Distinct mechanism for antidepressant activity by blockade of central substance P receptors.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group.

BACKGROUND: Based mainly on the selective antagonism of clozapine at D4 compared with D2 dopamine receptors, hopes have run high that a selective D4 dopamine receptor antagonist might improve the pharmacological treatment of patients with schizophrenia. We report, to our knowledge, the first multicenter study of the antipsychotic potential of a highly specific D4 dopamine receptor antagonist (ie, L-745,870) in patients with acute schizophrenia. METHODS: Thirty-eight acutely psychotic and neuroleptic responsive (by history) newly admitted inpatients with schizophrenia were randomized to 4 weeks of double-blind treatment (2:1) with either L-745,870 (n = 26), 15 mg/d, or placebo (n = 12) after a 3- to 5-day placebo run-in period. RESULTS: Overall, a greater percentage of patients receiving L-745,870 compared with patients receiving placebo discontinued the study for insufficient therapeutic response (32% vs 16%). At the end of 4 weeks by last observation carried forward analysis, the mean change from baseline to week 4 on the total Brief Psychiatric Rating Scale favored placebo (i.e., -8 points [-15% change from baseline] vs -1 point [-2% change from baseline] for placebo vs L-745,870, P = .09). Similar differences in favor of placebo in changes from baseline mean scores were observed for the not carried forward analysis on the total Brief Psychiatric Rating Scale (P < .03), for not carried forward and last observation carried forward analyses on the sum of selected positive symptom items of the Brief Psychiatric Rating Scale, and for the Clinical Global Impression analysis (P = .03, last observation carried forward). A greater percentage of patients receiving L-745,870 had scores indicative of some level of worsening (compared with baseline) on the total Brief Psychiatric Rating Scale and the Clinical Global Impressions' Severity of Illness Scale as well as positive symptoms compared with those receiving placebo. CONCLUSION: The selective D4 dopamine receptor antagonist L-745,870 was ineffective as an antipsychotic for the treatment of neuroleptic responsive inpatients with acute schizophrenia.

Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group.

BACKGROUND: Rizatriptan (MK-462) is a new 5-hydroxytryptamine1D (serotonin1D; 5-HT1D) receptor agonist for the acute treatment of migraine that has improved pharmacokinetic properties compared with sumatriptan succinate. OBJECTIVE: To assess the efficacy and tolerability of 10-, 20-, and 40-mg doses of oral rizatriptan vs a 100-mg dose of oral sumatriptan succinate and placebo for the acute treatment of migraine. DESIGN: Randomized, double-blind, parallel-group, placebo-controlled, outpatient trial. SETTING: Ten US and 4 Dutch investigator centers. PATIENTS: Patients who had migraine with or without aura (N = 449). MAIN OUTCOME MEASURE: The proportion of patients whose conditions improved from severe or moderate headache immediately before dosing to mild or no headache at 2 hours after drug administration (ie, headache relief). RESULTS: The proportion of patients with headache relief was 18% for placebo; 46% for sumatriptan; and 52% for 10-mg, 56% for 20-mg, and 67% for 40-mg rizatriptan. All differences with placebo were statistically significant (P < .001), and 40-mg rizatriptan was superior to sumatriptan (P = .01). The proportion of patients who became free of pain at 2 hours was 3% for the placebo-treated group; 22% for the sumatriptan-treated group; and 26%, 35%, and 47% for the group of patients who took the 10-, 20-, and 40-mg doses of rizatriptan, respectively (all differences with placebo, P < .005; 40-mg rizatripan vs sumatriptan, P = .001). The recurrence of headache within 24 hours was found to be equal across all treatment groups-approximately 40%. Adverse events (most commonly short-lasting mild or moderate dizziness and drowsiness) occurred more frequently after a 40-mg dose of rizatriptan was given than after the other treatments. CONCLUSIONS: The antimigraine effect of 10- and 20-mg rizatriptan was superior to placebo, and comparable with that of 100-mg sumatriptan succinate; the efficacy of 40-mg rizatriptan was superior to that of both placebo and 100-mg sumatriptan succinate, although it was associated with a high frequency of adverse events.

A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Rizatriptan Multiple Attack Study Group.

