Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial.

BACKGROUND: Triptans (5-HT(1B/1D) receptor agonists) are effective drugs for acute migraine, but the side-effect of coronary vasoconstriction restricts their use in patients who are at risk of coronary artery disease. We have studied the efficacy of LY334370, a selective serotonin 1F (5-HT(1F)) receptor agonist with preclinical efficacy and no vasoconstriction, for migraine relief. METHODS: We gave LY334370 (20, 60, or 200 mg) or placebo to 99 outpatients with moderate or severe migraine headaches in a double blind, parallel group study. We measured efficacy by sustained response, response at 2 h, pain free at 2 h, and sustained pain free. FINDINGS: The proportions of patients with defined endpoints for placebo and LY334370 20, 60, and 200 mg, respectively, were: sustained response, two of 26 (8%), three of 22 (14%), 11 of 30 (37%), and 11 of 21 (52%) (dose response p<0.001); response, five of 26 (19%), four of 22 (18%), 15 of 30 (50%), and 15 of 21 (71%) (p<0.001); pain free, one of 26 (4%), none of 22, eight of 30 (27%), and eight of 21 (38%) (p=0.001); sustained pain free, one of 26 (4%), none of 22, seven of 30 (23%), and seven of 21 (33%) (p=0.002); recurrence rates, one of five (20%), none of four, four of 15 (27%), and three of 15 (20%). More patients given LY334370 than placebo reported asthenia, somnolence, and dizziness. INTERPRETATION: Our findings show that LY334370 is effective in treatment of acute migraine through selective trigeminovascular neuronal inhibition.

Lanepitant, an NK-1 antagonist, in migraine prevention.

Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.

Efficacy of xanomeline in Alzheimer disease: cognitive improvement measured using the Computerized Neuropsychological Test Battery (CNTB).

The cognitive efficacy of the M1-selective muscarinic agonist xanomeline in mild-to-moderate Alzheimer disease (AD) was measured using the Computerized Neuropsychological Test Battery (CNTB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) in this 17-center, double-blind, placebo-controlled study. Three hundred forty-three patients were randomly assigned to receive 25, 50, or 75 mg xanomeline tartrate or placebo three times daily (t.i.d.) for 24 weeks, followed by placebo for 4 weeks in a single-blind washout phase. Cognitive function was assessed at randomization and after 4, 8, 12, 24, and 28 weeks. Three hundred nineteen patients were included in an intent-to-treat (ITT) analysis; 209 completers had evaluable data at week 24. ITT analysis showed a significant (p < or = 0.05) dose-response trend and a significant (p < or = 0.05) between-group comparison favoring 75 mg t.i.d. over placebo for the CNTB summary score but not for the ADAS-cog. In the completer analysis, however, the ADAS-cog showed a significant (p < or = 0.05) dose-response trend and between-group comparison, whereas the CNTB Summary Score did not. The ADAS-cog was less sensitive to treatment effects in mildly impaired patients (ADAS-cog < 21) than in moderately impaired patients (ADAS-cog > or = 21), whereas the CNTB was sensitive in the entire study population (mean ADAS-cog = 22.5+/-9.6). Significant (p < or = 0.05) beneficial treatment effects were seen in measures of simple reaction time and delayed verbal recall, which are included in the CNTB but not in the ADAS-cog. During the single-blind placebo washout period, the ADAS-cog score of the placebo group worsened dramatically (change of 2.63 points; p < or = 0.001), whereas the CNTB score remained stable (change of 1.04 points; p=0.694). Thus, the CNTB appears to be more objective than the ADAS-cog.

Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist.

