Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics.

We studied the genetically determined hydroxylation polymorphism of S-mephenytoin in a Korean population (N = 206) and the pharmacokinetics of diazepam and demethyldiazepam after an oral 8 mg dose of diazepam administered to the nine extensive metabolizers and eight poor metabolizers recruited from the population. The log10 percentage of 4-hydroxymephenytoin excreted in the urine 8 hours after administration showed a bimodal distribution with an antimode of 0.3. The frequency of occurrence of the poor metabolizers was 12.6% in the population. In the panel study of diazepam in relation to the mephenytoin phenotype, there was a significant correlation between the oral clearance of diazepam and log10 urinary excretion of 4-hydroxymephenytoin (rs = 0.777, p less than 0.01). The plasma half-life of diazepam in the poor metabolizers was longer than that in the extensive metabolizers (mean +/- SEM, 91.0 +/- 5.6 and 59.7 +/- 5.4 hours, p less than 0.005), and the poor metabolizers had the lower clearance of diazepam than the extensive metabolizers (9.4 +/- 0.5 and 17.0 +/- 1.4 ml/min, p less than 0.001). In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01). The findings indicate that the Korean subjects have a greater incidence of poor metabolizer phenotype of mephenytoin hydroxylation compared with that reported from white subjects and that the metabolism of diazepam and demethyldiazepam is related to the genetically determined mephenytoin hydroxylation polymorphism in Korean subjects.

Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquin, and mephenytoin.

Exposure to certain environmental agents may induce a scleroderma-like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S-mephenytoin, whereas the ability to hydroxylate debrisoquin and N-acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N-hydroxylators of dapsone had a tenfold increased risk of scleroderma (p = 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.

Synovial fluid characteristics and the lupus erythematosus cell phenomenon in drug-induced lupus. Findings in three patients and review of pertinent literature.

The characteristics of synovial fluid obtained from 3 patients with drug-induced lupus erythematosus are described. Two patients had "inflammatory" counts of synovial leukocytes, in the range of 2,500-39,000/mm3, with mononuclear predominance in 1 patient and neutrophil predominance in the other. The third patient had "noninflammatory" fluid, with mononuclear predominance. Lupus erythematosus cells formed in vivo were observed in the synovial fluid of 2 of the patients. Biopsy of the synovium of 1 patient showed nonspecific chronic inflammatory changes. Our findings in these patients with drug-induced lupus are indistinguishable from those previously described in patients with idiopathic lupus erythematosus.

[Clinical significance and pathogenesis of drug- or microbe-induced autoimmune hemolytic anemias]. / Klinische Bedeutung und Pathogenese medikamentös oder mikrobiell induzierter autoimmunhämolytischer Anämien.

Methyldopa and several other drugs, continuously taken over months or years, may induce autoimmunity in persons having a probably genetic predisposition. The autoimmunity is reversible after discontinuation of the drug. A number of infectious agents may lead to the same effect. The autoantibodies can react with different autologous targets, for instance red blood cells. This may occasionally cause an autoimmune haemolytic anaemia. The two pathogenetic cardinal points are discussed in the case of the methyldopa-induced autoimmune haemolytic anaemia: the induction of the process results very probably by inhibiting or blocking of the competent suppressor-T-lymphocytes, which normally prevent an autoantibody production, representing a form of chemical "contrasuppression". This has been demonstrated in cultures of peripheral human blood lymphocytes of patients on methyldopa therapy. The second pathogenetic cardinal point is the effect of the autoantibody after its binding to the drugs investigated up to now. Rarely it is pathogenic. This relation is exactly contrary to the idiopathic warm autoantibody anaemia and remains an unsolved problem. A reversible selective deficiency of suppressor-T-cells has also to be postulated for other autoimmune haemolytic anaemias and autoimmune diseases induced by drugs or infectious agents.

Evidence for the epoxide-diol pathway in the biotransformation of mephenytoin.

