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Sample records for phenytoin

  1. Phenytoin overdose

    MedlinePlus

    Phenytoin is a medicine used to treat convulsions and seizures. Phenytoin overdose occurs when someone takes too much of ... Phenytoin is the generic name of drugs such as: Antisacer Dilantin Dintoina Diphenylan sodium Epanutin Fenytoin Phenytek ...

  2. Phenytoin: neuroprotection or neurotoxicity?

    PubMed

    Keppel Hesselink, Jan M; Kopsky, David J

    2017-06-01

    Phenytoin is an 80-year young molecule and new indications are still emerging. The neuroprotective potential of phenytoin has been evaluated for decades. Recently, a positive phase II trial supported its further development in the treatment of optic neuritis in multiple sclerosis. In 1942, however, peripheral neuritis was first reported to be an adverse event of phenytoin, and since then a small but steady stream of publications discussed peripheral polyneuropathy as being a possible adverse event of phenytoin. We have reviewed the literature and concluded there is some supportive evidence for a reversible polyneuropathy after the oral use of phenytoin, though with no evidence for clear neurotoxicity on the level of peripheral nerves. This is probably due to the fact that the pharmacological effects of phenytoin, based on the stabilizing effect of the voltage-gated sodium channels, make impairment of nerve conduction in asymptomatic and symptomatic reversible polyneuropathies plausible. Clear toxically-induced phenytoin-related polyneuropathies, however, are extremely rare and are always related to high dose or high plasma levels of phenytoin, mostly developing during many years of therapy. We could only find one case of a probable reversible chronic phenytoin intoxication resulting in a biopsy proven axonal atrophy with secondary demyelination and signs of remyelination. All case series and case reports published are insufficient in detail to prove a clear causal relation between phenytoin intake and the induction of a peripheral polyneuropathy. Phenytoin does not lead to irreversible toxicity of the peripheral nerves and might, on the other hand, have neuroprotective properties.

  3. Psychiatric symptomatology, scholastics, and phenytoin

    PubMed Central

    Pandey, A. K.; Gupta, Sanjay

    2012-01-01

    Phenytoin is a commonly used antiepileptic medication because of its easy accessibility as well as affordability. However, scientific literature shows various types of side effects of phenytoin. We report a patient who was showing toxicity symptoms in the form of mood, behavior and cognitive symptoms along with scholastic problems and personality change on long term treatment with phenytoin. The patient's serum phenytoin was found to be quite high (>32.8 ng/ml).The symptoms were attributed to phenytoin toxicity which responded within twelve weeks by reducing the dose of phenytoin (with resultant fall in levels of serum phenytoin) and the addition of folic acid. While the mood and behavior symptoms recovered early, the cognitive symptoms responded slowly showing 80% -90 % improvement over a period of fifteen weeks. PMID:23226860

  4. Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

    PubMed Central

    2012-01-01

    Background Therapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard. Results In this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations. Conclusions The results suggest that a measured free phenytoin should be

  5. Cardiovascular adverse effects of phenytoin.

    PubMed

    Guldiken, B; Rémi, J; Noachtar, Soheyl

    2016-05-01

    Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less sedative effect. However, the possibility of cardiovascular adverse effects with the intravenous use of phenytoin cause a reluctance to its usage, and this has lead to a search for safer anticonvulsant drugs. In this study, we aimed to review the studies which evaluated the safety of phenytoin with respect to cardiovascular adverse effects. The original clinical trials and case reports listed in PUBMED in English language between the years of 1946-2014 were evaluated. As the key words, "phenytoin, diphenylhydantoin, epilepsy, seizure, cardiac toxicity, asystole, arrhythmia, respiratory arrest, hypotension, death" were used. Thirty-two clinical trials and ten case reports were identified. In the case reports, a rapid infusion rate (>50 mg/min) of phenytoin appeared as the major cause of increased mortality. In contrast, no serious cardiovascular adverse effects leading to death were met in the clinical trials which applied the recommended infusion rate and dosages. An infusion rate of 50 mg/min was reported to be safe for young patients. For old patients and patients with a cardiovascular co-morbidity, a slower infusion rate was recommended with a careful follow-up of heart rhythm and blood pressure. No cardiovascular adverse effect was reported in oral phenytoin overdoses except one case with a very high serum phenytoin level and hypoalbuminemia. Phenytoin is an effective and well tolerated drug in the treatment of epilepsy. Intravenous phenytoin is safe when given at recommended infusion rates and doses.

  6. Combination of capecitabine and phenytoin may cause phenytoin intoxication: a case report.

    PubMed

    Ciftci, Rumeysa; Tas, Faruk; Karabulut, Senem; Ciftci, Serkan

    2015-01-01

    Capecitabine is an oral antineoplastic agent, and phenytoin is an anticonvulsant drug with a narrow therapeutic index. Although the interaction between capecitabine and phenytoin is rare, it may be potentially fatal. This interaction is thought to be at the level of CYP2C9 isoenzyme system in the liver. Here, we present a patient with metastatic breast cancer who developed phenytoin intoxication when using capecitabine and phenytoin together. Closely monitoring plasma phenytoin levels is essential if capecitabine is used with phenytoin concurrently.

  7. Phenytoin dosage in ambulant epileptic patients.

    PubMed Central

    Terrence, C; Alberts, M

    1978-01-01

    Ambulant patients with recently diagnosed generalised or psychomotor seizure disorders or both were randomly assigned to two dosage regimens of phenytoin. Drug compliance was evaluated with subsequent blood phenytoin levels four to eight weeks after initial enrollment into the study. Although the two groups had similar mg-kg daily dosages of phenytoin, the mean blood levels were statistically different between the two groups, favoring the simplified dosage regimen. Once or twice a day dosage regimens of phenytoin had a beneficial effect on drug compliance when compared to more frequent regimens as measured by phenytoin blood levels. PMID:660211

  8. Phenytoin-induced encephalopathy in a child.

    PubMed

    Mehndiratta, Sumit

    2016-01-01

    Phenytoin is a commonly used antiepileptic medication in the pediatric age group, but it has a narrow therapeutic range. Various adverse effects have been reported commonly. We report a relatively rare case of encephalopathy in a child from overdose of injectable phenytoin due to ignorance of the previous treatment. Scrutiny of medical records and history is of utmost importance while administering such medications.

  9. Myristicin and phenytoin toxicity in an infant

    PubMed Central

    Sivathanu, Shobhana; Sampath, Sowmya; David, Henry Suresh; Rajavelu, Kulandai Kasthuri

    2014-01-01

    A developmentally normal infant presented with repeated episodes of afebrile status epilepticus following nutmeg ingestion. He had developed two episodes of afebrile status epilepticus and had received different treatments earlier, but the details of treatment were not available. On admission, he redeveloped convulsions and loading doses of phenytoin, phenobarbitone and midazolam were administered. However, seizures persisted and extrapyramidal movements, nystagmus and visual dysfunction were noted. Iatrogenic phenytoin toxicity was considered and confirmed by drug levels. His symptoms completely disappeared after discontinuation of phenytoin therapy. The initial seizures were attributed to myristicin, an active component of nutmeg, because of the temporal association. However, the subsequent seizures were due to phenytoin toxicity caused by administration of multiple loading doses. This case highlights that nutmeg, a spice, can cause serious toxic effects like status epilepticus. Furthermore, treatment of status epilepticus with phenytoin can cause iatrogenic seizures due to its narrow therapeutic range. PMID:24903724

  10. Bedsores successfully treated with topical phenytoin.

    PubMed

    Inchingolo, Francesco; Vermesan, Dino; Inchingolo, Alessio D; Malcangi, Giuseppina; Santacroce, Luigi; Scacco, Salvatore; Benagiano, Vincenzo; Girolamo, Francesco; Cagiano, Raffaele; Caprio, Monica; Longo, Lucia; Abbinante, Antonia; Inchingolo, Angelo M; Dipalma, Gianna; Tarullo, Angelo; Tattoli, Maria

    2017-04-28

    Phenytoin is normally used in epilepsy treatment. One of the side effect affecting a significative part of the treated patients is the gingival overgrowth. It could surely be a correlation between this stimulatory effect and the assessment of phenytoin in wound healing. In fact, some studies of the literature have shown that topical phenytoin promotes healing of traumatic wounds, burns and ulcers by decubitus or stasis (diabetic or venous) and we emphasize, in vitiligo, a particular attention into repigmentation. The related mechanism of action seems to be multifactorial. In the present paper topical phenytoin has been used as wound-healing agent in 19 documented cases of bedsores, divided in treated and placebo group. The used concentration of phenytoin was 5 mg/L dissolved in a water solution of 9 g NaCl /L (0.9% P/V of NaCl). Patches soaked with phenytoin solution were applied over the bedsores along 3 hours every 12 hours. Results showed that phenytoin treated patients healed their wounds significantly before (p<0.001) with respect to controls.

  11. Phenytoin kinetics during pregnancy and the puerperium.

    PubMed

    Knott, C; Williams, C P; Reynolds, F

    1986-10-01

    During pregnancy changes in maternal physiology and plasma composition may alter drug binding and dose requirements. We have measured plasma unbound and total phenytoin, and saliva concentrations at intervals in 11 pregnant epileptics. Plasma albumin concentrations were also measured in pregnant and non-pregnant women. Saliva phenytoin correlated closely with the plasma unbound concentrations (r = 0.98). The saliva:plasma (S:P) ratio, reflecting the free fraction, was variable during pregnancy but tended to increase to maximal values at delivery and return to non-pregnant values within 2-8 weeks thereafter. Plasma albumin concentrations correlated poorly with phenytoin binding. Binding in umbilical cord plasma appeared higher than that in maternal plasma and total fetal concentrations correlated closely with maternal plasma concentrations at delivery. No ill effects of phenytoin were detected in the newborn infant. During the third trimester phenytoin dose increments were necessary to maintain therapeutic concentrations. After delivery maternal saliva phenytoin concentrations rose, and dose reductions were necessary to avoid clinical symptoms of toxicity. It is therefore appropriate to monitor saliva phenytoin concentrations regularly both during pregnancy and the puerperium.

  12. Phenytoin toxicity secondary to an oxcarbazepine-phenytoin 2C19 interaction.

    PubMed

    Soskin, David P; Kane, Ari J; Stern, Theodore A

    2010-01-01

    Polytherapy is common in the management of bipolar disorder, as are the side effects associated with this treatment strategy. The authors review the literature on drug-drug interactions involving oxcarbazepine and identify specific mechanisms that may have clinical importance. The authors provide a case report of a patient who developed phenytoin toxicity associated with an oxcarbazepine-phenytoin interaction. Co-administration of phenytoin and oxcarbazepine resulted in toxic levels of phenytoin. Therefore, the patient's daily dosage of oxcarbazepine and phenytoin were reduced. Although oxcarbazepine is an inducer of the 3A4 isoenzyme, it acts as an inhibitor of the 2C19 isoenzyme, and it can raise levels of other agents, for example, phenytoin, that are also metabolized by this isoenzyme.

  13. Effect of a delayed-action phenytoin preparation on blood phenytoin concentration

    PubMed Central

    Bochner, F.; Hooper, W. D.; Tyrer, J. H.; Eadie, M. J.

    1972-01-01

    In a cross-over study in a group of epileptic patients it was shown that replacement of the evening dose of an ordinary phenytoin preparation with the same phenytoin dose in a delayed-action preparation produced no significant change in the next morning's mean blood phenytoin concentration. However, replacement of the entire daily dose of an ordinary phenytoin preparation with the delayed-action preparation did increase mean blood phenytoin levels after some days, possibly because the latter preparation contained an additional 6% active drug, as compared with the former. In most circumstances, it seems doubtful if the delayed-action preparation offers any advantage over ordinary phenytoin in treating epilepsy. PMID:5084136

  14. Phenytoin

    MedlinePlus

    ... talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. ... acid (Depakene); methadone (Dolophine, Methadose); methotrexate (Otrexup, Rasuvo); methylphenidate (Daytrana, Concerta, Metadate, Ritalin); mexiletine; nifedipine (Adalat, Afeditab), ...

  15. Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

    PubMed

    Miyazaki, Shohei; Satoh, Hiroki; Ikenishi, Masayuki; Sakurai, Miyuki; Ueda, Mutsuaki; Kawahara, Kaori; Ueda, Rie; Ohtori, Tohru; Matsuyama, Kenji; Miki, Akiko; Hori, Satoko; Fukui, Eiji; Nakatsuka, Eitaro; Sawada, Yasufumi

    2016-09-01

    Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

  16. Cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin in the emergency department.

    PubMed

    Rudis, Maria I; Touchette, Daniel R; Swadron, Stuart P; Chiu, Amy P; Orlinsky, Michael

    2004-03-01

    Oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin are all commonly used for loading phenytoin in the emergency department (ED). The cost-effectiveness of each was compared for patients presenting with seizures and subtherapeutic phenytoin concentrations. A simple decision tree was developed to determine the treatment costs associated with each of 3 loading techniques. We determined effectiveness by comparing adverse event rates and by calculating the time to safe ED discharge. Time to safe ED discharge was defined as the time at which therapeutic concentrations of phenytoin (>or=10 mg/L) were achieved with an absence of any adverse events that precluded discharge. The comparative cost-effectiveness of alternatives to oral phenytoin was determined by combining net costs and number of adverse events, expressed as cost per adverse events avoided. Cost-effectiveness was also determined by comparing the net costs of each loading technique required to achieve the time to safe ED discharge, expressed as cost per hour of ED time saved. The outcomes and costs were primarily derived from a prospective, randomized controlled trial, augmented by time-motion studies and alternate-cost sources. Costs included the cost of drugs, supplies, and personnel. Analyses were also performed in scenarios incorporating labor costs and savings from using a lower-urgency area of the ED. The mean number of adverse events per patient for oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin was 1.06, 1.93, and 2.13, respectively. Mean time to safe ED discharge in the 3 groups was 6.4 hours, 1.7 hours, and 1.3 hours. Cost per patient was 2.83 dollars, 21.16 dollars, and 175.19 dollars, respectively, and did not differ substantially in the Labor and Triage (lower-urgency area of ED) scenarios. When the measure of effectiveness was adverse events, oral phenytoin dominated intravenous phenytoin and intravenous fosphenytoin, with a lower cost and number of adverse

  17. Phenytoin intoxication during concurrent diazepam therapy

    PubMed Central

    Rogers, Howard J.; Haslam, Robert A.; Longstreth, James; Lietman, Paul S.

    1977-01-01

    Phenytoin elimination is a saturable process obeying Michaelis-Menten kinetics. Plasma phenytoin levels are not related linearly to dose, and small changes in enzyme activity produced by concurrent drug therapy could alter plasma levels. Two cases of phenytoin intoxication associated with simultaneous administration of diazepam are reported. Intravenous phenytoin infusions were given and the apparent Km and Vmax computed from the resulting plasma phenytoin levels. In one case `Km' and `Vmax' were 0.8 μmol/1 and 1.3 μmol/1/hour respectively during concurrent diazepam administration, and 50.3 μmol/1 and 4.4 μmol/1/hour after discontinuation of diazepam. In the second case phenytoin infusion with diazepam gave `Km' and `Vmax' values of 0.012 μmol/1 and 0.95 μmol/1/hour. Without diazepam these were 28.8 μmol/1 and 0.92 μmol/1/hour respectively. PMID:599366

  18. [A case of phenytoin intoxication caused by interaction between phenytoin and capecitabine].

    PubMed

    Taguchi, Yoshiharu; Takashima, Shutaro; Tanaka, Kortaro

    2015-02-01

    We report a case of phenytoin intoxication caused by an interaction between phenytoin and capecitabine. A 41-year-old woman was started on phenytoin (200 mg p.o. daily) for convulsive attacks due to breast cancer brain metastasis. Three months later, chemotherapy with 2,400 mg/d capecitabine (3 weeks on and 1 week off) and 1,250 mg/d lapatinib was initiated for the treatment of breast cancer. Approximately 10 weeks after starting chemotherapy, the patient began to complain of nausea, vomiting, and unsteadiness, and she was admitted to our hospital. Since her serum phenytoin level was more than 40 μg/mL, she was diagnosed with phenytoin intoxication. Phenytoin is metabolized in the liver, primarily by the CYP2C9 isozyme, which can be competitively inhibited by capecitabine. Thus, we determined that the patient developed phenytoin intoxication due to the interaction between phenytoin and capecitabine. This indicates the importance of considering the potential drug-drug interactions while prescribing anticancer agents and antiepileptic drugs simultaneously.

  19. Phenytoin intoxication induced by sulthiame in epileptic patients

    PubMed Central

    Houghton, G. W.; Richens, A.

    1974-01-01

    Routine estimation of serum phenytoin levels in patients newly admitted to a Special Centre for Epilepsy showed that 40% of those receiving sulthiame in addition to phenytoin had levels in the toxic range. Four long-stay patients became drug intoxicated when sulthiame treatment was started. Sulthiame appears to inhibit the hepatic hydroxylation of phenytoin. PMID:4151416

  20. Electroencephalography and phenytoin toxicity in mentally retarded epileptic patients.

    PubMed Central

    Iivanainen, M; Viukari, M; Seppäläinen, A M; Helle, E P

    1978-01-01

    There were significantly more diffuse and focal electroencephalographic abnormalities in 127 mentally retarded epileptic patients treated with phenytoin than in 68 epileptics without phenytoin. Phenytoin intoxication made the difference still more pronounced. Monitoring drug levels and electroencephalograms appears to be the method of choice for ensuring safe and effective medication in intractable epilepsy. PMID:632825

  1. Phenytoin pharmacokinetics in critically ill trauma patients.

    PubMed

    Boucher, B A; Rodman, J H; Jaresko, G S; Rasmussen, S N; Watridge, C B; Fabian, T C

    1988-12-01

    Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.

  2. Phenytoin Induced Cutaneous B Cell Pseudolymphoma

    PubMed Central

    Riyaz, Najeeba; Sasidharanpillai, Sarita; Aravindan, Karumathil P; Nobin, Babu K; Raghavan, Nisha T; Nikhila, Pappinissery K

    2015-01-01

    Cutaneous pseudolymphomas are benign lymphoproliferative processes mimicking lymphomas clinically and histologically. One of the precipitating factors for pseudolymphoma is drugs like anticonvulsants, antidepressants and angiotensin-converting enzyme inhibitors. According to existing literature phenytoin-induced cutaneous pseudolymphomas are usually T-cell predominant. Most often withdrawal of the drug with or without short-course systemic steroids can attain a cure. Rarely malignant transformation has been reported years later despite withdrawal of the offending drug, which necessitates a long-term follow up of the affected. We report an 80-year-old male patient who was receiving phenytoin sodium and who presented with diffuse erythema and infiltrated skin lesions which histologically resembled cutaneous B-cell lymphoma. Substituting phenytoin with levetiracetam achieved resolution of symptoms. Further evaluation was suggestive of a reactive process. A detailed drug history is of paramount importance in differentiating drug-induced pseudolymphoma from lymphoma. Searching literature we could not find any previous reports of phenytoin-induced cutaneous B-cell pseudolymphoma. PMID:26538730

  3. Topical phenytoin for treating pressure ulcers.

    PubMed

    Hao, Xiang Yong; Li, Hong Ling; Su, He; Cai, Hui; Guo, Tian Kang; Liu, Ruifeng; Jiang, Lei; Shen, Yan Fei

    2017-02-22

    Pressure ulcers are common in clinical practice and pose a significant health problem worldwide. Apart from causing suffering to patients, they also result in longer hospital stays and increase the cost of health care. A variety of methods are used for treating pressure ulcers, including pressure relief, patient repositioning, biophysical strategies, nutritional supplementation, debridement, topical negative pressure, and local treatments including dressings, ointments and creams such as bacitracin, silver sulphadiazine, neomycin, and phenytoin. Phenytoin is a drug more commonly used in the treatment of epilepsy, but may play an important role in accelerating ulcer healing. To assess the effects of topical phenytoin on the rate of healing of pressure ulcers of any grade, in any care setting. In September 2016, we searched the following electronic databases to identify relevant randomized clinical trials: the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library); Ovid MEDLINE; Ovid Embase; and EBSCO CINAHL Plus. We handsearched conference proceedings from the European Pressure Ulcer Advisory Panel, European Wound Management Association and the Tissue Viability Society for all available years. We searched the references of the retrieved trials to identify further relevant trials. We also searched clinical trials registries to identify ongoing and unpublished studies. There were no restrictions with respect to language, date of publication or study setting. We included all randomized controlled trials (RCTs) addressing the effects (both benefits and harms) of topical phenytoin on the healing of pressure ulcers of any grade compared with placebo or alternative treatments or no therapy, irrespective of blinding, language, and publication status. Two review authors independently selected studies, extracted information on participants, interventions, methods and results and assessed risk of bias using

  4. INFLUENCE OF SPIRULINA ON THE PHENYTOIN INDUCED HAEMATOLOGICAL CHANGES

    PubMed Central

    Thaakur, Santh Rani; Pushpakumari, B.

