Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia.

Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the European Union and United States as add-on treatment to levodopa in Parkinson's disease therapy. In addition to its selective and reversible monoamine oxidase B inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating behavioral, molecular, and neurochemical parameters associated with LID appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg), or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary movements, motor performance, molecular composition of the striatal glutamatergic synapse, glutamate, and GABA release were analyzed. In the striatum, safinamide prevented the rearrangement of the subunit composition of N-methyl-d-aspartate receptors and the levodopa-induced increase of glutamate release associated with dyskinesia without affecting the levodopa-stimulated motor performance and dyskinesia. Overall, these findings suggest that the striatal glutamate-modulating component of safinamide's activity may contribute to its clinical effects, where its long-term use as levodopa add-on therapy significantly improves motor function and "on" time without troublesome dyskinesia.

Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease.

BACKGROUND: ADX10059, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, has been shown to reduce gastro-oesophageal reflux events and oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD) and healthy subjects. AIM: To evaluate the effects of ADX10059 monotherapy for 2 weeks on symptom control in patients with GERD. METHODS: This was a double-blind, placebo-controlled, multi-centre trial in GERD patients who were responders to proton pump inhibitors (PPIs). Following PPIs withdrawal, a 2-week baseline washout period was followed by 2-week treatment with either ADX10059 120 mg or placebo b.d. The primary clinical efficacy endpoint was the number of GERD symptom-free days in treatment week 2 compared with the last 7 days of baseline. The effect on reflux events using 24-h impedance-pH monitoring was also determined in a subset of 24 patients. RESULTS: The full analysis set comprised 103 patients ADX10059 (N= 50), Placebo (N=53). In treatment week 2, ADX10059 significantly increased GERD symptom-free days (P=0.045) and heartburn-free days (P=0.037), reduced antacid use (P=0.017), improved total symptom score (P=0.048) including subscale heartburn/regurgitation (P=0.007) and sleep disturbance because of GERD (P= 0.022). ADX10059 significantly reduced total (P=0.034) and acidic reflux events (P=0.003). ADX10059 was well tolerated. Most common adverse events for ADX10059 were mild to moderate dizziness 16% and vertigo 12% (placebo 4% and 2%). CONCLUSIONS: Inhibition of mGluR5 with ADX10059 monotherapy reduces reflux events and improves symptoms in GERD patients. This mechanism has promise for the management of GERD.

Efficacy, tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH-impedance study in healthy subjects.

BACKGROUND: Animal studies show metabotropic glutamate receptor 5 inhibition reduces transient lower esophageal sphincter relaxations and increases lower esophageal sphincter tone. A preliminary, single-day study, demonstrated oral ADX10059 reduced 24-h esophageal acid exposure and clinical symptoms in gastro-esophageal reflux disease (GERD) patients, but had suboptimal tolerability, ascribable to the compound's rapid absorption. This study evaluated ADX10059 modified-release (MR) formulation pharmacokinetics, tolerability, and pharmacodynamics. METHODS: Randomized, double-blind placebo-controlled study. Three groups of eight healthy, male subjects received placebo (n = 2) or ADX10059 (n = 6) 50, 125 or 250 mg b.i.d. for 6 days. Esophageal pH-impedance was performed on day 1 and day 6 of treatment, for 1-h fasting and for 4 h post refluxogenic meal. Treatment effect was determined by Kruskall-Wallis test and placebo comparison by Wilcoxon rank sum. KEY RESULTS: Following placebo, reflux episodes increased from day 1 to day 6. Significant treatment effect was seen for total esophageal acid exposure (P = 0.048) and postprandial number of weakly acidic reflux episodes (P = 0.041). Significant differences from placebo were seen for 125 mg b.i.d.; 250 mg b.i.d. was not more effective than 125 mg b.i.d. Twice daily ADX10059 MR gave satisfactory 24-h exposure and good tolerability. CONCLUSIONS & INFERENCES: ADX10059 decreased reflux episodes in healthy subjects. The MR formulation is suitable for longer-term treatment to evaluate symptom control in GERD patients.

A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease.

BACKGROUND: In preclinical models, antagonism of metabotropic glutamate receptor 5 (mGluR5) reduces transient lower oesophageal sphincter relaxations (TLOSRs) and increases LOS pressure. This study evaluated the effect of ADX10059, a potent, selective, negative allosteric modulator of mGluR5, on oesophageal pH-metry and clinical symptoms in GORD. METHODS: Two groups of patients with GORD (n = 12 per group) underwent 24-h oesophageal pH-metry on two sequential treatment days. The patients received oral placebo three times daily (tds) 30 min before a high-fat meal on Day 1 and oral ADX10059 50 mg (Group 1) or 250 mg (Group 2) tds 30 min before a high-fat meal on Day 2. The primary variable was acid exposure (%time pH<4). Secondary variables included number and duration of reflux episodes, number and duration of symptomatic episodes and symptoms recorded in diaries. Comparisons were made for Day 2 (active) versus Day 1 (placebo) treatment and for Group 1 versus Group 2. RESULTS: ADX10059 250 mg tds significantly decreased the percentage of time with pH<4 from 7.2% to 3.6% (p = 0.01). ADX10059 250 mg tds reduced pH-metry-measured oesophageal acid exposure, throughout the 24 h period, nocturnally and postprandially, and significantly reduced the number and duration of symptomatic reflux episodes (p = 0.03). ADX10059 50 mg tds was not significantly superior to placebo. ADX10059 was generally well tolerated. CONCLUSION: The mGluR5 negative allosteric modulator ADX10059 reduced acid reflux which was associated with improvement in clinical symptoms in patients with GORD. ADX10059 appears to have a potential role in the clinical management of GORD.

