SUMMARY A rapid and inexpensive method to determine the degree of protein binding of diphenylhydantoin (and other anticonvulsants) is described; it is applicable to screening large samples of patients. The method was used in 25 selected subjects to test the hypothesis that degree of intoxication with diphenylhydantoin is related more to the serum concentration of free than of total diphenylhydantoin. The results support the hypothesis. It is suggested that the method could be used more widely and that it would reduce the variance between total serum concentration and clinical response for those anticonvulsants that are highly bound to serum proteins. RÉSUMÉ On décrit une méthode rapide et peu chère pour déterminer le degré de diphénylhydantoine liée aux protéïnes (et ďautres anticonvulsivants). Elle est applicable àľétude de larges échantillons de patients. La méthode a été utilisée sur 25 sujets sélectionnés pour tester ľhypothèse que le degréďintoxication aux hydantoïnes est plus en relation avec la concentration sérique de diphénylhydantoïne librequede la diphénylhydantoïne totale. Les résultats corroborent cette hypothèse. II est suggéré que la méthode devrait être utilisée plus largement et pourrait réduire les variations entre la concentration sérique totale et la réponse clinique pour les anticonvulsivants qui sont très largement liés aux protéïnes sériques. ZUSAMMENFASSUNG Beschreibung einer schnellen und billigen Methode zur Bestimmung des Grades der Eiweissbindung des Diphenylhydantoins (und andere Antikonvulsiva); sie ist als Screeningmethode für grosse Patientenkollektive geeignet. Die Methode wurde an 25 ausgewählten Patienten angewandt, um die Hypothese zu testen, dass das Ausmass der Intoxikation mit Diphenylhydantoin stärker von der Serumkonzentration des freien als der des Gesamtdiphenylhydantoins abhängt. Die Ergebnisse stützen die Hypothese. Es ist zu vermuten, dass die Methode weitere Anwendung finden wird und dass durch sie die lockere Beziehung zwischen der Gesamtserumkonzentration und dem klinischen Ansprechen auf solche Antikonvulsiva enger wird, die in hohem Masse an die Serumproteine gebunden sind. RESUMEN Se describe un método rápido y poco costoso para determinar la cantidad de difenilhidantoina (y otros anticonvulsivantes) que se une a las proteinas; séricas el método es aplicable al estudio de un amplio número de pacientes. Ha sido empleado en 25 enfermos seleccionados con objeto de comprobar la hipotesis de que el grado de intoxicatión por difenilhidantoina, está en relatión con la concentración en suero de difenilhidantoina libre, más que con la cifra total de dicha droga en sangre. Los resultados obtenidos estan en favor de dicha hipotesis. Se propone utilizar este método de forma más amplia con objeto de encontrar explicateón a las paradojas que se observan entre concentraciRoAn total en suero y respuesta clinica, en algunos anticonvulsivantes que se caracterizan por combinarse facilmente con las proteinas séricas.

Buffered lidocaine has been recently recommended for local anesthesia, as there is less pain on injection of the buffered solution. Reduced pain on injection of lidocaine and epinephrine buffered to a neutral pH was confirmed in 20 subjects (P less than .01). Concentrations of buffered lidocaine and epinephrine were performed in order to evaluate their stability. Buffered lidocaine dropped to 66.1% of initial concentrations after 4 weeks when stored at 25 degrees C. Buffered epinephrine fell to 1.34% of its initial concentration under similar conditions. Buffered lidocaine and epinephrine maintained 94.54% and 82.04%, respectively, of their initial concentrations after 4 weeks when refrigerated at 0-4 degrees C. Both lidocaine and epinephrine maintained greater than 90% concentration 2 weeks after buffering when stored at 0-4 degrees C. This permits batch buffering of lidocaine with epinephrine and storage for periods up to 2 weeks when properly refrigerated.

