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Biomedical subjects

W E Dodson

Publications and source records attributed to W E Dodson.

At least 37 records · Page 2Linked to original sources
PubMed1987

Special pharmacokinetic considerations in children.

Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.

Administration, Rectal↗
PubMed1987

Carbamazepine efficacy and utilization in children.

Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmaco-kinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.

Carbamazepine↗
PubMed1987

Phenytoin and carbamazepine, alone and in combination: anticonvulsant and neurotoxic effects.

Comedication with phenytoin and carbamazepine is frequently used in patients with refractory seizures, although the benefit of this strategy has not been established. To assess whether the combination is a rational anticonvulsant treatment, we determined the therapeutic index (toxicity:efficacy ratio) for the drugs, alone and together, in mice, The individual agents were virtually identical in anticonvulsant and neurotoxic activity, and combined use had no additional therapeutic advantage. Analysis of drug concentrations in brain showed an additive pharmacodynamic interaction for phenytoin and carbamazepine, indicating that the combination is unlikely to be superior to either drug alone. Thus, we find no experimental justification for the simultaneous use of phenytoin and carbamazepine in the treatment of epilepsy.

Animals↗
PubMed1984

Clinical investigation in Duchenne muscular dystrophy: IV. Double-blind controlled trial of leucine.

Ninety-six patients with Duchenne muscular dystrophy (DMD) were randomized and placed either on placebo or oral leucine at a dose of 0.2 g per kg per day. Patients were evaluated using a protocol that measured muscle strength, joint contracture, functional grade and activity, and pulmonary function tests. After 1 month there was a transient but significant difference in the strength of the two groups, the treated group being stronger than the placebo group. At 6 months there was also a transient difference in joint contracture measurements. Analysis of the data showed that the difference between the groups for both these measurements could not be ascribed to a therapeutic effect of leucine but rather to an unexpected drop in the placebo group. This was recognized only because the slope of deterioration for these functions had been well documented during the natural history phase of the study. These results indicate that oral leucine failed to produce a therapeutic response over a 1-year double-blind, controlled trial.

Child↗
PubMed1984

The steroid treatment of hereditary motor and sensory neuropathy.

A placebo or methylprednisolone (45-60 mg/M2) was administered in a crossover study as a single morning dose on alternate days to fourteen patients who had a familial progressive polyneuropathy that either began or was maximum in the distribution of the peroneal nerves. Neither the patients nor the examining physician were told whether the patient was taking a placebo or steroid but the steroid side-effects made a double-blind trial impossible. Patients were evaluated at the initiation of the study, the time of crossover, and at the conclusion of the study. Five patients with proven HMSN-I completed the study; eight patients with HMSN-I were placed on a placebo or on steroids for a six-month-period. In neither group was there any evidence of a significant increase in nerve conduction times, a decrease in terminal latencies, an increase in strength or a decrease in sensory loss when evaluated by quantitative methods. These patients were subject to a high incidence of complications from steroids possibly because of root hypertrophy, relative inactivity, and high CSF proteins. These included excessive weight gain, a compression fracture of T-12; cord compression from enlarged nerve roots; myopathy; pseudotumor; and psychiatric disturbances. Considering the lack of benefit of steroids and the high incidence of complications due to the medication further trials of adrenal-corticosteroids in patients who definitely have familial HMSN-I do not seem to be justified.

Adolescent↗
PubMed1984

Antiepileptic drug utilization in pediatric patients.

Children require larger relative doses of antiepileptic drugs than adults, and because of the greater patient-to-patient variability among children, an "average" dose is less likely to be correct for a given child. Newborns with convulsions initially have very slow drug elimination; as a group, they also have the widest range of pharmacokinetic values. After the first week of life, drug eliminating mechanisms mature and drug dosage requirements often increase dramatically. Thus in the first 6 weeks of life, intrapatient variation is a significant problem and frequent dosage changes are usually required. Thereafter a given child's kinetics are fairly stable. Infants 2 to 12 months old have the highest rates of drug clearance and often require relative doses that are 3 to 5 times larger than doses for adults. After infancy, relative dosage requirements progressively decline until adult values are reached by 10 to 15 years of age. Newborns, infants, and children, as well as adults, have nonlinear kinetics for phenytoin. Thus a wide range of apparent half-lives occur in children, depending on the phenytoin concentration and other factors. Because the kinetics of antiepileptic drugs are so highly variable in children, antiepileptic drug concentration measurements are an essential aspect of the contemporary treatment of children with epilepsy.

Adolescent↗
PubMed1983

Progressive CT abnormalities despite clinical improvement in SSPE treated with inosiplex.

Inosiplex has been utilized in the treatment of subacute sclerosing panencephalitis (SSPE), though without unequivocally established beneficial effect. We report a patient whose computerized tomographic (CT) scans demonstrated the development of progressive cerebral atrophy and multifocal white matter lesions despite continuous treatment with inosiplex and periods of considerable clinical improvement or stabilization. The findings suggest that inosiplex may not have altered the pathological consequences of SSPE and that clinical staging categories alone may not be reliable long-term correlates of the progression of the disease. Controlled studies utilizing assessment of brain mass by CT scan or other imaging devices in addition to clinical staging are required to evaluate the efficacy of inosiplex.

Adolescent↗
PubMed1983

Potentiation of the antiepileptic activity of phenobarbital by nicotinamide.