    2007-01-01

    Phenytoin is indicated for tonic clonic seizures and status epilepticus. Phenytoin is known to deplete vital nutrients such as calcium, folic acid, vitamin D, vitamin K, biotin, carnitine, copper, selenium and zinc. Depletion of nutrients is known to cause adverse effects such as ataxia, nystagmus, lethargy, slurred speech and hematological disturbances. Spirulina is a rich source of vital nutrients including iron. It is proposed to study the effect of spirulina on the hematological disturbances induced by phenytoin. Seven groups of male albino rats weighing 130-150g were used. Each group consisted of six animals. Phenytoin at a dose of 20mg/kg/day dissolved in water, spirulina 50, 100, 200 mg/kg/day suspended in 1% tween 80 alone or in combination with phenytoin was administered for 30 days. Hemoglobin content, total leucocyte and erythrocyte count were determined on 30th day. Phenytoin significantly decreased the hemoglobin content, total erythrocyte and leukocyte count. Spirulina did not show any effect at the lower dose of 50 and 100mg/kg and higher dose of 200mg/ kg significantly elevated hemoglobin content. Spirulina at a dose of 200mg/kg/day in combination with phenytoin reversed the phenytoin induced decrease in hemoglobin content, total erythrocyte and leukocyte count. The results of this study indicates that supplementation of phenytoin with spirulina may reverse the hematological disturbances induced by phenytoin. PMID:22557235

  5. Effect of dosage increments on blood phenytoin concentrations

    PubMed Central

    Bochner, F.; Hooper, W. D.; Tyrer, J. H.; Eadie, M. J.

    1972-01-01

    Blood phenytoin (diphenylhydantoin) concentrations were measured after each dosage change in 12 epileptic patients who were given increasing oral doses of phenytoin. In each of these patients a dosage increment beyond the dosage that produced a blood phenytoin level of 6-9 μg/ml. caused a disproportionately great increase in the blood concentration of drug. This effect might be expected if the limit of the body's capacity to metabolize phenytoin were being reached. As oral dosages were increased in one patient, measurements of the rate of urinary excretion of phenytoin metabolite showed that the phase of rapid rise in blood phenytoin concentration coincided with a failure to increase the rate of phenytoin metabolite excretion. Awareness of the non-linear relation between oral dose and blood concentration of phenytoin in the individual patient, and realization that the phase of rapid rise in blood phenytoin concentration occurs through the `therapeutic' range of 10-20 μg/ml., is of importance to those who use blood phenytoin levels as a guide to the adequacy of anticonvulsant therapy. PMID:4647859

  6. Phenytoin promotes Th2 type immune response in mice

    PubMed Central

    Okada, K; Sugiura, T; Kuroda, E; Tsuji, S; Yamashita, U

    2001-01-01

    The effects of chronic administration of phenytoin, a common anticonvulsive drug, on immune responses were studied in mice. Anti-keyhole limpet haemocyanin (KLH) IgE antibody response after KLH-immunization was enhanced in phenytoin-treated mice. Proliferative responses of spleen cells induced with KLH, concanavalin A (ConA), lipopolysaccharide and anti-CD3 antibody were reduced in phenytoin-treated mice. Accessory function of spleen adherent cells on ConA-induced T cell proliferative response was reduced in phenytoin-treated mice. KLH-induced IL-4 production of spleen cells was enhanced, while IFN-γ production was reduced in phenytoin-treated mice. In addition, production of IL-1α, but not IL-6 and IL-12 by spleen adherent cells from phenytoin-treated mice was reduced. Natural killer cell activity was reduced in phenytoin-treated mice. These results suggest that phenytoin treatment preferentially induces a Th2 type response. We also observed that plasma ACTH and corticosterone levels were increased in phenytoin-treated mice, and speculated that phenytoin might act directly and indirectly, through HPA axis activation, on the immune system to modulate Th1/Th2 balance. PMID:11472401

  7. Studies in man of phenytoin absorption and its implications.

    PubMed Central

    Gibberd, F B; Webley, M

    1975-01-01

    The absorption of phenytoin was studied in man. It is concluded that phenytoin absorbed from the intestine is recirculated via the bile, so that blood levels do not accurately reflect absorption. Phenytoin is loosely bound to serum proteins and is found in red cells in concentrations similar to those in plasma. It is rapidly lost from the blood stream after intravenous administration, which is an important factor to be considered in the treatment of status epilepticus. PMID:1151402

  8. Population pharmacokinetics of phenytoin in critically ill children.

    PubMed

    Hennig, Stefanie; Norris, Ross; Tu, Quyen; van Breda, Karin; Riney, Kate; Foster, Kelly; Lister, Bruce; Charles, Bruce

    2015-03-01

    The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration. © 2014, The American College of Clinical Pharmacology.

  9. TRPA1 Channels Mediate Human Gingival Fibroblast Response to Phenytoin.

    PubMed

    López-González, M J; Luis, E; Fajardo, O; Meseguer, V; Gers-Barlag, K; Niñerola, S; Viana, F

    2017-07-01

    Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications-the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium-permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. Collectively, these findings support an important role of TRPA1 channels in phenytoin-induced GE, provide insight into the pathophysiologic mechanism, and offer novel therapeutic opportunities for its treatment.

  10. Plasma protein binding of phenytoin in 100 epileptic patients.

    PubMed Central

    Peterson, G M; McLean, S; Aldous, S; Von Witt, R J; Millingen, K S

    1982-01-01

    The plasma protein binding of phenytoin was investigated in 100 epileptic patients, using equilibrium dialysis at 37 degrees C. The unbound fractions of phenytoin in plasma formed a skewed distribution, with a range of 9.7 to 24.7% and a median value of 12.3%. Most (80%) patients appeared to form one group with free phenytoin fractions from 9.7 to 14.5%, while the remainder formed a group with elevated free fractions (greater than 14.5%). Total and unbound plasma concentrations of phenytoin were strongly correlated (r=0.95, P less than 0.0001). There was a weak correlation between increasing age and the unbound phenytoin fraction (r=0.28, P less than 0.01). The results indicate that measurement of the total phenytoin concentration in plasma should usually provide a reliable index of anticonvulsant effect. However, determination of the unbound phenytoin fraction would be beneficial in the management of those patients in whom this fraction may be elevated, due to interacting drugs or biochemical abnormalities. PMID:7104186

  11. Abbott ARCHITECT iPhenytoin assay versus similar assays for measuring free phenytoin concentrations.

    PubMed

    Tacker, Danyel Hermes; Robinson, Randy; Perrotta, Peter L

    2014-01-01

    To measure free phenytoin (FP) concentrations in filtered specimens using the Abbott ARCHITECT iPhenytoin assay and to compare results from this method with results from the Abbott TDx/FLx assays. We verified accuracy, analytic measurement range, and precision for FP measurements. For correlation and therapeutic interval studies, we used filtered calibrators, controls, proficiency-testing materials, and surplus clinical samples. After implementation, we determined proficiency testing results. The analytic measurement range was 2.0 to 25.0 micromol/L. Quality control materials (6.1, 12.6, and 20.1 micromol/L) provided mean (SD) recoveries of 96.1 (5.0%), 99.2 (5.0%), and 99.3 (5.7%), respectively, and coefficients of variation of 5.2%, 5.0%, and 5.8%, respectively. Clinical specimens produced mean (SD) FP recovery levels of 103.7 (10.6%) (bias, 0.1 [0.3] micromol/L). Altering the FP therapeutic range (4.0-8.0 micromol/L) was unnecessary. Proficiency testing yielded consistently acceptable results. Our accuracy, precision, and correlation results were similar for the TDx/FLx and ARCHITECT assays, which demonstrates that the ARCHITECT iPhenytoin assay is acceptable for clinical FP measurements.

  12. Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration

    PubMed Central

    Purkins, Lynn; Wood, Nolan; Ghahramani, Parviz; Love, Edward R; Eve, Malcolm D; Fielding, Anitra

    2003-01-01

    Aims Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered. Methods Two placebo-controlled parallel-group studies were conducted in healthy male volunteers. Study A was an open-label study and investigated the effect of phenytoin (300 mg once daily) on the steady-state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double-blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady-state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCτ were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded. Results Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCτ were 60.7% [90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCτ were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCτ 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild

  13. Single point estimation of phenytoin dosing: a reappraisal.

    PubMed

    Koup, J R; Gibaldi, M; Godolphin, W

    1981-11-01

    A previously proposed method for estimation of phenytoin dosing requirement using a single serum sample obtained 24 hours after intravenous loading dose (18 mg/Kg) has been re-evaluated. Using more realistic values for the volume of distribution of phenytoin (0.4 to 1.2 L/Kg), simulations indicate that the proposed method will fail to consistently predict dosage requirements. Additional simulations indicate that two samples obtained during the 24 hour interval following the iv loading dose could be used to more reliably predict phenytoin dose requirement. Because of the nonlinear relationship which exists between phenytoin dose administration rate (RO) and the mean steady state serum concentration (CSS), small errors in prediction of the required RO result in much larger errors in CSS.

  14. The effect of polymorphic metabolism enzymes on serum phenytoin level.

    PubMed

    Ozkaynakci, Aydan; Gulcebi, Medine Idrizoglu; Ergeç, Deniz; Ulucan, Korkut; Uzan, Mustafa; Ozkara, Cigdem; Guney, Ilter; Onat, Filiz Yilmaz

    2015-03-01

    Phenytoin has a widespread use in epilepsy treatment and is mainly metabolized by hepatic cytochrome P450 enzymes (CYP). We have investigated CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in a Turkish population of patients on phenytoin therapy. Patients on phenytoin therapy (n = 102) for the prevention of epileptic seizures were included. Polymorphic alleles were analyzed by restriction fragment length polymorphism method. Serum concentrations of phenytoin were measured by fluorescence polarization immune assay method. The most frequent genotype was detected for CYP2C9 wild-type alleles (78.43 %), whereas CYP2C19*2/*2 (5.88 %) was the least frequent genotype group. According to the classification made with both enzyme polymorphisms, CYP2C9*1/*1-CYP2C19*1/*1 (G1: 41.17 %) genotype group was the most frequent whereas CYP2C9*1/*2-CYP2C19*1/*3 (G7: 0.98 %) was the least frequent one. The highest mean phenytoin level (27.95 ± 1.85 µg/ml) was detected in the G8 genotype group (CYP2C9*1/*3-CYP2C19*2/*3) and the G1 genotype group showed the lowest mean phenytoin level (7.43 ± 0.73 µg/ml). The mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients. These results show the importance of the genetic polymorphism analysis of the main metabolizing enzyme groups of phenytoin for the dose adjustment.

  15. Paradoxical Seizure Response to Phenytoin in an Epileptic Heroin Addict.

    PubMed

    Vasagar, Brintha; Verma, Beni R; Dewberry, Robert G; Pula, Thaddeus

    2015-06-01

    Phenytoin has a narrow therapeutic window and seizures can occur at both ends of the spectrum. A 41-year-old man with a history of a seizure disorder and heroin addiction presented with dizziness following 2 generalized tonic-clonic seizures that occurred earlier that day. The patient had received a loading dose of phenytoin for seizures associated with a subtherapeutic level 5 days previously. Initial evaluation revealed an elevated phenytoin level of 32.6 mcg/mL and an opiate-positive toxicology screen. Levetiracetam was started on the day of presentation and phenytoin was held until the level returned to the therapeutic range. The patient's dizziness resolved and he had no additional seizures. Evaluation for reversible causes of seizure activity along with anticonvulsant administration is generally the standard of care for breakthrough seizures. Phenytoin blood levels, if supratherapeutic, may be at least partially responsible for breakthrough seizure activity; in this circumstance, holding phenytoin and temporarily adding another anticonvulsant may be indicated.

  16. Velopharyngeal Incoordination Caused by Phenytoin-Induced Toxicity.

    PubMed

    Hwang, Chang Ho

    2017-02-01

    Phenytoin induces lymphoid proliferation, resulting in complications that can range from tissue hyperplasia to lymphoma. Some of the complications resolve spontaneously after drug discontinuation. This report describes for the first time a case of dysphagia with lack of velopharyngeal coordination and nasopharyngeal reflux combined with massive palatine tonsillar hypertrophy. The condition did not develop before phenytoin administration, was induced by phenytoin, and spontaneously resolved upon drug discontinuation. The patient was referred for a video-fluoroscopic swallowing study owing to a recurring nasal reflux of foods that had developed since phenytoin administration. The video-fluoroscopic swallowing study revealed incidentally that the large bilateral elongated masses extended downward into the larynx and disturbed velar elevation. This finding was confirmed by computed tomography of the neck, which showed that palatine tonsillar hypertrophy disturbed the laryngopharynx on both sides. The symptoms (sleep apnea and nasal reflux) and the abnormal imaging findings disappeared without surgery approximately 1 month after drug discontinuation. This case suggests that dysphagia related to phenytoin-induced lymphoid hypertrophy may be treated by phenytoin discontinuation followed by a sufficient amount of time to allow symptom resolution rather than by prompt surgery.

  17. Phenytoin Induced Erythema Multiforme after Cranial Radiation Therapy

    PubMed Central

    Tekkök, İsmail Hakkı

    2015-01-01

    The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM. PMID:26361537

  18. Effect of phenytoin (DPH) treatment on methoxyflurane metabolism in rats.

    PubMed

    Caughey, G H; Rice, S A; Kosek, J C; Mazze, R I

    1979-08-01

    The toxicity and metabolism of the fluorinated anesthetic methoxyflurane were compared in Fischer 344 rats pretreated with phenytoin or phenobarbital. Treatment with either drug potentiated the polyuric effects of methoxyflurane by more than 100%. Also, serum inorganic fluoride (F-) levels and urinary F- excretions after methoxyflurane exposure were comparable in phenytoin- and phenobarbital-treated rats, a 26 to 49% increase as compared to rats treated with methoxyflurane alone. In vitro, 10-fold increases in the rate of hepatic microsomal methoxyflurane defluorination were observed after treatment of rats with either phenytoin or phenobarbital. Kinetic studies with microsomes demonstrated inhibition of methoxyflurane defluorination in the presence of phenytoin. Defluorination of three additional fluorinated ether anesthetics, enflurane, isoflurane and sevoflurane, also was examined in vitro. Phenytoin and phenobarbital treatment resulted in similar enhancement of defluorination of the latter two anesthetics, but not enflurane. Phenytoin and phenobarbital treatment increase defluorination of fluorinated ether anesthetics to approximately the same extent in vitro and in vivo in Fischer 344 rats.

  19. Drug interaction between phenytoin and valproic acid in a child with refractory epilepsy: a case report.

    PubMed

    Carvalho, Indira Valadê; Carnevale, Renata Cavalcanti; Visacri, Marília Berlofa; Mazzola, Priscila Gava; de Fátima Lopes Ambrósio, Rosiane; dos Reis, Marcelo Conrado; de Queiroz, Rachel Alvarenga; Moriel, Patricia

    2014-04-01

    There are no published reports on pediatric phenytoin toxicity, resulting from the drug interaction between phenytoin and valproic acid. A 12-year-old patient with refractory epilepsy syndrome presented with phenytoin toxicity, following a concomitant treatment with phenytoin, valproic acid, and lamotrigine. The phenytoin concentration detected in the capsules used by the patient was in accordance with the prescribed dose and was appropriate for the age and weight of the patient. However, a supratherapeutic phenytoin serum concentration was observed (21.92 µg phenytoin/mL of blood). Consequently, the phenytoin dose was reduced, and the patient was monitored; 24 hours later the patient did not present with any signs/symptoms of toxicity. Despite the appropriate phenytoin concentration in the capsules, the patient presented with phenytoin toxicity. This toxicity likely resulted from the drug interaction between phenytoin and valproic acid that leads to phenytoin displacement from plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

  20. Differences between the Measured and Calculated Free Serum Phenytoin Concentrations in Epileptic Patients

    PubMed Central

    Hong, Ji-Man; Choi, Young-Chul

    2009-01-01

    Purpose The pharmacokinetics of phenytoin is complicated by genetic and environmental differences. It is, therefore, important to monitor the serum concentrations in patients who receive phenytoin. Because most of the phenytoin in serum is bound to proteins, the level of serum albumin influences the amount of free phenytoin. Materials and Methods We compared the measured and calculated free phenytoin levels in epileptic patients who were taking phenytoin monotherapy, using the Sheiner-Tozer equation. A total of 49 patients (30 men and 19 women; age range, 15 - 87 years) were included in the study and their trough serum phenytoin and albumin concentrations were analyzed. Results The linear correlation between free and total phenytoin concentrations was moderate (r = 0.822, p < 0.001). The mean difference between measured and calculated free phenytoin was large (0.65 ± 0.88 µg/mL; 95% confidence interval (CI), -1.11 to 2.41). After dividing the patients into groups by albumin concentration, hypoalbuminemic patients (< 3.5 g/dL) more often had a greater percent difference (≥ 20%) than observed in the normoalbuminemic (≥ 3.5 g/dL) group. Conclusion In hypoalbuminemic patients, the measurement of free phenytoin level is necessary to properly evaluate the phenytoin level than that calculated from total phenytoin level. PMID:19718399

  1. Phenytoin-induced toxic epidermal necrolysis: Review and recommendations

    PubMed Central

    Al-Quteimat, Osama M.

    2016-01-01

    Toxic epidermal necrolysis (TEN) is a serious, life-threatening skin reaction characterized by severe exfoliation and destruction of the epidermis of the skin. In most TEN cases, drugs are believed to be the causative agent; antipsychotics, antiepileptics, and other medications such as sulfonamides are among the most common causes of drug-induced TEN. Phenytoin, a commonly prescribed medication for seizure, was found to cause TEN. Evidence-based treatment guidelines are lacking, so the best strategy is to identify and avoid potential risk factors and to provide intensive supportive care. The aim of this literature review is to focus on phenytoin-induced TEN, to explore the risk factors, and to highlight the possible treatment options once phenytoin-induced TEN is confirmed. PMID:27651708

  2. Particular Film Formation of Phenytoin at Silica Surfaces

    PubMed Central

    2014-01-01

    Given the increasing number of poorly soluble and thus poorly bioavailable active pharmaceutical materials, there is a demand for innovative formulation platforms for such molecules. Thus a focus on enhancing dissolution properties of poorly soluble drugs exists. Within this study, the spin coating of acetone solutions containing 5,5-diphenyl-2,4-imidazolidinedione (phenytoin) in various concentrations is evaluated. The results reveal strong variations of the morphology of deposited phenytoin crystals at silica surfaces. Individual separated particles are obtained on low phenytoin concentrations, and closely packed particular films form when the concentration is increased. As the material is isomorphic, these various morphologies have the same crystalline structure. Dissolution experiments reveal that both the apparent maximum solubility and as the dissolution rate are strongly enhanced compared to bulk powder, suggesting that formulation based on this preparative technique will allow overcoming the low solubility problematic for a variety of drugs. PMID:24417472

  3. Neurological manifestation of phenytoin toxicity, resulting from drug interaction with chloramphenicol: a case report.

    PubMed

    Jokonya, L; Musara, A

    2015-01-01

    Phenytoin toxicity masquerading as deterioration of neurological symptoms caused by interaction with chloramphenicol is a very rare but real risk. To the authors’ knowledge only one such case occurring in humans has been reported in the English literature. No case of clinical phenytoin toxicity occurring at less than double the serum phenytoin therapeutic levels, occurring as a result of chlorampenicol interaction has been documented, hence our report. A 17 year old man, whose frontal subdural empyema had been drained, had his seizures well controlled on phenytoin. Shortly after, he had a parasagital subdural empyema which was also drained. He was put on chloramphenicol. He improved tremendously until he then developed cerebellar symptoms. Phenytoin levels were noted to be almost twice the maximum therapeutic value. On stopping chloramphenicol, phenytoin levels normalized and symptoms resolved. Possibility of phenytoin toxicity should always be entertained in patients who are also taking chlorampenicol, presenting with new or worsening neurological symptoms.

