Phenytoin Therapy Research Articles

Paediatric renal transplantation non-compliance.

The aim of this study was to quantify and where possible objectively confirm the magnitude of non-compliance (NC) in our paediatric renal transplant recipients. A total of 94 paediatric transplants were performed between 1984 and 1989; 17 were excluded due to graft loss (2), death (3), oxalosis (2) and transfer to the adult unit (10). NC was assessed as missed clinic visits plus medication shortages or actual admission of NC. NC was found in 22% (17/77) of transplanted patients. NC showed no correlation with parental marital status, sex, distance lived from the hospital, pre-emptive transplant status or total lymphoid irradiation. Most NC was peripubertal with a smaller NC in the late teenager group. Social class correlated positively with NC; 82.3% of NC was from social classes III and IV, who formed 52.4% of the patients. NC in social class II (3/26) was significantly different from social class IV (12/24) (P = 0.01); 91% of black patients with NC were from social class IV. Race, corrected for social class, failed to reach significance (P > 0.05). Confirmation of compliance was sought from retrospective cyclosporin A (CsA) trough levels (twice daily dosage). Concomitant phenytoin therapy and CsA given as a daily dosage were excluded as significant confounding variables. The CsA dosage was not significantly different between the compliant (C) and patients with NC. Patients with NC were 8 times more likely to have a CsA level < 10 ng/ml (P = 0.0026) than C patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Folic Acid improves Phenytoin Pharmacokinetics

Phenytoin (PHT) therapy to control seizures decreases serum folate levels in half of epileptic patients, thus increasing the risk of folate depletion. Supplementation with folic acid prevents deficiency but also changes PHT pharmacokinetics. Kinetic monitoring of PHT when folic acid is provided as a supplement has not been reported in women of child-bearing age. This study of six fertile women examined the interdependence of PHT and folic acid in a randomized crossover study of two treatments: treatment 1 consisted of 300 mg sodium PHT per day and treatment 2 consisted of 300 mg sodium PHT plus 1 mg folic acid per day. Dietary folic acid intake was calculated daily. During treatment 1, serum folate level decreased 38.0±18.6% (mean±standard deviation) and serum PHT concentration was in the low therapeutic range (43.92± 14.52 μmol/L). During treatment 2, serum folate level increased 26.0±33.4%, and serum PHT level (39.04±14.16 μmol/L) was similar to that in treatment 1. Only one subject attained PHT steady state during treatment 1, but four subjects achieved steady state during treatment 2. Dietary folate intakes during treatments 1 and 2 were not significantly different. This study suggests an interdependence between PHT and folic acid and supports the observation that fertile women treated with PHT require folic acid supplementation to maintain a normal serum folate level. J Am Diet Assoc. 1995; 95:352-356.

Phenytoin Causes a Rapid Increase in 6β‐Hydroxycortisol Urinary Excretion in Humans—A Putative Measure of CYP3A Induction

This study was conducted in eight healthy volunteers to assess the time course of induction of cytochrome P‐450 by phenytoin. Subjects received 200mg of phenytoin every 8h for 11 doses and 100mg every 8h for 8 doses. Trough concentrations of phenytoin in plasma were measured by HPLC. Urine samples were collected between 08:00 and 12:00 on days minus; 1, 1, 2, 3, 4, 5, and 7. Urinary concentrations of 6β‐hydroxycortisol (6β‐OHC) and cortisol (C) were determined by HPLC and were reported as a ratio (6β‐OHC/C); this ratio is a marker for the 3A isozyme family of cytochrome P‐450 (CYP3A). Mean plasma phenytoin concentrations on day 7 were 15.4 ± 7.20 µg/mL. Mean 6β‐OHC/C ratios increased by a factor of 2.37 from baseline during the course of the study. Values for the ratios on days 4, 5, and 7 were significantly higher than baseline by Dunnett's test (one‐sided) (p<0.05); the day 3 value was borderline statistically significant. These results show that phenytoin rapidly induces the activity of the CYP3A family of isozymes, with effects apparent within 48h after the initiation of phenytoin therapy.

