Biomedical subjects
Publications and source records attributed to J Bruni.
Protein binding of valproic acid was studied in four uremic patients on long-term hemodialysis. Before dialysis, the free fraction was 0.31 +/- 0.11 (SD); this was larger than in nonuremic subjects. During hemodialysis, the free fraction increased significantly (p less than 0.01) in three patients (mean, 0.64 +/- 0.32 SD).
The effect of the artificial kidney on the removal of carbamazepine was studied in four uremic patients undergoing chronic hemodialysis. Each patient received 500 mg of carbamazepine PO 8 hr prior to hemodialysis. Predialysis and postdialysis blood samples as well as dialysate samples were collected at various time intervals during a 4-hr hemodialysis. Samples were analyzed for carbamazepine content by HPLC. Dialysis clearance calculated from dialysate measurements averaged 53.6 +/- 10.0 mL/min which is double the reported mean plasma clearance of 27.5 mL/min. Since drug clearance by the dialyzer is twice the endogenous plasma clearance, we conclude that carbamazepine is dialyzable. Despite the significant dialysis clearance, a dosage regimen adjustment may not be necessary because of the long elimination half-life of carbamazepine of 35 hr compared to the short length of the usual hemodialysis treatment of 3-5 hr.
A high-performance liquid chromatographic method is described for monitoring plasma concentrations of cinromide (3-bromo-N-ethylcinnamamide) and its de-ethylated metabolite. Carbamazepine levels can be easily measured by the same technique. The N-isopropyl analogue of cinromide is used as internal standard, and all compounds are easily separated on a reversed-phase column operated at 55 degrees with a small-diameter pre-column maintained at the same temperature. The extraction is rapid and generally applicable to plasma and urine samples that are to be analyzed by reversed-phase chromatography. Short- and long-term reproducibility studies show less than 4% relative standard deviation for replicate determinations for all drugs. Limits of quantitation are 10-20 ng/ml with an internal standard concentration of 3 micrograms/ml. Another metabolite of cinromide, 3-bromocinnamic acid, which may have some anticonvulsant effect, can be analyzed simultaneously by buffering the mobile phase and adding an ion-pairing reagent.
Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug's bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.
Valproic acid is a new antiepileptic drug. It has a marked effect on generalized spike-wave discharges. The exact mechanism of action is uncertain; however, some evidence suggests an effect on the metabolism of gamma-aminobutyric acid. It is rapidly absorbed from the gastrointestinal (GI) tract. Concurrent administration with phenobarbital may result in elevated phenobarbital plasma concentrations. Administration with phenytoin sodium may transiently result in lower total phenytoin plasma levels. Side effects are generally mild and include fatigue, GI disturbances, weight gain, a fine postural and resting tremor, mild thrombocytopenia, and an increase in hepatic enzymes. Platelet counts and liver function monitoring should be done during valproic acid therapy. Drowsiness may be seen in patients receiving other antiepileptic drugs concurrently.
In vitro experiments using the equilibrium dialysis technique were performed to determine the binding of valproic acid to plasma components in the absence and presence of therapeutic concentrations of phenytoin. The free fraction of valproic acid was found to be dependent on the total valproic acid concentration. Phenytoin did not influence valproic acid protein binding.
The management of the pregnant epileptic requires close cooperation between the neurologist and obstetrician. To prevent complications, knowledge is required about the natural history of epilepsy during pregnancy, the possible teratogenic effects of antiepileptic drugs, and changes in their absorption, biotransformation, and excretion. Close plasma antiepileptic drug monitoring is required because of the change in the handling of antiepileptic drugs during pregnancy. The treatment of status epilepticus with intravenous phenytoin is effective. Drug interactions which may lead to toxic plasma levels of some drugs and subtherapeutic plasma levels of others should be anticipated. The risk of problems resulting from antiepileptic drug therapy during pregnancy appears to be minor, provided that proper medical supervision is available. Newer antiepileptic drugs should not be administered to the pregnant epileptic until their safety in pregnancy is fully established.
Valproic acid in therapeutic doses was used in the treatment of postanoxic intention myoclonus. Disappearance of the myoclonus occurred with marked improvement in the electroencephalogram. No significant side effects were noted. Hepatic function tests were monitored. Determination of valproic acid plasma levels was used to guide therapy. Levels above 55 micrograms were generally required. The patient remains free of myoclonus after four and one half months.
Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma phenytoin levels decreased. The interaction was transient and was not observed at the end of 1 year. Total plasma phenytoin levels returned to pre-valproic-acid levels in seven patients.
