AY-9944 (trans-1,4-bis(2-chlorobenzylaminoethyl)cyclohexane dihydrochloride), a cationic amphiphilic drug, caused a rapid, irreversible and dose-dependent reduction of acid sphingomyelinase activity in normal human fibroblasts without changing the activities of other lysosomal hydrolases tested. Examinations of activities against synthetic substrates and of the pH-dependency of sphingomyelinase in the drug-treated cells also suggested that the reduction of activity was specific to acid sphingomyelinase. Such a specific reduction was also found with 12 other cationic amphiphilic drugs, most of which have been shown to be inducers of experimental phospholipidosis in animals and/or cultured cells. These results strongly suggest that acid sphingomyelinase is involved in the process of drug-induced lipidosis. The reduction of acid sphingomyelinase seemed not to be due to direct inhibition by these drugs, a specific loss of the enzyme into the culture medium, the presence of inhibitor in the drug-treated cells, or impaired synthesis of the enzyme. There was no indication that changes in the catalytic properties of the enzyme, or changes in the requirement of detergents for its activity occurred in the cell. These results suggest that AY-9944 and other cationic amphiphilic drugs may cause the reduction of acid sphingomyelinase activity by inducing an increased rate of degradation of the enzyme or by causing an irreversible inactivation via some undetected factor.

No abstract

We studied the clinical efficacy of allopurinol as add-on therapy in 31 patients with intractable epilepsy. When administered for a short time, allopurinol was effective in 17 patients (55%); 8 were seizure-free, 8 had 75% decrease in seizure frequency, and 1 had greater than 50% decrease. Allopurinol was most effective in patients with localization-related epilepsy, especially in secondarily generalized tonic-clonic seizures. Allopurinol was not as effective in patients with Lennox syndrome or West syndrome, or in severe myoclonic epilepsy in infants. When allopurinol was administered greater than 1 year, its initial effectiveness continued in 8 of 14 patients who exhibited initial improvement. In 2 of the remaining 6 patients, the initial improvement disappeared during the course of treatment but control was regained by increasing the dosage of allopurinol. Mild side effects were observed in 4 patients (13%): drowsiness in 3 and abdominal pain in 1. Allopurinol may be a useful antiepileptic drug (AED), and a double-blind placebo-controlled trial should be performed.

An 8-year old girl with a not previously described type of complicated hereditary spastic paraplegia (HSP) is presented. Spasticity in her lower limbs had already been recognized during infancy and worsened progressively. Severe delay in mental development was observed. Peripheral neuropathy and optic atrophy developed at 5 years of age. On brain magnetic resonance imaging, an abnormally thin corpus callosum was observed. Involvement of the fasciculus gracilis was suggested by somatosensory evoked potentials. To our knowledge, there has been no reported case of complicated HSP with peripheral neuropathy, optic atrophy and mental retardation so far. We postulate that our patient is a sporadic case of not previously described complicated HSP.

Breath tests using fatty acids labeled with a stable isotope (carbon 13) were carried out on epileptic patients treated with valproic acid in order to detect abnormal fatty acid metabolism. The patients were given 13C-octanoic acid or 13C-palmitic acid orally, and expired air was collected at appropriate intervals for the analysis of 13CO2 content by a mass spectrometer. Eight patients were tested in the palmitic acid breath test and nine patients in the octanoic acid breath test. Controls for these tests were patients treated with antiepileptic drugs other than valproic acid and unmedicated cerebral palsy patients. In the valproic acid-treated group, 13C recovery was reduced by 56% in seven hours on the 13C-palmitic acid breath test, while the octanoic acid breath test showed a 52% reduction in one hour. This suppression of fatty acid oxidation was significantly correlated with dose of valproic acid in both tests. No influence of other drugs was detected, and the effect of administered carnitine was not conclusive. This study demonstrates the usefulness of 13C-labeled fatty acid breath tests in clinical practice.