Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine.

OBJECTIVE: To compare the safety and efficacy of isometheptene mucate, dichloralphenazone with acetaminophen to sumatriptan succinate for the treatment of mild-to-moderate migraine, with or without aura, when taken at the first sign of an attack. BACKGROUND: The Food and Drug Administration approved sumatriptan succinate and the combination of isometheptene mucate, dichloralphenazone with acetaminophen for the treatment of migraine. As part of the stratified treatment of migraine, those patients whose headaches are mild or moderate may benefit from nontriptan medications. Additionally, early treatment of acute migraine before the headache has become moderate or severe may improve response to treatment. METHODS: This was a multicenter, double-blind, randomized, parallel-group study to assess the safety and efficacy of the combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the early stages of a single migraine attack. Patients diagnosed with migraine, with or without aura, as defined by the International Headache Society diagnostic criteria were enrolled. RESULTS: One hundred thirty-seven patients were enrolled in the study. Data for efficacy were available for 126 patients; safety data were available for 128 patients. No statistically significant difference between the two active agents in the patient's response to treatment was demonstrated. Headache recurrence was not significantly different over the 24-hour evaluation period for those patients responding in the first 4 hours. In those with headache recurrence, it was statistically significantly more severe in those patients treated with sumatriptan succinate. Improvement in functional disability was, in general, better among those treated with isometheptene mucate, dichloralphenazone with acetaminophen. Global analysis of efficacy was similar in the two active groups. Patients treated with sumatriptan succinate were somewhat more likely to have adverse effects than the isometheptene mucate, dichloralphenazone with acetaminophen group. CONCLUSIONS: Both isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate are safe and effective when used early in the treatment of an acute migraine. Several parameters suggest that isometheptene mucate, dichloralphenazone with acetaminophen may have a slight advantage compared with sumatriptan succinate in the early treatment of mild-to-moderate migraine.

Hypocholesterolemic effects of a dietary fiber supplement.

The cholesterol-lowering effects of a fiber supplement were evaluated in patients with mild to moderate hypercholesterolemia. After a 9-wk diet stabilization period, patients were randomly assigned to treatment with 10 or 20 g/d of the fiber supplement or with a matching placebo. Among patients who completed the 15-wk treatment period, total cholesterol, LDL cholesterol, and the ratio of LDL to HDL (LDL/HDL) were significantly reduced (P < 0.05) for the 10- (n = 40) and 20-g/d (n = 39) groups compared with the placebo group (n = 48). In the placebo group and 10- and 20-g/d groups, the percent changes in total cholesterol were 0.4%, -5.8%, and -4.9%, in LDL cholesterol were -0.4%, -8.1%, and -7.3%, and in LDL/HDL were 1.0%, -5.6%, and -8.7%, respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol or triglycerides. The changes in lipoprotein concentrations could not be attributed to changes in diet or body weight because there were no significant changes in these variables during the 15-wk treatment period.

Dihydroergotamine/heparin in the prevention of deep-vein thrombosis after total hip replacement. A controlled, prospective, randomized multicenter trial.

In a randomized, double-blind, placebo-controlled multicenter trial, the efficacy and safety of dihydroergotamine mesylate/heparin sodium as a prophylactic agent for deep-vein thrombosis were evaluated in 148 patients who were forty years old or more and who underwent total hip replacement. The incidence of venographically proved postoperative deep-vein thrombosis was 52 per cent in the placebo group and 25 per cent in the dihydroergotamine mesylate/heparin sodium group (p = 0.002). Proximal thrombi developed in only 5 per cent and extensive thrombi, in only 10 per cent of the patients who received dihydroergotamine mesylate/heparin sodium. In contrast, proximal thrombi and extensive thrombi developed in 19 and 25 per cent, respectively, of the patients in the placebo group (p less than 0.05). Adverse reactions in the two groups did not differ significantly: in the treatment group they consisted primarily of hematoma at the site of injection (9 per cent), hematoma at the wound (5 per cent), and excessive postoperative bleeding, and in the placebo group there was hematoma at the site of injection (3 per cent). It was concluded that the combination agent dihydroergotamine mesylate/heparin sodium was effective and safe prophylaxis against deep-vein thrombosis for the patients who underwent total hip replacement in this study.

Symptomatic treatment of chronically recurring tension headache: a placebo-controlled, multicenter investigation of Fioricet and acetaminophen with codeine.

A double-blind, randomized, multicenter investigation was conducted to compare the efficacy and safety of Fioricet, acetaminophen with codeine, and placebo for the symptomatic treatment of tension headache. At the onset of a typical headache, the patients took two capsules of their assigned study medication and rated responses over the next four hours in three target symptoms areas: pain, emotional or psychic tension, and muscle contractions or stiffness in the head and neck. Physicians made global assessments of the same symptom responses and of adverse reactions for each patient. One hundred ninety-eight patients were evaluated. Both active analgesic preparations were more effective than placebo in relieving pain and muscle stiffness or contractions. Fioricet, but not acetaminophen with codeine, was significantly better than placebo in alleviating emotional or psychic tension; Fioricet was also significantly better than acetaminophen with codeine in relieving this symptom. Certain analyses suggested the possibility that Fioricet had a faster and more sustained analgesic effect than acetaminophen with codeine. By the end of the four-hour trial, significantly more patients achieved complete pain relief with Fioricet than with acetaminophen with codeine. The quality and quantity of adverse reactions did not differ significantly among the treatment groups. None was serious, and all abated without medical intervention.