  4. Urate synthesis and oxidative stress in phenytoin hepatotoxicity: the role of antioxidant vitamins.

    PubMed

    Ekaidem, Itemobong S; Usoh, Itoro F; Akpanabiatu, Monday I; Uboh, Friday E; Akpan, Henry D

    2014-11-01

    Phenytoin is known to induce microsomal enzymes including xanthine oxidase which catalyzes uric acid synthesis with superoxides as byproducts, thus contributing to the oxidative stress of phenytoin hepatotoxicity. To investigate the role of antioxidant vitamins in ameliorating phenytoin induced hepatic changes through possible actions on xanthine oxidase activities as measured by urate concentration. Growing albino rats of Wistar strain were randomly divided into 8 groups of 7 rats each. Group 2, 3, 4, 5, 6, 7 and 8 were treated with phenytoin alone, phenytoin + folic acid, phenytoin + vitamin E, phenytoin + vitamin E + vitamin C, phenytoin + vitamin C, phenytoin + folic acid + vitamin E and phenytoin + vitamin E + vitamin C + folic acid respectively while animals in group 1 were given normal saline to serve as control. Serum concentrations of uric acid, albumin, total protein and the activities of aspartate and alanine aminotransferases (AST and ALT) and catalase were measured spectrophotometrically using appropriate commercial reagent kits. Result showed that administration of phenytoin alone caused significant (p < 0.05) increase in serum levels of globulin, uric acid, AST and ALT activities while the levels of albumin and catalase were reduced significantly (p < 0.05). Supplementation of phenytoin treatment with vitamins resulted in various degrees of protection. However, the elevated level of uric acid in serum was not significantly (p < 0.05) affected by any of the vitamins used and there was no significant correlation between the activities of aminotransferases and uric acid concentration in the vitamin treated animals as was observed between aminotransferases and catalase. The findings in this study suggest that antioxidant vitamins were able to ameliorate phenytoin hepatotoxic effects by improving oxidant radicals removal in the animals but would not inhibit further generation of the superoxides by xanthine oxidase activity and that xanthine oxidase may

  5. [Follow-up of a cohort of patients after substitution of phenytoin for phenytoin sodium in an epilepsy center].

    PubMed

    Lavandier, N; Tourniaire, D

    2015-02-01

    In March 2012, the French Health Products Safety Agency interrupted the commercialization of di-hydan (phenytoin). It was replaced by diphantoïne (phenytoin sodium) and prescribers were informed that posology was equivalent for both products. We conducted a retrospective study of phenytoinemia and clinical effects comparatively for these two drugs in a population of adult patients with epilepsy admitted in La TEPPE. Forty-four patients were included. Mean age was 47.6 years. Phenytoinemia significantly decreased after substitution (17.14mg/L with di-hydan versus 12.17mg/L with diphantoïne, P<8 10(-6)). Moreover an increase in post substitution posology of diphantoïne was noticed (264.77mg/L with di-hydan versus 274.73mg/L with diphantoïne), although not significant (P=0.11). Increase of seizures was non-significant (P = 0.09). The decrease of phenytoinemia was probably due to the difference of composition between the drugs: a 100mg di-hydan tablet contains 100mg of phenytoin whereas a 100mg diphantoïne tablet contains 92mg. The specific non-linear kinetics of phenytoin reinforces this difference. A prospective study could better evaluate the risk of substituting di-hydan with diphantoïne. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  6. Phenytoin attenuates the hyper-exciting neurotransmission in cultured embryonic cortical neurons.

    PubMed

    Chou, Ming-Yi; Lee, Chun-Yao; Liou, Horng-Huei; Pan, Chien-Yuan

    2014-08-01

    Phenytoin is an effective anti-epileptic drug that inhibits Na(+) channel activities; however, how phenytoin modulates synaptic transmission to soothe epileptic symptoms is not clear. To characterize the effects of phenytoin regulation on neurotransmission, we studied the electrophysical properties of cultured embryonic cortical neurons. Phenytoin inhibited the inward Na(+) current in a dose-dependent manner with an IC50 of 16.8 μM, and at 100 μM, the inhibitory effect of phenytoin on the Na(+) current was proportional to the frequency applied. In cultured neurons, phenytoin significantly decreased the action potential firing rate and the peak potential. To study the effect of phenytoin in neurotransmission, we measured the Ca(2+) responses from stimulated target neurons and their neighboring neurons. Phenytoin significantly suppressed the Ca(2+) responses evoked by strong stimulations in the target and neighboring neurons, and exerted a decreased inhibitory effect under moderate stimulation. Picrotoxin, a GABAA receptor antagonist, enhanced the recorded spontaneous excitatory postsynaptic current activities. After picrotoxin-induced enhancement, phenytoin had a more pronounced effect on the suppression of the spontaneous hyper-exciting excitatory postsynaptic current (>100 pA), but it only mildly inhibited the general excitatory postsynaptic current. Our results demonstrate that phenytoin suppresses the efficacy of neurotransmission especially for the high-frequency stimulation by reducing the Na(+) channel activity and can potentially alleviate epileptiform activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Infusion dose requirement of rocuronium in patients on phenytoin therapy - A prospective comparative study.

    PubMed

    Sheshadri, Veena; Radhakrishnan, Arathi; Halemani, Kusuma; Keshavan, Venkatesh H

    2017-10-01

    Patients with intracranial tumour are usually on anticonvulsants. Patients on phenytoin therapy demonstrate rapid metabolism of nondepolarising muscle relaxants secondary to enzyme induction. Infusion dose requirement of rocuronium in such patients has been sparingly studied. We studied the continuous infusion dose requirement of rocuronium bromide in patients on phenytoin therapy and its correlation with serum levels of phenytoin. Seventy-five patients scheduled for supratentorial tumour surgery were included in the study. Patients not on phenytoin were taken as control. The primary outcome variable studied was the infusion dose requirement of rocuronium in patients on phenytoin. Based on pre-operative serum phenytoin levels, study group patients were divided into two groups: sub-therapeutic level group (phenytoin level <10 μg/mL) and therapeutic level group (phenytoin level >10 μg/mL). Following anaesthesia induction, rocuronium bromide 0.6 mg/kg was administered to achieve tracheal intubation. Rocuronium infusion was titrated to maintain zero response on the train-of-four response. Demographic data were comparable. Patients receiving phenytoin required higher infusion dose compared to the control group (0.429 ± 0.2 mg/kg/h vs. 0.265 ± 0.15 mg/kg/h, P < 0.001). The serum phenytoin level had no correlation to infusion dose requirement of rocuronium (0.429 ± 0.205 mg/kg/h vs. 0.429 ± 0.265 mg/kg/h ( P = 0.815). The recovery was faster in the phenytoin group compared to the control group. Haowever, it was not clinically significant. The infusion dose requirement of rocuronium bromide in patients on phenytoin is higher and the serum levels of phenytoin does not influence the dose required.

  8. Effect of phenytoin on cortical epileptic foci in cerveau isolé rats.

    PubMed

    Mares, P

    1994-01-01

    The action of phenytoin was studied in acute experiments in rats with brainstem transection at the midcollicular level. Symmetrical epileptogenic foci were elicited in sensorimotor cortical areas of both hemispheres by local application of penicillin. Seven rats formed a control group, ten animals were pretreated with phenytoin (60 mg/kg i.p., 10 min before penicillin application). Synchronization of interictal discharges in control rats was delayed in comparison to animals with an intact brainstem; phenytoin did not influence this synchronization. Spontaneous transition of interictal into ictal activity was not abolished by phenytoin, i.e. in cerveau isolé preparations phenytoin lost this activity. The loss of anticonvulsant activity was not complete. Ictal episodes were modified; they started as very short ones and their duration progressively increased. Structures localized below the level of transection represent a site of at least one of the mechanisms of phenytoin anticonvulsant action.

  9. Phenytoin intoxication with no symptoms correlated with serum drug level: a case study.

    PubMed

    Avcil, Mucahit; Duman, Ali; Turkdogan, Kenan Ahmet; Kapci, Mucahit; Akoz, Ayhan; Canakci, Selcuk Eren; Ozluer, Yunus Emre

    2015-01-01

    In high-dose intake of phenytoin, which is used frequently to treat epilepsy, nystagmus, diplopia, nausea-vomiting, lethargy, confusion, seizure, and coma can be observed. In recent studies on phenytoin intoxication, in which seizure and coma were observed in drug levels greater than 50 ug/mL. The serum phenytoin level of a patient, who consumed approximately 100 pcs of 100 mg phenytoin tablets in an effort to commit suicide, and who had no pathological finding in her neurologic examination, was 124 ug/mL. High drug level and the absence of toxic effect (or the absence of toxic effect correlated with the drug level) indicates that cytochrome P450 is functioning, but there can be a mutation in the MDR1 gene. In our case study, we report on phenytoin intoxication in a patient having a high level of phenytoin but no symptoms correlated with serum drug level, as supported by the findings in the literature.

  10. Cost-minimization analysis of phenytoin and fosphenytoin in the emergency department.

    PubMed

    Touchette, D R; Rhoney, D H

    2000-08-01

    To determine the value of fosphenytoin compared with phenytoin for treating patients admitted to an emergency department following a seizure. Cost-minimization analysis performed from a hospital perspective. Hospital emergency department. Two hundred fifty-six patients participating in a comparative clinical trial. Estimation of adverse event rates and resource use. In our base case, phenytoin was the preferred option, with an expected total treatment cost of $5.39 compared with $110.14 for fosphenytoin. One-way sensitivity analyses showed that the frequency and cost of treating purple glove syndrome (PGS) possibly could affect the decision. Monte Carlo simulation showed phenytoin to be the preferred option 97.3% of the time. When variable costs of care are used to calculate the value of phenytoin compared with fosphenytoin in the emergency department, phenytoin is preferred. The decision to administer phenytoin was very robust and changed only when both the frequency and cost of PGS was high.

  11. Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a population-based study

    PubMed Central

    Antoniou, Tony; Gomes, Tara; Mamdani, Muhammad M; Juurlink, David N

    2011-01-01

    AIMS Pharmacokinetic studies suggest that trimethoprim (TMP) can inhibit the hepatic metabolism of phenytoin, but the clinical relevance of this is uncertain. We studied the risk of phenytoin toxicity following the prescription of trimethoprim/sulfamethoxazole (TMP/SMX), a commonly used antibiotic, among elderly patients receiving phenytoin. METHODS We conducted a population-based, nested case–control study of a cohort of Ontario residents aged 66 years of age or older treated with phenytoin over a 17-year period (April 1 1992 to March 31 2009). Within this group, case patients were those hospitalized with phenytoin toxicity. For each case, we identified up to four control patients from the same cohort, matched for age and sex, and determined the odds ratio (OR) for the association between phenytoin toxicity and receipt of TMP/SMX in the preceding 30 days. RESULTS Among 58 429 elderly patients receiving phenytoin during the study period, we identified 796 case patients hospitalized for phenytoin toxicity and 3148 matched controls. Following multivariable adjustment for potential confounders, we observed a more than doubling of the risk of phenytoin toxicity following the receipt of TMP/SMX [adjusted OR 2.11, 95% confidence interval (CI) 1.24, 3.60]. In contrast, we observed no such risk with amoxicillin, an antibiotic with similar indications but not expected to interact with phenytoin (adjusted OR 1.12, 95% CI 0.64, 1.98). CONCLUSION Among older patients receiving phenytoin, treatment with TMP/SMX is associated with a more than twofold increase in the risk of phenytoin toxicity. When clinically appropriate, alternate antibiotics should be considered for these patients. PMID:21395647

  12. Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients.

    PubMed

    Buckley, Mitchell S; Reeves, Brittany A; Barletta, Jeffrey F; Bikin, Dale S

    2016-04-01

    Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial. The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations. A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia. A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level. There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized. © The Author(s) 2016.

  13. Control of ethanol withdrawal symptoms in mice by phenytoin.

    PubMed

    Sprague, G L; Craigmill, A L

    1976-12-01

    Mice were made physically dependent upon ethanol using either of two methods which involved ethanol vapor inhalation. Following the cessation of exposure to ethanol, the severity of handling-induced convulsions and changes in the response to an electric foot shock (startle reflex) were recorded. Animals given isotonic saline or propylene glycol:ethanol vehicle during withdrawal exhibited handling-induced convulsions, and ethanol (2.0-4.0 g/kg) or phenytoin (5-20 mg/kg) administration during withdrawal resulted in a reduction in the severity of these convulsions. A reduced startle reflex threshold was also evident during withdrawal in mice given isotonic saline or propylene glycol:ethanol vehicle. Ethanol (0.5-4.0 g/kg) or phenytoin (10-20 mg/kg) administration during withdrawal resulted in a significant elevation of the startle reflex threshold compared to control animals. The results are discussed as they relate to others obtained in experimental and clinical studies.

  14. Quantification of Dynamic 11C-Phenytoin PET Studies.

    PubMed

    Mansor, Syahir; Boellaard, Ronald; Froklage, Femke E; Bakker, Esther D M; Yaqub, Maqsood; Voskuyl, Rob A; Schwarte, Lothar A; Verbeek, Joost; Windhorst, Albert D; Lammertsma, Adriaan

    2015-09-01

    The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, (11)C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of (11)C-phenytoin studies in humans. Dynamic (11)C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single- and 2-tissue-compartment models with and without a blood volume parameter. Global and regional test-retest (TRT) variability was determined for both plasma to tissue rate constant (K1) and volume of distribution (VT). According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K1 and from 0.5% to 5.8% for VT. Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K1 and VT values as a 60-min scan. A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic (11)C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K1 and VT, although this still needs to be confirmed under pathologic conditions. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  15. Phenytoin overdose treated with hemodialysis using a high cut-off dialyzer.

    PubMed

    Cormier, Monique J; Desmeules, Simon; St-Onge, Maude; Ghannoum, Marc

    2017-01-01

    We describe the case of a 52-year-old man who presented after having ingested an unknown quantity of phenytoin. Peak phenytoin concentration was 51.2 mg/L (therapeutic range 10-20 mg/L). Five days after admission, the patient became comatose and was intubated. Because of persistent toxic phenytoin levels and unchanged clinical status for 12 days, hemodialysis (HD) was prescribed to enhance elimination of phenytoin. HD was performed using a Gambro Theralite TM filter (Baxter International Inc., Deerfield, USA), a high cut-off filter that allows the removal of molecules of up to 45 kDa. Phenytoin concentration readily decreased during the 8-hour HD treatment from 38.9 mg/L to 27.8 mg/L (28.5% decrease); during HD, phenytoin half-life was 18.5h (compared to 1109.8h before HD and 56.3h after HD), phentyoin clearance averaged 80.1 mL/min and a total of 1.1 g of phenytoin was removed. Albumin removal from the Theralite filter was most important at the beginning of HD. The high clearance of phenytoin obtained with this filter was likely due to its high surface area rather than its capacity to remove the albumin-phenytoin complex. © 2016 International Society for Hemodialysis.

  16. Phenytoin sensitivity of fibroblasts as the basis for susceptibility to gingival enlargement.

    PubMed Central

    Hassell, T. M.; Gilbert, G. H.

    1983-01-01

    A side effect of long-term administration of the anti-epileptic drug phenytoin is overgrowth of the connective tissues surrounding the teeth. In this in vitro study of protein and collagen synthesis by diploid fibroblasts from 17 nonepileptic young persons with healthy gingivae, only seven strains of cells responded to phenytoin in culture medium. Because not all phenytoin-treated individuals develop gingival overgrowth, we suggest that susceptibility is predicated upon the presence of a (genetically determined) phenytoin-sensitive subpopulation of gingival fibroblasts. The concept of the participation of sensitive cell subpopulations in other connective tissue disorders is supported by these findings. Images Figure 1 PMID:6881288

  17. Clinical outcomes associated with brand-to-generic phenytoin interchange.

    PubMed

    Kinikar, Shilpa A; Delate, Thomas; Menaker-Wiener, C Mindy; Bentley, William H

    2012-05-01

    Concerns that antiepileptic brand-to-generic interchange results in disruption of seizure control are widespread. However, little within-patient evidence exists examining such interchanges. To compare within-patient seizure control before and after the interchange of a branded to a single-source generic phenytoin among patients with seizures in a managed care organization. This was a pre-post, self-controlled, retrospective study. Adults with a history of seizure who used Dilantin Kapseals 100 mg extended phenytoin sodium, USP, capsules and whose therapy was interchanged to Taro Pharmaceuticals' AB-rated generic extended phenytoin sodium capsules, USP, 100 mg between July 2007 and May 2008 were included. Study outcomes included the comparisons of the proportions of patients with at least emergency department (ED) visit/inpatient hospitalization and medical office visit/nonoffice consultation for acute seizure in the 6 months before and after interchange. Outcomes were confirmed with manual chart reviews and adjusted for potential confounding medication use. A total of 222 patients were included in the study. Patients were primarily middle-aged (mean 56 years), equally mixed by sex (47% female); most had nonintractable seizures. The majority of patients (~70%) were on phenytoin as monotherapy and had equivalent rates of purchases for potentially confounding medications in both pre- and postinterchange time periods (all p > 0.05). Low serum concentrations were detected more often in the postinterchange study period (adjusted p < 0.001). Despite this, there were low proportions of patients with confirmed seizure events that resulted in an ED visit/inpatient hospitalization in both pre- and postinterchange periods (both 6.3%, adjusted p = 0.937). The proportion of patients with confirmed seizure events diagnosed at a medical office visit was not significantly different between the preinterchange and postinterchange periods (12.2% vs 11.3%, adjusted p = 0.545). No

  18. Phenytoin is an estrogen receptor α-selective modulator that interacts with helix 12.

    PubMed

    Fadiel, A; Song, J; Tivon, D; Hamza, A; Cardozo, T; Naftolin, Frederick

    2015-02-01

    Phenytoin (Dilantin(®); DPH) is used to treat epilepsy but causes estrogen agonist-antagonist-like side effects. We investigated the interaction of phenytoin with estrogen receptors (ERs) α and β by computational molecular docking, ER competition binding, transcriptional assays, and biological actions, comparing outcomes with estradiol (E2), estrone (E1), and tamoxifen (TMX). (1) The DPH docking to 3-dimensional crystal structures of the ERα ligand-binding domain (LBD) showed a high degree of structural complementarity (-57.15 calculated energy units, approximating kcal/mol) with the ligand-binding pocket, including a contact at leucine (L540) in helix 12. Estrogen receptor β showed slightly less favorable interactions (-54.27 kcal/mol), without contacting L450. Estradiol, E1, and TMX contact points with ERα and ERβ do not include L450. (2) Cellular actions: Incubation of cells transfected with ERα or ERβ and a luciferase promoter phenytoin was several orders weaker than E2 as an agonist through ERα and had no effect through ERβ. However, phenytoin at clinical concentrations (10(-11) to 10(-6) mol/L) powerfully antagonized action of E2 on ERα-expressing cells. Similarly, phenytoin at clinically effective concentrations marginally induced alkaline phosphatase by ERα- and ERβ-expressing endometrial cancer cells but at doses well below clinical effectiveness blocked E2-induced alkaline phosphatase. (3) ER competition: In Scatchard plots comparing phenytoin with 17β-estradiol against endometrial cancer cell cytosol E2-alone more effectively displaced labeled E2 than phenytoin, but phenytoin was approximately equimolar effective to E2 in inhibiting E2's displacement of the radiolabel, further confirming that phenytoin is a strong E2 antagonist. At clinically effective concentrations, phenytoin is a strong ERα cell antagonist but a many-fold weaker agonist. Although it interacts with ERβ LBD residues, phenytoin has no effects on ERβ-only expressing

  19. The effect of tenidap sodium on the disposition and plasma protein binding of phenytoin in healthy male volunteers

    PubMed Central

    Blum, R. A.; Schentag, J. J.; Gardner, M. J.; Wilner, K. D.

    1995-01-01

    1 The effects of tenidap sodium 120 mg day-1 at steady state and placebo on the plasma protein binding and pharmacokinetics of phenytoin were compared in this randomised, double-blind, placebo-controlled, parallel-group study, involving 12 healthy young men, conducted over 34 days. 2 Single oral doses of phenytoin 200 mg were given on days 1-3 and 29-31, and intravenous phenytoin, 250 mg infused over 20 min, was given on days 4 and 32. Tenidap (120 mg day-1), or matching placebo, was administered as single oral daily doses from days 8 to 34 inclusive. 3 The plasma protein binding of phenytoin was determined immediately before oral phenytoin administration on days 1 and 29. Pharmacokinetic parameters were estimated from the serum phenytoin concentration-time curves derived on days 4 and 32 following the phenytoin infusions. The differences between the pre- and post-treatment mean percentage of unbound plasma phenytoin and mean pharmacokinetic parameters were compared between treatment groups. 4 Tenidap sodium 120 mg day-1, at steady state, increased the percentage of unbound phenytoin in plasma by approximately 25%, but did not significantly affect AUC(0,48h) or Cmax. 5 Since tenidap increases the percentage of unbound phenytoin in plasma, when monitoring phenytoin plasma concentrations free concentrations of phenytoin should be considered. 6 Tenidap was well tolerated throughout the study. PMID:7547092

  20. Prevention of Phenytoin-Induced Gingival Overgrowth by Lovastatin in Mice

    PubMed Central

    Assaggaf, Mohammad A.; Kantarci, Alpdogan; Sume, Siddika S.; Trackman, Philip C.