OBJECTIVE: To examine the safety and efficacy of rizatriptan 10 mg PO in the treatment of multiple migraine attacks. BACKGROUND: Rizatriptan is a potent and rapidly absorbed 5-HT1B/1D receptor agonist. Efficacy and general safety have been examined in controlled trials treating single migraine attacks. In the current placebo-controlled study, we report constancy of safety and efficacy of rizatriptan for patients treating four discrete migraine attacks. METHODS: Patients with moderate or severe migraine (n = 473) were randomized to one of five sequence groups, in which each patient was to treat four migraine attacks. Patients in four groups received rizatriptan 10 mg for three of four attacks and placebo for the remaining attack. Patients in the fifth group received rizatriptan 10 mg for four attacks. Headache severity, functional disability, and migraine symptoms were measured immediately before dosing and at 0.5, 1, 1.5, 2, 3, and 4 hours postdose. RESULTS: After the first attack, response rates were 77% for rizatriptan and 37% for placebo (p < 0.001). Similar efficacy of rizatriptan, ranging from a 75 to 80% response, was observed in each of the subsequent attacks with no evidence of tolerance to therapeutic effects. Most patients (93%) responded to rizatriptan 10 mg during the first or second attack. Adverse experiences were generally mild and transient, the most common being dizziness and somnolence. Incidence of adverse experiences per attack decreased after the first attack. CONCLUSIONS: Rizatriptan 10 mg PO is efficacious and generally well tolerated in acute migraine. Its efficacy is maintained throughout the treatment of multiple, discrete migraine attacks.

Pharmacokinetics and dose proportionality of D2-agonist MK-458 (HPMC) in parkinsonism.

To investigate the pharmacokinetic profile, bioavailability, and dose proportionality of the D2-agonist MK-458 (hydroxypropylmethylcellulose tablet, a sustained release formulation), a 4-period crossover study was conducted in 10 patients with mild to moderate Parkinson's disease (mean age = 63 y; 1 woman, 9 men). Following a titration phase to induce tolerance, each patient was given single oral doses of 6, 12 and 18 mg and a single intravenous 40 micrograms dose (5 micrograms/h over 8h). The maximum concentrations of MK-458 observed in plasma after oral administration were 139, 240 and 344 ng/L for the 6, 12 and 18 mg doses, respectively, and occurred after 8.0, 9.0 and 5.5 h, respectively. Mean areas under the plasma concentration-time curves were 1728, 2849 and 5484 ng/L.h, respectively. The mean plasma half-life was 3.8 h and mean plasma clearance was 3390 ml/min (203.4 L/h). The bioavailability (approximately 5%) was very similar for the 3 tablet formulations tested. The disposition of MK-458 was independent of the dose over the range of doses studied.

A multiple-dose safety trial of eptastigmine in Alzheimer's disease, with pharmacodynamic observations of red blood cell cholinesterase.

A placebo-controlled multiple dose study was conducted to evaluate the safety, tolerability, and pharmacodynamics of multiple dose levels of eptastigmine in 25 patients with probable Alzheimer's disease (AD). Twenty patients (12 M, 8 F; mean age 74, range 57-84) were randomized to receive 12mg (N = 3), 20mg (N = 6), 28mg (N = 6) or placebo (N = 5) tid on a double-blind basis for 14 days, followed by seven days of single blind placebo, in successively rising dose groups. All patients completed the study without intolerable or severe adverse events. All doses significantly (p < 0.001) reduced peak and trough RBC cholinesterase (AChE) activity as compared to baseline. Percent inhibition for Day 14 peak and trough RBC AChE peak and trough values, respectively, appeared proportional to dose: 18% and 21% (12mg); 36% and 35% (20mg); 40% and 44% (28mg). In order to determine the maximum tolerated dose of eptastigmine, an additional single-blind study was performed in five patients (2 M, 3 F; mean age 78, range 72-80) utilizing a rising dose schedule of eptastigmine (N = 4) or placebo (N = 1), starting with the previously tolerated 28mg tid dose and increasing by 4mg tid up to a potential maximum of 56mg tid. Dose-limiting adverse events occurred requiring discontinuation of medication in one patient at 48mg tid and two patients at 52mg tid; RBC AChE inhibition was proportional to dose, with peak values up to 70% inhibition at 48mg tid. The maximum tolerated dose of 48mg tid was identified as a basis for potential Phase II multicenter efficacy trials.

Pharmacokinetics of rizatriptan tablets during and between migraine attacks.

Gastric stasis during migraine attacks results in delayed absorption of several orally administered antimigraine agents. This study, as part of a larger trial, was conducted to examine the pharmacokinetics of rizatriptan tablets during and between migraine attacks. Participating patients met IHS criteria for migraine with or without aura, and suffered between one and eight migraines per month for the previous 6 months. In part 1 of the study, 21 patients were randomized to receive a single 5-mg tablet of rizatriptan or placebo in the migraine-free state. In part 2, the same patients were treated during migraine with rizatriptan 5-mg tablets (n=18) or placebo (n=3). Blood samples were obtained before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration profile (ie, AUC((0-infinity)), C(max), T(max)) of rizatriptan 5-mg tablets administered during and between migraine attacks were comparable. The median T(max) for rizatriptan between and during attacks was 1 hour, indicating rapid absorption even during a migraine attack. Rizatriptan 5 mg was well tolerated and 67% of the patients experienced headache relief 2 hours postdose.