United States trial of dihydroergotamine and heparin prophylaxis of deep vein thrombosis.

DVT involving the lower extremities is a frequent (25-40 percent of patients) complication of major thoracic, abdominal, and pelvic surgery in patients beyond the age of 40 years. Herein, we have reported a recently completed large prospective, randomized multicenter investigation of the prophylaxis of postoperative DVT in the United States. A total of 880 patients were randomized into five treatment groups: 0.5 mg of dihydroergotamine plus 5,000 IU of heparin (DHE/H5,000), 0.5 mg of dihydroergotamine plus 2,500 IU of heparin (DHE/H2,500), 5,000 IU of heparin alone (H5,000), 0.5 mg of dihydroergotamine alone (DHE), or placebo. Administration was by the subcutaneous route, using the anterior abdominal wall on a twice daily schedule. Treatment was initiated preoperatively and continued twice daily for 5 days. Daily radiofibrinogen uptake tests revealed the following DVT rates: DHE/H5,000 9.4 percent, DHE/H2,500 16.8 percent, H5,000 16.8 percent, DHE 19.4 percent, and placebo 24.4 percent. DHE/H5,000 was significantly superior (p less than 0.05) to all other treatments in this respect. Adverse drug experiences did not differ significantly between groups and consisted primarily of postoperative bleeding (2 to 3 percent of patients), injection site hematoma (6 to 12 percent of patients), and wound hematoma (1 to 3 percent of patients).

Limitation of impedance plethysmography in assessing efficacy of dihydroergotamine-heparin prophylaxis of deep vein thrombosis.

The sensitivity of impedance plethysmography (IPG) for diagnosing deep vein thrombosis was evaluated in the presence of dihydroergotamine, an agent with significant venoconstrictor activity. In a prospective, randomized, controlled clinical trial, 105 patients undergoing total hip replacement surgery were investigated to evaluate the thromboprophylactic efficacy of DHE-Heparin using IPG and 125I-Fibrinogen Leg Scanning to monitor the incidence of DVT. Retrospective analysis of the IPG data indicated that DHE-Heparin impaired the sensitivity of impedance plethysmography by decreasing venous capacitance and venous outflow. Although the patient sample size was relatively small, the results showed trends which suggested that the utility of impedance plethysmography for diagnosing DVT was limited in the presence of a vasoactive agent. Alternate noninvasive diagnostic methods may need to be considered in select patients receiving concomitant medications possessing venoconstrictor activity.

Effect of bromocriptine mesylate on induced hyperprolactinemia in stabilized psychiatric outpatients undergoing neuroleptic treatment.

Therapeutic doses of phenothiazines increased serum levels of prolactin, resulting in a number of side effects. Bromocriptine, a potent dopamine agonist, appears to effectively reduce the serum prolactin level. In this open pilot study, bromocriptine mesylate (Parlodel, Sandoz) was administered in an escalating dose schedule to 11 stabilized psychiatric outpatients with hyperprolactinemia resulting from thioridazine HCl (Mellaril, Sandoz) treatment. 6 of 9 patients showed decreases. Overall global psychiatric evaluations were unchanged over the course of combined therapy for all but 1 patient, who showed improvement. The trend of decreased prolactin serum levels indicates that bromocriptine mesylate may prove a useful adjunct to reduce the side effects of hyperprolactinemia.

The pharmacokinetics and bioavailability of subcutaneously administered dihydroergotamine, heparin and the dihydroergotamine-heparin combination.

Subcutaneously administered dihydroergotamine (DHE) becomes rapidly and completely available to the human systemic circulation, with peak plasma levels of 1.4-3.5 ng/mL/mg achieved in less than 1 h. The elimination of DHE from plasma is biphasic, t 1/2 alpha = 1h, t 1/2 beta = 4-5 h. DHE exhibits linear dose proportionality. Coadministration of heparin results in a statistically significant increase of 25% in the area under the plasma level/time curve for DHE (bioavailability). Coinjection of DHE and heparin in the same subcutaneous site furthermore causes a decrease in the rate of DHE absorption by 63%, resulting in delayed time to peak (by 110%) and reduced peak levels (by 15%) of DHE. In contrast, there is no effect by coadministered DHE on heparin pharmacokinetic parameters. Heparin peak plasma levels (0.3 I.U./mL by activated factor X, 0.1 I.U./mL by protamine titration with a 15,000 I.U. s.c. bolus) are achieved in 3.6 h. Pharmacokinetic analysis suggests that the subcutaneous route of administration provides only 19% of the bioavailable heparin that would be obtained following administration of an equipotent intravenous dose. DHE-heparin formulated for injection in combination demonstrates systemic availability identical to that of the two components injected separately, but with a reduced rate of absorption for the DHE component and a corresponding attenuation of fluctuations in steady state DHE levels.