Generic inhaled salbutamol versus branded salbutamol. A randomised double-blind study.

Generic substitution of salbutamol lags behind that of other drugs in Scotland and a negative perception by both patients and doctors may explain this. The aim of this study was to assess whether, in clinical practice, there was any difference in efficacy between branded salbutamol (Ventolin) and a generic preparation. Asthmatic patients using a Ventolin metered-dose inhaler at least twice a day for symptom relief were entered into a double-blind cross-over study, comparing Ventolin, blinded Ventolin and a generic salbutamol in random order for two weeks each. Daily peak flows, inhaler use and bronchodilator response were recorded. At the end of each treatment period patients rated their inhaler against their usual Ventolin on a 5-point scale. Forty patients were entered into the study; 90% received 1000 micrograms or more of inhaled steroids per day. Eleven patients dropped out during the run-in phase. In the remaining 29 patients, no significant difference between treatments could be found in any of the objective parameters measured. Fifty-five per cent of patients said they could detect a difference between the inhalers, and 45% noted a difference between their usual Ventolin and the open or blinded Ventolin. This study showed clinical equivalence between a generic and branded salbutamol. Patients' own assessment of their relief inhaler seems to be influenced by factors other than efficacy. The study highlights that careful encouragement is required when changing to a generic product and has particular implications for the forthcoming conversion to CFC-free products.

Observations on primary health care in Ontario, Canada.

The Canadian health care system has developed very differently from that of its neighbour, the United States of America. It has a publicly financed and administered universal insurance plan which provides good access to high quality medicine, free at the point of delivery. Increasing costs, however, mean that painful political decisions on health will have to be made. Experiments with alternative means of financing primary health care provision and the Canadian approach to postgraduate education may offer useful ideas for general practice in the United Kingdom.

Effect of gamma aminobutyric acid on the carbon dioxide rebreathing response of normal subjects: a study using vigabatrin.

Animal studies suggest that gamma aminobutyric acid (GABA) may be an important neurotransmitter in the control of respiration. Vigabatrin, a new drug for the treatment of epilepsy, is thought to exert its effect by increasing GABA concentrations in the brain. To assess the effect of increased GABA concentrations in the brain on human respiration we measured the ventilatory response to carbon dioxide in seven normal subjects after they had taken vigabatrin or placebo for three days in a double blind crossover study. There was no change in either the slope or the intercept of the curve of the ventilatory response to carbon dioxide after vigabatrin by comparison with placebo. This study suggests that GABA does not have an important role in the control of respiration in normal individuals.

Interaction between vigabatrin and phenytoin.

1. The study was designed to determine the mechanism by which vigabatrin causes a fall in plasma phenytoin concentrations when added to the drug therapy of eight epileptic patients. 2. Total plasma phenytoin concentration was measured before and at intervals during 5 weeks' treatment with vigabatrin. 3. Plasma protein binding of phenytoin, the urinary ratio of phenytoin to 5-(p-hydroxyphenyl)-5-phenylhydantoin, and antipyrine clearance were measured before and at the end of treatment period. 4. Mean plasma phenytoin concentration fell significantly by 23% during the fifth week. 5. No change was found in any of the other measures. 6. Although an interaction between phenytoin and vigabatrin has been confirmed, the mechanism has not been elucidated.

A comparison of the acute effect of single doses of vigabatrin and sodium valproate on photosensitivity in epileptic patients.

The acute effect of oral administration of a single dose of vigabatrin, a new antiepileptic drug which acts by irreversible enzyme-activated inhibition of the brain enzyme, GABA-aminotransferase, on the photoconvulsive response in patients with photosensitive epilepsy, was compared with that of the established antiepileptic drug, sodium valproate. Both drugs significantly suppressed the photoconvulsive response in 3 out of 6 subjects. This result was interpreted as further evidence of vigabatrin's potential value in the future treatment of patients with epilepsy.

Micro-vacuolation in rat brains after long term administration of GABA-transaminase inhibitors. Comparison of effects of ethanolamine-O-sulphate and vigabatrin.