    2016-01-01

    Drug-induced gingival overgrowth is caused by the antiseizure medication phenytoin, calcium channel blockers, and ciclosporin. Characteristics of these drug-induced gingival overgrowth lesions differ. We evaluate the ability of a mouse model to mimic human phenytoin-induced gingival overgrowth and assess the ability of a drug to prevent its development. Lovastatin was chosen based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition. Data indicate that anterior gingival tissue overgrowth occurred in phenytoin-treated mice based on gross tissue observations and histomorphometry of tissue sections. Molecular markers of epithelial plasticity and fibrosis were regulated by phenytoin in gingival epithelial tissues and in connective tissues similar to that seen in humans. Lovastatin attenuated epithelial gingival tissue growth in phenytoin-treated mice and altered the expressions of markers for epithelial to mesenchymal transition. Data indicate that phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that lovastatin normalizes the tissue morphology and the expression of the molecular markers studied. Data are consistent with characterization of phenytoin-induced human gingival overgrowth in vivo and in vitro characteristics of cultured human gingival epithelial and connective tissue cells. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required. PMID:25843680

  1. CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects.

    PubMed

    Franco, Valentina; Perucca, Emilio

    2015-01-01

    Phenytoin, a widely prescribed old-generation antiepileptic drug, requires careful individualization of dosage to compensate for its prominent pharmacokinetic variability. This article reviews the contribution of genetic polymorphisms affecting the activity of CYP2C9, the main enzyme responsible for phenytoin metabolism, to the variation in phenytoin clearance and susceptibility to adverse effects. Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile. There is extensive evidence that CYP2C9 polymorphisms are an important determinant of the rate of phenytoin metabolism, although other factors including expression of other enzymes such as CYP2C19 and the influence of drug interactions, physiological and disease-related factors may also play a role. Patients carrying CYP2C9 genotypes associated with reduced phenytoin clearance are at greater risk of developing CNS adverse effects as well as serious cutaneous adverse reactions when given usual dosages of phenytoin. The clinical value and cost-effectiveness of CYP2C9 genotyping in improving the safety of phenytoin therapy, however, have not been clearly established and require formal testing in well-designed prospective studies.

  2. Release profiles of phenytoin from new oral dosage form for the elderly.

    PubMed

    Watanabe, A; Hanawa, T; Sugihara, M; Yamamoto, K

    1994-08-01

    Utilization of the solid mass containing phenytoin, sodium caseinate and microcrystalline cellulose (MCC) as a new dosage form for the elderly was studied. The solid mass was prepared by treatment of the powder mixture with high pressure steam at 115 degrees C for 10 min. The stability of phenytoin in the solid mass was confirmed by infrared spectroscopy and high performance liquid chromatography. The extent of swelling of the solid mass containing phenytoin was investigated by water absorption test and gel strength test, and the swelling property was almost independent of the presence of phenytoin. The release profile of phenytoin from the solid mass was determined under various conditions, and was found to be influenced by the extent of swelling and the swollen state. It was observed that the protein adsorption to the phenytoin crystal surface and the addition of digestive enzyme also affected the release profile. In water, the solid mass prepared from a ground mixture of phenytoin and MCC showed remarkable improvement of release profile of phenytoin.

  3. Influence of an acidic beverage (Coca-Cola) on the pharmacokinetics of phenytoin in healthy rabbits.

    PubMed

    Kondal, A; Garg, S K

    2003-12-01

    This study was carried out to evaluate the influence of an acidic beverage (Coca-Cola) on the pharmacokinetics of phenytoin in rabbits. In a cross-over study, phenytoin was given orally at a dose of 30 mg/kg and blood samples were taken at different intervals from 0-24 h. After a washout period of 7 days, Coca-Cola (5 ml/kg) was administered in combination with phenytoin (30 mg/kg) and blood samples were taken at various time intervals from 0-24 h. The same rabbits continued to receive Coca-Cola (5 ml/kg) for another 7 days. On the 8th day, Coca-Cola (5 ml/kg) in combination with phenytoin (30 mg/kg) was administered and blood samples were taken at similar intervals. Plasma was separated and assayed for phenytoin by high performance liquid chromatography (HPLC) and various pharmacokinetic parameters were calculated. It was concluded that an acidic beverage (Coca-Cola) increases the extent of absorption of phenytoin by significantly increasing the Cmax and AUC(o-á) of phenytoin. These results warrant the reduction of phenytoin dose when administered in combination with Coca-Cola to avoid any toxicity. (c) 2003 Prous Science

  4. Phenytoin as a countermeasure for motion sickness in NASA maritime operations

    NASA Technical Reports Server (NTRS)

    Woodard, Daniel; Knox, Glenn; Myers, K. J.; Chelen, William; Ferguson, Becki

    1993-01-01

    Seasickness is the most prevalent form of motion sickness and is an operational problem during Space Shuttle Solid-fueled Rocket Booster (SRB) retrieval. Phenytoin has been shown to protect against motion sickness induced by Coriolis stress. We exposed SRB recovery personnel to off-vertical rotation and sea motion after phenytoin or placebo. Phenytoin blood levels of at least 9 micrograms/ml were protective against motion sickness at sea. No change in susceptibility to nitrogen narcosis was seen in divers in chamber tests at 460 KPa. Phenytoin was used during the performance of critical and hazardous tasks during training and actual SRB recovery operations. Phenytoin is an effective operational countermeasure for motion sickness for selected SRB crew members.

  5. Use of multi-dose activated charcoal in phenytoin toxicity secondary to genetic polymorphism.

    PubMed

    Chan, Betty S H; Sellors, Kate; Chiew, Angela L; Buckley, Nicholas A

    2015-02-01

    Phenytoin is metabolised in the liver by cytochrome (CYP)2C9 and 2C19 enzymes. Due to saturation of enzyme capacity, the elimination half-life is prolonged at supratherapeutic levels. Genetic polymorphisms of CYP2C9 and 2C19 are reasonably common and further prolong the elimination of phenytoin. There are conflicting reports regarding whether multiple-dose activated charcoal (MDAC) significantly increases the clearance of phenytoin in poisoning. We present 3 patients with phenytoin toxicity and very slow elimination secondary to reduced CYP enzyme function from genetic polymorphisms. MDAC was used in two patients and led to rapid and large reductions in the measured elimination half-lives. This is contrasted with very prolonged elimination in a third patient who did not receive MDAC. MDAC may play a role in the management of chronic phenytoin toxicity, especially in those with very slow endogenous elimination secondary to genetic polymorphisms.

  6. Avoiding errors when administering injectable phenytoin to a child in status epilepticus.

    PubMed

    Douglass, Callum

    2018-02-07

    Errors often occur in the prescribing, preparing, administering and monitoring of intravenous phenytoin ( NHS Improvement 2016 ). Following two fatal incidents involving injectable phenytoin, with contributing factors such as wrong weight estimation, a disregard for existing phenytoin prescriptions and confusion about the final concentration, an alert was issued by NHS Improvement in 2016. This article explores research into the use of injectable phenytoin and why adverse events occur when it is used. The article will inform nurses and doctors who work with children in acute settings about the risks associated with using injectable phenytoin and implications for practice on how to negate these risks. Applying this knowledge to nursing practice can result in reduced adverse events, and a safer and more effective care environment. ©2018 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

  7. Human exposures to pentobarbital-phenytoin combination veterinary drugs.

    PubMed

    Forrester, M B

    2017-07-01

    A combination of pentobarbital and phenytoin is used as a veterinary euthanasia drug. Because of its lethal effect, this study described pentobarbital-phenytoin combination veterinary drug human exposures reported to Texas poison centers during 2000-2015. Of 66 exposures, 73% involved female and 27% male patients. The distribution by patient age was 3% 0-5 years, 5% 6-19 years, 91% 20+ years, and 2% unknown. The most common routes were ocular (41%), ingestion (32%), injection (23%), and dermal (18%). The exposure reasons were unintentional (77%) and intentional (23%). The exposure site was the workplace (52%), patient's own residence (38%), health-care facility (2%), and other/unknown (9%). The management site was managed on site (48%), at/en route to health-care facility (45%), referred to health-care facility (5%), and other (2%). The medical outcomes were no effect (23%), minor effect (30%), moderate effect (8%), major effect (8%), not followed nontoxic (3%), not followed minimal effects (24%), unable to follow potentially toxic (2%), and unrelated (3%). The most common adverse effects were ocular irritation/pain (18%), drowsiness/lethargy (15%), and coma (9%). The most common treatments were dilution/irrigation (70%), intravenous fluids (21%), and oxygen (14%). This study found few pentobarbital-phenytoin combination veterinary drug exposures were reported to Texas poison centers during a 16-year period. Although meant to be administered intravenously, the most common exposure routes were ocular and ingestion. Many of the exposures appeared to be unintentional and occurred at the workplace.

  8. Chronic administration of phenytoin induces efflux transporter overexpression in rats.

    PubMed

    Alvariza, Silvana; Fagiolino, Pietro; Vázquez, Marta; Feria-Romero, Iris; Orozco-Suárez, Sandra

    2014-12-01

    Efflux transporters overexpression has been proposed as one of the responsible mechanism for refractory epilepsy by preventing access of the antiepileptic drug to the brain. In this work we investigated whether phenytoin (PHT), could induce efflux transporters overexpression, at different biological barriers and to evaluate the implication it could have on its pharmacokinetics and therapeutic/toxic response. Forty-two adult females Sprague Dawley divided in five groups were treated with oral doses of 25, 50 and 75mg/kg/6h of PHT for 3 days and two additionally groups were treated with intraperitoneal (ip) doses of 25mg/kg/6h or 100mg/kg/24h. At day 4 PHT plasma concentrations were measured and, obtained several organs, brain, parotid gland, liver and duodenum in which were analyzed for the Pgp expression. At day 4 PHT plasma concentrations were measured and several tissues: brain, parotid gland, liver and duodenum were obtained in order to analyze Pgp expression. In order to evaluate the oral bioavailability of PHT, two groups were administered with oral or intraperitoneal doses of 100mg/kg and plasma level were measured. An induction of the expression of efflux transporter mediated by phenytoin in a concentration-and-time dependent manner was found when increasing oral and ip doses of phenytoin, One week after the interruption of ip treatment a basal expression of transporters was recovered. Overexpression of efflux transporters can be mediated by inducer agents like PHT in a local-concentration dependent manner, and it is reversible once the substance is removed from the body. The recovery of basal Pgp expression could allow the design of dosing schedules that optimize anticonvulsant therapy. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Derivative spectrophotometric analysis of benzophenone (as an impurity) in phenytoin

    PubMed Central

    2011-01-01

    Three simple and rapid spectrophotometric methods were developed for detection and trace determination of benzophenone (the main impurity) in phenytoin bulk powder and pharmaceutical formulations. The first method, zero-crossing first derivative spectrophotometry, depends on measuring the first derivative trough values at 257.6 nm for benzophenone. The second method, zero-crossing third derivative spectrophotometry, depends on measuring the third derivative peak values at 263.2 nm. The third method, ratio first derivative spectrophotometry, depends on measuring the peak amplitudes of the first derivative of the ratio spectra (the spectra of benzophenone divided by the spectrum of 5.0 μg/mL phenytoin solution) at 272 nm. The calibration graphs were linear over the range of 1-10 μg/mL. The detection limits of the first and the third derivative methods were found to be 0.04 μg/mL and 0.11 μg/mL and the quantitation limits were 0.13 μg/mL and 0.34 μg/mL, respectively, while for the ratio derivative method, the detection limit was 0.06 μg/mL and the quantitation limit was 0.18 μg/mL. The proposed methods were applied successfully to the assay of the studied drug in phenytoin bulk powder and certain pharmaceutical preparations. The results were statistically compared to those obtained using a polarographic method and were found to be in good agreement. PMID:22152156

  10. Free phenytoin assessment in patients: measured versus calculated blood serum levels.

    PubMed

    Tobler, Andrea; Hösli, Raphael; Mühlebach, Stefan; Huber, Andreas

    2016-04-01

    Total serum drug levels are routinely determined for the therapeutic drug monitoring of selected, difficult-to-dose drugs. For some of these drugs, however, knowledge of the free fraction is necessary to adapt correct dosing. Phenytoin, with its non-linear pharmacokinetics, >90 % albumin binding and slow elimination rate, is such a drug requiring individualization in patients, especially if rapid intravenous loading and subsequent dose adaptation is needed. In a prior long-term investigation, we showed the excellent performance of pharmacy-assisted Bayesian forecasting support for optimal dosing in hospitalized patients treated with phenytoin. In a subgroup analysis, we evaluated the suitability of the Sheiner-Tozer algorithm to calculate the free phenytoin fraction in hypoalbuminemic patients. To test the usefulness of the Sheiner-Tozer algorithm for the correct estimation of the free phenytoin concentrations in hospitalized patients. A Swiss tertiary care hospital. Free phenytoin plasma concentration was calculated from total phenytoin concentration in hypoalbuminemic patients and compared with the measured free phenytoin. The patients were separated into a low (35 ≤ albumin ≥ 25 g/L) and a very low group (albumin <25 g/L) for comparing and statistically analyzing the calculated and the measured free phenytoin concentration. Calculated and the measured free phenytoin concentration. The calculated (1.2 mg/L (SD = 0.7) and the measured (1.1 mg/L (SD = 0.5) free phenytoin concentration correlated. The mean difference in the low and the very low albumin group was: 0.10 mg/L (SD = 1.4) (n = 11) and 0.13 mg/L (SD = 0.24) (n = 12), respectively. Although the variability of the data could be a bias, no statistically significant difference between the groups was found: t test (p = 0.78), the Passing-Bablok regression, the Spearman's rank correlation coefficient of r = 0.907 and p = 0.00. The Bland-Altman plot including the regression analysis revealed no systematic

  11. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

    PubMed

    Chung, Wen-Hung; Chang, Wan-Chun; Lee, Yun-Shien; Wu, Ying-Ying; Yang, Chih-Hsun; Ho, Hsin-Chun; Chen, Ming-Jing; Lin, Jing-Yi; Hui, Rosaline Chung-Yee; Ho, Ji-Chen; Wu, Wei-Ming; Chen, Ting-Jui; Wu, Tony; Wu, Yih-Ru; Hsih, Mo-Song; Tu, Po-Hsun; Chang, Chen-Nen; Hsu, Chien-Ning; Wu, Tsu-Lan; Choon, Siew-Eng; Hsu, Chao-Kai; Chen, Der-Yuan; Liu, Chin-San; Lin, Ching-Yuang; Kaniwa, Nahoko; Saito, Yoshiro; Takahashi, Yukitoshi; Nakamura, Ryosuke; Azukizawa, Hiroaki; Shi, Yongyong; Wang, Tzu-Hao; Chuang, Shiow-Shuh; Tsai, Shih-Feng; Chang, Chee-Jen; Chang, Yu-Sun; Hung, Shuen-Iu

    2014-08-06

    The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin

  12. Limited value of the urinary phenytoin metabolic ratio for the assessment of cytochrome P4502C9 activity in vivo

    PubMed Central

    TASSANEEYAKUL, WICHITTRA; BIRKETT, DONALD J.; PASS, MICHAEL C.; MINERS, JOHN O.

    1996-01-01

    Relationships between the ratio of p-hydroxyphenytoin (p-HPPH), the major metabolite of phenytoin, to unchanged phenytoin excreted in urine (the urinary metabolic ratio or MR) were compared with a number of indices of the metabolic clearances of phenytoin and tolbutamide published previously for seventeen subjects separately administered these known cytochrome P4502C9 (CYP2C9) substrates. Significant correlations (rs=0.50–0.60, P<0.05) were observed between the phenytoin MR, derived from either 0–24 or 24–48 h urine collections, and inverse areas under the plasma unbound concentration-time curves (measured over various time intervals) of phenytoin and with plasma unbound tolbutamide clearance. Significant correlations (rs =0.59–0.74) were also observed between the phenytoin MRs and metabolic unbound clearances for p-hydroxyphenytoin formation. Despite the significant correlations, variability in tolbutamide and phenytoin metabolic clearance parameters tended to account for <50% of the variability in phenytoin MR. Correlations between the renal clearance of phenytoin and the phenytoin MRs suggest that variability in the renal clearance of unchanged drug limits the usefulness of the phenytoin MR for the investigation of factors influencing CYP2C9 activity in vivo. PMID:8971435

  13. Parametric Methods for Dynamic 11C-Phenytoin PET Studies.

    PubMed

    Mansor, Syahir; Yaqub, Maqsood; Boellaard, Ronald; Froklage, Femke E; de Vries, Anke; Bakker, Esther D M; Voskuyl, Rob A; Eriksson, Jonas; Schwarte, Lothar A; Verbeek, Joost; Windhorst, Albert D; Lammertsma, Adriaan A

    2017-03-01

    In this study, the performance of various methods for generating quantitative parametric images of dynamic 11 C-phenytoin PET studies was evaluated. Methods: Double-baseline 60-min dynamic 11 C-phenytoin PET studies, including online arterial sampling, were acquired for 6 healthy subjects. Parametric images were generated using Logan plot analysis, a basis function method, and spectral analysis. Parametric distribution volume (V T ) and influx rate ( K 1 ) were compared with those obtained from nonlinear regression analysis of time-activity curves. In addition, global and regional test-retest (TRT) variability was determined for parametric K 1 and V T values. Results: Biases in V T observed with all parametric methods were less than 5%. For K 1 , spectral analysis showed a negative bias of 16%. The mean TRT variabilities of V T and K 1 were less than 10% for all methods. Shortening the scan duration to 45 min provided similar V T and K 1 with comparable TRT performance compared with 60-min data. Conclusion: Among the various parametric methods tested, the basis function method provided parametric V T and K 1 values with the least bias compared with nonlinear regression data and showed TRT variabilities lower than 5%, also for smaller volume-of-interest sizes (i.e., higher noise levels) and shorter scan duration. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  14. Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital.

    PubMed

    Methaneethorn, Janthima; Panomvana, Duangchit; Vachirayonstien, Thaveechai

    2017-09-26

    Therapeutic drug monitoring is essential for both phenytoin and phenobarbital therapy given their narrow therapeutic indexes. Nevertheless, the measurement of either phenytoin or phenobarbital concentrations might not be available in some rural hospitals. Information assisting individualized phenytoin and phenobarbital combination therapy is important. This study's objective was to determine the relationship between the maximum rate of metabolism of phenytoin (Vmax) and phenobarbital clearance (CLPB), which can serve as a guide to individualized drug therapy. Data on phenytoin and phenobarbital concentrations of 19 epileptic patients concurrently receiving both drugs were obtained from medical records. Phenytoin and phenobarbital pharmacokinetic parameters were studied at steady-state conditions. The relationship between the elimination parameters of both drugs was determined using simple linear regression. A high correlation coefficient between Vmax and CLPB was found [r=0.744; p<0.001 for Vmax (mg/kg/day) vs. CLPB (L/kg/day)]. Such a relatively strong linear relationship between the elimination parameters of both drugs indicates that Vmax might be predicted from CLPB and vice versa. Regression equations were established for estimating Vmax from CLPB, and vice versa in patients treated with combination of phenytoin and phenobarbital. These proposed equations can be of use in aiding individualized drug therapy.

