Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia.

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.

Effects of a fish oil concentrate in patients with hypercholesterolemia.

The effects of a fish oil supplement on lipid and lipoprotein levels, platelet function, and vital signs were investigated in 31 hypercholesterolemic patients. Thirteen patients took 5 g of encapsulated fish oil per day and 18 patients took 5 g of encapsulated safflower oil "placebo" per day for 28 days. Diet and exercise patterns were kept as constant as possible during the study. The fish oil group had significant increases in several lipid/lipoprotein values at the end of the treatment, including an increase of total cholesterol of 14% (P = 0.0001), LDL of 16% (P = 0.003), HDL of 13% (P = 0.015) and HDL2 of 36% (P = 0.009). The triglyceride level fell 24%, a nonsignificant change (P = 0.217). The ratios of total cholesterol/HDL and LDL/HDL were increased at the end of fish oil treatment, and returned to baseline 30 days after fish oil was stopped. The placebo group had no significant changes in any of the lipid/lipoprotein values. Neither the fish oil nor the placebo group had significant changes in vital signs or platelet function tests (bleeding time, thromboxane B2, platelet factor 4 and beta-thromboglobulin) during the study. These results suggest that fish oil supplements may have an adverse effect on lipid/lipoprotein values in hypercholesterolemic patients.

Double-blind comparison of alprazolam and diazepam for subchronic withdrawal from alcohol.

The efficacy and safety of a new triazolobenzodiazepine, alprazolam, was compared to diazepam in 46 alcoholics in a double-blind study. The drugs were administered for 21 days starting on the fifth day after the last drink. The mean optimal daily oral dose of alprazolam was 2.2 mg and of diazepam 20.2 mg given in a t.i.d. fashion. Alprazolam was as effective as diazepam in the relief of anxiety as measured by the Hamilton Anxiety Rating Scale, Physician's Global Impressions, Patient's Global Impressions, Hopkins Symptom Checklist and Target Symptoms Record. At the end of the trial 95% of patients in both groups experienced moderate to marked therapeutic effect and felt much or very much better as compared to the start of the study. The number of side effects was similar in both groups and they were mostly described by patients as "mild".

Emotional status during weight reduction program.

The Hopkins Symptom Checklist was administered to 205 chronically obese patients to assess their emotional status. The results indicate that: a) the extent of mental problems in this population was not much different from other outpatient clinics; b) patients with a childhood or maturity onset of obesity had similar emotional profile; c) successful weight loss improved the emotional difficulties; d) no increase in emotional symptomatology occurred in patients before their dropout from the clinic; and e) clinic attendance and dieting did not affect the patients' mental status. These findings correlate well with the global clinical impressions obtained during interviews at each patient visit by the physician and/or clinical psychologist.

A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations.

A randomized, double-blind study was designed to evaluate the therapeutic effect and safety of prostacyclin (epoprostenol) in patients undergoing cardiopulmonary bypass. One hundred patients having isolated coronary bypass grafting received 300 units/kg of heparin and then either prostacyclin (12.5 ng/kg/min from heparinization until cardiopulmonary bypass, 25 ng/kg/min during bypass) or buffer/diluent in a similar manner. Standardized anesthetic, perfusion, and surgical techniques were used. Drug and placebo groups were similar in demographic data and bypass times, and there were no deaths. Activated coagulation time and platelet count were significantly higher during cardiopulmonary bypass in patients receiving prostacyclin. Platelet count remained significantly higher 24 hours after bypass in the active drug group. Immediately after operation, there was significantly less prolongation of bleeding time (1.3 versus 2.9 minutes; p = 0.009) in the patients receiving prostacyclin. Blood loss was significantly reduced during the first 4 hours postoperatively in the prostacyclin group (261 +/- 159 versus 347 +/- 197 ml; p = 0.02). There was no significant difference between the groups when total blood loss was compared (710 +/- 351 versus 869 +/- 498 ml; p = 0.07). Patients receiving prostacyclin required an average of 257 ml less blood transfused in the intensive care unit (p = 0.02). We conclude that the clinical impact of prostacyclin in patients undergoing coronary artery operations was demonstrable, but small. Prostacyclin may provide clinical benefits in patients undergoing cardiopulmonary bypass when there are contraindications to or other difficulties with blood transfusion. With prostacyclin, reduced heparin dose is possible and therefore reduced protamine requirement would offer a potential benefit of less cardiovascular depression immediately after bypass. However, the advantages offered by prostacyclin are not sufficient to recommend its routine use during cardiopulmonary bypass.

