Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man.

Although 7-hydroxymethotrexate is a major metabolite of methotrexate during high-dose therapy, negligible methotrexate-oxidizing activity has been found in-vitro in the liver in man. The goals of this study were to determine the role of aldehyde oxidase in the metabolism of methotrexate to 7-hydroxymethotrexate in the liver and to study the effects of inhibitors and other substrates on the metabolism of methotrexate. Methotrexate, (+/-)-methotrexate and (-)-methotrexate were incubated with partially purified aldehyde oxidase from the liver of rabbit, guinea-pig and man and the products analysed by HPLC. Rabbit liver aldehyde oxidase was used for purposes of comparison. In-vitro aldehyde oxidase from the liver of man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, but the turnover is low. However, formation of 7-hydroxy-methotrexate from all forms of methotrexate by the liver in guinea-pig and man was significantly inhibited in the presence of 100 microM menadione and chlorpromazine, potent inhibitors of aldehyde oxidase. Allopurinol (100 microM) had a negligible inhibitory effect on liver aldehyde oxidase from guinea-pig and man. Allopurinol is a xanthine oxidase inhibitor. The production of 7-hydroxymethotrexate was enhanced in the presence of allopurinol. Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate. By employing potent selective inhibitors of aldehyde oxidase, menadione and chlorpromazine, we have demonstrated for the first time that liver aldehyde oxidase from man is minimally involved in methotrexate oxidation.

Monitoring of intra-operative visual evoked potentials during functional endoscopic sinus surgery (FESS) under general anaesthesia.

Functional endoscopic sinus surgery (FESS) is an effective treatment for inflammatory sinus disease. The potential for major complications during FESS is high particularly under general anaesthesia. The most serious of these is injury to the eye leading to blindness. We looked at the feasibility of monitoring flash visual evoked potentials (VEP) simultaneously from both eyes during FESS. Five patients were included in this preliminary study. A haptic contact lens connected by fibreoptic cable to a photostimulator was placed on the eyes and stimulus of comparable intensity to a conventional strobe was delivered. We found that an increase in P100 latency to be an indicator of optic nerve compression. However, for this to be useful the diastolic blood pressure should not fall below 50 mmHg, the oxygen saturation should be maintained at 98 per cent and bleeding should be minimized during surgery. The changes in the amplitude of P100 was not found to be useful. While there is no substitute for learning endoscopic surgery by cadaveric dissection and supervised training we believe that in selected cases VEP monitoring can be employed with profit.

Sodium valproate in the treatment of resistant epilepsy.

A series of 115 patients was treated with sodium valproate (Epilim) for periods ranging from 6 to 24 months and in dosages ranging from 400 mg to 2400 mg daily. All but six of these patients had intractable epilepsies and had been previously treated unsuccessfully with other anti-epileptic agents. Eighty patients had generalised seizures and 35 had partial seizures which, in 26 cases, were secondarily generalised. Reduction of seizure frequency by over 50 per cent occurred in about 70 per cent of patients with generalised seizures but in only 37 per cent of those with partial seizures. A number of patients reported increased alertness, improvement of mood, increased appetite and improved performance at school. The adverse effects encountered were gastro-intestinal symptoms, weight gain and hair loss.