Nicotinamide is a ligand of the benzodiazepine receptor and has been reported to have anticonvulsant activity. In addition, our previous clinical experience has raised the possibility that it may also potentiate the action of barbiturates. Therefore, we have examined the anticonvulsant activity and neurotoxicity of nicotinamide alone and in combination with phenobarbital in mice. Nicotinamide had its maximal anticonvulsant effect 15 min and its maximal sedative effect 45 min after intraperitoneal injection. At 15 min, the median effective dose was 586.5 mg/kg against bicuculline and 2,019 mg/kg against pentylenetetrazol. Nicotinamide was ineffective against maximal electroshock. It had a sedative effect, with a median toxic dose of 874.8 mg/kg by the Rotorod Toxicity Test at 45 min. At doses that were ineffective by themselves (0.01 effective dose) nicotinamide potentiated the anticonvulsant activity of phenobarbital against bicuculline and pentylenetetrazol, but the toxicity was not potentiated and therefore the therapeutic index of phenobarbital was improved by nicotinamide. These results suggest that nicotinamide may be useful as a therapeutic adjunct for the treatment of epilepsy with phenobarbital or primidone.

Animals↗
PubMed1983

Chronic valproate administration reduces fasting ketonemia in children.

We previously found that chronic administration of sodium valproate to suckling infant mice reduced plasma beta-hydroxybutyrate levels but had no effect on plasma free fatty acid or glycerol concentrations. We now report that valproate has a similar effect in children taking the drug for epilepsy. In larger doses, valproate also depleted the infant mouse liver glycogen content. These findings may relate to the hepatic toxicity of valproate. We advise caution if the drug is being considered for use in chronically malnourished children or when the caloric intake of normal children is likely to be reduced during periods of acute illness.

Child↗
PubMed1983

Phenytoin elimination in newborns.

We measured the apparent half-life (t50%) of phenytoin (PHT) 30 times in 16 infants (aged 2 to 36 days) who had seizures. During the first week of life, the t50%s ranged from 6 to 140 hours. After the first week, the concentration dependence of PHT elimination was demonstrated; the t50% was related to the initial concentration (Ci). The t50% also decreased with postnatal age. Controlling for a Ci of 18 mg per liter, the average t50% decreased threefold between the first (57.3 +/- 48.2 hours) and fourth weeks (19.7 +/- 1.31). In newborns, both age-related changes and the concentration dependence of PHT elimination can cause PHT levels to decrease when constant doses are given.

Age Factors↗
PubMed1983

Primidone, phenobarbital, and PEMA: I. Seizure protection, neurotoxicity, and therapeutic index of individual compounds in mice.

Neurotoxicity and protection against maximal electroshock and Metrazol seizures from primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA) were determined in mice for each drug separately and expressed in terms of brain concentrations. Compared with PB, PEMA was 16 times less potent against electroshock and Metrazol seizures but only 8 times less toxic. Primidone was markedly less neurotoxic than PB and equally potent against electroshock, but PRM had no effect against Metrazol or bicuculline. PRM is a relatively nontoxic anticonvulsant with a different action than PB, and PEMA is both a weak and a relatively toxic anticonvulsant.

Animals↗
PubMed1983

Primidone, phenobarbital, and PEMA: II. Seizure protection, neurotoxicity, and therapeutic index of varying combinations in mice.

Neurotoxicity and protection against maximal electroshock (MES) and pentylenetrazol (Metrazol) seizures were determined in mice for various combinations of primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA). The results suggest that PRM and PB together are superior to either one alone in terms of spectrum of activity and relative toxicity. The protection against Metrazol and the toxicity of PB are both potentiated by PEMA at low concentrations. PEMA also potentiates the toxicity of combined PRM plus PB, without altering their protection against MES, thus lowering their therapeutic index. We conclude that PRM and PB together have an advantage over PB alone, especially when their brain concentration ratio is at or above 1 and PEMA concentrations are low. These conditions are usually not present at steady state in patients treated with PRM.

Animals↗
PubMed1982

Nonlinear kinetics of phenytoin in children.

The nonlinear kinetics of phenytoin were evaluated in 54 children by measuring phenytoin concentrations at steady state at three or more doses. There was good correlation between phenytoin doses and concentrations when a nonlinear kinetic model was used (r = 0.896). Increasing age was associated with a reduction in the apparent Vmax. The apparent Km was influenced primarily by drug interactions. Phenobarbital increased the Km and Vmax for phenytoin. Carbamazepine reduced both Km and Vmax. Valproic acid reduced the Km. The low Km (less than 2.6 mg per liter) found in 28% of patients makes titration of the phenytoin dose to therapeutic levels difficult.

Adolescent↗
PubMed1982

Interactions between primidone, carbamazepine, and nicotinamide.

The effect of nicotinamide on the conversion of primidone to phenobarbital was studied in mice and in three epileptic patients. In mice, 200 mg per kilogram of nicotinamide increased the half-life of primidone by 47.6%, and the conversion to phenobarbital and phenylethylmalonamide was decreased by 32.4% and 14.5%, respectively. Nicotinamide also decreased the conversion of primidone to phenobarbital in patients. The dose of nicotinamide correlated directly with the primidone-phenobarbital ratio (r = 0.861, p less than 0.01). Nicotinamide also increased carbamazepine levels in two patients treated with this drug. The data demonstrate that nicotinamide inhibits metabolism of primidone in mice and metabolism of primidone and carbamazepine in humans. This probably occurs by inhibition of cytochrome P-450 by nicotinamide.

Animals↗