passage of the calculus or 5 days. There were 41 patients entered into the study protocol and complete followup was available for 26. Mean calculus size was 3.4mm. in the indomethacin group versus 3.1mm. in the placebo group. All 13 patients in the control group had recurrent episodes of colic and 8 of these 13 had more than 1 recurrent episode. Five patients in the placebo group required admission to the hospital for control of pain. In contrast, only 4 of the 13 patients in the treatment group had colic and only 1 had more than 1 episode of colic. No patient in the active drug group required admission to the hospital for control of pain. Over-all the ratio of supplemental narcotic used by the placebo group versus the indomethacin group was 7.6:1 (p < 0.005). The mean interval time to passage of the calculus was slightly lower in the indomethacin group (89 versus 82 hours) but this difference was not statistically significant (p > 0.10). Our data strongly support the use of indomethacin suppositories in the prevention of recurrent colic secondary to ureteral calculi.

Cough and the Common Cold

To determine whether the cough of the common cold arises from upper respiratory stimuli and whether antihistamine-decongestant therapy is an effective treatment for this cough, we prospectively evaluated volunteers with uncomplicated common colds in a randomized, double-blind, placebo-controlled study. After completing a standardized questionnaire and undergoing a physical examination, throat-culturing, and pulmonary function testing, subjects took the active drug or identical-appearing placebo for 7 days while they kept a diary in which they ranked the severity of 17 symptoms for 14 days. Pulmonary function testing was repeated, on average, on Days 4, 8, and 14. Forty-six percent of the variation in cough severity could be explained by throat-clearing and 47% of the variation in throat-clearing severity by postnasal drip. FIF50%, the only physiologic parameter that significantly correlated with cough, rose as cough severity fell. Antihistamine-decongestant therapy reduced postnasal drip and significantly decreased the severity of cough, nasal obstruction, nasal discharge, and throat-clearing during the first few days of the common cold. In addition, cough was 20 to 30% less prevalent in the active drug group within 3 days of starting therapy. We conclude that the cough of the common cold arose from upper respiratory tract stimuli and that cough and other cardinal symptoms of the common cold were reduced with antihistamine-decongestant therapy when these symptoms were at their worst.

Aspirin and Dipyridamole in the Prevention of Re-Stenosis after Percutaneous Transluminal Coronary Angioplasty

To examine the role of antiplatelet therapy in the prevention of arterial restenosis after percutaneous transluminal coronary angioplasty (PTCA), we conducted a randomized, double-blind, placebo-controlled study in 376 patients. The active treatment consisted of an oral aspirin-dipyridamole combination (330 mg-75 mg) given three times daily, beginning 24 hours before PTCA. Eight hours before PTCA, the oral dipyridamole was replaced with intravenous dipyridamole at a dosage of 10 mg per hour for 24 hours, and oral aspirin was continued. Sixteen hours after PTCA, the initial combination was reinstituted. Treatment was continued in patients with a successfully dilated vessel until follow-up angiography four to seven months after PTCA--or earlier, if symptoms dictated. Of 249 patients who underwent follow-up angiography, 37.7 percent of patients receiving the active drug had restenosis in at least one segment, as compared with 38.6 percent of patients taking placebo (P not significant). The number of stenotic segments was virtually the same in the two groups. Among the 376 randomized patients, there were 16 periprocedural Q-wave myocardial infarctions--13 in the placebo group and 3 in the active-drug group (6.9 percent vs. 1.6 percent, P = 0.0113). Although the use of this antiplatelet regimen before and after PTCA did not reduce the six-month rate of restenosis after successful coronary angioplasty, it markedly reduced the incidence of transmural myocardial infarction during or soon after PTCA. Thus, the short-term use of antiplatelet agents in relation to PTCA can be recommended.