Two "suicide" inhibitors of GABA-aminotransferase which are known to raise the concentration of GABA in vivo and to have anti-convulsant properties, have been compared for the extent to which they produce micro-vacuoles in the brains of rats. The compounds gamma-vinyl-GABA (Vigabatrin) and ethanolamine-O-sulphate were administered orally for six months to rats at doses that produced the same increase in brain GABA levels. Micro-vacuolation was found to be present in the brains of animals treated with either compound but to be more severe in those treated with Vigabatrin. A quantitative assessment using computerised image analysis revealed that both the number of vacuoles, and the area occupied by them, was twice as high in the Vigabatrin treated animals as in those treated with ethanolamine-O-sulphate. This quantitative difference could be seen to be due to the fact that in the Vigabatrin treated animals the vacuoles extended into the white matter tracts between the cerebellar folia whereas in those animals treated with ethanolamine-O-sulphate it was confined to the roof nucleus.

Pharmacokinetics of antipyrine in epileptic patients.

The pharmacokinetics of antipyrine were examined after oral and intravenous administration to 20 epileptic subjects receiving antiepileptic drug therapy. Bioavailability was essentially complete (mean bioavailability 101.2% +/- 14.4 (s.d.] indicating that even in enzyme induced subjects, antipyrine behaves as a restrictively eliminated compound with negligible presystemic elimination in the gut or liver. Of the generally used measures of enzyme induction (oral clearance, oral half-life and intravenous half-life) oral clearance was the most closely related to the intravenous clearance of antipyrine (r = 0.919, P less than 0.001). Oral antipyrine administration is an alternative to intravenous administration in epileptic subjects who are enzyme-induced.

An update on sodium valproate.

Sodium valproate has been in clinical use for the treatment of epilepsy in Great Britain since 1973 and in the United States since 1978. It is chemically quite different from the existing antiepileptic drugs. Although most authorities concentrate on its modification of GABAergic inhibitory transmission in the central nervous system, its mechanism of action remains obscure. It has been shown to be an effective antiepileptic drug in a wide variety of seizure types, but clinically, its major use to date has been in generalized seizures. It is particularly effective in photosensitive epilepsy and myoclonus. Most adverse reactions to sodium valproate are mild and reversible, but with increasing experience, the drug's rare, idiosyncratic, adverse effects are becoming apparent, particularly hepatotoxicity and teratogenicity. The role of therapeutic drug monitoring in the management of patients taking sodium valproate is controversial.

Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy.

Twenty-four patients with frequent drug-resistant seizures took part in a randomised double-blind placebo-controlled crossover trial of the GABA-transaminase inhibitor, gamma-vinyl GABA. It was added to their usual drug treatment in a dose of 3 g daily. The total number of seizures during the 9-week active treatment period was less than that in the placebo period (p less than 0.001, two-way analysis of variance). The greatest effect was on complex partial seizures. Mean weekly seizure frequency (complex partial and tonic-clonic) was 6.2 fits/week for the placebo period and 3.5 fits/week for the gamma-vinyl GABA period. Adverse effects, particularly drowsiness and mood changes, occurred more often during administration of active drug. Serum concentrations of phenytoin were lower during gamma-vinyl GABA treatment than during placebo (p less than 0.05), but the concentrations of other anticonvulsants given concomitantly did not change. These results suggest that gamma-vinyl GABA is an effective antiepileptic compound.

Should we routinely measure free plasma phenytoin concentration?

The plasma protein binding of phenytoin was investigated in 56 epileptic patients attending the outpatient clinic. The free phenytoin fraction was measured by equilibrium dialysis at 37 degrees C and the total concentration by a homogenous enzyme immunoassay technique. The free fraction ranged from 0.123 to 0.177 (median 0.144, mean +/- s.d. = 0.145 +/- 0.12). Distribution was consistent with normality. Four of the patients were also taking sodium valproate. The median free fraction of phenytoin in these patients was 0.174, 21% higher than that of the total group (P less than 0.05). The total concentration of phenytoin varied from 0.3 to 29.4 micrograms/ml (median 12 micrograms/ml, mean +/- s.d. = 13.31 +/- 6.13 micrograms/ml) and the free fraction was not related to the total drug concentration. There was a highly significant relationship between free phenytoin concentration and total phenytoin concentration (r = 0.986, P less than 0.001). There appears to be very little variability in protein binding of phenytoin in epileptic patients and thus total plasma phenytoin concentration closely reflects the free (unbound) drug concentration. Routine estimation of free plasma phenytoin concentration is therefore unnecessary and should be reserved for those patients where alteration in binding is likely, e.g. renal or hepatic disease or where adverse effects occur at unexpectedly low total phenytoin concentrations.