  15. Evaluation of the effect and mechanism of action of local phenytoin in treatment of vitiligo.

    PubMed

    Abdou, Asmaa Gaber; Abdelwahed Gaber, Mohammed; Elnaidany, Nada Farag; Elnagar, Ayat

    2017-01-01

    There are many theories explaining vitiligo such as genetic, autoimmune, neural, free radicals, biochemical, intrinsic defect, melanocytorrhagy, and convergent theories. Phenytoin is a widely used anticonvulsant, which is used in cutaneous medicine for treatment of ulcers and epidermolysis bullosa. The aim of this study is to assess the effectiveness of topical phenytoin gel in the treatment of vitiligo patients and explaining the underlying mechanism using immunohistochemistry for evaluation of HMB45, CD4, and CD8. Only 9 patients out of 28 experienced response to phenytoin in the form of dull, white color change and light brown color. Post-phenytoin treatment biopsies showed decreased density of inflammation, increased melanin and increased HMB45 positive cells together with an increased number of CD4 positive lymphocytes and decreased number of CD8 positive lymphocytes. These observations did not reach significant level (P > 0.05). A high percentage of CD4 positive lymphocytes was significantly associated with a long duration of vitiligo (p = 0.03) and segmental vitiligo type (p = 0.02). The current study applied phenytoin as 2% concentrated gel for 3 months, which is a relatively short duration without observed side effects throughout the period. These results indicate that topical phenytoin of low concentrations may have beneficial effects through immunomodulatory activity by affecting CD4 and CD8 counts and subsequently the ratio between them. Further studies are recommended to combine phenytoin with other antivitiligo agents as local corticosteroids or phototherapy to clarify if it could potentiate their effects.

  16. Impact of a phenytoin loading dose program in the emergency department.

    PubMed

    Brancaccio, Adam; Giuliano, Christopher; McNorton, Kelly; Delgado, George

    2014-11-01

    The use of a combined physician-and pharmacist-directed phenytoin loading dose program in an emergency department (ED) was evaluated. This single-center, observational, preimplementation-postimplementation study evaluated adult patients who received a phenytoin loading dose in the ED. The primary outcome compared the proportion of optimal phenytoin loading doses in the preimplementation and postimplementation groups. The postimplementation group was further stratified into pharmacist- and prescriber-dosing groups. Other outcomes evaluated included the numbers of appropriate serum phenytoin concentrations measured, adverse drug reactions (ADRs), and recurrence of seizures within 24 hours of loading dose administration in the preimplementation and postimplementation groups. There was no difference in the proportion of optimal phenytoin loading doses between the preimplementation and postimplementation groups (50% versus 62%, respectively; p=0.19). When stratified by individual groups, the rate of optimal phenytoin loading doses increased by 64% in the postimplementation pharmacist group (50% versus 82%, p=0.007), while the rate in the prescriber-dosing group remained relatively unchanged (50% versus 49%, p=0.91). The number of appropriate serum phenytoin concentrations significantly improved in the postimplementation versus preimplementation group (65% versus 40%, p=0.025). Rates of ADRs and recurrence of seizures did not differ across the study groups. No change in the percentage of optimal phenytoin loading doses in the ED was observed after implementation of a combined pharmacist- and physician- dosing program. When stratified into pharmacist or prescriber dosing, the pharmacist-led dosing program significantly improved the proportion of patients who received optimal phenytoin loading doses. Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  17. Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus

    PubMed Central

    Ogutu, Bernhards R; Newton, Charles R J C; Muchohi, Simon N; Otieno, Godfrey O; Edwards, Geoffrey; Watkins, William M; Kokwaro, Gilbert O

    2003-01-01

    Aims Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. Methods Children received intravenous (i.v.) phenytoin as a 18 mg kg−1 loading dose infused over 20 min followed by a 2.5 mg kg−1 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg min−1 phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg kg−1 loading dose followed by 2.5 mg kg−1 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. Results After all routes of administration, a plasma unbound phenytoin concentration of more than 1 µg ml−1 was rapidly (within 5–20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08–0.17), 0.37 (0.33–0.67) and 0.38 (0.17–2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64

  18. The role or non-role of ATPase activation by phenytoin in the stabilization of excitable membranes.

    PubMed

    Deupree, J D

    1977-09-01

    The role or non-role of NaK ATPase, Mg ATPase, and CaMg ATPase involvement in stabilization of excitable membranes by phenytoin is critically evaluated. There is no substantial evidence to indicate that the membrane-stabilizing effect of phenytoin is due to activation of the NaK ATPase. Previous reports of activation of the NaK ATPase at low potassium and high sodium are probably not due to phenytoin but to a potassium contamination in the phenytoin solution. In vitro experiments do not provide any clear evidence of any alterations of NaK ATPase properties by phenytoin. However, one cannot rule out the possibility that phenytoin alters the efficiency of the sodium-potassium pump. Likewise, the Ca ATPase is not inhibited by phenytoin. However, there is some evidence that the Mg ATPase in synaptic vesicles is substantially inhibited by phenytoin. There is substantial evidence indicating that phenytoin partially blocks passive diffusion of sodium into stimulated nerves. The mechanism by which phenytoin blocks sodium influx and the relationship of this effect to the drug's anticonvulsant action remain to be determined.

  19. Cefepime Associated With Phenytoin Induced Stevens-Johnson Syndrome.

    PubMed

    Marco-Del Río, José; Domingo-Chiva, Esther; Cuesta-Montero, Pablo; Valladolid-Walsh, Ana; García-Martínez, Eva María

    We describe a recent case of Stevens-Johnson Syndrome. A 49-year-old man was admitted to the Intensive Care Unit of an Anaesthesia and Resuscitation Department because of a Fournier gangrene that derived in a sepsis, ventilator-associated pneumonia, and renal failure. He was under treatment with cefepime and suffered a generalized status epilepticus, so started treatment with phenytoin. The next day he developed a "maculous cutaneous eruption in trunk and lower limbs" compatible with a Stevens-Johnson Syndrome. Stevens-Johnson Syndrome is a very severe and potentially fatal multiorganic disease, especially when present in critically ill patients, with a strong drug-related etiology, especially with antiepileptic drugs.

  20. Phenytoin-induced severe gingival overgrowth in a child

    PubMed Central

    Kumar, Rakesh; Singh, Rajeev Kumar; Verma, Nidhi; Verma, Umesh Pratap

    2014-01-01

    Gingival enlargement or overgrowth (GO) is a common complication of the anticonvulsant drug phenytoin (PHT). GO is evident in almost half of the patients receiving PHT therapy. PHT-induced gingival overgrowth (PGO) is more common in children than in adults and affects both males and females equally. PGO may vary from mild to severe and does not seem to be dose dependant. It is supposed that PHT and its metabolites cause a direct effect on the periodontal tissues; however, poor oral hygiene may contribute to the severity of gingival inflammation in patients with PGO. Management of PGO includes meticulous oral hygiene practice to reduce inflammation and surgical excision of the overgrown tissue, known as gingivectomy. We present a case of PHT-induced severe GO in a 10-year-old boy and discuss the clinical features, aetiology, pathogenesis and management of PGO. PMID:25053668

  1. Topical phenytoin nanostructured lipid carriers: design and development.

    PubMed

    Motawea, Amira; Borg, Thanaa; Abd El-Gawad, Abd El-Gawad H

    2018-01-01

    Phenytoin (PHT) is an antiepileptic drug that was reported to exhibit high wound healing activity. Nevertheless, its limited solubility, bioavailability, and inefficient distribution during topical administration limit its use. Therefore, this study aims to develop, characterize nanostructured lipid carriers (NLCs), and evaluate their potential in topical delivery of PHT to improve the drug entrapment efficiency and sustained release. The NLCs were prepared by hot homogenization followed by ultra sonication method using 2 3 factorial design. NLC formulations were characterized regarding their particle size (PS), zeta potential (ZP), entrapment efficiency percent (%EE), surface morphology, physicochemical stability, and in vitro release studies. The optimized NLC (F7) was further incorporated in 1%w/v carbopol gel and then characterized for appearance, pH, viscosity, stability, and in vitro drug release. The prepared NLCs were spherical in shape and possessed an average PS of 121.4-258.2 nm, ZP of (-15.4)-(-32.2) mV, and 55.24-88.80 %EE. Solid-state characterization revealed that the drug is dispersed in an amorphous state with hydrogen bond interaction between the drug and the NLC components. NLC formulations were found to be stable at 25 °C for six months. The stored F7-hydrogel showed insignificant changes in viscosity and drug content (p>.05) up to six months at 25 °C that pave a way for industrial fabrication of efficient PHT products. In vitro release studies showed a sustained release from NLC up to 48 h at pH 7.4 following non-Fickian Higuchi kinetics model. These promising findings encourage the potential use of phenytoin loaded lipid nanoparticles for future topical application.

  2. Pharmacokinetic Behavior of Phenytoin in Head Trauma and Cerebrovascular Accident Patients in an Iranian Population.

    PubMed

    Alimardani, Shahnaz; Sadrai, Sima; Masoumi, Hamidreza Taghvaye; Salari, Pooneh; Najafi, Atabak; Eftekhar, Behzad; Mojtahedzadeh, Mojtaba

    2017-01-01

    Acute brain injury is one of the leading causes of morbidity and mortality worldwide. Phenytoin has been commonly used as an anticonvulsant agent for the treatment or prophylaxis of seizures following acute brain injury. After a severe head injury, several pharmacokinetic changes occur. The aim of this study is the comparative evaluation of phenytoin serum concentration in patients with traumatic and nontraumatic brain injury (TBI). This prospective observational study was performed on twenty adult brain injury patients who were admitted to an Intensive Care Unit and required phenytoin for the treatment or prophylaxis of postinjury seizures. For all the patients, phenytoin serum concentration was determined in three scheduled time points. Phenytoin serum concentration and pharmacokinetic parameters were compared between patients with TBI and cerebrovascular accident (CVA). The V max and K m were significantly higher in head trauma (HT) patients than the CVA group. The phenytoin concentration (C p ) and the C p /dose ratio were significantly higher in the CVA group patients during the first sampling ( P < 0.05). The Acute Physiology and Chronic Health Evaluation П (APACHE П) score was significantly lower than the baseline at the end of the study in each group of patients ( P < 0.05). In addition, no significant correlation was observed between V max , K m , C p , C p /dose ratio, and APACHE II scores at the time of sampling. Due to significant differences in phenytoin plasma concentration and pharmacokinetic parameters between HT and CVA patients, close attention must be paid to the pharmacokinetic behavior of phenytoin in the efforts to improve the patient's outcome after a severe HT.

  3. Impact of Body Habitus on Phenytoin Levels Following Fosphenytoin Loading Dose in Pediatric Patients.

    PubMed

    Messinger, Mindl M; Moffett, Brady S; Wilfong, Angus

    2015-12-01

    Obesity has been shown to affect the disposition of water-soluble medications in pediatric patients. There are no published data describing serum phenytoin concentrations in obese pediatric patients. A retrospective descriptive study was designed that included patients from 2011 to 2013 between 2 and 19 years of age who received a dose of fosphenytoin with a subsequent serum phenytoin concentration, drawn 2-4 hours postloading dose. Body mass index (BMI) was calculated and patients were categorized by BMI percentiles into underweight (<5th percentile), normal weight (5th-84th percentile), overweight (85th-94th percentile), and obese (≥95th percentile). Descriptive statistical analysis and comparisons between groups occurred to determine differences in serum phenytoin concentrations. Multivariable linear regression analysis was performed to determine the effect of body habitus on serum phenytoin concentrations. One hundred ten patients met study criteria (male 51.8%, mean age: 8.3 ± 4.9 years). Patients were normal weight (47.3%), underweight (20.9%), overweight (14.6%), and obese (17.3%). No significant differences were identified between groups in regard to patient demographics, with the exception of weight (P < 0.05). The mean fosphenytoin dose was 23.4 ± 5.7 mg Phenytoin Equivalents (PE)/kg and the serum phenytoin concentration was 22.4 ± 6.8 mg/L measured at 2.9 ± 0.6 hours after dose, and this did not vary significantly across groups (P > 0.05). Multivariable linear regression identified body habitus as a nonsignificant predictor of serum phenytoin concentrations (P > 0.05). Patients of higher BMI did not require further antiepileptic therapy as compared with patients with lower BMI (P > 0.05). Contrary to the adult population, loading dose adjustments do not seem to be required in pediatric patients. Obesity does not affect serum phenytoin concentrations in pediatric patients after intravenous bolus fosphenytoin administration.

  4. The ‘apparent clearance’ of free phenytoin in elderly vs. younger adults

    PubMed Central

    Wright, Daniel F B; Begg, Evan J

    2010-01-01

    AIMS To test the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in elderly patients. METHODS Two separate studies were conducted comparing free phenytoin ‘apparent clearance’ in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly. RESULTS In the retrospective study (n = 29), free phenytoin ‘apparent clearance’ was 0.27 ± 0.04 l kg−1 day−1 (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg−1 day−1 (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ‘apparent clearance’ showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg−1 day−1, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg−1 day−1, 95% CI 0.09, 0.26) in those not taking interacting drugs (n = 21). CONCLUSIONS This research does not prove the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect. PMID:20642556

  5. Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base.

    PubMed

    Burstein, A H; Fisher, K M; McPherson, M L; Roby, C A

    2000-05-01

    To compare phenytoin pharmacokinetics following administration of an oral suspension and a rectal suppository formulated with a polyethylene glycol base. Unblinded, single-dose, randomized, crossover trial. University-affiliated pharmacokinetics and biopharmaceutics laboratory. Six healthy subjects. Subjects were given a single 200-mg dose of phenytoin as an oral suspension and a rectal suppository separated by a 1-week washout. Blood for plasma phenytoin concentrations was obtained at baseline and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. Plasma was analyzed by high-performance liquid chromatography (coefficient of variation < 6%) for total phenytoin concentration. Phenytoin maximum concentration (Cmax), time to Cmax (Tmax), time to first measurable concentration (Tlag), and area under the curve from time zero to time of last measurable concentration (AUClast) were estimated for oral and rectal administration by WinNonlin (v 1.1) and compared using Wilcoxon's signed rank test (p<0.05 for statistical significance). Two subjects did not have detectable plasma phenytoin concentrations after rectal administration. For the other four subjects, median rectal Cmax was significantly lower than oral Cmax (0.4 vs 1.9 microg/ml, p=0.028), median rectal Tmax did not differ from oral Tmax (11.9 vs 8.0 hrs, p=0.465), and median rectal AUClast, although highly variable, was significantly lower than oral AUClast (5.4 vs 36.2 microg x hr/ml, p=0.046). No Tlag was seen after oral administration, but with rectal administration the median Tlag was 2 hours. The estimated relative bioavailability of rectal phenytoin suppositories based on AUC0-24 was 4.7%, with individual values ranging from 0-58.3%. It appears that absorption of phenytoin from polyethylene glycol rectal suppositories in healthy subjects is highly variable and unpredictable. Thus this formulation is not recommended.

  6. Effect of food on absorption of Dilantin Kapseals and Mylan extended phenytoin sodium capsules.

    PubMed

    Wilder, B J; Leppik, I; Hietpas, T J; Cloyd, J C; Randinitis, E J; Cook, J

    2001-08-28

    Because of phenytoin's narrow therapeutic index and nonlinear pharmacokinetics, food-induced alterations in absorption may markedly influence drug concentrations and, in turn, safety and effectiveness. Potential food-associated differences between 100-mg Mylan (Mylan Pharmaceuticals) extended-release phenytoin sodium capsules and Parke-Davis 100-mg Dilantin Kapseals were examined. A single-dose, two-way crossover study was conducted in 24 healthy subjects to determine the effect of a high-fat meal on the pharmacokinetics of both formulations. Pharmacokinetic parameters were estimated by noncompartmental methods. The impact of switching products on steady-state phenytoin concentrations was investigated through simulation using pharmacokinetic data previously obtained from 30 epileptic patients. Based on AUC(0-infinity), bioavailability of the Mylan product administered with food was 13% lower than that observed with Dilantin Kapseals. Simulations of substituting the Mylan product for Dilantin suggested that the 13% decrease in bioavailability would result in a median 37% decrease (range 19 to 58%) in plasma phenytoin concentrations when the drug is given with food; in 46% of patients, phenytoin concentrations would likely fall below the therapeutic range of 10 to 20 mg/L. Simulations of substituting Dilantin for the Mylan product suggested that the 15% increase in bioavailability would result in a median 102% increase (range 24 to >150%) in plasma phenytoin concentrations, with 84% of patients having phenytoin concentrations above the therapeutic range. Results suggest that when taking phenytoin sodium with food, product switches may result in either side effects or loss of seizure control.

  7. Effect on survival after myocardial infarction of long-term treatment with phenytoin.

    PubMed Central

    Peter, T; Ross, D; Duffield, A; Luxton, M; Harper, R; Hunt, D; Sloman, G

    1978-01-01

    A prospective, randomised, open trial was performed in 150 patients to test for any beneficial effects on 2-year mortality of long-term antiarrhythmic therapy with phenytoin in patients with acute myocardial infarction. Patients were stratified according to age, sex, past history of myocardial infarction, and the presence of absence of electrical or mechanical complications in the course of acute infarction. They were then randomised to treatment or control groups (74 v. 76). The former received phenytoin in doses aimed at maintaining plasma phenytoin levels between 40 and 80 mumol/litre. All patients entered the study before discharge from the coronary care ward. Plasma phenytoin levels were in the therapeutic range in between 51 and 75 per cent of subjects at any follow up visit. There were 19 withdrawals from the treatment group, 10 of which were the result of side effects. There were 5 withdrawals from the control group. According to the original intention to treat, there were 18 deaths at 2 years in the treatment group and 14 deaths in the control group. There was no reduction in the incidence of instantaneous or sudden deaths. Deaths on treatment were not associated with a low phenytoin plasma level. Phenytoin treatment showed no beneficial effects on mortality and was associated with a high incidence of side effects. PMID:367406

  8. The effect of activated dimethicone and a proprietary antacid preparation containing this agent on the absorption of phenytoin.

    PubMed Central

    McElnay, J C; Uprichard, G; Collier, P S

    1982-01-01

    1 The bioavailabilty of phenytoin sodium (Epanutin both alone and in combination with activated dimethicone and Asilone (a proprietary antacid preparation containing activated dimethicone) was examined in six healthy male volunteers. 2 The bioavailability of phenytoin when given concomitantly with Asilone was decreased in five of six volunteer subjects (by greater than 30% in three subjects) although this decrease was not shown to be statistically significant. 3 Dimethicone, which has been shown to decrease phenytoin absorption in vitro did not affect phenytoin bioavailability in vivo. 4 It is recommended that when treating patients stabilised on phenytoin one should exercise caution with concomitant phenytoin and antacid therapy to guard against possible changed drug absorption. PMID:7066165

  9. Lack of efficacy of phenytoin in the syndrome of inappropriate anti-diuretic hormone secretion of neurological origin.

    PubMed Central

    Decaux, G.; Przedborski, S.; Soupart, A.