A late defect in wound healing associated with recurrent spontaneous pneumothoraces: a presumptive role for abnormal collagenase activity

This case report concerns an individual with a defect in wound healing which resulted in recurring, bilateral pneumothoraces during the late postoperative period. This patient had no history of systemic disease or wound healing abnormalities before his recurrent wound disruption. Physical examination and routine biochemical studies failed to identify any causative agent for the multiple wound dehiscences in the patient. Histologic examination of scar tissue showed collagen fiber bundles with a diameter 50% less than that of normal fibrils. Elastic fibers were barely visible, and the scar tissue included a large number of inflammatory cells. A significant finding was an elevated and aberrant expression of collagenase by a fibroblast cell line established from a skin biopsy specimen. This enhanced level of collagenase expression could be inhibited by treatment of the cells with diphenylhydantoin, an inhibitor of collagenase biosynthesis. After initiation of diphenylhydantoin therapy, the patient's scar formation normalized with the recurrent pneumothoraces. These findings support the conclusion that an abnormal expression of collagenase resulted in enhanced degradation of collagen in the patient's wounds, thereby leading to wound dehiscence.

Osteomalacia and Phenytoin Therapy

Letters1 October 1994Osteomalacia and Phenytoin TherapyJacqueline A. French, MDJacqueline A. French, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-121-7-199410010-00031 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. Siddiqui is correct that osteomalacia is the common metabolic bone problem resulting from phenytoin therapy. This may occur in as many as one third of patients, but the effects are more common in polytherapy than in monotherapy. It also may be seen with other antiepileptic drugs that induce hepatic metabolism. However, the changes are minor during the first 2 years of monotherapy with phenytoin [1-4].

Phenytoin Induced Resistance to Vecuronium

Chronic phenytoin therapy causes resistance to some nondepolarising muscle relaxants. We have confirmed that this resistance is seen with vecuronium and suggest that at least a week of phenytoin therapy is required for a significant effect to develop. The mechanism of this resistance is not known. We have shown that an exaggerated rise in serum potassium after succinylcholine does not occur in patients with demonstrated resistance to vecuronium from chronic phenytoin therapy. This would suggest that significant extrajunctional acetylcholine receptor proliferation is an unlikely mechanism.

Effects of phenytoin on the in vivo kinetics of thiamine and its phosphoesters in rat nervous tissues

The in vivo effects of chronic (30 days) and subchronic (10 days) intragastric treatment with phenytoin (PHT) (500 mg/kg) b.wt., suspended in 10% arabic gum water solution) on the uptake and metabolism of thiamine (T), T monophosphate (TMP) and T pyrophosphate (TPP) were evaluated in rat nervous regions (cerebral cortex, brainstem, cerebellum and sciatic nerve) by determining the radioactivity of T and its phosphoesters in plasma and tissues at fixed time intervals (0.25–240 h) after an i.p. injection of thiazole-[2- 14Cthiamine (30 μg: 1.25 μCi). A nutritionally adequate diet containing T in excess was given to the animals in order to produce a virtually stable content of T compounds in the tissues. Analytical data were processed by using a compartmental model which allowed the calculation of fractional rate constants (FRC), turnover rates (TR) and turnover times. Compared with vehicle-treated controls, animals treated chronically with PHT exhibited lower levels of radiolabelled T compounds in all nervous regions except for the cerebral cortex. These alterations were not found in animals receiving subchronic treatment. Evaluation of FRC values indicated that PHT-induced effects on T metabolism differed depending on the length of PHT treatment and the nervous region considered. Overall, PHT appeared to interfere mainly with T and TMP uptake, TPP dephosphorylation to TMP and TPP turnover times, these effects being particularly prominent in the cerebellum and in the brainstem of chronically treated animals. Since all changes in T uptake and metabolism were observed in the absence of overt behavioural toxicity, these findings may have potential clinical relevance in highlighting possible mechanisms by which PHT therapy can alter brain metabolism.

Rotatory seizures of frontal lobe origin

We report a patient with true rotatory seizures. The CT scan showed a right frontal calcified lesion and the EEG showed focal epileptiform discharges over the right frontal region. The seizures responded well to phenytoin therapy.

Epidermolysis bullosa in the eastern province of Saudi Arabia.

Epidermolysis bullosa is recognized to be rare, but its prevalence in the Eastern Province of Saudi Arabia had not been previously established. We reviewed 49,902 dermatology cases seen in our clinic over a 7-year period (1984 through 1990) and carried out a therapeutic trial of oral phenytoin in three severe cases of epidermolysis bullosa dystrophica (Recessive dystrophic type). Sixteen cases of epidermolysis bullosa were found in this series, ten (62.5%) of which were of the dermolytic type (epidermolysis bullosa dystrophica), and four (25%) of the epidermolytic type (epidermolysis bullosa simplex). Parental consanguinity was established in fourteen (87.5%) of these cases. All ten cases of epidermolysis bullosa dystrophica developed complications. Three severe cases were treated with oral phenytoin and managed with meticulous nursing and nutrition with blended foods and protein and vitamin supplements and responded satisfactorily. This study confirmed the rarity of epidermolysis bullosa in this province (population 3,000,000), and demonstrated the usefulness of oral phenytoin therapy, meticulous nursing, and good nutrition in the management of epidermolysis bullosa dystrophica.

