Ranitidine pharmacokinetics and adverse central nervous system reactions.

BACKGROUND: Treatment with histamine2-receptor antagonists has been associated with adverse central nervous system reactions (CNS-ADRs). Previous studies of cimetidine have shown an association between CNS-ADRs and high cimetidine drug levels. While case reports of ranitidine CNS-ADRs have appeared, we wanted to study a series of patients, some of whom were critically ill, for the presence of CNS-ADRs and to correlate these with ranitidine pharmacokinetics. METHODS: A prospective, observational, open study included 163 consecutive patients, of whom 41 met entry criteria. A nonlinear least-squares regression analysis was used to establish a ranitidine pharmacokinetic dosing model. Ranitidine levels were determined by a high-performance liquid chromatographic assay. Individual ranitidine pharmacokinetics were determined by means of a bayesian model. Observations on 13 possible CNS-ADRs were recorded. The CNS-ADRs were evaluated by the Naranjo rating system. RESULTS: Ranitidine-associated CNS-ADRs, particularly lethargy, confusion, somnolence, and disorientation, occurred more frequently in patients with renal function impairment, and these were associated with higher peak concentrations, average plasma concentrations, and area under the curve. CONCLUSIONS: Ranitidine, when given in conventional doses, can cause CNS-ADRs, particularly in older patients who have substantial renal function impairment. These CNS-ADRs occur as a consequence of altered ranitidine disposition. Ranitidine doses should be reduced when renal function impairment is present, and patients should be carefully observed for CNS-ADRs.

Seizure activity and anticonvulsant drug concentration.

Current methods permit frequent, accurate serum anticonvulsant drug concentration measurements and continuous, 24-hour electroencephalographic recording with minimal environmental restriction. These techniques were used to perform longitudinal, 24-hour recordings of electroencephalographic paroxysmal activity and sleep-wake state concurrently with frequent measurements of serum anticonvulsant drug concentrations in two patients with poorly controlled convulsions. Drug administration was designed with the intent of producing high serum concentrations at times of maximum electroencephalographic paroxysmal activity. The suppression of clinical seizures coincided with decreased numbers of paroxysmal bursts in the electroencephalogram and increased serum anticonvulsant drug concentration.

Interlaboratory variability in determination of plasma antiepileptic drug concentrations.

The usefulness of plasma antiepileptic drug concentrations in treatment of epilepsy has been established, and many laboratories provide this service. A "blind" survey utilizing pooled patient plasma samples was conducted among 197 laboratories in the United States and Canada to establish the interlaboratory reproducibility. Three "patient specimens" containing different amounts of phenobarbital, phenytoin (diphenylhydantoin), primidone, and ethosuximide were employed; 112 laboratories reported results within five weeks. The average cost for analyzing four drugs in a single sample was $43.27. Half of the laboratories reported results outside +/- 1 standard deviation of the mean of five reference laboratories. Wide interlaboratory variability must be considered by the practicing physician. Until certified antiepileptic drug standards in a biologic matrix are available from the National Bureau of Standards, a volunteer quality control program among laboratories is needed.

High-dose monotherapy in treatment of intractable seizures.

We evaluated the therapeutic efficacy and toxicity of high-dose monotherapy, using carbamazepine or phenytoin, in patients with previously uncontrolled seizures. Treatment with a single drug was equal to or better than polypharmacy, but only a few patients became free of seizures. Toxicity was mild and associated with higher total plasma levels after polypharmacy. Free fractions ranged from 0.14 to 0.30 for carbamazepine and from 0.60 to 0.13 for phenytoin. Toxicity was associated with free phenytoin levels above 3 micrograms/ml; there was no clear relationship between free carbamazepine level and toxicity.

Salivary levels of anticonvulsants: a practical approach to drug monitoring.

Phenobarbital, phenytoin, carbamazepine, primidone, and ethosuximide were measured in saliva and plasma obtained simultaneoulsy from 115 patients. A method to correct for the effect of salivary pH on phenobarbital concentration of saliva was developed. Salivary concentrations of these drugs were found to be equivalent to the plasma free drug and to correlate closely with the total plasma levels. Expressed as percent of total plasma drug, the salivary (S) and plasma free (P) concentrations were: phenytoin, S 11.1 +/- 2.0 percent (mean +/- SD), P 10.1 +/- 2.4 percent (r = 0.97); carbamazepine, S 26.0 +/- 2.4 percent, P 25.9 +/- 3.4 percent (r = 0.97); phenobarbital, S 43.1 +/- 5.2 percent, P 40.8 +/- 7.9 percent (r = 0.91); primidone, S 75.4 +/- 24.9 percent, P 66.4 +/- 8.8 percent (r = 0.76). Ethosuximide was not bound by plasma proteins, and its plasma and salivary levels were equal.

Familial paroxysmal hypnogenic dystonia.

We studied a family with dystonic spasms that occurred with non-REM sleep. This familial disorder may be related to the sporadic cases reported previously.

Comparison of whole-blood cyclosporine levels and the frequency of endomyocardial lymphocytic infiltrates (the Quilty lesion) in cardiac transplantation.