SUMMARY The serum half‐life of primidone was determined in 6 subjects and was found to be 10 to 12 hours. In 2 subjects who were taking phenobarbital, no difference in the absorption curve and serum half‐life of primidone was noted. This suggests that phenobarbital does not influence the half‐life of primidone. No detectable phenobarbital was present in the serum of the volunteer subjects following the single 500 mg dose of primidone, even up to 48 hours. This suggests that the bioconversion of primidone to phenobarbital occurs slowly. On the other hand, clinic subjects who were taking primidone chronically with no barbiturate showed a mean phenobarbital level 3 times higher than the primidone level. This could be explained by an increasing rate of biotransformation of primidone to phenobarbital following chronic administration. However, a low transformation rate and the marked difference in the serum half‐life of phenobarbital and primidone could also explain the results. Toxic side effects similar to those attributed to phenobarbital and diphenylhydantoin were seen in the volunteer subjects even though these drugs were not present in their serum. In addition, data from a small group of clinic patients suggest that ataxia, somnolence and lethargy could be attributed to high primidone levels. Data relating the mean and range of primidone levels to daily dose are presented as a guide for evaluating the status of an individual patient. A significant increase in blood level with increasing dose was present. Some data relevant to the therapeutic serum level of primidone are presented. They suggest that a serum level below 10–12 μg/ml should be maintained, as the risk of side effects increases greatly above this level. There was no evidence from the present study to suggest that higher levels would be associated with an increase in seizure control. RÉSUMÉ Chez 6 sujets on a trouvé que la demi‐vie de la primidone était de 10 à 12 heures. Chez 2 sujets qui prenaient aussi du phénobarbital on n'a retrouvé aucune différence de la courbe 'absorption et de la demi‐vie de la primidone. Ches des sujets volontaires qui avaient pris une seule dose de 500 mg de primidone on ne retrouvait pas de phénobarbital dans le sérum, même 48 h après. Ceci suggère que la transformation de la primidone en phénobarbital se fait lentement. 'autre part, les sujets qui prenaient de la primidone 'une façon chronique, sans barbituriques, avaient des taux moyens de phénobarbital trois fois plus élevés que le taux de primidone. Ceci peut s'expliquer par une augmentation de la vitesse de transformation de la primidone en phénobarbital à la suite du traitement chronique. Toutefois, les résultats peuvent s'expliquer aussi par une lente vitesse de transformation et par 'importante différence entre la demi‐vie dans le sérum du phénobarbital et celle de la primidone. On a observé des effets toxiques secondaires semblables à ceux qu'on dit être consécutifs au phénobarbital et aux hydantoïnes chez les sujets volontaires, bien que ces produits ne fussent pas...

We have reported on t h e toxic e f f e c t s to 8 members of a rural Wisconsin family who, for 3 years, burned chromium-copper-arsenic (CCAI-trated lumber in a kitchen stove (1,2,3). Symptoms included recurrent alopecia in t h e winter ( t h a t grew back in t h e summer), dermatitis, muscle cramps, malaise, black outs, paresthesias, recurring respiratory symptoms, thrombocytopenia and colic. Concentrations of arsenic in t h e hair of t h e parents were 12-87 parts/million and levels of 105-5,006 ppm were found in t h e fingernails of the family members.The living a r e a of t h e home was heavily contaminated with ashes containing over 1,000 ppm pentavalent arsenate. T h e hazard of improper disposal of CCA-treated lumber is now being publicized, and control e f f o r t s by t h e EPA have been announced (4).

The antiepileptic drugs diphenylhydantoin and phenobarbital were measured in serum by a new commercially available enzyme immunoassay procedure ("EMIT," Syva Corp.). The procedure requires <5 min and no more than 50 µl of serum per determination. It is simple; only four steps (pipetting and diluting with an automatic pipettor-dilutor) are required before spectrophotometry. Twenty replicate analyses of a serum containing phenobarbital and diphenylhydantoin gave results with a CV of 6.8% and 9.1%, respectively. Results attained in a large series of patients were compared with results by a gas/liquid chromatographic procedure. For phenobarbital r = 0.97, and for diphenylhydantoin r = 0.98. No false negatives or false positives were encountered.