Unmasking the Significant Enzyme-Inducing Effects of Phenytoin on Serum Carbamazepine Concentrations during Phenytoin Withdrawal

We report on two patients who appeared to exhibit profound induction of carbamazepine metabolism during cotherapy with phenytoin. Gradual withdrawal of phenytoin confirmed this impression. Two case studies. Two patients receiving carbamazepine and phenytoin as combination anticonvulsant therapy were admitted for comprehensive rehabilitation. A 23-year-old man had therapeutic serum phenytoin concentrations, but his serum carbamazepine concentrations were so low that they were nonquantifiable. Doubling the daily carbamazepine dosage did not yield quantifiable serum concentrations. When the daily phenytoin dosage was tapered from 500 to 200 mg, the carbamazepine concentration rose to 10.0 micrograms/mL. No further changes in serum carbamazepine concentrations were observed when the phenytoin was discontinued. A 49-year-old man was receiving large daily dosage of phenytoin (600 mg) and carbamazepine (2300 mg). In the process of tapering and discontinuing phenytoin, the patient became lethargic and confused. These signs and symptoms suggested carbamazepine toxicity. The patient was eventually stabilized on a carbamazepine dosage of 1200 mg/d, which produced a serum concentration of 8.4 micrograms/mL. When this patient had been receiving concurrent phenytoin therapy, approximately twice as much carbamazepine (2300 mg) was required to maintain a similar serum concentration. Phenytoin is a potent inducer of carbamazepine metabolism. Whenever phenytoin dosages are tapered and discontinued in patients receiving these medications concomitantly, frequent serum carbamazepine monitoring is recommended during the ensuing deinduction phase.

Lidocaine in refractory status epilepticus: A forgotten drug in the emergency department

Generalized tonic-clonic status epilepticus is usually treated with intravenous benzodiazepines and phenytoin. Patients who do not respond to this treatment are generally treated with phenobarbital or general anesthetics both of which may require intubation to maintain respiration. Our experience of four cases with status epilepticus treated with intravenous lidocaine who had failed to respond to diazepam and phenytoin therapy is presented. Two cases responded to a single dose of lidocaine, one required a second dose of lidocaine to control seizures, and the fourth patient failed to respond and died as a result of associated severe head injury. Therefore, there is a need to conduct further studies to establish the efficacy of intravenous lidocaine in the treatment of refractory status epilepticus.

Phenytoin-induced resistance to vecuronium.

Chronic phenytoin therapy causes resistance to some nondepolarising muscle relaxants. We have confirmed that this resistance is seen with vecuronium and suggest that at least a week of phenytoin therapy is required for a significant effect to develop. The mechanism of this resistance is not known. We have shown that an exaggerated rise in serum potassium after succinylcholine does not occur in patients with demonstrated resistance to vecuronium from chronic phenytoin therapy. This would suggest that significant extrajunctional acetylcholine receptor proliferation is an unlikely mechanism.

Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers.

Some macrolide antibiotics cause clinical drug interactions, resulting in altered metabolism of concomitantly administered drugs, via formation of an inactive cytochrome P-450 complex. In the present study, the formation of a cytochrome P-450 type I binding spectrum and a metabolic intermediate complex by troleandomycin and dirithromycin was assessed in liver microsomes obtained from untreated rats and phenobarbital- or dexamethasone-pretreated rats. Troleandomycin produced a type I binding spectrum and metabolic intermediate complex in microsomes from dexamethasone- and phenobarbital-pretreated rats. Dirithromycin did not produce a detectable type I binding spectrum but formed a small cytochrome P-450 metabolic intermediate complex (6% of that formed by troleandomycin) in microsomes from dexamethasone-pretreated rats only. The formation of a cytochrome P-450 type I binding spectrum and a metabolic intermediate complex by troleandomycin, erythromycin, dirithromycin, and erythromycylamine was also assessed in microsomes prepared from human livers. Troleandomycin and erythromycin formed a type I binding spectrum and a metabolic intermediate complex which were larger in microsomes from subjects on barbiturate therapy than in microsomes from subjects with no recent barbiturate exposure. Erythromycylamine did not form a detectable type I binding spectrum with any of the human microsomal samples, but a small metabolic intermediate complex was formed with microsomes from a subject on phenobarbital, phenytoin, and propranolol therapy. Dirithromycin did not form a detectable type I binding spectrum or a metabolic intermediate complex in any human liver sample. Preclinical quantitation of the human metabolic intermediate complex may be helpful in predicting the possibility of clinical drug interactions of new drug candidates.