A prospective, randomized study of the effects of prostacyclin on neuropsychologic dysfunction after coronary artery operation.

This randomized, double-blind study was designed to evaluate the effect of prostacyclin (epoprostenol) on the incidence and severity of postoperative neuropsychologic dysfunction in patients undergoing coronary artery operation. Four days before operation and 1 week after operation, 100 patients having coronary artery bypass grafting underwent detailed neurologic and psychologic examinations and computed tomographic scans of the brain. The psychologic examination was repeated 2 months after operation. During cardiopulmonary bypass, all patients received 300 U/kg of heparin and then either buffer-diluent or prostacyclin (12.5 ng/kg/min from the time of heparinization until onset of cardiopulmonary bypass and 25 ng/kg/min during cardiopulmonary bypass). No deaths or major neurologic complications occurred in this series. Ninety-six patients completed the psychologic and neurologic evaluations 1 week after operation; 74 of these patients were evaluated psychologically 2 months after operation. Psychologic testing demonstrated similar declines in postoperative performance in both the prostacyclin-treated and the control groups; these changes were no longer present in either group 2 months after operation. Results of neurologic examinations and computed tomographic scans of the brain were unchanged. We conclude that the administration of prostacyclin during cardiopulmonary bypass in patients undergoing routine coronary artery operation has no effect on perioperative cognitive changes.

The effect of encapsulated, low-dose colestipol in patients with hyperlipidemia.

Colestipol is an effective cholesterol (C)-lowering agent, but it must be taken in large doses and the palatability is poor. In an open-label study, the effects of low doses (2-10 g) of encapsulated colestipol (size: 1 g or 0.65 g) were investigated. There were 16 men and 16 women with an average age of 59 +/- 11 years and with hyperlipidemias IIA, IIB, or IV. Patients were on AHA I diet and stayed in the study for up to 2 years with regular follow-up every 3 to 4 months. Colestipol was started after several months of dietary baseline; it was tolerated well with only two patients reporting mild constipation. A group mean for total cholesterol (T-C), LDL-C, HDL-C, VLDL-C and triglycerides (TG) was calculated at each of four daily dose intervals, i.e., 2 to 4 g, 4 to 6 g, 6 to 8 g and 8 to 10 g. Each patient usually received more than one of the four dosage intervals. A paired t test and a rank sum test were performed to test for significant (P less than or equal to .05) differences between baseline and drug treatment. With the exception of the lowest dose, total C was significantly decreased by all dosage ranges and LDL-C changes were similar. There was no significant effect on HDL-C and VLDL-C whereas TG levels increased at 4 to 6 g and 8 to 10 g dose. The use of diet and low colestipol doses may be considered in patients with moderate hypercholesterolemia who do not respond to diet alone.

Tolerance and pharmacology of ciprostene, a stable epoprostenol (prostacyclin) analogue in humans.

Safety, tolerance, and pharmacology of 9-beta-methylcarbacyclin calcium (ciprostene calcium) was investigated in healthy male volunteers. This stable prostacyclin analogue was infused intravenously into groups of 12, 11, and three volunteers for three, six, and eight hours, respectively, in doses up to 480 ng/kg/min. Based on the tolerance data obtained, a single-blind, placebo-controlled study was conducted. Seven subjects were infused for 8 hr/d for three days with ciprostene at a maximum dose of 160 ng/kg/min and seven subjects received placebo. One subject from each group did not complete the infusion schedule, and they were not included in the final analysis. During infusion of ciprostene, consistent changes in blood pressure and heart rate did not occur. Most frequent adverse drug reactions consisted of headache, restlessness, nausea, perspiration, flushing, and jaw pain. As compared with placebo, ADP-induced platelet aggregation was inhibited during the infusion period (P = .048). Significant (P = .04) elevations of platelet cyclic AMP were observed in subjects during infusion of ciprostene. Pre- versus postinfusion routine laboratory evaluations, fibrinogen concentration, antiplasmin activity, and plasminogen and template bleeding times remained unchanged. Placebo- and drug-treated subjects had a daily postinfusion shortening of euglobulin clot lysis time (ECLT). The preinfusion minus postinfusion ECLT for ciprostene subjects on days 2 and 3 (133 and 118 min, respectively) compared with placebo (239 and 217 min) suggest a trend to increased fibrinolytic activity. Based on the outcome of this trial, it is estimated that ciprostene is about 15 times less potent than prostacyclin.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical safety of flurbiprofen.