A dihydrodiol metabolite of mephenytoin (5-dihydroxycyclohexadienyl)-5-ethyl-3-methylhydantoin and other mono- and dihydroxylated and N-demethylated metabolites were identified in urine from a male epileptic patient receiving therapy with mephenytoin (300 mg/day). Metabolites, extracted from urine before and after enzymatic hydrolysis, were derivatized with a trimethylsilyl reagent and analyzed by combined gas chromatography and mass spectrometry. Two previously unreported metabolites were characterized: 5-ethyl-5-(di-hydroxyphenyl)-3-methylhydantoin and 5-ethyl-5-(hydroxy-methoxy-phenyl)-3-methylhydantoin. The structures of several other metabolites were confirmed: N-demethylmephenytoin, 5-ethyl-5-hydroxyphenylhydantoin, 5-ethyl-5-hydroxyphenyl-3-methylhydantoin and mephenytoin dihyrodiol. The dihydrodiol metabolite was of special interest since it was probably produced via an epoxide intermediate, 5-(epoxy-cyclohexadienyl)-5-ethyl-3-methylhydantoin. Previous reports have demonstrated that epoxides of this structural class are extremely reactive compounds, capable of alkylating biologic macromolecules. Covalent binding of the mephenytoin epoxide to macromolecules may be an important factor in the production of adverse and sometimes fatal side effects observed in patients receiving long-term therapy with mephenytoin.

Mucocutaneous eruptions due to antiepileptic drug therapy in children.

Three children with bullous erythema multiforme and 1 with toxic epidermal necrolysis associated with antiepileptic drug therapy are described. One patient is unique because of seven mucocutaneous eruptions caused by three classes of antiepileptic drugs. Lymphocyte stimulation by antiepileptic drugs could not be demonstrated in the 2 patients in whom appropriate studies were performed, and no precipitating antibodies to antiepileptic drugs were found. Observation of four diagnostic and therapeutic principles, which are illustrated by the course of our patients, may reduce the incidence of life-threatening mucocutaneous eruptions and simplify the long-term management of individuals in whom such reactions occur.

[A progressive systemic sclerosis like disease due to anticonvulsive therapy? (author's transl)]. / Eine der progressiven Sklerodermie ähnliche Erkrankung als Folge der antikonvulsiven Therapie?

Two cases are presented which have been treated anticonvulsively for many years - especially with Phenytoin and Mephenytoin. The clinical syndrom as well as the changes of the connective tissue show transitions of Progressive systemic sklerosis (PSS) to systemic Lupus Erythematodes (SLE) and Dermatomyositis. The correlation with the therapy is reflected in consideration of immunological phenomenons.

Rickets in children receiving anticonvulsant drugs. Biochemical and hormonal markers.

Forty-one epileptic children, aged 2 to 16 years, receiving combinations of phenobarbital, phenytoin, and primidone, and 39 control children were studied. The epileptics demonstrated slight but significant reductions in serum calcium, phosphorus, and 25-hydroxyvitamin D concentrations, and a significant increase in serum alkaline phosphatase values. No significant difference in serum immunoreactive parathyroid hormone levels was noted. Further analysis of the data revealed that patients whose drug therapy included primidone had the lowest serum levels of calcium and 25-hydroxyvitamin D. They had also received the largest number of drugs for the longest duration, and had serum phenobarbital levels that were significantly higher than those of other patients. The minimal degree of vitamin D deficiency in our epileptic children contrasts with the results of other investigations and warrants emphasis. The reasons for this difference are not apparent.

Peripheral blood lymphocytes in systemic lupus erythematosus. Relation to activity.

Peripheral blood lymphocytes from 20 patients with systemic lupus erythematosus (SLE), 3 patients with drug-induced lupus and 20 normal controls were studied. The absolute number of E-rosette-forming cells (ERFC) and surface immunoglobulin-bearing cells were determined during active and inactive stages of the disease. An attempt was made to establish the relationship between the number of ERFC and the clinical stages of the disease on one hand and treatment on the other. A decrease in ERFC was observed in all SLE patients, but it was most prominent in patients with active disease. No correlation was found between treatment and the decreased numbers of ERFC.

Mephenytoin: a reappraisal.

Serum levels of mephenytoin (Mesantoin) and its metabolite nirvanol were correlated with effectiveness and side effects in 93 patients. Mean mephenytoin level was 8% of the combined mephenytoin plus nirvanol levels. "Total mephenytoin" level should be used clinically, as neither individual component is as well correlated with clinical phenomena. Serum levels of 25 to 40 mug/ml usually yield improvement in seizure control without discomfort, and three-quarters of patients had fewer seizures. Side effects frequently associated with phenytoin were absent, but drowsiness, an occasional rash, and a single, fatal case of aplastic anemia were found. Performance on psychological tests of cognitive-attentional skills showed a modest improvement during mephenytoin administration. The drug merits wider employment in refractory seizure problems, but vigilant follow-up is required.

