Necrolisis epidérmica tóxica inducida por difenilhidantoina. a propósito de un caso / Diphenylhydantoin-induced toxic epidermal necrolysis: a case report

La Necrólisis Epidérmica Tóxica (NET) o síndrome de Lyell y el Síndrome de Stevens-Johnson (SSJ) constituyenun espectro de la misma enfermedad, ambas comparten aspectos etiopatogénicos, histológicos y terapéuticos. La NET es un síndrome agudo de escasa ocurrencia y representa probablemente la entidad dermatológica másgrave conocida, cursa clínicamente con la formación de ampollas, necrosis de la epidermis y desprendimiento de la misma. Las manifestaciones sistémicas son fundamentalmente respiratorias, gastrointestinales y renales; lamortalidad es de 70%. Generalmente es desencadenada por fármacos, especialmente los anticonvulsivantes como la Difenilhidantoína. Se presenta el caso de un varón de 60 años, con antecedente de crisis convulsivas que fueron tratadas con Difenilhidantoína, quien desarrolló posteriormente un exantema vesículo-ampollar cuya presentación, distribución, compromiso sistémico, asociación temporal con el fármaco y el grado de extensión, apoyaron al diagnóstico de NET.

Toxic epidermal necrolysis (TEN) or Lyell´ syndrome and Stevens-Johnson´s syndrome are variants of a same disease sharing pathogenic, histopathological and therapeutic approaches. TEN is an acute and rare presentation and it is considered the most severe dermatologic entity, characterized by blisters, necrosis and sloughing of the dermis. Systemic manifestations are basically respiratory, gastrointestinal and renal; mortality is 70%. TEN is usually druginduced, especially by antiseizure medications including diphenylhydantoin. We present the case of a 60 year-oldmale treated with diphenylhydantoin for seizures that developed a bullous rash whose clinical presentation; body distribution; systemic involvement and temporal association supported the diagnosis of TEN.

In vitro cytotoxic activity evaluation of phenytoin derivatives against human leukemia cells.

Hydantoin derivatives, including phenytoin (5,5-diphenylhydantoin), have recently gained attention as they possess a variety of important biochemical and pharmacological properties. Nevertheless, available information on anticancer activity of hydantoin derivatives is still scarce. Here, we evaluated possible antileukemic potential of four phenytoin analogs, namely: methyl 2-(2,4-dioxo-5,5-diphenylimidazolidin-3-yl)propanoate (1), methyl 2-(1-(3-bromopropyl)-2,4-dioxo-5,5-diphenylimidazolidin-3-yl)propanoate (2), 1-(3-bromopropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (3) and 1-(3-bromobutyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (4). The experiments were performed on human acute histiocytic lymphoma U937 cells and human promyelocytic leukemia HL-60 cells. The present study was conducted using spectrophotometric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay and the electronic Beckman-Coulter method. We observed temporary changes in the leukemia cell viability, volume and count. The effects of the four 5,5-diphenylhydantoin derivatives on U937 and HL-60 cells depended on the agent tested and its concentration, the time intervals after the compound application, and the leukemia cell line used. HL-60 cells were more sensitive than U937 cells to the action of the phenytoin analogs (1-4). The antileukemic activities of the three bromoalkyl diphenylhydantoin derivatives (2, 3, and 4) were stronger than that of the compound 1 [methyl 2-(2,4-dioxo-5,5-diphenylimidazolidin-3-yl) propanoate], with no bromoalkyl substituent. The structural modifications of 5,5-diphenylhydantoin are responsible for such varied antileukemic potential of its four derivatives.

Nodular lymphocyte predominant Hodgkin lymphoma and diphenylhydantoin: Report of a case and review of the literature.

A variety of lymphoma types have been reported in patients being treated with anticonvulsant therapy. Non-Hodgkin lymphomas have been reported twice as frequently as Hodgkin lymphomas. Association of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) with dilantin therapy is extremely uncommon. We report a case of Hodgkin lymphoma in a 25-year-old male patient who had been treated with diphenylhydantoin sodium for generalized tonic clonic seizures for 15 years. Patient presented with left cervical and axillary lymphadenopathy persisting for more than 2 years after cessation of treatment with diphenylhydantoin. Computerized tomography scan of thorax, abdomen and pelvis revealed no signifi cant lymphadenopathy or any organomegaly. Diagnosis of NLPHL was made on excision biopsy of the cervical lymph node. Although the association between diphenylhydantoin therapy and the development of immunosuppression and lymphoma is well-documented, the role of the drug in the etiology of these disorders is still controversial.