    1989-01-01

    Phenytoin has been proposed in the management of patients with the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) of neurological origin who fail to respond to water restriction. We have conducted a prospective study in order to evaluate the role of phenytoin in the management of seven consecutive patients with SIADH of neurological origin which could not be controlled by limited water intake. Only one patient was successfully treated with chronic phenytoin regimen. This patient, like one previously reported, had suffered a basal skull fracture. It seems likely that in the majority of cases of SIADH of neurological origin phenytoin is ineffective on a long-term basis. PMID:2602236

  10. Phenytoin pharmacokinetics and clinical effects in African children following fosphenytoin and chloramphenicol coadministration

    PubMed Central

    Ogutu, Bernhards R; Newton, Charles R J C; Muchohi, Simon N; Otieno, Godfrey O; Kokwaro, Gilbert O

    2002-01-01

    Aims Some children with malaria and convulsions also have concurrent bacterial meningitis. Chloramphenicol is used to treat the latter whereas phenytoin is used for convulsions. Since chloramphenicol inhibits the metabolism of phenytoin in vivo, we studied the effects of chloramphenicol on phenytoin pharmacokinetics in children with malaria. Methods Multiple intravenous (i.v.) doses of chloramphenicol succinate (CAP) (25 mg kg−1 6 hourly for 72 h) and a single intramuscular (i.m.) seizure prophylactic dose of fosphenytoin (18 mg kg−1 phenytoin sodium equivalents) were concomitantly administered to 15 African children with malaria. Control children (n= 13) with malaria received a similar dose of fosphenytoin and multiple i.v. doses (25 mg kg−1 8 hourly for 72 h) of cefotaxime (CEF). Blood pressure, heart rate, respiratory rate, oxygen saturation, level of consciousness and convulsion episodes were monitored. Cerebrospinal fluid (CSF) and plasma phenytoin concentrations were determined. Results The area under the plasma unbound phenytoin concentration-time curve (AUC(0,∞); means (CAP, CEF): 58.5, 47.6 µg ml−1 h; 95% CI for difference between means: −35.0, 11.4), the peak unbound phenytoin concentrations (Cmax; medians: 1.12, 1.29 µg ml−1; 95% CI: −0.5, 0.04), the times to Cmax(tmax; medians: 4.0, 4.0 h; 95% CI: −2.0, 3.7), the CSF:plasma phenytoin ratios (means: 0.21, 0.22; 95% CI: −0.8, 0.10), the fraction of phenytoin unbound (means: 0.06, 0.09; 95% CI: −0.01, 0.07) and the cardiovascular parameters were not significantly different between CAP and CEF groups. However, mean terminal elimination half-life (t1/2,z) was significantly longer (23.7, 15.5 h; 95% CI: 1.71, 14.98) in the CAP group compared with the CEF group. Seventy per cent of the children had no convulsions during the study period. Conclusions Concomitant administration of chloramphenicol and a single i.m. dose of fosphenytoin alters the t1/2,z but not the other pharmacokinetic

  11. Effects of topical phenytoin on nasal wound healing after mechanical trauma: An experimental study.

    PubMed

    Şimşek, Gökçe; Ciftci, Osman; Karadag, Neşe; Karatas, Erkan; Kizilay, Ahmet

    2014-12-01

    Impaired postoperative wound healing is the second most common morbidity after synechia formation in endoscopic sinus surgery. The aim of this experimental study was to investigate the potential effects of topical phenytoin on wound healing after nasal mucosal trauma in rats. An experimental study at the Inonu University Faculty of Medicine. Twenty-four rats were randomized into three groups: 1) phenytoin group (n = 8), 2) control group (n = 8), and 3) vehicle group (n = 8). After damaging the right nasal cavity, in the phenytoin group, 1% topical phenytoin cream was applied for 7 days. The rats in the control group did not receive any treatment. The vehicle group was treated with daily topical cold cream for 1 week. The rats were sacrificed at the end, and the nasal cavities were excised. Tissue edema and inflammatory cell infiltration were compared among the groups. Additionally, proliferating cell nuclear antigen (PCNA) and cluster of differentiation 31 (CD31) immunoexpression levels were evaluated. Furthermore, in biochemical analysis, the tissue levels of vascular endothelial growth factor and (EGF) of the groups were investigated. In the phenytoin group, tissue edema and inflammatory cell infiltration were significantly decreased, and PCNA and CD31 immunoexpression levels were more prominent (P < .001) and the tissue EGF levels were significantly higher (P < .01). Topical phenytoin treatment may alter the nasal wound healing after mechanical trauma. The potential beneficial effects of topical phenytoin on nasal mucosa should be investigated by further experimental and human trials. NA. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

  12. Reduced Anticoagulant Effect of Dabigatran in a Patient Receiving Concomitant Phenytoin.

    PubMed

    Wiggins, Barbara S; Northup, Amanda; Johnson, Dominic; Senfield, Jeffrey

    2016-02-01

    Dabigatran, a direct thrombin inhibitor, is an oral anticoagulant indicated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. Dabigatran, as well as the other new anticoagulants-rivaroxaban, apixaban, and edoxaban-are substrates for P-glycoprotein (P-gp). Although the U.S. labeling for rivaroxaban and apixaban states to avoid concomitant use with phenytoin, a known P-gp inducer, the U.S. labeling for dabigatran and edoxaban are less clear. We describe the first case report, to our knowledge, documenting a drug interaction between phenytoin and dabigatran by using laboratory measurements of dabigatran serum concentrations. A 45-year-old African-American man was admitted to the inpatient cardiology service following defibrillations from his implantable cardioverter defibrillator. The patient was evaluated and received appropriate antitachycardia pacing for atrial tachyarrhythmias for an episode of ventricular tachycardia (VT), and antiarrhythmic therapy with sotalol was initiated to reduce both his AF and VT burden. On review of the patient's medications for potential interactions, it was discovered that the patient was taking both dabigatran and phenytoin. To determine the magnitude of this drug interaction prior to making a change in his anticoagulation regimen, a dabigatran serum concentration was measured. This concentration was undetectable, indicating that phenytoin had a significant influence on dabigatran's metabolism and that this patient was at high risk for stroke. Clinicians should be aware of this interaction between phenytoin and dabigatran as well as with all other new oral anticoagulants. In patients taking phenytoin who require an anticoagulant, only warfarin should be prescribed to minimize the risk of stroke. In addition, the prescribing information for dabigatran should be updated to include other medications that result in a significant

  13. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury

    PubMed Central

    Jones, Kristen E.; Puccio, Ava M.; Harshman, Kathy J.; Falcione, Bonnie; Benedict, Neal; Jankowitz, Brian T.; Stippler, Martina; Fischer, Michael; Sauber-Schatz, Erin K.; Fabio, Anthony; Darby, Joseph M.; Okonkwo, David O.

    2013-01-01

    Object Current standard of care for patients with severe traumatic brain injury (TBI) is prophylactic treatment with phenytoin for 7 days to decrease the risk of early posttraumatic seizures. Phenytoin alters drug metabolism, induces fever, and requires therapeutic-level monitoring. Alternatively, levetiracetam (Keppra) does not require serum monitoring or have significant pharmacokinetic interactions. In the current study, the authors compare the EEG findings in patients receiving phenytoin with those receiving levetiracetam monotherapy for seizure prophylaxis following severe TBI. Methods Data were prospectively collected in 32 cases in which patients received levetiracetam for the first 7 days after severe TBI and compared with data from a historical cohort of 41 cases in which patients received phenytoin monotherapy. Patients underwent 1-hour electroencephalographic (EEG) monitoring if they displayed persistent coma, decreased mental status, or clinical signs of seizures. The EEG results were grouped into normal and abnormal findings, with abnormal EEG findings further categorized as seizure activity or seizure tendency. Results Fifteen of 32 patients in the levetiracetam group warranted EEG monitoring. In 7 of these 15 cases the results were normal and in 8 abnormal; 1 patient had seizure activity, whereas 7 had seizure tendency. Twelve of 41 patients in the phenytoin group received EEG monitoring, with all results being normal. Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556). Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003). Conclusions Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG analysis. PMID:18828701

  14. Protective effect of rutin on cognitive impairment caused by phenytoin

    PubMed Central

    Dubey, Shagun; Ganeshpurkar, Aditya; Bansal, Divya; Dubey, Nazneen

    2015-01-01

    Objective: To study the effect of the co-administration of phenytoin (PHT) and rutin in comparison with PHT and piracetam (PIM) on seizure control, cognitive, and motor functions in mice. Materials and Methods: Increasing current electroshock seizure (ICES) test was used to evaluate the effect of the co-administration of PHT and PIM on convulsions. Cognitive functions in mice were assessed by a spontaneous alternation in behavior on a plus maze while motor functions were screened using rolling roller apparatus and by counting the number of arms entries on a plus maze. Brain acetyl-cholinesterase (AChE) activity was also estimated. Statistical Analysis: The expression of data was done as mean ± standard error of the mean. The normally distributed data were subjected to one-way ANOVA followed by Dunnett's test. P < 0.05 was considered significant. Results: The study showed that rutin when co-administered with PHT, significantly reversed PHT-induced reduction in spontaneous alternation without altering the efficacy of PHT against ICES, in both acute and chronic studies. Further, it also reversed PHT-induced increase in AChE activity. Conclusion: Rutin alleviated the PHT-induced cognitive impairment without compromising its antiepileptic efficacy. PMID:26729954

  15. Controlled Dissolution of Phenytoin by Hybridizing with Silica Nanoparticles

    NASA Astrophysics Data System (ADS)

    Goto, H.; Isobe, T.; Senna, M.

    1999-06-01

    A sparingly soluble model drug, phenytoin (5,5-diphenyl-hydantoin, denoted as PT), was incorporated during or after hydrolysis and polycondensation of tetra orthoethyl silicate (TEOS) to obtain silica-drug hybrids. We also compare the hybrids obtained by sol-gel process with those obtained by simple adsorption on nonporous silica particles. The initial rate of dissolution in water increases by a factor of 40 with respect to the intact PT by aging silica before drug addition. The IR results show that νC=O in the position 2 of PT and νN-H shift toward the higher wavenumber, showing that intermolecular hydrogen bonds between C=O and N-H are loosened or broken to form new hydrogen bonds between C=O in PT and Si-OH in silica. The dissolution rate of PT is determined by the degree of the breakage of hydrogen bonds between PT molecules and the intensity of the interaction between silica and PT.

  16. Phenytoin accelerates tendon healing in a rat model of Achilles tendon rupture.

    PubMed

    Hajipour, B; Navali, A M; Mohammad, S Ali; Mousavi, G; Akbari, M Gahvechi; Miyandoab, T Maleki; Roshangar, L; Saleh, B Mohammadi; Kermani, T Asvadi; Laleh, F Moutab; Ghabili, M

    2016-01-01

    Tendons are vulnerable to various types of acute or chronic injures. Different methods have been investigated to achieve better healing. Phenytoin is a drug which could stimulate fibroblasts to produce collagen. This experimental study was performed to assess the effect of phenytoin on tendon healing in a rat model of tendon rupture. Thirty healthy rats were divided into 3 groups, 1) Sham group; 2) Tendon rupture; 3) Tendon rupture+phenytoin (100 mg/kg intraperitoneally) for 21 days. On 21st day after tendon injury, the rats were anesthetized and tendon tissue was sampled for studying by light and electron microscopy. Qualitative and quantitative microscopic comparisons of the repair tissues of both groups were made on the 21st day. The results obtained from light and electron microscopy studies showed that tendon tissue healing was significantly better in phenytoin group compared to the control group (p < 0.05). Systemic administration of phenytoin may have a positive effect on tendon healing by increasing fibroblast quantity, fibrillar collagen synthesis, vascularity, and suppressing inflammation (Tab. 2, Ref. 25).

  17. Pharmacokinetics of the cytochrome P-450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs

    PubMed Central

    KuKanich, Butch; Nauss, Jon L

    2011-01-01

    The purpose of this study was to determine the pharmacokinetics of phenytoin, theophylline, and diazepam in six healthy Greyhound dogs. Additionally the pharmacokinetics of the diazepam metabolites oxazepam and nordiazepam after diazepam administration were determined. Phenytoin sodium (12 mg/kg), aminophylline (10 mg/kg), and diazepam (0.5 mg/kg) were administered IV on separate occasions and blood obtained at predetermined time points for the quantification of plasma drug concentrations by florescence polarization immunoassay (phenytoin, theophylline) or mass spectrometry (diazepam, oxazepam, nordiazepam). The terminal half-life was 4.9, 9.2, and 1.0 hours, respectively for phenytoin, theophylline, and diazepam, and 6.2 and 2.4 hours for oxazepam and nordiazepam after IV diazepam. The clearance was of 2.37, 0.935, and 27.9 mL/min/kg respectively for phenytoin, theophylline, and diazepam. The CMAX was 44.7 and 305.2 ng/mL for oxazepam and nordiazepam, respectively, after diazepam administration. Temazepam was not detected above 5 ng/mL in any sample after IV diazepam. PMID:21692812

  18. The antiepileptic medications carbamazepine and phenytoin inhibit native sodium currents in murine osteoblasts.

    PubMed

    Petty, Sandra J; Milligan, Carol J; Todaro, Marian; Richards, Kay L; Kularathna, Pamuditha K; Pagel, Charles N; French, Chris R; Hill-Yardin, Elisa L; O'Brien, Terence J; Wark, John D; Mackie, Eleanor J; Petrou, Steven

    2016-09-01

    Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage-gated sodium (NaV ) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels. Immunocytochemistry was performed on primary calvarial osteoblasts extracted from neonatal C57BL/6J mice and additional RNA sequencing (RNASeq) was included to confirm expression of NaV . Whole-cell patch-clamp recordings were made to identify the native currents expressed and to assess the actions of carbamazepine (50 μm) or phenytoin (50 μm). NaV expression was demonstrated with immunocytochemistry, RNA sequencing, and functionally, with demonstration of robust tetrodotoxin-sensitive and voltage-activated inward currents. Application of carbamazepine or phenytoin resulted in significant inhibition of current amplitude for carbamazepine (31.6 ± 5.9%, n = 9; p < 0.001), and for phenytoin (35.5 ± 6.9%, n = 7; p < 0.001). Mouse osteoblasts express NaV , and native NaV currents are blocked by carbamazepine and phenytoin, supporting our hypothesis that AEDs can directly influence osteoblast function and potentially affect bone strength. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  19. Possible long-acting risperidone-induced hypothermia precipitating phenytoin toxicity in an elderly patient.

    PubMed

    Brandon Bookstaver, P; Miller, A D

    2011-06-01

    Thermodysregulation, including hypothermia, is recognized as a potential adverse effect secondary to atypical antipsychotics. We report the first known case of hypothermia possibly associated with long-acting risperidone depot injection, precipitating further adverse events secondary to supratherapeutic phenytoin concentrations. A 75-year-old African-American female presented as a transfer from an outpatient psychiatric center with hypothermia (35·1 °C), bradycardia, altered mental status and a series of witnessed tonic-clonic seizures. The patient was discovered to be profoundly neutropenic (absolute neutrophil count = 266 × 10(9) /L) and a corrected phenytoin concentration was 147·708 μm. During the 3 months preceding admission, phenytoin dosing was stable and consecutive therapeutic concentrations were documented. The only recent change in medication regimen was a switch from oral risperidone to the long-acting injectable formulation. Upon discontinuation of the risperidone and phenytoin, the patient's mental status and laboratory abnormalities returned to baseline. The patient did not experience additional seizure activity. This unintentional significant drop in core body temperature may have resulted in altered metabolism of phenytoin leading to supratherapeutic concentrations and subsequent tonic-clonic seizures, bradycardia and neutropenia. Low core body temperatures can alter the pharmacokinetic profiles of hepatically metabolized medications, prompting careful patient assessment especially in those receiving medications with a narrow-therapeutic index. Hypothermia should be recognized as a potential adverse event with the long-acting injectable formulation of risperidone. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

  20. Pharmacokinetics of the cytochrome P-450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs.

    PubMed

    KuKanich, B; Nauss, J L

    2012-06-01

    The purpose of this study was to determine the pharmacokinetics of phenytoin, theophylline, and diazepam in six healthy Greyhound dogs. Additionally, the pharmacokinetics of the diazepam metabolites, oxazepam and nordiazepam, after diazepam administration was determined. Phenytoin sodium (12 mg/kg), aminophylline (10 mg/kg), and diazepam (0.5 mg/kg) were administered IV on separate occasions, and blood was collected at predetermined time points for the quantification of plasma drug concentrations by fluorescence polarization immunoassay (phenytoin, theophylline) or mass spectrometry (diazepam, oxazepam, and nordiazepam). The terminal half-life was 4.9, 9.2, and 1.0 h, respectively, for phenytoin, theophylline, and diazepam, and 6.2 and 2.4 h for oxazepam and nordiazepam after IV diazepam. The clearance was of 2.37, 0.935, and 27.9 mL · min/kg, respectively, for phenytoin, theophylline, and diazepam. The C(MAX) was 44.7 and 305.2 ng/mL for oxazepam and nordiazepam, respectively, after diazepam administration. Temazepam was not detected above 5 ng/mL in any sample after IV diazepam. © 2011 Blackwell Publishing Ltd.

  1. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism--A case report.

    PubMed

    Veeravigrom, Montida; Jaroonvanichkul, Vorapol; Netbaramee, Wiracha; Phaisarn, Pichaya; Uyathanarat, Thanita

    2016-01-01

    Phenytoin is one of the most well established and most effective antiepileptic medications for the treatment of focal seizures. In our clinical practice, it has proven difficult to maintain therapeutic phenytoin levels in infants less than three months of age. Incidence of phenytoin toxicity in infants is very rare. The cytochrome P450 super family plays an important role in phenytoin metabolism, especially CYP2C9 and CYP2C19. In this case report, we profiled a two-month-old Thai infant who developed phenytoin toxicity resulting from CYP2C9 gene polymorphism. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  2. The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children.

    PubMed

    ter Heine, Rob; van Maarseveen, Erik M; van der Westerlaken, Monique M L; Braun, Kees P J; Koudijs, Suzanne M; Berg, Maarten J Ten; Malingré, Mirte M

    2014-06-01

    Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity. © The Author(s) 2013.

  3. Quantification of Free Phenytoin by Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS).

    PubMed

    Peat, Judy; Frazee, Clint; Garg, Uttam

    2016-01-01

    Phenytoin (diphenylhydantoin) is an anticonvulsant drug that has been used for decades for the treatment of many types of seizures. The drug is highly protein bound and measurement of free-active form of the drug is warranted particularly in patients with conditions that can affect drug protein binding. Here, we describe a LC/MS/MS method for the measurement of free phenytoin. Free drug is separated by ultrafiltration of serum or plasma. Ultrafiltrate is treated with acetonitrile containing internal standard phenytoin d-10 to precipitate proteins. The mixture is centrifuged and supernatant is injected onto LC-MS-MS, and analyzed using multiple reaction monitoring. This method is linear from 0.1 to 4.0 μg/mL and does not demonstrate any significant ion suppression or enhancement.

  4. Vibrational spectra and normal coordinate analysis of diazepam, phenytoin and phenobarbitone

    NASA Astrophysics Data System (ADS)

    Gunasekaran, S.; Thilak Kumar, R.; Ponnusamy, S.

    2006-12-01

    Vibrational spectroscopy is an important tool for the structural investigation of the organic molecules. In the present investigation, a normal coordinate analysis has been carried out on some anti-epileptic drugs, viz. diazepam, phenytoin and phenobarbitone. Diazepam is a derivative of benzodiazepine, phenytoin is a derivative of hydanation and pheonobarbitone is a barbiturate. The infrared spectra of the compounds are recorded in the region 4000-400 cm -1 and Raman spectra are recorded in the region 3500-50 cm -1. From the structural point of view, diazepam, phenytoin and phenobarbitone have been assumed to C s point group. A systematic set of symmetry coordinates has been constructed for these compounds and Wilson's FG matrix method has been applied for the normal coordinate analysis using general quadratic valance force field. The potential energy distribution is also calculated to check the vibrational band assignments.

  5. Activated Charcoal Does Not Reduce Duration of Phenytoin Toxicity in Hospitalized Patients.

    PubMed

    Cumpston, Kirk; Stromberg, Paul; Wills, Brandon K; Rose, S Rutherfoord

    2016-01-01

    Phenytoin toxicity frequently results in a prolonged inpatient admission. Several publications avow multidose activated charcoal (MDAC) will enhance the elimination of phenytoin. However, these claims are not consistent, and the mechanism of enhanced eliminaiton is unproven. The aim of this investigation is to compare the time to reach a clinical composite end point in phenytoin overdose patients treated with no activated charcoal (NoAC), single-dose activated charcoal (SDAC), and MDAC. This was a retrospective study using electronic poison center data. Patients treated in a health care facility with phenytoin concentrations >20 mg/L were included. Patients were grouped by use of SDAC, MDAC, and NoAC. The primary end points were either time to resolution of symptoms, hospital discharge, or the case was closed by a toxicologist. After applying inclusion and exclusion criteria, 132 cases were included for analysis. There were 88 NoAC, 13 SDAC, and 31 MDAC cases. The groups were similar in symptomatology, age, and chronicity of expsoure. Mean peak phenytoin concentrations (SD) were 42 mg/L (12), 41 mg/L (11), and 42 mg/L (11) for NoAC, SDAC, and MDAC, respectively. Mean time to reach the study end point was 39 hours [95% confidence interval (CI), 31-48], 52 hours (95% CI, 36-68), and 60 hours (95% CI, 45-75) for NoAC, SDAC, and MDAC, respectively. The groups appeared similar with respect to peak phenytoin concentrations and prevalence of signs and symptoms. In this observational series, the use of activated charcoal was associated with increased time to reach the composite end point of clinical improvement.

  6. Phenytoin speciation with potentiometric and chronopotentiometric ion-selective membrane electrodes.

    PubMed

    Jansod, Sutida; Afshar, Majid Ghahraman; Crespo, Gastón A; Bakker, Eric

    2016-05-15

    We report on an electrochemical protocol based on perm-selective membranes to provide valuable information about the speciation of ionizable drugs, with phenytoin as a model example. Membranes containing varying amounts of tetradodecylammonium chloride (TDDA) were read out at zero current (potentiometry) and with applied current techniques (chronopotentiometry). Potentiometry allows one to assess the ionized form of phenytoin (pKa~8.2) that corresponds to a negatively monocharged ion. A careful optimization of the membrane components resulted in a lower limit of detection (~1.6 µM) than previous reports. Once the pH (from 9 to 10) or the concentration of albumin is varied in the sample (from 0 to 30 g L(-1)), the potentiometric signal changes abruptly as a result of reducing/increasing the ionized concentration of phenytoin. Therefore, potentiometry as a single technique is by itself not sufficient to obtain information about the concentration and speciation of the drug in the system. For this reason, a tandem configuration with chronopotentiometry as additional readout principle was used to determine the total and ionized concentration of phenytoin. In samples containing excess albumin the rate-limiting step for the chronopotentiometry readout appears to be the diffusion of ionized phenytoin preceded by comparatively rapid deprotonation and decomplexation reactions. This protocol was applied to measure phenytoin in pharmaceutical tables (100mg per tablet). This tandem approach can likely be extended to more ionizable drugs and may eventually be utilized in view of pharmacological monitoring of drugs during the delivery process. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis.