OBJECTIVE: Higher than normal cellular levels of the phospholipid catabolic intermediate glycerophosphocholine have been found in postmortem brain tissue of persons with Alzheimer's disease. Proton magnetic resonance spectroscopy (1H-MRS) can detect a choline resonance that is largely due to glycerophosphocholine. The authors tested the hypothesis that treatment with xanomeline, an M1 selective muscarinic cholinergic agonist, would be associated with a decrease in the 1H-MRS choline resonance. METHOD: Patients with mild to moderate Alzheimer's disease received placebo or xanomeline for 6 months. 1H-MRS spectra were collected at baseline and after treatment discontinuation for 12 patients, two taking placebo and 10 taking xanomeline at a dose of 25 mg t.i.d. (N = 4), 50 mg t.i.d. (N = 3), or 75 mg t.i.d. (N = 3). RESULTS: For the combined group of patients taking xanomeline, there was a significant decrease in the choline/creatine ratio from baseline to endpoint. CONCLUSIONS: Treatment of Alzheimer's disease with a cholinergic agonist is associated with a decrease in the MRS choline resonance. Xanomeline may reduce breakdown of cholinergic neuron membranes by reducing the cellular requirement for free choline for acetylcholine synthesis.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

OBJECTIVE: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). DESIGN: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout. SETTING: Outpatients at 17 centers in the United States and Canada. PARTICIPANTS: A total of 343 men and women at least 60 years of age with mild to moderate AD. INTERVENTIONS: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. OUTCOME MEASURES: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). RESULTS: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P < or = .02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. CONCLUSIONS: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease.

The therapeutic effects of selective cholinergic replacement using oral xanomeline, an m1/m4 receptor agonist, were assessed in a multicenter study of 343 patients with Alzheimer disease (AD). Patients were randomized to parallel treatment arms (placebo, 25, 50, and 75 mg t.i.d. xanomeline) and followed through 6 months of double-blind therapy and 1 month of single-blind placebo washout. Completer analysis, using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), revealed a significant treatment effect (75 mg t.i.d. vs. placebo; p = 0.045). Similar assessment of global status, using the Clinician's Interview-Based Impression of Change, was also significant (75 mg t.i.d. vs. placebo; p = 0.022). Treatment Emergent Signs and Symptoms analysis of the Alzheimer's Disease Symptomatology Scale, revealed highly significant (p < or = 0.002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, the Nurses' Observational Scale for Geriatric Patients also showed a significant dose-response relationship (p = 0.018). The improvement in ADAS-Cog provides the first clinical evidence of involvement of the m1 muscarinic receptor in cognition. Furthermore, the favorable effects of xanomeline on disturbing behaviors suggest a novel approach for treatment of the noncognitive symptoms of AD. Although adverse effects (mainly gastrointestinal) associated with the oral formulation appear to limit its use, a large-scale study investigating the safety and efficacy of transdermal xanomeline is under way.

Nizatidine versus placebo in gastro-oesophageal reflux disease: a 12-week, multicentre, randomised, double-blind study.

Two doses of nizatidine (150 mg twice daily and 300 mg at bedtime), an H2-receptor antagonist, were compared with placebo in a 12-week, multicentre, randomised, double-blind, parallel study in 466 patients with endoscopically documented gastro-oesophageal reflux disease. Antacid tablets were given concomitantly as needed for pain. Compared with placebo, nizatidine 150 mg twice daily was highly effective in rapidly reducing the severity of heartburn, regardless of oesophagitis severity at entry. Significantly greater complete mucosal healing of oesophagitis occurred after 6 weeks of therapy with nizatidine 150 mg bid (vs nizatidine 300 mg at bedtime or placebo) only in patients with erosive oesophagitis [16/68 (24%) vs 8/65 (12%)] and erosive and ulcerative oesophagitis combined [21/99 (21%) vs 10/94 (11%)]. At week 12, healing with nizatidine 150 mg bid was also significantly greater than placebo in erosive [19/68 (28%) vs 9/65 (14%)], ulcerative [10/31 (32%) vs 3/29 (10%)], and erosive and ulcerative oesophagitis combined [29/99 (29%) vs 12/94 (13%)]. These results show that twice-daily therapy with nizatidine 150 mg is very effective at relieving heartburn, and can also heal erosive and ulcerative oesophagitis. Nizatidine 300 mg at bedtime was not effective at healing oesophagitis, compared with placebo.