Frovatriptan for the acute treatment of migraine: a dose-finding study.

OBJECTIVE: To determine the optimal dose and tolerability of frovatriptan in the acute treatment of migraine. BACKGROUND: Frovatriptan has a distinctive pharmacological and pharmacokinetic profile compared with sumatriptan. A previous study has shown that frovatriptan doses of 2.5, 5, 10, 20, and 40 mg are equally effective in relieving headache with no evidence of a dose-response relationship. The incidence of adverse events tended to increase with doses of 10 mg and above. METHODS: This study was a randomized, double-blind, placebo-controlled, parallel-group multicenter trial. Patients (n=635) took a single oral dose of placebo or frovatriptan, 0.5, 1, 2.5, or 5 mg, at the onset of a moderate or severe migraine headache and recorded headache intensity, functional impairment, and migraine-associated symptoms over 24 hours. RESULTS: Frovatriptan 2.5 mg produced clinically and statistically significant headache relief 2 hours post-dose, whereas the effect of lower doses was not significantly different from that of placebo at that time point. The 2.5-mg dose also produced significant symptom relief and improvement in functional impairment. All doses of frovatriptan were well tolerated, and the majority of adverse events were of mild or moderate severity. CONCLUSION: It is concluded that the 2.5-mg dose of frovatriptan offers optimal efficacy and tolerability in the treatment of acute migraine. Higher doses do not appear to confer greater efficacy and are associated with an increased incidence of adverse effects.

Clinical pharmacokinetics of frovatriptan.

OBJECTIVE: To review available data on the clinical pharmacokinetics of frovatriptan. BACKGROUND: Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. METHODS: Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. RESULTS: Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. CONCLUSIONS: Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence.

Clinical efficacy of frovatriptan: placebo-controlled studies.

OBJECTIVE: To confirm the clinical efficacy of frovatriptan 2.5 mg. BACKGROUND: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) receptor agonist being developed for the acute treatment of migraine with or without aura. Results from preclinical and clinical pharmacology studies showed frovatriptan to be a potent 5-HT(1B) receptor agonist with a long terminal elimination half-life (26 hours) and a broad therapeutic index. DESIGN: Three randomized, placebo-controlled, double-blind, parallel-group trials, in a total of 2676 patients, were performed to confirm the clinical efficacy of frovatriptan 2.5 mg for the acute treatment of migraine. RESULTS: In all three studies, headache response 2 hours after frovatriptan dosing was significantly greater than that seen with placebo (P < or = .001) with approximately a two-fold measure of effect over placebo for headache response at 2 and 4 hours postdosing. Time to headache response occurred within 1.5 hours in a substantial proportion of patients. The incidence of 24-hour headache recurrence with frovatriptan was low (10% to 25%). Frovatriptan therapy also was associated with a high degree of patient satisfaction. CONCLUSIONS: Frovatriptan represents a consistently effective acute treatment for migraine and accompanying symptoms.

Need for invasive cardiological assessment and intervention: a ten year review.

The uptake of invasive cardiological investigation and cardiopulmonary bypass procedures by the North West Surrey Health District was audited over the years 1979-88. Growth was almost continuous throughout the ten year period. The need within the district each year for coronary angiography seemed to be between 111 and 171 and for surgical revascularisation of the myocardium between 63 and 96 procedures; the first figure is the mean of the second quinquennial period (1984-88) and the second figure the total for 1988. After correction for the standardised mortality ratio and catchment area, the national requirement should lie between 690 and 1070 coronary angiograms and 390 and 600 coronary artery bypass graft operations per million population each year. There is a further national requirement for 70 valvar heart operations and 30 miscellaneous procedures per million population each year. Owing to delays in the provision of services, 20 patients died of a cardiovascular cause while they were on the waiting list for investigation or surgery. In the United Kingdom the annual target to be achieved by 1990 was 300 coronary artery bypass procedures per million population.

Angiotensin converting enzyme inhibitors and magnesium conservation in patients with congestive cardiac failure.

OBJECTIVE: To investigate whether angiotensin converting enzyme inhibitors reduce diuretic induced magnesium excretion in patients in congestive cardiac failure. DESIGN: Cohort analytic study. SETTING: A London district general hospital. SUBJECTS: Thirty four patients with chronic congestive cardiac failure caused by ischaemic heart disease or cardiomyopathy selected consecutively from inpatients under the care of two consultant cardiologists. Nineteen patients (group 1) on diuretics alone were compared with 15 patients (group 2) taking diuretics plus either enalapril or captopril. All drug regimens were stable for at least three months before the study. Patients with impaired renal function (plasma creatinine greater than 120 mumol/l) were excluded. INTERVENTIONS: An intravenous loading dose of magnesium sulphate was given to minimise the variability in baseline magnesium state. MAIN OUTCOME MEASURE: Total urine magnesium excretion and creatinine clearance in 24 hour urine collections. RESULTS: Plasma magnesium was similar in the two groups. However, 24 hour urine magnesium excretion was significantly lower in group 2 than in group 1. Furthermore, creatinine clearance was also significantly lower in group 2 and correlated strongly with magnesium excretion. There was no such relation in group 1. There was no difference in fractional clearance of magnesium between groups. CONCLUSION: Angiotensin converting enzyme inhibitors have an important magnesium conserving action, possibly via their effect on glomerular filtration rate.