Antinuclear antibodies and lupus-like syndromes in children receiving anticonvulsants.

Drug-induced systemic lupus erythematosus (SLE)-like syndromes in children are most commonly associated with the administration of ethosuximide, diphenylhydantoin, and trimethadione. Five children receiving ethosuximide who presented with syndromes suggestive of SLE were studied. Each and fever, malar rash, arthritis, and lymphadenopathy. Two children had pleural effusions and another developed myocarditis and pericarditis. Three patients had anti-DNA antibodies associated with low serum C3. In four of five children symptoms disappeared with the discontinuation of ethosuximide; two of these continue to have antinuclear antibodies (ANA). One child continues to have active SLE with nephritis. A group of 101 children from a seizure clinic were tested for the presence of ANA. ANA were found in 14 of 70 children receiving ethosuximide and/or diphenylhydantoin; 2 of 14 had anti-DNA antibodies. Serum ANA titers in the drug-induced SLE group did not differ significantly from those of the asymptomatic seizure patients. ANA were also present in 5 of 23 children receiving phenobarbital only. The induction of ANA by phenobarbital is a possible hypothesis. Quantitative immunoglobulins and C3 were not significantly altered in the asymptomatic children with ANA. Follow-up studies at ten months showed no asymptomatic child with ANA to have developed clinical with ANA to have developed clinical evidence of SLE. This study suggests that asymptomatic children who develop ANA should have careful observation, but need not have their anticonvulsants discontinued.

Effect of 2 br-alpha-ergocryptin (CB 154) on serum prolactin and the clinical picture in a case of progressive gigantomastia in pregnancy.

A 24 year old woman who had epilepsy since the age of 7 years and who was still using antiepileptics, developed an excessive mamary growth (gigantomastia) during pregnancy. Treatment with CB 154 (Sandoz), 2 Br-alpha-ergocryptin in a dose of 2.5 mg three times a day from the 27th week of pregnancy, resulted in prompt improvement with a corresponding decrease in the plasma prolactin, return of the breast temperature to normal, and disappearance of the EEG-abnormalities. After parturition and subsequent mammoplasty the woman soon became pregant again. During this pregnancy, which terminated in the birth of a normal child, treatment with CB 154 was started early and continued throughout pregnancy with success and without side effects.

Generalized lymphadenopathy and nephrotic syndrome as a manifestation of mephenytoin (mesantoin) toxicity.

This report describes a patient who developed marked generalized adenopathy and nephrotic syndrome while receiving mephenytoin (mesantoin) for a seizure disorder. Renal biopsy showed a diffuse proliferative glomerulonephritis. Lymph node histopathology revealed replacement of parenchyma with lymphocytes, eosinophils, and reticuloendothelial cells. A hypersensitivity reaction is postulated as the etiology of both these processes.

Lyell's syndrome: histological, immunohistochemical and serological observations.

Observations of Lyell's syndrome in two girls, one 2 and the other 7 years of age, investigated serologically, histologically and by immunofluorescent technique, are reported. In both cases. the disease had been preceded by a prolonged or repeated treatment with acetylsalicylic acid, in the first case in combination with sulphonamides and antibiotics and in the second in combination with mephenytoin. Immunofluorescent staining revealed immunoglobulins in subepidermal blisters and along the dermal vessels. Acetylsalicylic acid has been assumed to have been one of the causative factors of the violent progression of toxic epidermal necrolysis, probably by an antigen-antibody reaction. This has been supported by serologic demonstration of antibodies to acetylsalicylic acid in both cases.

Anticonvulsant osteomalacia.

Drug-induced osteomalacia appears to be a relatively common disorder in patients receiving long-term anticonvulsant drug therapy. The severity of clinical manifestations in any given individual appears to be a function of the combined effects of a variety of factors including drug type and total drug dose, dietary vitamin D intake, sunlight exposure, and physical activity level. Aided by the recent development of sensitive techniques such as the serum 25-hydroxyvitamin D assay and the photon absorption methods for bone mass determination, one can now detect abnormalities in vitamin D and bone metabolism with much greater precision. As a consequence, the incidence of disordered mineral metabolism in patients receiving long-term anti-convulsant therapy can be determined with greater precision and therapeutic regimens instituted to prevent the associated morbidity.