    PubMed

    Nelson, Michaela; Yang, Ming; Dowle, Adam A; Thomas, Jerry R; Brackenbury, William J

    2015-01-27

    Voltage-gated Na(+) channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets. We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen. This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.

  8. Phenobarbitone versus phenytoin for treatment of neonatal seizures: an open-label randomized controlled trial.

    PubMed

    Pathak, Garima; Upadhyay, Amit; Pathak, Umesh; Chawla, Deepak; Goel, Sneh P

    2013-08-01

    To compare the efficacy of phenobarbitone and phenytoin for treatment of neonatal seizures in term and near-term neonates. Open labeled randomized controlled trial. Neonatal intensive care unit of a level II unit from India, from November 2008 to September 2009. All term and late pre-term neonates admitted with clinically apparent seizures and not having any transient metabolic disorders (hypoglycemia or hypocalcemia) were randomly assigned. Phenobarbitone (n=54) or phenytoin (n=55) intravenously 20 mg/kg/dose over 20-30 min. Neonates whose seizures were not controlled by the assigned drug were then crossed over to be treated with other drug in same dose. Clinical control of seizures (seizure free period of 24 hours after giving anticonvulsant). Baseline characteristics including mean birthweight, gestation age and sex were comparable in both groups. Seizures were controlled in 8 of the 55 (14.5%) neonates who received phenytoin, as compared to 39 of 54 (72.2%) neonates who received phenobarbitone (P <0.001). In babies not responding to assigned drugs, after cross-over to the other drug, seizure control was achieved in 44/55 (80%) of the neonates assigned to receive phenytoin first as compared to 49/54 (91%) of those assigned to receive phenobarbitone first (P=0.014). After maximum dose of phenobarbitone seizures were controlled in 49/55(89%) in phenytoin group and 52/54 (96%) in phenobarbitone group (P<0.05). Phenobarbitone is more efficacious than phenytoin in control of clinical seizures in term or near-term neonates, irrespective of etiology. To evaluate serum vascular endothelial growth factor (VEGF) levels in children with acute lymphoblastic leukemia (ALL) during the induction phase of chemotherapy.

  9. Phenytoin activates Smad3 phosphorylation and periostin expression in drug-induced gingival enlargement.

    PubMed

    Kim, Shawna S; Nikoloudaki, Georgia; Darling, Mark; Rieder, Michael J; Hamilton, Douglas W

    2018-06-19

    Drug-induced gingival enlargement (DIGE) is a fibrotic condition associated with systemic administration of the anti-epileptic drug, phenytoin. We have previously demonstrated that periostin, which is transforming growth factor-beta (TGF-β) inducible gene, is upregulated in various fibrotic conditions including gingival enlargement associated with nifedipine. The objective of this study was to assess periostin expression in phenytoin-induced gingival enlargement (PIGE) tissues and to investigate the mechanisms underlying periostin expression. Human PIGE tissues were assessed using Masson's trichrome, with cell infiltration and changes in extracellular matrix composition characterized through labeling with antibodies to periostin, phospho-SMAD 3, TGF-β, as well as the macrophage markers CD68 and RM3/1. Using human gingival fibroblasts (HGFs) in vitro we examined the pathways through which phenytoin acts on fibroblasts. In PIGE tissues, which demonstrate altered collagen organization and increased inflammatory cell infiltration, periostin protein was increased compared with healthy tissues. p-SMAD2/3, the transcription factor associated with canonical TGF-β signaling, is localized to the nuclei in both gingival fibroblasts and oral epithelial cells in PIGE tissues, but not in healthy tissue. In vitro culture of HGFs with 15 and 30 μg/ml of phenytoin increased periostin protein levels, which correlated with p-SMAD3 phosphorylation. Inhibition of canonical TGF-β signaling with SB431542 significantly reduced phenytoin induction of SMAD3 phosphorylation and periostin expression in HGFs. Analysis of PIGE tissues showed a subset of CD68 stained macrophages were TGF-β positive and that RM1/3 regenerative macrophages were present in the tissues. Our results demonstrate that phenytoin up-regulates periostin in HGFs in a TGF-β-dependent manner.

  10. Phenytoin inhibits contractions of rat gastrointestinal and portal vein smooth muscle by inhibiting calcium entry.

    PubMed

    Patejdl, R; Leroux, A-C; Noack, T

    2015-10-01

    Phenytoin is widely used as a second-line treatment for status epilepticus. Besides its well-known cardiac pro-arrhythmogenicity, side effects on other organ systems have received less attention. This study investigates the effects of phenytoin on gastrointestinal tissue function using an in vitro model of smooth muscle preparations from rats by combining registrations of pharmacological effects on mechanical contractions, electric field potentials, and dynamic intravital fluorescence microscopy. When added to the bathing solution at a concentration of 30 μM, phenytoin reduced the frequency of spontaneous activity significantly in antrum and portal vein preparations to 72.2 ± 36.5% (p = 0.022) and 80.7 ± 24.4% (p = 0.037) of control values, respectively. At a concentration of 100 μM, the height of spontaneous contractions declined to 9.8 ± 19.6% (p = 0.005) (antrum), 15.7 ± 28.2% (p = 0.004) (portal vein), and 31.8 ± 31.3% (p = 0.005) (colon) in comparison to the control conditions before the application of phenytoin. Depolarization triggered increases in calcium dependent fluorescence signals were reduced by 52.8 ± 39.1% (p = 0.012) The inhibition of spontaneous activity caused by phenytoin was reduced in the presence of the L-type calcium channel agonist BAY K8644(-). Phenytoin exerts strong inhibitory effects on the spontaneous and stimulated contractile activity of smooth muscles from both the upper and lower gastrointestinal tract. The mechanism underlying this effect is not related to the sodium channel blocking activity of phenytoin, but is rather caused by an inhibition of calcium entry through voltage dependent L-type calcium channels. The results of this study should raise vigilance to gastrointestinal complications in patients treated with phenytoin. © 2015 John Wiley & Sons Ltd.

  11. Computational Modeling of Hydroxypropyl-Methylcellulose Acetate Succinate (HPMCAS) and Phenytoin Interactions: A Systematic Coarse-Graining Approach.

    PubMed

    Huang, Wenjun; Mandal, Taraknath; Larson, Ronald G

    2017-03-06

    We present coarse-grained (CG) force fields for hydroxypropyl-methylcellulose acetate succinate (HPMCAS) polymers and the drug molecule phenytoin using a bead/stiff spring model, with each bead representing a HPMCAS monomer or monomer side group (hydroxypropyl acetyl, acetyl, or succinyl) or a single phenytoin ring. We obtain the bonded and nonbonded interaction parameters in our CG model using the RDFs from atomistic simulations of short HPMCAS model oligomers (20-mer) and atomistic simulations of phenytoin molecules. The nonbonded interactions are modeled using a LJ 12-6 potential, with separate parameters for each monomer substitution type, which allows heterogeneous polymer chains to be modeled. The cross interaction terms between the polymer and phenytoin CG beads are obtained explicitly from atomistic level polymer-phenytoin simulations, rather than from mixing rules. We study the solvation behavior of 50-mer and 100-mer polymer chains and find chain-length-dependent aggregation. We also compare the phenytoin CG force field developed in this work with that in Mandal et al. (Soft Matter, 2016, 12, 8246-8255) and conclude both are suitable for studying the interaction between polymer and drug in solvated solid dispersion formulation, in the absence of drug crystallization. Finally, we present simulations of heterogeneous HPMCAS model polymer chains and phenytoin molecules. Polymer and drug form a complex in a short period of simulation time due to strong intermolecular interactions. Moreover, the protonated polymer chains are more effective than deprotonated ones in inhibiting the drug aggregation in the polymer-drug complex.

  12. Formulation and in vitro and in vivo characterization of a phenytoin self-emulsifying drug delivery system (SEDDS).

    PubMed

    Atef, Eman; Belmonte, Albert A

    2008-11-15

    The aim of this study is to develop and characterize a self-emulsifying drug delivery system (SEDDS) of phenytoin, and to compare its relative bioavailability to a commercially available suspension. Four phenytoin SEDDS were prepared and evaluated. Following emulsification, the optimized formula was selected to have the smallest mean particle size and the highest absolute zeta potential, which should yield the formation of a stable emulsion. Its dissolution characteristics were superior to the other SEDDS formulas. In vivo and in vitro tests were run to compare the optimized formula, SEDDS II, to a commercially available Dilantin suspension. The in vitro dissolution indicated a significant improvement in phenytoin release characteristics. The in vivo study using male rats showed a clear enhancement in phenytoin oral absorption from SEDDS compared to Dilantin suspension. The area under the curve AUC((-10min-->10h)) of phenytoin after SEDDS administration increased by 2.3 times compared to Dilantin (p<0.05), and the rate of absorption of phenytoin was significantly faster from the SEDDS. The concentration after 30min (C(30min)) of SEDDS administration was 4.9 times higher than C(30min) after Dilantin administration (p<0.05). A sustained effect of phenytoin in plasma was also observed. After 12 weeks storage, SEDDS II was found to be chemically and physically stable under stressed conditions.

  13. Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers.

    PubMed

    Tanaka, Jun; Kasai, Hidefumi; Shimizu, Kenji; Shimasaki, Shigeki; Kumagai, Yuji

    2013-03-01

    We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range. We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10-20 μg/mL. We used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg. The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.

  14. Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action.

    PubMed

    Keppel Hesselink, Jan M; Kopsky, David J

    2017-08-01

    In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin's anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937-1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin's activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 μM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.

  15. In Vitro Evaluation of Novel Phenytoin-Loaded Alkyd Nanoemulsions Designed for Application in Topical Wound Healing.

    PubMed

    Teo, Siew Yong; Yew, Mei Yeng; Lee, Siang Yin; Rathbone, Michael J; Gan, Seng Neon; Coombes, Allan G A

    2017-01-01

    Phenytoin-loaded alkyd nanoemulsions were prepared spontaneously using the phase inversion method from a mixture of novel biosourced alkyds and Tween 80 surfactant. Exposure of human adult keratinocytes (HaCaT cells) for 48 h to alkyd nanoemulsions producing phenytoin concentrations of 3.125-200 μg/mL resulted in relative cell viability readings using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide of 100% confirming nontoxicity and suggesting cell proliferation activity. Phenytoin-loaded alkyd nanoemulsions generally resulted in higher mean cell viability compared with equivalent concentration of phenytoin solutions, suggesting that the nanoemulsions provided a controlled-release property that maintained the optimum phenytoin level for keratinocyte growth. HaCaT cell proliferation, measured by 5-bromo-2-deoxyuridine uptake, was found to increase following exposure to increasing phenytoin concentration from 25 to 50 μg/mL in solution or encapsulated in nanoemulsions but declined at a drug concentration of 100 μg/mL. An in vitro cell monolayer wound scratch assay revealed that phenytoin solution or nanoemulsions producing 50 μg/mL phenytoin concentration resulted in 75%-82% "scratch closure" after 36 h, similar to medium containing 10% fetal bovine serum as a cell growth promoter. These findings indicate that phenytoin-loaded alkyd nanoemulsions show potential for promoting topical wound healing through enhanced proliferation of epidermal cells. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. Purple Glove Syndrome after Phenytoin or Fosphenytoin Administration: Review of Reported Cases and Recommendations for Prevention.

    PubMed

    Garbovsky, Lyudmila A; Drumheller, Byron C; Perrone, Jeanmarie

    2015-12-01

    The aim of our study was to identify all previously reported cases of phenytoin- or fosphenytoin-associated purple glove syndrome (PGS) and summarize the most current understanding of the pathophysiology, clinical presentation, diagnosis, and treatment of the disease. We searched the English language references from MEDLINE, EMBASE, CINAHL, TOXNET, and gray literature that featured one or more case descriptions of phenytoin- or fosphenytoin-associated PGS after administration and provided information on the clinical setting of the event and associated outcome(s). Descriptive statistics were employed to summarize relevant facts about the cases. We identified 82 unique cases of parenteral phenytoin-associated PGS and 5 cases of fosphenytoin-associated PGS that were published from 1984 to 2015. Additionally, we found two cases of PGS associated with oral formulation of phenytoin published from 1999 to 2015. The spectrum of tissue injury ranged from mild local cutaneous reactions around the infusion site to frank limb ischemia. Just over a half of cases reported symptoms after one dose of IV phenytoin. Pathologic findings included evidence for microvascular thrombosis and possible microvascular or subclinical extravasation as a contributing mechanism. Dopper ultrasound and conventional angiography were used in some patients to identify arterial or venous thrombosis. Various treatments were documented including the use of supportive care such as limb elevation and heat or cold application, utilization of systemic antibiotics, anticoagulants, or vasodilators, and local infiltration of hyaluronidase, heparin, or other compounds. In a small number of patients, invasive interventions such as regional anesthesia, thrombectomy, fasciotomy, and debridement were described. Time to resolution varied from days to weeks. Resolution of PGS without deficits was documented in the majority of cases. Skin changes followed by sensory and motor deficits were described in 16, 6, and 5

  17. Amitriptyline and phenytoin prevents memory deficit in sciatic nerve ligation model of neuropathic pain.

    PubMed

    Abdulmajeed, Wahab Imam; Ibrahim, Ridwan Babatunde; Ishola, Azeez Olakunle; Balogun, Wasiu Gbolahan; Cobham, Ansa Emmanuel; Amin, Abdulbasit

    2016-03-01

    Phenytoin and amitriptyline are often reported to attenuate pain in chronic conditions. Information on their ability to ameliorate cognitive impairment associated with neuropathic pain remains unclear due to mixed results from studies. This study investigated the effects of phenytoin and amitriptyline on memory deficit associated with neuropathic pain. Twenty-eight adult male Wistar rats were randomly divided into four groups: A, B, C, and D (n=7). Groups A, B, C, and D served as sham control, sciatic nerve ligated untreated, sciatic nerve ligated receiving amitriptyline (5 mg/kg), and sciatic nerve ligated receiving phenytoin (10 mg/kg) respectively. Treatments lasted for 14 days, after which both 'Y' maze and novel object recognition test (NOR) were performed. On the last day of treatment, the animals were anesthetized and their brain excised, and the prefrontal cortices and sciatic nerve were processed histologically using hematoxylin and eosin. There was memory impairment in the sciatic nerve ligated untreated group which was statistically significant (p<0.05) when compared to the phenytoin-treated, amitriptyline-treated, and sham control groups using the 'Y' maze and NOR tests. Histological quantification showed that the prefrontal cortices of the ligated animals showed increased neural population in comparison to normal control. These increases were significantly marked in the untreated ligated group. Sciatic nerve of untreated ligated group showed high demyelination and axonal degeneration which was ameliorated in the treated animals. The administration of amitriptyline and phenytoin can ameliorate neuronal injury, demyelination, and memory impairment associated with neuropathic pain in Wistar rats.

  18. Phenytoin (Dilantin) and acupuncture therapy in the treatment of intractable oral and facial pain.

    PubMed

    Lu, Dominic P; Lu, Winston I; Lu, Gabriel P

    2011-01-01

    Phenytoin is an anti-convulsant and anti-arrhythmic medication. Manufactured by various pharmaceutical companies with various brand names, phenytoin (PHT) is also known as Dilantain, Hydantoin or Phenytek in the United States; Dilantain or Remytoine in Canada; Epamin, Hidantoina in Mexico; and Fenidatoin or Fenitron or other names elsewhere in the world. Phenytoin (PHT) is especially useful for patients suffering from intractable oral and facial pain especially those who exhibit anger, stress, depression and irrational emotions commonly seen in the patients with oral and facial pain. When used properly, Phenytoin is also an effective anxiolysis drug in addition to its theraputic effects on pain and can be used alone or, even better, if combined with other compatible sedatives. Phenytoin is particularly valuable when combined with acupuncture for patients with trigeminal neuralgia, glossopharyneal neuralgia, Bell's palsy, and some other facial paralysis and pain. It also has an advantage of keeping the patient relatively lucid after treatment. Either PHT or acupuncture alone can benefit patients but the success of treatment outcome may be limited. We found by combining both acupuncture and PHT with Selective Drug Uptake Enhancement by stimulating middle finger at the first segment of ventral (palmar) and lateral surfaces, as well as prescribing PHT with the dosage predetermined for each patient by Bi-Digital O-Ring Test (BDORT), the treatment outcome was much better resulted with less recurrence and intensity of pain during episodes of attack. Patients with Bell's palsy were most benefited by acupuncture therapy that could completely get rid of the illness.

  19. N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.

    PubMed

    Adole, Prashant S; Kharbanda, Parampreet S; Sharma, Sadhna

    2016-05-01

    Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.

  20. N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study

    PubMed Central

    Adole, Prashant S.; Kharbanda, Parampreet S.; Sharma, Sadhna

    2016-01-01

    Background & objectives: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Methods: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. Results: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Interpretation & conclusions: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures. PMID:27488001

  1. Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.

    PubMed

    Nevitt, Sarah J; Marson, Anthony G; Weston, Jennifer; Tudur Smith, Catrin

    2017-02-27

    This is an updated version of the original Cochrane Review published in Issue 2, 2002 and its subsequent updates in 2010 and 2015.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, although the confidence intervals generated by these studies are wide. Differences in efficacy may therefore be shown by synthesising the data of the individual trials. To review the time to withdrawal, six- and 12-month remission, and first seizure with carbamazepine compared to phenytoin, used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures), or generalised tonic-clonic seizures, with or without other generalised seizure types. For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (1st November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1st November 2016), MEDLINE (Ovid, 1946 to 1 November 2016), ClinicalTrials.gov (1 November 2016), and the World Health Organization (WHO) International Clinical Trials

  2. Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.

    PubMed

    Nolan, Sarah J; Marson, Anthony G; Weston, Jennifer; Tudur Smith, Catrin

    2015-08-14

    This is an updated version of the original Cochrane review published in Issue 2, 2002 and its subsequent update in 2010.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first line treatment due to concerns over adverse events associated with its use, however the drug is still commonly used in low- to middle-income countries due to it's low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, however the confidence intervals generated by these studies are wide. Therefore, differences in efficacy may be shown by synthesising the data of the individual trials. To review the time to withdrawal, six- and 12-month remission, and first seizure of carbamazepine compared to phenytoin when used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures) or generalised tonic-clonic seizures, with or without other generalised seizure types. We searched the Cochrane Epilepsy Group's Specialised Register (16 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 8), MEDLINE (1946 to 16 September 2014), SCOPUS (1823 to 16 September 2014), ClinicalTrials.gov (16 September 2014), and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP (18 September 2014). We

  3. Population Pharmacokinetics of Phenytoin Based on NONMEM in Patients with Intracranial Tumor During the First Week of Post-Craniotomy.

    PubMed

    Li, Zhong-Dong; Liu, Meng; Li, Liang; Wan, Jing-Hai; Lei, Zhaojin; Huang, Yong-An

    2016-01-01

    It was reported that phenytoin can prevent early post traumatic seizures. The present study aims to establish a population pharmacokinetic (PPK) model of oral phenytoin in patients with intracranial tumor during the early periods, the first week, of post-craniotomy to optimize phenytoin dosage regimen. Sixty-two patients with intracranial tumor were genotyped for CYP2C9 and CYP2C19 by real time PCR (TaqMan probe), and subsequently their phenytoin dosage regimens were designed according to the results of previous literature. A total of 123 plasma concentrations of oral phenytoin during the early periods of post-craniotomy, patient demographics, clinical biochemical indicators and drug combination were collected. A PPK model was performed using the nonlinear mixed effects model (NONMEM) program. The final PPK model equations of oral phenytoin were found to be as follows: for patients with CYP2C9 *1/*1, Vmax=22.66.(BWT/60.96)0.454(mg/h) and Km; =4.03 (mg/L); for patients with CYP2C9*1/*3, Vmax = 16.65.(BWT / 60.96 )0.454(mg/h) and Km =5.96 (mg/L). The PPK model was proved to be stable and effective by bootstrap method. Clinical individualized dosage regimens of additional 50 patients were designed by above PPK model. Concentrations on the morning of Day 7 (D7 concentrations) of 56% (28/50) of these patients were within the therapeutic range (10.20mg/L), which demonstrated better improvement than that of 37.1% of above 62 patients. The final PPK model of oral phenytoin may be helpful to design phenytoin individualized dosage regimen at the early stage of post-craniotomy when characteristics of patients meet these of subpopulation in the study.