Effects of Single and Long - term Phenytoin Therapy on the Neuromuscular Blocking Actions of Vecuronium in the Rat

Effects of Single and Long - term Phenytoin Therapy on the Neuromuscular Blocking Actions of Vecuronium in the Rat

重症心身障害者施設入所者の歯科保健状況

The oral health status of 144 institutionalized severely handicapped persons was studied. The parameters assessed were dental caries, OHI-S, gingival hyperplasia, and gingival index newly modified by us (GI modified).The main results were as follows:1. Prevalence of dental caries in the subjects was significantly lower than in the National Survey of Dental Health (1987).2. Severe deposits of dental calculus was observed in teenagers and progressed as the subjects aged.3. Progressed periodontal disease was detected in teenagers and most of the subjects in their 30s and 40s had severe periodontitis.4. The prevalence rate of gingival hyperplasia was 47% in the subjects who had received phenytoin medication.5. Phenytoin medication had no relation with periodontal status or OHI-S.6. Also, the severity of gingival hyperplasia had no correlation with duration of phenytoin therapy in the hospital, periodontal status, or OHI-S.In conclusion, it is necessary to establish a dental health system for severely handicapped persons especially for the improvement and prevention of periodontal disease.

Hydantoin-Induced Cutaneous Pseudolymphoma With Clinical, Pathologic, and Immunologic Aspects of Sézary Syndrome

The phenytoin-induced hypersensitivity syndrome is characterized by the development of fever, rash, lymphadenopathy, and hepatitis associated with leukocytosis and eosinophilia. This article describes the unusual occurrence of a pseudo-Sézary syndrome in the days following the introduction of phenytoin treatment. A phenytoin-induced erythroderma developed in a 60-year-old woman the histologic, cytologic, and immunologic characteristics of an erythrodermal cutaneous T-cell lymphoma of the Sézary syndrome type with lymph node involvement. The dramatic improvement after withdrawal of drug therapy and the absence of recurrence 5 years after led us to consider it as a hydantoin-induced pseudolymphoma. Although lymph node pseudolymphomas induced by phenytoin are well known, few cases of hydantoin-induced mycosis fungoides have been reported in the literature. We present herein the first case of a Sézary-like syndrome associated with phenytoin therapy. Such a patient must be monitored regularly because of the risk of a true malignant lymphoma developing even many years later.

Decreased sensitivity to metocurine during long-term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes.

Long-term phenytoin therapy induces resistance to the neuromuscular blocking effects of metocurine. The hypothesis that this is attributable to increased plasma protein binding of the drug (decreased free fraction) related to increased concentrations of alpha 1-acid glycoprotein (AAG) or attributable to the proliferation of acetylcholine receptors (AChR) at the muscle membrane was tested in the rat. After 14 days of phenytoin 40 mg.kg-1, administered intraperitoneally twice daily (n = 12), the neuromuscular pharmacodynamics were evaluated and compared with those of time-matched controls (n = 10). Protein binding was measured by equilibrium dialysis, AAG concentrations by radial immunodiffusion assay, and AChR by 125I-alpha-bungarotoxin binding. The effective dose for 50% inhibition of baseline twitch height (ED50) was significantly greater in the phenytoin group than in the control group (15.03 +/- 1.65 micrograms.kg-1 vs. 9.98 +/- 0.69 micrograms.kg-1, respectively). The concentrations of AAG increased gradually from 133.8 +/- 7.8 micrograms.ml-1 at day 0, to 343.1 +/- 58.0 micrograms.ml-1 at day 7, to 1,729.5 +/- 422.3 micrograms.ml-1 at day 14 in the phenytoin group. The induction of AAG concentrations in plasma was dependent on plasma phenytoin concentrations and was most prominent after 14 days of phenytoin (r = 0.77; P less than 0.01; n = 22). The free fraction of metocurine was significantly decreased in the phenytoin group compared to the control group (67.2 +/- 0.18% vs. 74.5 +/- 2.5%). There was a significant negative correlation between increased AAG concentrations and decreased free fraction (r = 0.65).(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil-induced gingival hyperplasia in children