Endomyocardial lymphocytic infiltrates (ELI), or "Quilty" lesions are morphologically and immunohistochemically distinct and are thought to be due in part to Cyclosporine therapy. In order to evaluate the relationship of ELI to CsA therapy, we compared the whole-blood CsA levels (WBCsA) with the frequency of ELI in our cardiac transplant patients. From January 1, 1987 to January 1, 1988, 364 concurrent endomyocardial biopsies and WBCsA were performed on 43 cardiac transplant patients. All biopsies were evaluated for acute rejection. ELI were recognized as well-circumscribed, flat or pedunculated lesions within the endomyocardium composed of mature T lymphocytes with pockets of B lymphocytes and occasional macrophages and plasma cells. All WBCsA were trough levels and were determined by high-pressure liquid chromatography. Results were evaluated using a logistic regression model for clustered data. ELI were observed in 17.9% (65/364) biopsies, and 60.5% (26/43) of patients had at least one ELI during the study period. The mean WBCsA was 155.2 ng/ml (SD = 62.9) in the ELI-positive group, and 190.2 ng/ml (SD = 97.0) in the ELI-negative group. Applying the regression model revealed a statistically significant negative correlation between WBCsA and the presence of ELI (P = 0.033)--that is, a lower WBCsA was associated with an increased probability of ELI. The frequency of clinically significant rejection was lower in the ELI-positive biopsies, and this correlation approached statistical significant (P = 0.053). These data suggest that ELI are unrelated to increased WBCsA and may represent an idiosyncratic reaction to CsA, or be related to factors other than CsA therapy.

Effect of dietary protein and carbohydrate on theophylline metabolism in children.

Theophylline metabolism can be altered by a variety of abnormal physiologic states as well as by exogenous factors. Adult studies demonstrate a significant influence of dietary composition on theophylline biotransformation. To examine this effect of diet, 14 children with bronchial asthma were studied during long-term theophylline administration. Each patient was maintained for 12 days on three separate diets with varying proportions of protein and carbohydrate and with constant calories and fat. Results showed significant differences in drug half-life and metabolic clearance rate parameters. Compared to the normal diet, high protein diet markedly decreased the half-life, and high carbohydrate diet greatly prolonged it (P < .001). Multiple regression analysis demonstrated these differences to correlate only with the dietary alterations. Adverse reactions and blood chemistry abnormalities were not detected during any test period. These findings firmly establish that nutritional factors exert a significant influence on theophylline pharmacokinetics in children.

The relation of anticonvulsant drug levels to complete seizure control.

This study was undertaken to determine the relationship of serum ACD levels to dosage in a group of patients who had been seizure free for at least two years. It demonstrated that some patients remain completely seizure free with DPH and/or phenobarbital serum concentrations which are well below the reported "optimal" therapeutic ranges. In addition, medicating patients with anti-convulsant drugs solely on the basis of mg/kg of body weight does not assure optimal ACD levels in any given patient. Certain patients can be maintained completely seizure free controlled with DPH and/or Pb levels of less than 10 micrograms/ml. There are several explanations for the medication concentrations observed in these patients: (1) patient noncompliance in ingestion of prescribed medication; (2) altered drug utilization; (3) a mild focus which is maintained under control with lower DPH levels than those necessary to control a more active focus; or (4) epilepsy in remission. Our observations emphasize the importance of individual regulation of medications for seizure control.

Evaluation of EMIT methods for the determination of the five major antiepileptic drugs on an automated kinetic analyser.

We have evaluated the performance of enzyme-multipled immunoassay methods for the five major antiepileptic drugs on an automated system, the Perkin-Elmer Model KA-150 Kinetic Analyzer. The precision in the normal duplicate mode was found to be in the range of 6% to 10% for all five tests over a typical working day. All EMIT methods were compared to gas-liquid chromatographic procedures and, in addition, the phenytoin and phenobarbital assays were compared to a liquid-chromatographic method. The phenytoin assay was also compared to RIA and to a manual spectroscopic method. In general, most of the comparison studies resulted in acceptable correlation, although one gas chromatographic method did not correlate very well with the phenytoin and phenobarbital immunoassays.

Pharmacodynamic interactions between phenytoin and valproate: individual and combined antiepileptic and neurotoxic actions in mice.

Although the current trend is to use monotherapy in the treatment of epilepsy, combination therapy is still employed in patients who have failed to respond to monotherapy. There is little clinical or experimental documentation of evidence against or in favor of anticonvulsant combination therapy. In this context, anticonvulsant and neurotoxic pharmacodynamic interactions between phenytoin (PHT) and valproate (VPA) were assessed in an experimental model in mice. All results were expressed in terms of brain drug concentrations for eliminating any pharmacokinetic interaction from the analysis. Both the median neurotoxic and the median anticonvulsant brain concentrations were determined for each drug used alone and for the combination. The interaction for the combination of PHT and VPA was shown to be supraadditive for the anticonvulsant activity, indicating an antiepileptic potentiation, whereas neurotoxicity was simply additive. These results suggest a potential benefit in terms of overall efficacy versus toxicity for the combination of PHT and VPA, as compared with PHT or VPA used alone.