Early clinical trials in Alzheimer's disease: selection and evaluation of drug candidates.

Clinical research in Alzheimer's disease (AD) is complicated by inadequate understanding of the etiology and pathogenesis of the disorder, lack of good animal models to predict potentially useful compounds, and methodological issues such as the need for new diagnostic tools and validated assessment criteria. These and other issues which are specific to clinical research in AD occur in the larger context of drug development as it is conducted by major pharmaceutical companies throughout the world. This paper begins with a discussion of the scientific and regulatory requirements for establishing the safety and efficacy of new drugs, with emphasis on drug development in the United States and Europe. Compounds used to ameliorate symptoms of AD are emphasized, as most work to date has focused on such drugs. Examples of animal models currently used to choose compounds for clinical testing are presented, as well as other methods and rationales which have been employed in selecting the compounds currently undergoing clinical trials. Finally, issues in clinical assessment specific to the study of patients with AD are addressed.

New fluorescent hydrazide reagents for the oxidized 3'-terminus of RNA.

The synthesis and properties of four new fluorescent reagents capable of forming moderately stable links to the 3' oxidized end of RNA are reported. All are hydrazide derivatives: pyrene butyric acid hydrazide, proflavine monosemicarbazide, proflavine monosuccinic acid hydrazide, and anthracene-9-carboxaldehyde carbohydrazone. In addition, procedures are given for coupling the bifunctional reagent carbohydrazide to the 3' end of RNA. These carbohydrazide adducts can easily be coupled in turn to a wide variety of fluorescent reagents having specificity for aliphatic amino groups, including isothiocyanates and sulfonyl halides. Thus a route exists for the preparation of an enormous variety of 3' fluorescent labeled RNAs. The carbohyrazide adducts are also useful for other synthetic procedures such as preparation of covalent tRNA dimers.

Attachment of protein affinity-labeling reagents of variable length and amino acid specificity to E. coli tRNAfMet.

Transamination with bifunctional amines in the presence of bisulfite has been used to attach side chains of variable length to the N4-position of single stranded cytidine residues in E. coli tRNAfMet. Such side chains, terminating in reactive primary amino groups, have been coupled to a variety of N-hydroxysuccinimide esters. The resulting modified tRNAs carry protein affinity labeling groups capable of covalent reaction with a variety of amino acids.

Migraine prevention with timolol. A double-blind crossover study.

One hundred seven patients (77 women and 30 men) with migraine headache were given prophylactic treatment with timolol maleate, 20 to 30 mg/day, or matching placebo during a 20-week, double-blind crossover study. Among the 94 patients who completed the study, timolol was significantly better than placebo in terms of decrease in frequency of headaches from baseline, numbers of patients who had a 50% reduction in headache frequency, global response, and patient preference. Overall global response rates were 65% with timolol compared with 40% with placebo. The severity and duration of headaches that occurred were unchanged. Few side effects were reported with either timolol or placebo. The study demonstrates that the beta-blocker timolol is a safe and effective treatment in patients with frequent migraine headaches.

Validation of a questionnaire for comparing the tolerability of ophthalmic medications.

PURPOSE: The Comparison of Ophthalmic Medications for Tolerability (COMTOL) questionnaire was developed for use in clinical trials to compare the tolerability of topical ophthalmic medications used in the treatment of glaucoma. The questionnaire captures the frequency and bother of common side effects (i.e., ocular and other local effects, and effects on visual function) of topical therapy for lowering intraocular pressure. In addition, the questionnaire measures the extent to which these side effects and any associated limitations in routine living activities interfere with health-related quality of life, medication compliance, and patient satisfaction with the medication. This study was designed to assess the measurement characteristics of the COMTOL questionnaire. METHODS: The internal consistency, reliability, reproducibility, construct validity, discriminant validity, and responsiveness of the questionnaire were assessed in 70 adult patients with glaucoma in a clinical trial comparing timolol and pilocarpine. RESULTS: The questionnaire showed good-to-excellent internal consistency (0.73 to 0.98), reliability (0.76 to 0.94), and reproducibility (0.75 to 0.93). In general, there was a strong correlation in the expected direction between the frequency and bother of side effects and patient-perceived global measures. The questionnaire discriminated between patients receiving timolol and patients receiving pilocarpine. The questionnaire demonstrated significant responsiveness to change. CONCLUSIONS: The COMTOL questionnaire showed acceptable measurement characteristics for inclusion as a tolerability measure to supplement spontaneous adverse event reporting in clinical trials of topical ophthalmic therapy.

Efficacy and safety of rizatriptan versus standard care during long-term treatment for migraine. Rizatriptan Multicenter Study Groups.

