Bronchodilating effects of salbutamol from a novel inhaler Airmax.

This randomized, placebo-controlled, evaluator-blind, five-way crossover study compared the equivalence in terms of FEV1 response to single ascending cumulative doses of salbutamol (100-400 micrograms) from Airmax, a new multidose dry powder inhaler, in comparison with placebo, the same dose from a standard pressurized metered dose inhaler (Ventolin) or at double the dose from the dry powder inhalers Diskhaler and Accuhaler. Sixty-one adult asthmatic subjects with FEV150-80% predicted and > or = 15% increase in FEV1 to salbutamol took part. Equivalence was declared if the 95% CI for the ratio of the FEV1 responses to the two treatments was within the range 90-111%. Following the cumulative four doses, FEV1 (1) changes pre-dose to the highest dose were: 2.53-3.31, 2.47-3.30, 2.51-3.35, 2.52-3.31 and 2.57-2.55 for Airmax salbutamol, salbutamol Ventolin, salbutamol Diskhaler, salbutamol Accuhaler and placebo, respectively. The 95% CIs for the ratio of Airmax salbutamol to each of the active devices were within +/- 5% demonstrating a 1:1 dose equivalence between Airmax salbutamol and Ventolin and a 1:2 dose equivalence between each of the other two salbutamol dry powder devices. Adverse events profiles were similar for all treatments. In conclusion, the novel multidose inhaler Airmax salbutamol is as efficacious and safe as the pressurized metered dose inhaler without the need for co-ordinating actuation and inhalation and with the added benefit of a dose counter.

Inhaled beclomethasone (BDP) with non-CFC propellant (HFA 134a) is equivalent to BDP-CFC for the treatment of asthma.

As part of a development programme for a range of new CFC-free beclomethasone dipropionate (BDP) inhalers, two multicentre double-blind studies have been conducted to compare the therapeutic equivalence of a new HFA-134a propellant-formulated BDP metered-dose inhaler (Norton Healthcare Ltd, London, U.K.) with a CFC counterpart for the management of adult patients with all grades of asthma. Doses of 100 micrograms qds for 6 weeks were administered in a low dose study and in a high dose study 500 micrograms qds doses were given for 12 weeks. Efficacy assessments included lung function (FEV1) in the clinic and asthma symptoms, peak flow rates and bronchodilator use by patients on diary cards. Safety parameters measured included routine haematology and biochemistry (including serum cortisols), clinical adverse events and throat swabs for Candida spp. Both CFC and HFA-formulations of inhaled BDP produced similar and significant improvements in lung function and asthma symptoms. In the low dose study, baseline to endpoint FEV1 increased from 2.2 +/- 0.51 to 2.5 +/- 0.81 (P = 0.0001) with BDP-CFC and from 2.2 +/- 0.51 to 2.6 +/- 0.81 with BDP-HFA (P = 0.0001), with no significant difference between treatments. In the high dose study, corresponding increases were 2.1 +/- 0.71 to 2.4 +/- 0.91 (P = 0.0002) for BDP-CFC and 2.1 +/- 0.71 to 2.3 +/- 0.71 (P = 0.017) for BDP-HFA. PEF also improved similarly on both treatments in both studies. Both formulations were well tolerated with no difference in the pattern of adverse events, effect on serum cortisol or Candida colonization. These studies showed that, in the management of asthma, the new HFA-formulated BDP metered dose inhaler is equivalent to, and directly substitutable for, the older CFC-formulated product at the same dose, making change-over for patients straightforward.

Overview of initial clinical studies with intravenous and oral GR43175 in acute migraine.

The novel 5-HT 1-like receptor agonist GR43175 has been evaluated as a treatment for acute migraine in a series of open, dose-ranging and controlled clinical trials. Patients with severe attacks of migraine have attended special pain or headache clinics for treatment and assessment. Given intravenously as a bolus, GR43175 is capable of aborting all migraine symptoms within 10-30 min in over 90% of cases at a dose of 64 micrograms/kg. Characteristic transient and reversible side effects with such a regimen include feelings of heaviness, pressure and occasionally warmth or tingling which can be diminished by extending the duration of drug administration to a short infusion. Initial dose-ranging studies with a dispersible tablet formulation of GR43175 have revealed an efficacy of 70-85% within 2 h with doses of 70-280 mg. Furthermore, tolerability is excellent. These encouraging early results warrant larger-scale controlled studies of GR43175 in acute migraine.

Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine.

GR43175, a selective 5-HT1-like agonist, was given as an intravenous infusion in an open dose-ranging study to treat 46 attacks of severe migraine in 34 patients. The highest dose, 2 mg infused over 10 min in 24 severe attacks, resulted in rapid and complete relief of symptoms in 17 attacks (71%) and in improvement to a non-migrainous residual headache in 7 attacks. Treatment was well tolerated, the only adverse effects being transient feelings of heaviness and pressure, predominantly in the head. GR43175 may represent an important advance in the treatment of acute migraine.

Clinical pharmacokinetics of ergotamine in migraine and cluster headache.

Ergotamine has been in use for the treatment of migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks. Only during the last few years have assays been developed, enabling its pharmacokinetics to be studied. Appropriate assays for determining ergotamine concentrations in plasma are radioimmunoassay and high-performance liquid chromatography. There is great interindividual variation in absorption of ergotamine in both patients and normal volunteers. Bioavailability is of the order of 5% or less by oral or rectal administration. After intramuscular or intravenous administration, plasma concentrations decay in a biexponential fashion. The elimination of half-life is 2 to 2.5 hours and clearance is about 0.68 L/h/kg. As yet, formal pharmacokinetics following oral dosing have not been determined. There is some evidence that ergotamine enters the cerebrospinal fluid. Metabolism occurs in the liver, and the primary route of excretion is biliary. Up to 90% of migraine patients experience complete or partial symptom relief after ergotamine, providing the drug is given as early in their attack as possible. Efficacy is greatest after parenteral administration, although adverse effects may make the rectal or inhaled routes preferable. There is some evidence to suggest that good responses are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration. The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation. Principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities. Ergotamine dependence is not uncommon, resulting in an exacerbation of the above symptoms. Dosage must therefore be limited to no more than 10mg per week to minimise toxicity.

Gastric ulcer healing with ranitidine and cimetidine. A multicentre study.

A single-blind study of 339 patients in 19 centres compared the efficacy and tolerance of ranitidine in treating endoscopically confirmed gastric ulcers. Ranitidine (150 mg twice daily) was compared with cimetidine (1 g daily in divided doses) over 4 weeks, followed by a second 4-week treatment for any patient whose ulcer was not healed. In 292 patients who completed the study, endoscopy showed healing in 69% of patients receiving ranitidine and 59% receiving cimetidine after 4 weeks, and 90% and 88%, respectively, by 8 weeks. These results were not significantly different, and, similarly, healing rates for different ulcer sites did not differ. There were no serious adverse drug reactions during the study. Ranitidine is an effective and safe treatment for healing gastric ulcers, with a tendency to produce a faster healing rate than cimetidine during the first 4 weeks of treatment.