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Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one-compartment model, predicted and observed valproic acid plasma concentrations were compared. Valproic acid assay was performed by gas-liquid chromatography. There was good agreement between predicted and observed plasma concentrations. Most patients had predicted half-lives (t1/2s) of 6 to 8 hr, independent of the plasma concentration of valproic acid. Five patients had predicted t1/2s of 12 hr. The correlation between dose and plasma level was poor. Most patients had valproic acid plasma levels between 55 and 100 microgram/ml. Administration of valproic acid three times a day with determination of individual plasma concentrations offers a reliable method of monitoring. Constant levels are maintained in individual patients, but there is substantial intersubject variation.
Valproic acid is a new antiepileptic drug recently introduced in the United States for the treatment of absence seizures. In this study on patients with absence and other seizure types, the majority of patients achieved optimal control within four weeks of therapy. No patient responded to valproic acid who did not show an initial clinical response by four weeks of active therapy. Optimal response was generally achieved when plasma levels were greater than 55 microgram/ml. Excellent clinical response was observed in the treatment of absence and myoclonic seizures. Twenty-two patients continued in a long term study have maintained the same degree of seizure control as observed at the time of optimal control.
Twenty-five patients with absence seizures were treated with valproic acid in doses from 17 to 62.5 mg per kilogram per day. Nineteen patients experienced reduction of spike and wave discharges; in 11 it was greater than 75 percent. Twenty-one patients had a reduction of the total time of spike and wave discharge. Four patients had increase of spike and wave discharges. Nineteen patients had fewer absence seizures. There was no correlation between plasma concentration of valproic acid and EEG change, but clinical improvement occurred when plasma levels of valproic acid reached 50 to 60 microgram per milliliter.
The interaction of valproic acid and other antiepileptic drugs was studied in 25 patients for 5 to 9 months. Clinical evaluations, seizure records, and antiepileptic drug levels were followed regularly. Eleven of the 13 patients required a reduced phenobarbital dose when concurrently treated with valproic acid. This reduction was prompted by sedation. An average dose reduction of 46 percent resulted in an average serum phenobarbital decrease of 15 percent. Ten of 15 patients had decreased phenytoin concentrations during concurrent administration with valproic acid. No definitive conclusion was reached about other antiepileptic drugs. Decreased phenobarbital excretion because of urine acidification and displacement of phenytoin from protein binding sites may account for the observations. Careful monitoring of anticonvulsant levels is required in anticipation of the documented interactions.
Altered hepatic function tests occurred in four of 25 patients treated with valproic acid. An average dose reduction in three patients of 10 mg per kilogram per day resulted in reversion of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) to normal. The drug was discontinued in one patient. Careful monitoring of hepatic function is required of patients being treated with valproic acid, but our experience suggests that dose reduction alone may be effective in preventing untoward hepatic side effects.
The clinico-pathological features of five patients with vascular amyloid restricted to the central nervous system are presented. In three normotensive patients, intracerebral hemorrhage was the dramatic manifestation of amyloid angiopathy. In two other cases, one of amyloid in an arteriovenous malformation, the other of amyloid following therapeutic radiation, amyloid deposition was asymptomatic. Clinically, amyloid angiopathy must be considered in the different diagnosis of intracerebral hemorrhage, independent of the presence of dementia. Pathologically, a factor common to the syndrome of cerebrovascular amyloid appears to be locally increased vascular permeability resulting from a variety of previous tissue injuries.
The clinical and histologic features of a malignant intramedullary lymphoma of the spinal cord are reported. The duration of the disease was 9 months and the course was similar to other malignant intramedullary cord tumors. The tumor was confined to the cervical segment of the cord and histologically was composed of lymphocytes and plasmacytoid histiocytes. Effective treatment depends on tissue diagnosis.
A 38-year-old patient with the clinical picture of a progressive myopathy resembling limb girdle muscular dystrophy is presented. Muscle biopsy showed amyloid deposits in the walls of small endomysial blood vessels. There was no clinical or physiological evidence of peripheral nerve involvement, no plasma cell dyscrasia and no generalized amyloidosis. There was no muscle fiber hypertrophy, inflammation or neurogenic change. Theere was no response to steroid therapy. The etiopathogenesis of this amyloid angiopathy is undetermined. The extensive vessel involvement with amyloid deposition and the absence of changes indicative of muscular dystropyy or inflammatory myopathy leads us to favor an ischemic basis for this patient's myopathy.