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Notes: Abstract The aim of this study was to determine whether phenytoin (PHT) could be detected in gingival crevicular fluid (GCF), and to relate its concentration to both plasma level and degree of gingival overgrowth. 23 patients medicated with phenytoin for at least 6 months were clinically examined for signs of periodontal disease and gingival overgrowth. 12 patients out of these demonstrated clinically significant overgrowth and their plaque scores and gingival inflammation were greater than for the non-overgrowth group (p〈0.001). Phenytoin concentrations were determined by high performance liquid chromatography, and was detected in GCF. There was a significant correlation between the GCF and plasma phenytoin concentrations (p〈0.05), but it was not related to the extent of gingival overgrowth. Inflammation increased the GCF volume, but was not a determinant of GCF phenytoin concentration. It is concluded that effusion of phenytoin into GCF is regulated by the plasma levels of the drug, but its concentration in GCF is not related to the incidence of gingival overgrowth.

Notes: Interspecies differences in phenytoin (PHT) metabolism to 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) were examined in human, cat and rat hepatic microsomes in vitro. Rat liver microsomes were 25 and 650 times more efficient at the conversion of PHT to HPPH than human and cat liver microsomes, respectively. Sulphaphenazole (83%) and tolbutamide (TOL) (64%) were the most potent inhibitors of HPPH formation in human liver microsomes, while ciprofloxacin (27%), enoxacin (27%) and TOL (26%) produced the greatest inhibition in cat liver microsomes. TOL was tested for its effect on HPPH formation and gingival overgrowth in cats in vivo. Eight cats received PHT sodium (4 mg/kg/d) and another 8 cats received PHT sodium together with TOL (20 mg/kg/d) for 10 wk. Six cats (75%) in the PHT group and 4 cats (50%) in the PHT & TOL group developed significant gingival overgrowth by the end of the study. However, the extent and incidence of the overgrowth were similar in the 2 groups. There were no significant differences in mean AUC0-10weeks for plasma PHT (552.90 ± 29.36 μg·d/mL [PHT alone] vs. 582.41 ± 24.49 μg·d/mL [PHT & TOL]) and unconjugated HPPH (1016.4 ± 295.5 ng·d/mL [PHT alone] vs. 1174.5 ± 397.2 ng·d/mL [PHT & TOL]) concentrations between the 2 groups of cats. Neither PHT nor HPPH were detectable in the plasma of 8 rats which received PHT (4 mg/kg/d) over a 10-wk period. The rats showed no sign of gingival inflammation (mean gingival index = 0) or gingival overgrowth (mean gingival overgrowth index=0). Thirty-six adult epileptic patients on chronic PHT therapy were examined; 17 (47%) of the patients demonstrated clinically significant overgrowth. The mean steady-state plasma PHT concentration was comparable to, and the mean plasma unconjugated HPPH concentration 5-fold greater than, that observed in the cats. The results suggest that the rapid metabolism and elimination of PHT and HPPH in the rat may enable it to become more resistant towards developing gingival overgrowth, compared to the cat and man.

Notes: Abstract. The potential effect of co-medication with phenobarbitone, primidone and carbamazepine on plasma and saliva concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-HPPH), the major metabolite of phenytoin in man and on the incidence of phenytoin-induced gingival overgrowth was investigated in a group of 36 adult epileptic patients. There were no signifiant differences in plasma or saliva concentrations of 4-HPPH or phenytoin in patients prescribed phenytoin alone, compared to those who received phenytoin with either phenobarbitone, primidone, or carbamazepine. In addition, the extent and the incidence of gingival overgrowth were similar in the 2 groups. The results suggest that chronic co-medication with other anti-convulsant drugs which induce phenytoin metabolism, does not affect the plasma or saliva 4-HPPB steady-state levels, nor the degree of gingival overgrowth in adult epileptic patients on therapy with phenytoin.〈section xml:id="abs1-1"〉〈title type="main"〉ZusammenfassungDie Wirkimg einer multiplen antikonvulsiven Therapie auf die Ausprägung der durch Phenytoin ausgelösten GingivahyperplasieIn einer Gruppe von 36 erwachsenen Epileptikern wurde der potentielle Effekt der Ko-Medikation von Phenobarbiton, Primidon und Carbamizepin auf die Plasma- und Speichelkonzentration von 5-(4-Hydroxyphenyl)-5-Phenylhydantoin (4-HPPH), dem Hauptmetaboliten von Phenytoin beim Menschen, und die Inzidenz der durch Phenytoin ausgelösten Gingivahyperplasie untersucht. Verglichen mit den Patienten denen allein Phenytoin verschrieben wurde, gab es bei den Patienten, die Phenytoin mit entweder Phenobarbiton, Primidon oder Carbamizepin verschrieben bekamen, keine signifikanten Unterschiede in der Plasma- und Speichelkonzentration von 4-HPPH oder Phenytoin. Des weiteren waren das Ausmaß und die Inzidenz der Gingivahyperplasie in beiden Gruppen ähnlich. Die Ergebnisse lassen annehmen, daß die chronische Ko-Medikation mit anderen antikonvulsiven Medikamenten, die den Phenytoin-Metabolismus induzieren, weder die plasma- und Speicheltiter von 4-HPPH noch den Grad der Gingivahyperplasie bei erwachsenen Epileptikern mit Phenytoinbehandlung beeinflußt.〈section xml:id="abs1-2"〉〈title type="main"〉RésuméEffect du traitement anticonvulsivant multiple sur l'expression de l'hypertrophie gingivale induite par la phénytoïneNous avons étudié dans un groupe de 36 épileptiques adultes l'effet potentiel d'une médication combinant phénobarbital, primidone et carbamazépine sur les concentrations plasmatiques et salivaires de 5-(4-hydroxyphényl)-5-phénylhydantoïne (4-HPPH), métabolite principal de la phénytoïne chez l'humain, et sur l'incidence des hypertrophies gingivales induites par la phénytoïne. Il n'existait pas de différences statistiquement significatives dans les concentrations plasmatiques et salivaires de 4-HPPH ou de phénytoïne chez les patients à qui on avait prescrit la phénytoïne seule par rapport à ceux qui receivaient la phénytoïne avec phénobarbital, primidone ou carbamazépine. De plus, l'étendue et l'incidence de l'hypertrophie gingivale étaient de même ordre dans les deux groupes. Ces résultats semblent indiquer qu'une co-médication chronique avec d'autres anticonvulsivants induisant le métabolisme de la phénytoïne n'a pas d'influence sur les niveaux plasmatiques ou salivaires de 4-HPPH à l'état d'équilibre, ni sur le degré d'hypertrophie gingivale chez les épileptiques adultes traités par la phénytoïne.