Nizatidine versus placebo in gastro-oesophageal reflux disease: a 6-week, multicentre, randomised, double-blind comparison. Nizatidine Gastroesophageal Reflux Disease Study Group.

In a randomised, multicentre trial, nizatidine 150 mg or 300 mg or placebo was administered twice daily for 6 weeks to 515 patients with gastro-oesophageal reflux disease (GORD). Antacid tablets were taken as needed for pain. Significantly superior rates of endoscopically proven complete healing (normal-appearing mucosa) versus placebo occurred after 3 weeks with nizatidine 150 mg and after 6 weeks with nizatidine 300 mg. Six-week healing rates were 38.5% for nizatidine 300 mg, 41.1% for nizatidine 150 mg, and 25.8% for placebo. The nizatidine 150 mg treatment group had significantly greater improvement in daytime and nighttime heartburn severity after 1 day of therapy versus placebo. Twice-daily administration of nizatidine 150 mg or 300 mg provides prompt relief from the major symptom of GORD, heartburn, and complete healing of oesophagitis is seen in many patients.

A simple stopping rule for declaring treatment ineffectiveness in clinical trials.

We consider the problem of stopping a clinical trial before its scheduled termination due to the apparent ineffectiveness of the experimental therapy, as compared with a control. We propose a simple-to-implement, intuitive decision rule based on the unadjusted attained significance levels from any appropriate statistical test. The proposed procedure may be used at any time during the study as an aid to help determine whether the study of an experimental treatment should be terminated early with the conclusion of treatment ineffectiveness. Much of the power of the usual fixed-sample test is retained while maintaining the nominal test size.

Nizatidine versus placebo in active benign gastric ulcer disease: an eight-week, multicenter, randomized, double-blind comparison. The Nizatidine Benign Gastric Ulcer Disease Study Group.

STUDY OBJECTIVE: To determine if 150 mg nizatidine twice daily or 300 mg nizatidine at bedtime are similarly effective and to compare each dose with placebo in healing benign gastric ulcers and relieving peptic ulcer symptoms. METHODS: This study was a randomized, double-blind, placebo-controlled parallel comparison. The study was conducted at 74 gastroenterology and internal medicine clinics in the United States and Canada. Four hundred fifty-six patients with active benign gastric ulcer documented by endoscopy participated in the study. On the basis of a computer-generated randomization list, patients were assigned sequentially to receive either 150 mg nizatidine twice daily (n = 151), 300 mg nizatidine once daily at bedtime and identically appearing placebo capsules in the morning (n = 153), or placebo capsules twice daily (n = 152). Treatment lasted for 8 weeks unless healing was documented by endoscopy after 4 weeks. Antacid tablets (aluminum hydroxide, magnesium hydroxide, simethicone combination) were supplied for relief of symptoms. MEASUREMENTS AND MAIN RESULTS: Both doses of nizatidine significantly improved healing rates at 8 weeks compared with placebo. Daytime and nighttime symptom severity was improved by both nizatidine regimens at end point (p less than 0.015 versus placebo, two-tailed test). Antacid use was similar for all groups in the end point analysis. Patient well-being was significantly better in patients treated with nizatidine than in patients in the placebo group ((p less than 0.04, two-tailed test). No clinically significant differences in the incidence of adverse clinical or laboratory events were noted. CONCLUSION: Nizatidine, 300 mg at bedtime and 150 mg twice daily, resulted in greater healing of benign gastric ulcers than placebo treatment after 8 weeks. Relief of the symptoms of gastric ulcer was significantly better in the patients receiving nizatidine treatment versus placebo treatment.

Nizatidine versus placebo in gastroesophageal reflux disease. A six-week, multicenter, randomized, double-blind comparison. Nizatidine Gastroesophageal Reflux Disease Study Group.