Data from 58 premarketing studies of the nonsteroidal antiinflammatory drug flurbiprofen were pooled for analyses of adverse drug reactions (ADRs). These studies included 5602 patients treated with flurbiprofen (N = 4123), aspirin (N = 1033), or placebo (N = 446) for varying durations. Diagnoses included rheumatoid arthritis, osteoarthritis, and other painful musculoskeletal conditions. In these studies serious upper gastrointestinal ADRs occurred in flurbiprofen-treated patients at less than one half the rate seen in aspirin-treated patients. The incidence of serious urinary tract ADRs was lower with flurbiprofen than with aspirin. The flurbiprofen group had no serious clinical ADRs related to the hemic/lymphatic system. The most common laboratory abnormality was a decrease in hematocrit, which occurred less often than in the aspirin group. We also evaluated serious flurbiprofen-related ADRs in 4370 patients in a variety of other studies and reviewed published reports of flurbiprofen clinical trials and case reports. These reviews showed no additional, unanticipated patterns of intolerance. These clinical safety data indicate that in the doses studied, flurbiprofen is a well tolerated agent for patients requiring nonsteroidal antiinflammatory drug therapy.

Epoprostenol (prostacyclin) in unstable angina.

The purpose of this randomized, double-blind multicenter trial was to investigate the potential therapeutic effect of epoprostenol (prostacyclin, PGI2) in patients with unstable angina, as compared with placebo, and to investigate the safety of this agent. Of the 184 patients enrolled, 28 did not fit the study criteria; of the remaining 156 patients, 30 received prostacyclin in an open-label fashion. In the double-blind portion of the study, 63 patients each received prostacyclin or placebo. The drug or its vehicle was infused intravenously up to 5 ng/kg/min dose for 72 hours with a tapering off period for the last 12 hours. Both treatment groups from the double-blind portion were comparable in regard to the demographic data, length of infusion, and total dose received. There were no significant differences between the placebo and prostacyclin group in the following clinical endpoints: levels of cardiac enzymes throughout hospitalization period (with the exception of lower SGOT level in the prostacyclin group at day 2), and severity of angina (throughout the study), and at the end of the study (day 30). The number of patients who had congestive heart failure, new myocardial infarction, balloon pump insertion, coronary artery bypass grafting, or percutaneous coronary angioplasty was similar in both groups. Similar results in regard to the efficacy endpoints were also apparent in the prostacyclin group that was treated under open-label fashion. There was also no difference in the New York Heart Association (NYHA) functional status at the end of the double-blind study.(ABSTRACT TRUNCATED AT 250 WORDS)

Ciprostene in patients with peripheral vascular disease (PVD). An open-label, tolerance trial.

Epoprostenol (Prostacyclin) has been studied with various success in patients with peripheral vascular disease (PVD). We investigated the tolerance of a new, stable prostacyclin derivative ciprostene (9-beta-methyl carbacyclin) in 9 PVD patients. The drug was infused intravenously for 8 hours a day, once a week for 4 consecutive weeks, at a dose of 120 ng/kg/min. There were 6 men and 3 women with a mean age of 63 years (42-78). The PVD was verified by arteriography (9 patients) and by clinical findings. Patient #9 was lost to follow up after the first infusion and, consequently, was excluded from further evaluation. In patient #5 with a history of arrhythmias, the last ciprostene infusion had to be discontinued at 4.5 hours due to arrhythmias but his data were included into the evaluation. The cardiac disturbances were not judged to be ciprostene-related. Patients were followed monthly for 3 months after last infusion. Ciprostene was well tolerated although it produced adverse medical events (AMEs); most of them were rated as mild. The most frequent were those typical of prostacyclin: headache, facial flushing and warmth, body warmth, jaw pain and sleepiness. No consistent changes in blood pressure and heart rate were observed. One patient who initially had 9 ischemic ulcers underwent transmetatarsal amputation at month 4. The absolute and relative claudication time was measured by treadmill. As compared to baseline, the absolute claudication time increased significantly at week 2 and 4 of the infusion period and also at the end of month 3, but not at the end of month 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality of life effects of alprostadil therapy for erectile dysfunction: results of a trial in Europe and South Africa.