Rizatriptan is a novel, selective 5-HT1B/1D receptor agonist with a rapid onset of action after oral dosing for the acute treatment of migraine. We conducted a long-term (up to 1 year), multicenter, randomized study in 1831 patients treating more than 46,000 attacks to compare the efficacy and tolerability of rizatriptan 5 mg and 10 mg to standard care medications routinely used for the acute treatment of migraine attacks. Both doses of rizatriptan were highly effective, without evidence of tachyphylaxis. Rizatriptan 10 mg was consistently superior (P < 0.05), both to the 5-mg dose and to standard care, in providing relief in 90% of attacks, with 50% pain-free by 2 hours after dosing. The most common dose-related adverse events were nausea, somnolence, and asthenia/fatigue. Based on this large, multicenter, long-term trial, rizatriptan is an important new oral agent for the acute treatment of migraine.

Pilot study of a CCKB antagonist in patients with panic disorder: preliminary findings.

L-365,260 is a CCKB antagonist which has been shown to completely prevent CCK-4-induced symptoms of panic attack in single-dose (50 mg) placebo-controlled studies in patients with panic disorder. The present report is data from one site (n = 38) in a multicenter study (n = 88) designed to assess the preliminary efficacy and safety of L-365,260 in patients meeting DSM-III-R criteria for panic disorder, with or without agoraphobia. In order to participate, male and female patients were between 18-55 years of age and in good physical health. Following a one-week single-blind placebo lead-in, patients were randomized to 30 mg four times daily of L-365,260 (n = 18; 7 M, 11 F) or placebo (n = 20; 9 M, 11 F) for six weeks. At end of study, none of the efficacy measures, including the frequency of panic attacks, the Physician's Global Improvement Scale, and the Hamilton Rating Scale for Anxiety, were significantly improved over baseline values. L-365,260 was well-tolerated; the most common drug-related adverse events were headache and lightheadedness. Further testing of L-365,260 at higher dosages, or testing of other CCKB antagonists, is required to rule out the usefulness of this novel treatment approach.

Pilot study of MK-462 in migraine.

MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg (n = 8) and 40 mg (n = 36) vs placebo (n = 21), administered to 65 male and post-menopausal female migraine patients aged 22-51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly (p < 0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (40 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine.

Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study.

BACKGROUND: Inflammatory mechanisms have been implicated in the pathogenesis of Alzheimer's disease (AD) and may be mediated via the cyclo-oxygenase-2 enzyme. This study sought to evaluate the effect of rofecoxib, a nonsteroidal anti-inflammatory drug that selectively inhibits cyclo-oxygenase-2, in slowing the progression of dementia in patients with established AD. METHODS: A double-blinded, multicenter trial was conducted in which 692 patients with mild or moderate AD aged 50 years or older were randomly assigned to receive 25 mg rofecoxib or placebo daily for 12 months. The key efficacy measures were mean change from baseline at month 12 on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and score on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+). RESULTS: Four hundred eighty-one patients (70%) completed assessments and remained on treatment at 12 months. No significant differences between treatments were found on the mean change from baseline error score for the ADAS-cog (rofecoxib = 4.84; placebo = 5.44; difference = -0.60) or mean score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference = 0.03) over 12 months. This result persisted after adjusting for severity of dementia at baseline, presence of the APOE-epsilon4 allele, and donepezil use. Secondary analyses did not reveal any significant differences on any other measures. CONCLUSION: The failure of selective cyclo-oxygenase-2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase-2 does not play a significant role in the pathogenesis of the disorder.

Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group.

Rizatriptan is a potent, oral, 5-HT1B/1D agonist with more rapid absorption and higher bioavailability than oral sumatriptan. It was postulated that this would result in more rapid onset of effect. This randomized, double-blind, triple-dummy, parallel-groups study compared rizatriptan 5 mg, rizatriptan 10 mg, sumatriptan 100 mg, and placebo in 1268 outpatients treating a single migraine attack. Headache relief rates after rizatriptan 10 mg were consistently higher than sumatriptan at all time points up to 2 hours, with significance at 1 hour (37% versus 28%, P = 0.010). All active agents were significantly superior to placebo with regard to headache relief and pain freedom at 2 hours (P < or = 0.001). The primary efficacy endpoint of time to pain relief through 2 hours demonstrated that, after adjustment for age imbalance, rizatriptan 10 mg had earlier onset than sumatriptan 100 mg (P = 0.032; hazard ratio 1.21). Rizatriptan 10 mg was also superior to sumatriptan on pain-free response (P = 0.032), reduction in functional disability (P = 0.015), and relief of nausea at 2 hours (P = 0.010). Significantly fewer drug-related clinical adverse events were reported after rizatriptan 10 mg (33%, P = 0.014) compared with sumatriptan 100 mg (41%). We conclude that rizatriptan 10 mg has a rapid onset of action and relieves headache and associated symptoms more effectively than sumatriptan 100 mg.