Racial differences in free radical scavenging enzyme activity in children.

Oxygen-derived free radicals play an important role in multiple pediatric neurologic diseases. Five intracellular free radical scavenging enzymes and three trace elements provide a significant portion of the body's defenses against free radical-mediated injury. Although the effects of age, sex, and ethnicity on the body's antioxidant defenses have been described, no study has examined whether racial differences exist. This pilot study sought to determine the effect of racial differences on the activity of five free radical scavenging enzymes and the concentrations of three associated trace elements in normal, healthy American children. The erythrocyte and plasma activities of five major free radical scavenging enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutase) and plasma concentrations of three associated trace elements (selenium, copper, and zinc) were determined for 83 healthy American children, aged 1 to 18 years. One- and two-way interactions of race, age, and sex with each dependent variable were analyzed. African-Americans had higher erythrocyte glutathione peroxidase activity, erythrocyte superoxide dismutase activity, and selenium and copper concentrations than Caucasians. Racial inequalities do exist in free radical scavenging enzyme activity and trace element concentration in healthy children. African-American children had higher activity in the two most important free radical scavenging enzymes used by the brain compared to age- and sex-matched Caucasian children. Future clinical research in free radical-mediated pediatric neurologic diseases needs to consider race along with age and sex in both study design and data analysis.

The pediatric acute care laboratory.

The acute care laboratory service is an integral part of the total care required by the critically ill pediatric patient. Successful laboratory support for the intensive care unit requires optimal location, and sample collection, analysis, and reporting. These needs may be met with proper commitment on the part of laboratory staff and by application of the analytical technology now available. Testing support must reflect the special medical needs of pediatric patients in terms of sample size, test menu, instrumentation, and results interpretation.

Phenobarbital plasma levels in neonates.

This pilot study demonstrated marked variation in neonatal phenobarbital utilization. In order to rapidly achieve therapeutic levels, it is suggested that a loading dose of 8 to 10 mg per kg be administered for 2 days followed by reduction of dosage to a maintenance level of 5 to 6 mg per kg with frequent monitoring of plasma phenobarbital concentrations. The optimal plasma concentration of phenobarbital for control of neonatal seizures or withdrawal syndromes appeared to be between 15 to 30 mug per ml.

Lemon-flavored cod liver oil and a multivitamin-mineral supplement for the secondary prevention of otitis media in young children: pilot research.

We measured blood levels of fatty acids, vitamin A, and trace metals in children undergoing ambulatory surgery for placement of tympanostomy tubes and a comparison group having other ambulatory surgical procedures. We then performed a small, outpatient, secondary prevention study using nutritional supplements chosen on the basis of those blood levels. The study subjects had lower levels of red blood cell eicosapentaenoic acid (EPA) than did adult controls. Consistent with previous reports, the levels of vitamin A were < or = 40 microg/dL for 69% of our subjects, and the plasma selenium levels for children were lower than published values for adults. We then studied one otitis media (OM) season; 8 children (0.8 to 4.4 years of age) received 1 teaspoon of lemon-flavored cod liver oil (containing both EPA and vitamin A) and 1 half-tablet of a selenium-containing children's chewable multivitamin-mineral tablet per day. During this OM season, study subjects received antibiotics for OM for 12.3% +/- 13.4% (SD; p < .05) fewer days during supplementation than before supplementation. Larger, controlled trials are warranted to assess the utility of cod liver oil (of acceptable purity and taste) and a children's multivitamin-mineral preparation containing selenium, both for the prevention of OM and for the acceptance of delayed prescription of antibiotics for this disorder.

Comparison of erythrocyte antioxidant enzyme activities and embryologic level of neural tube defects.

Increased exposure to oxidant-derived free radicals or inadequate systems for antioxidant defense could alter cellular response at critical points in development. We measured 5 antioxidant enzymes, glutathione peroxidase (GSH-Px), glutathione reductase, glutathione-S-transferase, catalase and superoxide dismutase in erythrocytes and their plasma cofactor trace elements (Se, Zn, Cu) in 37 children with myelomeningocele and in 37 age-matched controls. We placed the patients into 3 groups according to motor level of the lesion at birth. We found significantly lower GSH-Px activities (p = 0.007) in children with myelomeningocele. For paired comparisons among the 3 patient groups and controls, there were significant differences (p < 0.05) between controls and both high (thoracic) and raid (lumbar) level embryologic lesions. The finding of antioxidant enzyme variations in our patients with myelomeningocele may indicate a role for abnormal oxidative metabolism in the development of this defect. The contribution of oxidative stress to human birth defects warrants investigation. We discuss potential relationships between oxidative stress and energy metabolism during primary neurulation.

Choosing an antiepileptic drug. The case for individualized treatment.

The range of drugs available for seizure control is broad, but selection of the drug and the dosage most likely to be effective for an individual patient is complex. In general, drug choice is determined by type of seizures involved and total daily dosage is based on milligrams per kilogram, so that plasma levels for all patients can be easily interpreted. Optimal seizure control is often possible with use of a single drug; in fact, in most patients with epilepsy, single-drug therapy is more effective than multiple-drug therapy and more desirable.