In a randomized, multicenter trial, nizatidine 150 mg or 300 mg, or placebo, was administered twice daily for six weeks to 515 patients with gastroesophageal reflux disease (GERD). Gelusil antacid tablets were taken as needed for pain. Significantly superior rates of endoscopically proven complete healing (normal-appearing mucosa) versus placebo occurred after three weeks with nizatidine 150 mg, and after six weeks with nizatidine 300 mg. Six-week healing rates were 38.5% for nizatidine 300 mg, 41.1% for nizatidine 150 mg, and 25.8% for placebo. The nizatidine 150 mg treatment group had significantly greater improvement in daytime and nighttime heartburn severity after one day of therapy versus placebo. Twice-daily administration of nizatidine 150 mg or 300 mg provides prompt relief from the major symptom of GERD, heartburn, and complete healing of esophagitis is seen in many patients.

Nizatidine versus placebo in gastroesophageal reflux disease: a 12-week, multicenter, randomized, double-blind study.

Two doses of nizatidine (150 mg bid and 300 mg hs), an H2-receptor antagonist, were compared with placebo in a 12-wk, multicenter, randomized, double-blind, parallel study in 466 patients with endoscopically documented gastroesophageal reflux disease. Antacid tablets were given concomitantly as needed for pain. Compared with placebo, nizatidine 150 mg twice daily was highly effective in rapidly reducing the severity of heartburn, regardless of esophagitis severity at entry. Significantly greater complete mucosal healing of esophagitis occurred after 6 wk of therapy with nizatidine 150 mg bid (vs. nizatidine 300 mg hs or placebo) only in patients with erosive esophagitis [16/68 (24%) vs. 8/65 (12%)] and erosive and ulcerative esophagitis combined [21/99 (21%) vs. 10/94 (11%)]. At wk 12, healing with nizatidine 150 mg bid was also significantly greater than placebo in erosive [19/68 (28%) vs. 9/65 (14%)], ulcerative [10/31 (32%) vs. 3/29 (10%)], and erosive and ulcerative esophagitis combined [29/99 (29%) vs. 12/94 (13%)]. These results show that twice-daily therapy with nizatidine 150 mg is very effective at relieving heartburn, and can also heal erosive and ulcerative esophagitis. Nizatidine 300 mg hs was not effective in healing esophagitis, compared with placebo.

Relationship between steady-state plasma nizatidine concentrations and inhibition of basal and stimulated gastric acid secretion.

Steady-state plasma nizatidine concentrations were related in a linear fashion to nizatidine infusion rate. Infusion rates of 2.5, 10, and 20 mg/hr resulted in mean plasma nizatidine concentrations of 69, 247, and 575 ng/ml. Basal acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 60 and 430 ng/ml. Protein-stimulated acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 75 and 490 ng/ml. The mean pH of basal gastric secretions was 1.6 during placebo infusion and 4.6 when the mean plasma nizatidine concentration was 575 ng/ml.

Healing and recurrence of active duodenal ulcer with nizatidine.

Nizatidine, a new H2-receptor antagonist for treatment of duodenal ulcer disease, was evaluated in a unique two-phase, placebo-controlled, randomized, double-blind, multicenter clinical trial. Patients received either 150 mg nizatidine twice daily or placebo for 4 weeks (phase I). If ulcer healing did not occur during phase I, patients were randomly reallocated to receive either 150 mg nizatidine twice daily or placebo for an additional 4 weeks (phase II). Patients with a healed ulcer continued on the same therapy. All patients were endoscoped at week 8. Healing rates at week 2 were 93 of 265 (35%) nizatidine-treated patients and 55 of 260 (21%) placebo-treated patients (p less than 0.001); at week 4, healing rates were 198 of 259 (76%) nizatidine-treated patients and 95 of 243 (39%) placebo-treated patients (p less than 0.001). In phase II, ulcer healing occurred in 46 of 86 (53%) nizatidine-treated patients and in 23 of 90 (26%) placebo-treated patients (p = 0.002). In patients who had a healed ulcer at previous endoscopies, 18 of 178 (10%) nizatidine-treated patients and 10 of 81 (12%) placebo-treated patients had a recurrence of duodenal ulcer. Smokers who had histories of previous ulcers were more likely to have an early recurrence.