OBJECTIVES: Quality of life (QOL) data were used to evaluate the effects of self-administered intracavernosal injection of alprostadil for erectile dysfunction, when used for up to 18 months during a 13 country Phase III clinical trial. METHODS: The Duke Health Profile was used to measure patients' physical and psychosocial QOL at baseline, 3, 6, 12 and 18 months. Changes from baseline were measured using paired t-tests, with additional analyses by cause of dysfunction, starting dosage, and prior treatment. RESULTS: Patients displayed significant improvements in mental and social health and self-esteem at six months (P < 0.01, n = 570), with greater improvements at 12 and 18 months. Anxiety and depression measures also improved significantly at 12 and 18 months, as did the summary general health score. Worse pain scores were observed in the first year but not at 18 months. Those with a starting dosage of 10-20 micrograms, those with psychogenic causes of dysfunction, and those with no prior treatment for erectile dysfunction generally showed the greatest improvements. CONCLUSION: In this study, the clinical improvements in erectile function due to intracavernosal alprostadil therapy were complemented by QOL improvements, particularly in the mental health, of many patients.

Hypnotic efficacy of triazolam and methyprylon ininsomniac in-patients.

The hypnotic effects of a new triazolobenzodiazepine, triazolam (Halcion) 0-5 mg and methyprylon 300 mg was compared in twenty oncologic in-patient volunteers with insomnia using the preference technique. On the first night of the two-night trial, or methyprylon was given on a double-blind basis and on the second night the patients received the alternate medication. Following each trial night the patients were interviewed in regard to their sleep. Of the seventeen patients who completed the study, eleven patients preferred triazolam, three preferred methyprylon and three had no preference (p=0-057). Analysis of the various sleep parameters showed that triazolam helped the patients sleep more than methyprylon (p=0-13), induced more rapid sleep onset (p=0-003), gave a longer duration of sleep (p=0-013). The treatment was considered a success if the patient went to sleep in thirty minutes or less and slept for at least six hours. Triazolam was more successful than methyprylon in this respect (p=0-012). There were no side-effects reported on either of the drugs.

Long-term efficacy of medical treatments of obesity.

Obesity is a chronic, usually life-long condition. Therefore, the success of any treatment should be measured by the long-term weight loss. More patients lose weight than maintain the weight loss after the active phase of therapy has ended. Conservative approaches like dietary restrictions or behavior modification techniques have been only modestly successful in weight maintenance. Both are, therefore, suitable for patients with milder degrees of obesity. Anorexicants seem to have specific but limited use in the treatment of obesity. Fasting and protein sparing modified fast are indicated for patients with a high degree of obesity, i.e. for those who are at least 30% or 25 kg or more over their ideal body weight. Both these procedures have definite risks. Rapid weight loss is induced by fasting but long-term follow-ups showed gradual regain of weight loss. Combinations of various techniques such as behavior modification, exercise, proper nutritional instruction and protein-sparing modified fast seem to have the best chance for long-term success.

Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group.