Effect of diphenylhydantoin sodium polybutylcyanoacrylate nanoparticles on rat models of epilepsy / 中华神经医学杂志

Objective To evaluate the effects of diphenylhydantoin sodiumpolybutylcyanoacrylate nanoparticles (DPH-PBCA-NPs) and DPH-PBCA-NPs modified with Tween-80on rat models of epilepsy, and investigate the advantage of nanoparticle as the drug delivery system.Methods The rat models of acute epilepsy induced by lithium pilocarpine were established and randomly divided into 5 groups: group Ⅰ (performing injection of DPH-PBCA-NPs modified with Tween-80), group Ⅱ (performing injection of DPH-PBCA-NPs), group Ⅲ (performing injection of diphenylhydantoin sodium), group Ⅳ (performing injection of PBCA-NPs) and group Ⅴ (performing injection of physiological saline). The changes of electroencephalogram (EEG) manifestations of these rats were observed by using video-EEG monitoring; and their behavioral changes were noted too.Results The lithium pilocarpine induced rat models of acute epilepsy were successfully established and their status epilepticus were confirmed by EEG and their behaviors. The effective rate of DPH-PBCA-NPs modified with Tween-80 and DPH-PBCA-NPs was 91.67% and 54.55%, respectively;the effective rate of rats in group Ⅲ was 50%, and the effective rate of rats in group Ⅳ and Ⅴ was 0%;DPH-PBCA-NPs modified with Tween-80 enjoyed a better effect than DPH-PBCA-NPs and DPH (P＜0.05). Conclusion DPH-PBCA-NPs and DPH-PBCA-NPs modified with Tween-80 can be used to improve the behaviors of rats with acute epilepsy and modify the results of EEG of these rats.Nanoparticles as drug delivery system can help the drugs having their effects much quickly and effectively.

IGF-1 protection against cerebellar granule neurons apoptosis induced by diphenylhydantoin through a PI3K/Akt dependent pathway / 中国药理学通报

Aim: To investigate the effects of insulin like growth factor1 (IGF-1) on apoptosis of cerebellar granule neurons (CGNs) induced by diphenylhydantoin (DPH) and its possible relationship with PI3K/Akt. Methods: Rat cerebellar granule neurons (CGNs), primarily cultured for 8 days, were co-incubated with 100 μmol·L-1 DPH and 1 μmol·L-1 IGF-1 for 48 h and then submitted to apoptotic analysis. CGNs, pretreated with 100 μmol·L-1 DPH and 1 μmol·L-1 IGF-1 for 48 h, were incubated with LY294002, a specific inhibitor of PI3K for 30 minutes, and then performed cell viability assays to explore the relationship of IGF-1 with PI3K/Akt pathway. Western blotting was employed to further study whether Akt was involved in the apoptotic effect of DPH and the protection of IGF-1. Results 1 μmol·L-1 IGF-1 demonstrated significant protective effects on apoptosis of CGNs treated with DPH, which could be abolished by LY294002, a specific inhibitor of PI3K/Akt pathway. IGF-1 also upregulated the activity of Akt in CGNs, which was markedly decreased by DPH. Conclusions: IGF-1 blocked the DPH-induced apoptosis of CGNs possibly through a PI3K/Akt dependent pathway.

Paroxysmal kinesigenic choreoathetosis

Paroxysmal kinesigenic choreoathetosis (PKC) is characterized by short paroxysms of focal or generalized involuntary movement induced by sudden movements, and is a well-known disease in the neurologic literature, but only 4 cases have been reported in Korea. The purpose of the presentation is to clarify the clinical features of PKC in Korea. We clinically analyzed 20 patients with PKC between 1986 and 1994 at Yongdong Severance Hospital, Yonsei Medical Center, with a minimum of a 1 to 2 year follow-up period. There were 14 men and 6 women. The age at onset of the condition ranged from 8 to 17 years (mean, 13.1 years). Six patients (30%) had a family history of the condition and the mode of inheritance was suggestive of an autosomal recessive pattern. The involuntary movements seemed to be dystonic rather than choreoathetonic upon a mild attack, and the paroxysms were precipitated by sudden movements. The attacks occurred on one or both sides, and were often associated with dysarthria, upward gaze and sensory aura. Consciousness was never lost. Their duration were usually 10 to 30 seconds, and never more than two minutes. All laboratory tests including electroencephalographic and neuroimaging studies showed no abnormality. All patients responded well to diphenylhydantoin. PKC is not rare in Korea and has a benign course.