Dose-effect and concentration-effect relationships of pinacidil and hydrochlorothiazide in hypertension.

To determine dose-effect and concentration-effect relationships in hypertension for pinacidil and hydrochlorothiazide when given alone and together, we conducted a randomized, double-blind, 4 X 3 factorial, modified fixed-dose multicenter trial. Three hundred and eighty-four patients with essential hypertension (supine diastolic blood pressure, 95 to 110 mm Hg) were assigned to one of 12 groups that received all combinations of four doses of pinacidil (0, 12.5, 25, and 37.5 mg, b.i.d.) with three doses of hydrochlorothiazide (0, 12.5, and 25 mg, b.i.d.). Significant dose- and concentration-effect relationships were seen for pinacidil and hydrochlorothiazide on diastolic blood pressure. For pinacidil, dose- and concentration-effect relationships were steeper after the dose than before the dose. A significant interaction with hydrochlorothiazide was noted such that, when combined with 12.5 mg hydrochlorothiazide, 12.5 mg pinacidil had near-maximal effects on blood pressure at both peak and trough. Edema occurred in 47% of those who received 37.5 mg pinacidil monotherapy (19% discontinued). The administration of 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appears to be optimal for efficacy and safety.

Comparison of nizatidine and cimetidine as once-nightly treatment of acute duodenal ulcer. Nizatidine Multicenter Duodenal Ulcer Study Group.

Nizatidine, a new H2-receptor antagonist for the treatment of duodenal ulcer disease, was compared with cimetidine in an 8-wk, randomized, double-blind, multicenter clinical trial. Patients were randomly allocated to receive either nizatidine 300 mg h.s. or cimetidine 800 mg h.s. Patients were treated for 8 wk, regardless of the healing status of their ulcers. An endoscopy was performed at Wk 2, 4, and 8. Healing rates with nizatidine 300 mg h.s. were numerically, but not statistically significantly, superior to those with cimetidine 800 mg h.s. at each treatment period. Ulcer healing rates at Wk 2, 4, and 8 were 41% (78/191), 73% (130/179), and 81% (145/179) for nizatidine and 33% (60/184), 67% (116/174), and 75% (126/168) for cimetidine, respectively. Symptoms of peptic ulcer disease were similarly reduced at each treatment period by nizatidine and cimetidine. Patients with healed ulcers at either Wk 2 or Wk 4 were continued on therapy and an endoscopy was performed at Wk 8. Ulcer recurrence occurred in 10% of nizatidine-treated and 19% of cimetidine-treated patients at Wk 8 (p = 0.085). The observation of recurrence of duodenal ulcer while patients were receiving full-dose H2-receptor antagonist therapy has not been reported previously.

Pinacidil with and without hydrochlorothiazide. Dose-response relationships from results of a 4 x 3 factorial design study.

Utilising a modified fixed-dose, 4 x 3 factorial design, the antihypertensive effects of all combinations of 4 doses of pinacidil (0, 12.5, 25 and 37.5 mg bid) with 3 doses of hydrochlorothiazide (0, 12.5 and 25 mg bid) were studied in patients with supine diastolic blood pressure of 95 to 110mm Hg. The decreases in supine diastolic blood pressure from baseline were dose-related for both drugs. The response to the highest monotherapy dose of pinacidil was less in patients with oedema. When given in combination, hydrochlorothiazide blunted the differences among pinacidil doses so that 12.5 mg pinacidil with 12.5mg hydrochlorothiazide administered twice daily produced nearly maximal antihypertensive efficacy. For pinacidil monotherapy, the incidence of oedema was 3%, 26% and 47% at dosages of 12.5, 25, and 37.5mg bid, respectively, with significant attenuation of these effects at both hydrochlorothiazide dosage levels. Based upon these data, low (12.5-25mg bid) doses of pinacidil are effective and safe as monotherapy for hypertension. The optimal combination of pinacidil with hydrochlorothiazide given twice daily for hypertension contains 12.5mg of each drug.