BACKGROUND: Erectile dysfunction is a common medical problem affecting many men. Although several intracavernosal therapies are available, their efficacy and safety have not been studied systematically. METHODS: We investigated the efficacy and safety of alprostadil formulated for intracavernosal treatment in three separate multi-institutional, prospective studies in men with erectile dysfunction of vasculogenic, neurogenic, psychogenic, and mixed causes. Clinical and laboratory evaluations of erection and the feasibility of satisfactoriness of sexual activity as assessed both by the men and by their partners were the primary measures of efficacy. RESULTS: In a dose-response study of 296 men, all doses of alprostadil were superior to placebo and there was a significant dose-response relation (P < / = 0.001), resulting in higher response rates with increasing doses of alprostadil (from 2.5 to 20 microg). In a dose-finding study of 201 men, the minimal effective dose was < / = 2 microg in 23, 20, 38 and 23 percent of men with erectile dysfunction of neurogenic, vasculogenic, psychogenic, or mixed causes, respectively. In a six-month self-injection study in 683 men, the participants reported being able to have sexual activity after 94 percent of the injections. The men and their partners rated the sexual activity as satisfactory after 87 and 86 percent of the injections, respectively. Penile pain, usually mild, occurred in 50 percent of the men at some time but after only 11 percent of the injections. Prolonged erections occurred in 5 percent of the men, priapism in 1 percent, penile fibrotic complications in 2 percent, and hematoma or ecchymosis in 8 percent. CONCLUSIONS: In men with erectile dysfunction, intracavernosal injection of alprostadil is an effective therapy with tolerable side effects.

Evaluation of real-time RigiScan monitoring in pharmacological erection.

PURPOSE: The clinical assessment of pharmacologically induced erectile response was compared to the real-time RigiScan* monitoring response. MATERIALS AND METHODS: Erection was induced by 521 intracavernous injections of a new alprostadil formulation. The clinical end point was "full rigidity" and the RigiScan criterion was radial rigidity of 70% or more for 10 consecutive minutes or longer. RESULTS: For 752 prostaglandin E1 injections the sensitivity and specificity of the RigiScan device compared to clinical evaluation were 53.8% (133 of 247 cases) and 92.9% (469 of 505), respectively. For rigidity of 60% or greater the sensitivity increased to 70.8% (175 of 247 cases) and specificity decreased to 85.0% (429 of 505). CONCLUSIONS: The RigiScan device is useful to document objectively a pharmacologically induced erection yet it appears to be more conservative than clinical evaluation.

Intracavernous prostaglandin E1 in erectile dysfunction.

Prostaglandin E1 (PGE1) is a naturally occurring substance that is present in a variety of mammalian tissues, including the semen of fertile men. Its use in the diagnosis and treatment of erectile dysfunction has been extensively studied. In doses of 10-20 micrograms, PGE1 produces full erections in 70-80% of patients with erectile dysfunction. In diagnostic use PGE1 is employed as a simple office test and in conjunction with various hemodynamic tests. Self-injection of PGE1, either with the patient or his partner administering the injection, is a minimally invasive and effective treatment for erectile dysfunction in patients with organic or psychogenic erectile dysfunction. Its use is contraindicated in patients with sickle cell anemia, severe coagulopathy, schizophrenia or severe psychiatric disorder, poor manual dexterity, severe venous incompetence, or severe systemic disease. As calculated from data in the published literature, the most frequent side effects are pain at the injection site or during erection (occurring in 16.8% of patients), hematoma/ecchymosis (1.5% of patients), and prolonged erection/priapism (1.3% of patients). The potential for prolonged erection/priapism, the most serious side effect, can be minimized by careful titration of the dose and through patient education. Systemic side effects occur rarely during PGE1 use. During extended use, patients should be monitored for potential long-term side effects, such as fibrosis and angulation.

Comparison of triazolam and methyprylon as a hypnotic in insomniacs.

The hypnotic effect of a new triazolobenzodiazepine, triazolam (0.5 mg) and methyprylon was compared in 30 outpatient volunteers with insomnia using the preference technique. On the first night of the 2 night trial, triazolam or methyprylon was given on a double-blind basis and on the 2nd night the outpatients received the alternate medication. Following each trial night the patients were interviewed in regard to their sleep. Of the 28 patients who completed the study, 21 patients preferred triazolam, 5 preferred methyprylon and 2 had no preference (p = 0.001). Analysis of the various sleep parameters showed that triazolam helped the patients sleep more than methyprylon (p = 0.026), there were fewer awakenings on triazolam (p = 0.064), a longer duration of sleep (p = 0.064) and a better feeling in the a.m. (p = 0.020). The sleep onset was the same after both medications. The number and severity of the side effects was considerably higher after methyprylon.