Ultrastructural Changes in the Neurulation of Early Chick Embryos Treated with Diphenylhydantoin

Teratogenic effects of a diphenylhydantoin on the neurulation of the explanted early chick embryos were studied using the punched-out filter paper explantation technique. The 6th to 9th Hamburger and Hamilton staged chick embryos were explanted and cultured in the Ham's F-10 media treated with 15 microgram/ml, 30 microgram/ml, 60 microgram/ml, 90 microgram/ml, 120 microgram/ml of diphenylhydantoin in the CO2 incubator for 6-9 hours. The morphological chracteristics and the ultrastructural changes of the neuroepithelium of early chick embryos were compared with the control and experimental group using the stereomicroscope and the electron microscope. Of th 40 chick embryos cultured in the Ham's F-10 media without drug, 37 embryos(92.5%) developed normally and 3 embryos(7.5%) developed abnormally in 94 embryos(61.4%). The frequent anomalous features of the embryos were deformities of the neural folds in the cranial regions, failure of neural tube closure, dispersion of somites and developmental arrest. The scanning electron microscopic findings of neuropithelial cells of abnormally developed embryos were diminished surface blebs and microvilli, flattened and smooth cellular surfaces, and irregular size of cells. The transmission electron microscopic findings of neuroepithelial cells of abnormally developed embryos showed no significant changes of the development of intracellular organelles except the smooth cellular surface and mild underdevelopment of microfilaments.

Axillary Artery Occlusion Following Accidental Injection of Diphenylhydantion via Radial Artery Catheter / 대한마취과학회지

Direct arterial pressure monitoring by means of an intra-arterial catheter has been considered benefit for assessment of the critically ill patients, safe conduct of controlled hypotension and frequent obtaining arterial samples for blood gas analysis. However in stead of these advantages, there would be high incidence of potential complications of arterial catheterization, such as pain, trauma to the artery and surrounding tissues(e. g., nerve), hematoma, infection, thrombosis, and distal embolization of air, clot, pieces of the catheter, and other debris. We have recently experienced an unexpected episode of amputation of the upper extremity resulting from axillary arterial occlusion following accidental injection of diphenylhydantoin through the radial arterial catheter in 57 year old neurosurgical patient. To prevent these serious and unexpected complications following arterial cannulation, we have to keep a continuous interest and vigilance to those who have invasive monitorings and those who are stranger to handle the arterial cannulation.

Pure Red Cell Aplasia Associated with Diphenylhydantoin: Case Report

The authors have described a case with pure red cell aplasia (P.R.C.A.) caused by the administration of diphenylhydantoin after head injury. P.R.C.A. associated with diphenylhydantoin is very rare and easily treated with a discontinuation of diphenylhydantoin & steroids.

Effects of Diphenylhydantoin on CBF, CMRO2, CMRG, and SEP in Experimental Cerebral Ischemia

Phenytoin(DPH) has been reported to be a benefit in the cerebral ischemia. To study the effect of DPH in an experimental stroke model. We subjected 45 cats to middle cerebral artery(MCA) occlusion 4 hrs after the placement of a MCA clip by a retro-orbital approach. Infarct size was determined 2 days after MCA occlusion. 20 animals served as control and received saline 2 ml bolus. All of these animal observed 1 hour, 1 day and 2 days after the removal of clip. In 20 treated animals, DPH was administered 50 mg/kg bolus every 6 hours intravenously after removal of clip. Infarct size was not significantly different between the control and treated groups. However, in DPH treated group, CBF, CMRO2, CMRG SEP were improved in early stage of ischemia.

A Study on Pharmacokinetics of Diphenylhydantoin in Human Body with ~(125)I-RIA / 第三军医大学学报

0.05) , so it would not be suitable for the study of the pharmacokinetics of DPH in human body.

INHIBITORY EFFECT OF DEXAMETHASONE AND DIPHENYLHY\| DANTOIN ON THE EXPRESSION OF GFAP AND Fos IN THE BRAIN OF EPILEPTIC RATS / 解剖学报

Objective To explore the antiepileptic effect and mechanism of glucocorticoid. Methods Animal behaviour observation and immunocytochemical staining. Results Major epilepsy was induced by pentylenetetrazole(PTZ).Dexamethasone or diphenylhydantoin(DPH) administered in rat 30?min before administration of PTZ could suppress or inhibit epileptiform.Immunocytochemistry demonstrated that there was a large number of hypertrophic astrocytes with GFAP immunoreaction in cerebral cortex,hippocampal gyrus and dentate gyrus of epileptic rats induced by PTZ.The immunoreaction of GFAP was obviously weakened,the number of positive cells was reduced,the processes were shorter and less in both groups of antiepilepsy by GC or DPH.The expression of Fos protein was in a great quantity in cerebral cortex 1 to 1^5 hours after seizure induced by PTZ,whereas their expressions were remarkable suppressed in GC or DPH antiepileptic groups. Conclusion 1^The antiepileptic effect of GC was further proved by comparing with the antiepileptic effects of DPH(a traditional antiepileptic drug). 2^Inhibited activity of astrocytes might be involved in antiepileptic mechanism of GC. 3^The change of expression of Fos protein might be closely related to epileptic actions. [