Gingival hyperplasia (GH) occurs in 20 % to 40 So of all patients receiving long-term oral phenytoin therapy and phenytoin is probably the most common cause of GH in children and young ado1escents.l Several other drugs including nifedipine, a calcium channel blocker, have been reported infrequently to cause GH.2-4 We report here a similar GH in two children following the long-term administration of a large dose of verapamil for the management of supraventricular tachycardia (SVT). Verapamil-associated GH has not been reported previously in the English literature. Case Ntj. 1. SL is a 12-year-old girl who was first noted to have tachycardia during the prenatal period. She had a trial of digoxin, quinidine, and propranolol in high doses in various combinations, with partial control of her SVT. At 3 years of age, a diagnosis of a permanent form of junctional reciprocating tachycardia (long R-P’ tachycardia) was made by electrophysiologic study, and an intravenous verapamil trial (0.2 mg/kg) was successful. She had no ventricular dysfunction by echocardiography. She was started on oral verapamil, 80 mg twice a day (9 mg/kg/day), with partial control, and was maintained on a similar dose with respect to body weight for the next 4 years. At 7 years of age, she was changed to sustained-release verapamil, 240 mg twice a day (15 mg/kg/day). Following 2 weeks of therapy on this dose, her verapamil level was 1030 Fg/L and 590 PglL at 6 hours and 12 hours, respectively, after the oral dose of verapamil (therapeutic trough level 100 to 600 pg/ L). Following 6 weeks of verapamil therapy, she developed marked GH. The labial gingivae of the anterior maxillary and mandibular teeth were firm, red, and nodular, with minimal bleeding. Despite good dental hygiene and frequent dental visits, she had persistent GH. There were no other adverse effects of verapamil. At 11 years of age verapamil was discontinued because of partial control of the tachycardia. Six weeks later her GH significantly improved. Subsequently she was started on a regimen of oral propafenone without success. At present she is maintained on a regimen of oral Aecainide with fairly good control of the tachycardia. Case No. 2. DM is a 16-year-old young woman patient who was noted to have a tachycardia during the prenatal

Enhanced prostaglandin biosynthesis in human gingival fibroblasts isolated from patients treated with phenytoin

Prostaglandin E2 (PGE2) formation was studied in human gingival fibroblasts derived from three epileptic patients before and after 9 months of phenytoin (PHT) therapy. Interleukin 1 (IL-1 alpha; 0.3-6.0 ng/ml), (IL-1 beta; 10-1000 pg/ml) and tumour necrosis factor (TNF alpha; 0.01-0.1 microgram/ml) dose-dependently stimulated the formation of PGE2 in 24 h cultures. In fibroblasts, derived after 9 months of PHT therapy, IL-1 alpha, IL-1 beta and TNF alpha induced a significantly higher formation of PGE2 compared to that in fibroblasts derived before PHT therapy. IL-1 beta induced a significantly higher release also of 3H-arachidonic acid (3H-AA) from prelabelled PHT fibroblasts compared to that in prelabelled gingival fibroblasts isolated before the drug therapy. Addition of exogenous AA caused a spontaneous increase of PGE2 formation in PHT fibroblasts compared to that in fibroblasts isolated before the PHT treatment. The results indicate that PHT medication results in an upregulation of prostanoid formation in gingival fibroblasts partly due to an increased phospholipase A2 activity and partly due to an increased cyclooxygenase activity.

Urinary caffeine metabolites in man

In an exploratory study the 24-h urinary excretion pattern of caffeine and 14 of its major metabolites was studied in 32 volunteers (adults, adolescents and children), 14 patients either with end stage renal disease or liver cirrhosis, 7 heavy smokers and 27 patients on therapy with cimetidine, allopurinol, theophylline or phenytoin. Caffeine and its metabolites were quantified by UV-absorption after liquid/liquid-extraction and HPLC-separation, which ensured proper analysis of 1-methyluric acid. In adults the renal excretion of caffeine derivatives corresponded to an intake of 509 mg caffeine/day, with 1-methyluric acid as the predominant metabolite. About 69% of caffeine was degraded by the paraxanthine pathway, and theobromine- (19%) and the theophylline pathway (14%) were less important. The ratio of paraxanthine formation to urinary caffeine concentration (= clearance equivalent) was about 2.2 ml.min-1.kg-1 in adults, and the corresponding ratios for theophylline and theobromine were 0.43 ml.min-1.kg-1 and 0.59 ml.min-1.kg-1, respectively. As expected, caffeine degradation was impaired in patients with cirrhosis and was increased in persons who smoked heavily or who were on phenytoin therapy. The results document the possibility of noninvasively investigating gross differences in caffeine disposition by analysis of the urinary pattern of its metabolites.