  4. Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup.

    PubMed

    Anseeuw, Kurt; Mowry, James B; Burdmann, Emmanuel A; Ghannoum, Marc; Hoffman, Robert S; Gosselin, Sophie; Lavergne, Valery; Nolin, Thomas D

    2016-02-01

    The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  5. The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study

    PubMed Central

    2013-01-01

    Background Status epilepticus (SE) is a serious neurological condition and requires prompt treatment. Sodium valproate has been used to treat SE successfully but its role as the first-line antiepileptic drug (AED) is still controversial. This study evaluated the efficacy of intravenous sodium valproate to determine if it is non-inferior to intravenous phenytoin in SE treatment. Methods Patients diagnosed as SE during 2003–2010 who were of an age of more than 15 years and received either intravenous sodium valproate or intravenous phenytoin as the first-line treatment were enrolled. Clinical characteristics and outcomes of SE were recorded and analyzed. The differences of outcomes between sodium valproate and phenytoin group were determined by descriptive statistics. Results During the study period, there were 37 and 17 SE patients who received intravenous phenytoin and intravenous sodium valproate as the first-line treatment, respectively. All patients received diazepam 10 mg intravenously as a rescue medication before starting the antiepileptic agents if uncontrolled except one patient in the sodium valproate group. There were no significant differences between the phenytoin and sodium valproate groups in all outcome variables including numbers of patients with clinically-controlled seizures, non-dependent patients, time to seizure control, and duration of hospitalization, and death. No serious cardiovasculars event such as hypotension occurred in either group. Conclusion Intravenous sodium valproate is non-inferior to intravenous phenytoin as the first-line treatment in SE with no significant cardiovascular compromises. PMID:23889906

  6. Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer.

    PubMed

    Ohgami, Masahiro; Kaburagi, Takayuki; Kurosawa, Atsuhiko; Homma, Masato

    2016-11-01

    Erlotinib, a substrate drug metabolized by the CYP3A4 enzyme, is an epidermal growth factor receptor tyrosine kinase inhibitor used to treat nonsmall cell lung cancer (NSCLC). Concomitant use of erlotinib and the antiepileptic drug phenytoin, an inducer of CYP3A4, may result in a drug-drug interaction accompanied by changes in the blood concentrations of both drugs. We determined the blood concentration of each drug to confirm the interaction between phenytoin and erlotinib in a case of NSCLC with brain metastases. The phenytoin blood concentration (8.2-10.0μg/mL) gradually increased 3-fold (to 24.2μg/mL) 7 months after the start of erlotinib (150mg/d) co-administration. The erlotinib blood concentration which was maintained at 0.15-0.37μg/mL under phenytoin co-administration, increased 12-fold (to 1.77μg/mL) after the stoppage of phenytoin co-administration. The present case revealed that blood phenytoin increased and blood erlotinib decreased subsequent to the interaction of the 2 drugs in the CYP3A4 metabolic enzyme system. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation.

    PubMed

    Soriano, Vincent V; Tesoro, Eljim P; Kane, Sean P

    2017-08-01

    The Winter-Tozer (WT) equation has been shown to reliably predict free phenytoin levels in healthy patients. In patients with end-stage renal disease (ESRD), phenytoin-albumin binding is altered and, thus, affects interpretation of total serum levels. Although an ESRD WT equation was historically proposed for this population, there is a lack of data evaluating its accuracy. The objective of this study was to determine the accuracy of the ESRD WT equation in predicting free serum phenytoin concentration in patients with ESRD on hemodialysis (HD). A retrospective analysis of adult patients with ESRD on HD and concurrent free and total phenytoin concentrations was conducted. Each patient's true free phenytoin concentration was compared with a calculated value using the ESRD WT equation and a revised version of the ESRD WT equation. A total of 21 patients were included for analysis. The ESRD WT equation produced a percentage error of 75% and a root mean square error of 1.76 µg/mL. Additionally, 67% of the samples had an error >50% when using the ESRD WT equation. A revised equation was found to have high predictive accuracy, with only 5% of the samples demonstrating >50% error. The ESRD WT equation was not accurate in predicting free phenytoin concentration in patients with ESRD on HD. A revised ESRD WT equation was found to be significantly more accurate. Given the small study sample, further studies are required to fully evaluate the clinical utility of the revised ESRD WT equation.

  8. Phenytoin silver: a new nanocompound for promoting dermal wound healing via comprehensive pharmacological action.

    PubMed

    Ai, Xiao-Yu; Liu, Hui-Juan; Lu, Cheng; Liang, Cai-Li; Sun, Yan; Chen, Shuang; Sun, Bo; Li, Yang; Liu, Yan-Rong; Zhang, Qiang; Liu, Xue-Qiang; Xiao, Ting; Jing, Xue-Shuang; Sun, Tao; Zhou, Hong-Gang; Yang, Cheng

    2017-01-01

    Phenytoin, an antiepileptic drug, has been widely used for wound healing. Inspired by previous studies, phenytoin silver (PnAg), a sparingly soluble silver nanocompound, was synthesized which exhibited good therapeutic efficacy in tissue repair with low toxicity (LD50 >5 g/kg). In vivo studies showed that PnAg could accelerate dermal wound healing and strong inflammation control in Sprague-Dawley rats (SD rat) and Bama minipigs. Due to its low solubility, PnAg led to low toxicity and blood enrichment in animals. Furthermore, PnAg could upregulate the promoter activity of Jak, Stat3, and Stat3 downstream proteins. Therefore, PnAg may serve as an effective therapeutic compound for wound healing through regulating the gp130/Jak/Stat3 signaling pathway.

  9. The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

    PubMed Central

    Sheldon, P. W.; Clarke, C.; Dawson, K. B.

    1984-01-01

    Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour. PMID:6696821

  10. Lack of pathogenic mutations in SOS1 gene in phenytoin-induced gingival overgrowth patients.

    PubMed

    Margiotti, Katia; Pascolini, Giulia; Consoli, Federica; Guida, Valentina; Di Bonaventura, Carlo; Giallonardo, Anna Teresa; Pizzuti, Antonio; De Luca, Alessandro

    2017-08-01

    Gingival overgrowth is a side effect associated with some distinct classes of drugs, such as anticonvulsants, immunosuppressants, and calcium channel blockers. One of the main drugs associated with gingival overgrowth is the antiepileptic phenytoin, which affects gingival tissues by altering extracellular matrix metabolism. It has been shown that mutation of human SOS1 gene is responsible for a rare hereditary gingival fibromatosis type 1, a benign gingival overgrowth. The aim of the present study is to evaluate the possible contribution of SOS1 mutation to gingival overgrowth-related phenotype. We selected and screened for mutations a group of 24 epileptic patients who experienced significant gingival overgrowth following phenytoin therapy. Mutation scanning was carried out by denaturing high-performance liquid chromatography analysis of the entire coding region of the SOS1 gene. Novel identified variants were analyzed in-silico by using Alamut Visual mutation interpretation software, and comparison with normal control group was done. Mutation scanning of the entire coding sequence of SOS1 gene identified seven intronic variants and one new exonic substitution (c.138G>A). The seven common intronic variants were not considered to be of pathogenic importance. The exonic substitution c.138G>A was found to be absent in 100 ethnically matched normal control chromosomes, but was not expected to have functional significance based on prediction bioinformatics tools. This study represents the first mutation analysis of the SOS1 gene in phenytoin-induced gingival overgrowth epileptic patients. Present results suggest that obvious pathogenic mutations in the SOS1 gene do not represent a common mechanism underlying phenytoin-induced gingival overgrowth in epileptic patients; other mechanisms are likely to be involved in the pathogenesis of this drug-induced phenotype. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. In vivo and in vitro alteration of nicotine metabolism by the major metabolite of phenytoin

    SciTech Connect

    Lubawy, W.C.; Kostenbauder, H.B.; McGovren, J.P.

    1978-02-01

    The influence of hydroxyphenytoin (HPPH), the major metabolite of phenytoin, on the in vitro and in vivo metabolism of nicotine was examined. In rat liver 9,000 g supernatant HPPH decreased the appearance of cotinine from nicotine by 65% while not influencing the disappearance of nicotine or the appearance of nicotine-1'-N-oxide. In vivo, HPPH inhibited both nicotine elimination and cotinine formation but did not affect nicotine-1'-N-oxide formation.

  12. CYP2C9 Amino Acid Residues Influencing Phenytoin Turnover and Metabolite Regio- and Stereochemistry

    PubMed Central

    Mosher, Carrie M.; Tai, Guoying; Rettie, Allan E.

    2009-01-01

    Phenytoin has been an effective anticonvulsant agent for over 60 years, although its clinical use is complicated by nonlinear pharmacokinetics, a narrow therapeutic index, and metabolically based drug-drug interactions. Although it is well established that CYP2C9 is the major cytochrome P450 enzyme controlling metabolic elimination of phenytoin through its oxidative conversion to (S)-5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), nothing is known about the amino acid binding determinants within the CYP2C9 active site that promote metabolism and maintain the tight stereocontrol of hydroxy metabolite formation. This knowledge gap was addressed here through the construction of nine active site mutants at amino acid positions Phe100, Arg108, Phe114, Leu208, and Phe476 and in vitro analysis of the steady-state kinetics and stereochemistry of p-HPPH formation. The F100L and F114W mutants exhibited 4- to 5-fold increases in catalytic efficiency, whereas the F100W, F114L, F476L, and F476W mutants lost >90% of their phenytoin hydroxylation capacity. This pattern of effects differs substantially from that found previously for (S)-warfarin and (S)-flurbiprofen metabolism, suggesting that these three ligands bind within discrete locations in the CYP2C9 active site. Only the F114L, F476L, and L208V mutants altered phenytoin's orientation during catalytic turnover. The L208V mutant also uniquely demonstrated enhanced 6-hydroxylation of (S)-warfarin. These latter data provide the first experimental evidence for a role of the F-G loop region in dictating the catalytic orientation of substrates within the CYP2C9 active site. PMID:19258521

  13. Modulatory role of kolaviron in phenytoin-induced hepatic and testicular dysfunctions in Wistar rats.

    PubMed

    Owoeye, Olatunde; Adedara, Isaac A; Adeyemo, Oluwatobi A; Bakare, Oluwafemi S; Egun, Christa; Farombi, Ebenezer O

    2015-03-01

    Phenytoin, an anticonvulsant agent used for the treatment of epilepsy has been reported to exhibit toxic side effects on the liver and testes. The present study investigated the protective effects of kolaviron (KV, a bioflavonoid from Garcinia kola seeds) against hepatic and testicular damage in rats exposed to phenytoin. The study consisted of four groups of six rats per group. Group I rats received 2 mL/kg of corn alone while group II received 75 mg/kg of phenytoin (PHT) alone. Groups III and IV were co-treated with kolaviron (200 mg/kg KV) and vitamin E (500 mg/kg VTE), respectively, for 14 days. The antioxidant status, hepatic and reproductive functional parameters were subsequently determined. PHT treatment significantly (p < 0.05) increased superoxide dismutase (SOD) and catalase (CAT) activities, elevated lipid peroxidation (LPO) and hydrogen peroxide (H2O2) levels along with significant reduction in the hepatic and testicular levels of glutathione (GSH). Moreover, PHT exposure elicited significant increases in alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels. The significant reduction in seminal epithelium thickness and the diameter of seminiferous tubules was accompanied with marked decrease in sperm motility, sperm count, and viability in PHT-treated rats. However, antioxidant status and the functional indices of liver and testes were restored to near control levels in rats co-treated with KV and VTE. In conclusion, KV and VTE protect the liver and testes against functional impairment due to PHT treatment.

  14. Misonidazole in patients receiving radical radiotherapy: pharmacokinetic effects of phenytoin tumor response and neurotoxicity

    SciTech Connect

    Moore, J.L.; Biol, F.I.; Patterson, I.C.M.

    1982-03-01

    In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed an initial peripheral neuropathy rate of 55%, despite a dose limitation of 12 g/m/sup 2/ of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970's. Neuropathy was a serious side effect but the drug phenytoin has been shown tomore » shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed.« less

  15. Characterization of sodium phenytoin co-gelled with titania for a controlled drug-release system

    SciTech Connect

    Lopez, T.; Instituto Nacional de Neurologia y Neurocirugia 'MVS', Av. Insurgentes Sur 3877. Col. La Fama. P.O. Box 14269 Mexico D. F.; Quintana, P.

    2007-08-15

    Sodium phenytoin, C{sub 15}H{sub 11}N{sub 2}NaO{sub 2}, in several concentrations was co-gelled with titania (TiO{sub 2}), by a sol-gel process. This technique is a promising method to encapsulate several drugs, in this case, phenytoin is an anticonvulsant used to control epileptic seizures. Samples were prepared by adding different concentrations (X = 50, 100, 200 and 250 mg per 20 g of titania matrix) of sodium phenytoin (Ph) to a solution of titanium n-butoxide. The resulting titania-Ph-X materials were characterized by transmission electron microscopy (TEM), Fourier transformed infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and Brunauer-Emmet-Teller (BET) surface areas. The porous nanomaterialsmore » showed a wide range of particle size, from 10 to 210 nm, with a mean pore diameter of 5 nm. X-ray diffraction showed an amorphous structure of the prepared samples.« less

  16. Chronic administration of phenytoin and pleomorphic adenoma: A case report and review of literature.

    PubMed

    Maharshi, Vikas; Nagar, Pravesh

    2017-01-01

    Adverse drug effects that are uncommon or appear only on chronic administration of a drug may not be detected in clinical trials. This explains the need of strict post-marketing vigilance on drug use. Phenytoin administration has been shown in the literature to be associated with development of neoplasia (benign/malignant). In our knowledge current work represents the first case of pleomorphic-adenoma of sub-mandibular salivary gland developed following chronic phenytoin use. A 40 year old male having a history of head trauma twenty years back, had been on tablet phenytoin 100 mg thrice daily since then. One year back he noticed a small swelling in left sub-mandibular region and gradually increasing in size. FNAC and CECT revealed the diagnosis of pleomorphic-adenoma of sub-mandibular salivary gland. Other causes were ruled out. Surgical excision was performed successfully and continuing follow-up with no recurrence at the end of 6 months. Histo-pathogical examination of the tissue did not show any malignant changes.

  17. An automated real-time free phenytoin assay to replace the obsolete Abbott TDx method.

    PubMed

    Williams, Christopher; Jones, Richard; Akl, Pascale; Blick, Kenneth

    2014-01-01

    Phenytoin is a commonly used anticonvulsant that is highly protein bound with a narrow therapeutic range. The unbound fraction, free phenytoin (FP), is responsible for pharmacologic effects; therefore, it is essential to measure both FP and total serum phenytoin levels. Historically, the Abbott TDx method has been widely used for the measurement of FP and was the method used in our laboratory. However, the FP TDx assay was recently discontinued by the manufacturer, so we had to develop an alternative methodology. We evaluated the Beckman-Coulter DxC800 based FP method for linearity, analytical sensitivity, and precision. The analytical measurement range of the method was 0.41 to 5.30 microg/mL. Within-run and between-run precision studies yielded CVs of 3.8% and 5.5%, respectively. The method compared favorably with the TDx method, yielding the following regression equation: DxC800 = 0.9**TDx + 0.10; r2 = 0.97 (n = 97). The new FP assay appears to be an acceptable alternative to the TDx method.

  18. Influence on Busilvex pharmacokinetics of clonazepam compared to previous phenytoin historical data.

    PubMed

    Carreras, E; Cahn, J Y; Puozzo, C; Kröger, N; Sanz, G; Buzyn, A; Bacigalupo, A; Vernant, J P

    2010-07-01

    This study investigated the effect of seizure prophylaxis on busulfan (Bu) plasma exposure. Twenty-four adult patients received an intravenous Bu-cyclophoshamide conditioning regimen prior to bone marrow transplantation. Busilvex (0.8 mg/kg) was administered every six hours during four consecutive days. Clonazepam (0.025 to 0.03 mg/kg/day as a continuous 12-h i.v. infusion) was administered at least 12 hours prior to i.v. Bu dosing and continued until 24 hours after the last dose. Pharmacokinetic (PK) data were compared with those previously collected in patients (n=127) treated with phenytoin for seizure prophylaxis. Through population PK analysis, a 10% average increase (coefficient of variation, RSE=5.35%) in total clearance of Bu was quantified when Bu was associated with clonazepam as compared to phenytoin, which was considered as not being clinically relevant. The suspected induction on Bu metabolism by phenytoin should have resulted in the opposite effect. The patient efficacy and safety profiles were comparable between the two cohorts.

  19. Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study.

    PubMed

    Chandrasekaran, Saravanan; Patil, Sooraj; Suthar, Renu; Attri, Savita Verma; Sahu, Jitendra Kumar; Sankhyan, Naveen; Tageja, Mini; Singhi, Pratibha

    2017-04-01

    Long-term therapy with phenytoin and carbamazepine is known to cause hyperhomocysteinaemia. We evaluated the prevalence of hyperhomocysteinaemia in North Indian children receiving phenytoin or carbamazepine monotherapy for >6 months duration and the effect of folic acid supplementation on plasma homocysteine. In this cross-sectional observational study we enrolled consecutive children aged 2-12 years with epilepsy who had received phenytoin or carbamazepine monotherapy for >6 months. Plasma total homocysteine, folic acid, vitamin B12 and antiepileptic drug concentrations were measured. Healthy age- and sex-matched controls were recruited. Children with homocysteine >10.4 µmol/L received folic acid supplementation for 1 month and homocysteine and folic acid concentrations were measured after 1 month follow-up. A total of 112 children receiving antiepileptic monotherapy for >6 months were enrolled. Hyperhomocysteinaemia was present in 54 children (90%) receiving phenytoin, 45 children (90%) receiving carbamazepine therapy and 17 (34%) controls (p<0.05). Mean plasma homocysteine concentrations were significantly higher (18.9±10.2 vs 9.1±3 µmol/L) and serum folic acid concentrations (10.04±8.5 ng/ml vs 12.6±4.8 p<0.001) and vitamin B12 concentrations (365±155 pg/mL vs 474±332 pg/mL, p=0.02) were significantly lower in the study group compared with the control group. Duration of antiepileptic drug therapy correlated significantly with elevated homocysteine and reduced folic acid concentrations (p<0.05). Supplementation with folic acid for 1 month led to a reduction in plasma homocysteine concentrations in the study group (from 20.9±10.3 µmol/L to 14.2±8.2 µmol/L, p<0.05). Phenytoin or carbamazepine monotherapy for >6 months duration is associated with hyperhomocysteinaemia in 90% of North Indian children. Elevated homocysteine concentrations were normalised in these children with folic acid supplementation. Published by the BMJ

  20. THERAPEUTIC HYPOTHERMIA DECREASES PHENYTOIN ELIMINATION IN CHILDREN WITH TRAUMATIC BRAIN INJURY

    PubMed Central

    Empey, Philip E.; Velez de Mendizabal, Nieves; Bell, Michael J.; Bies, Robert R.; Anderson, Kacey B.; Kochanek, Patrick M.; Adelson, P. David; Poloyac, Samuel M.

    2013-01-01

    Objective Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurological injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome p450(CYP)-mediated drug metabolism and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by CYP2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of the study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe TBI. Design Pharmacokinetic analysis of subjects participating in a multicenter randomized Phase III study of therapeutic hypothermia for severe TBI. Setting Intensive care unit at the Children’s Hospital of Pittsburgh Patients Nineteen children with severe TBI. Interventions None Measurements and Main Results A total of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia- and 9 normothermia-treated children who were randomized to 48h of cooling to 32–33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and post-treatment periods(8 days). A trend towards elevated free phenytoin levels in the hypothermia group(p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism(Vmax) 4.6-fold(11.6 to 2.53 mg/h) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period. Conclusions Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe TBI leading to increased drug levels for an

  1. [Oral loading dose of phenytoin in the treatment of serial seizures, prevention of seizure recurrence and rapid drug substitution].

    PubMed

    Sokić, D; Janković, S M

    1994-01-01

    Over a period of nine months twenty-five epileptic patients were treated with the oral loading dose of phenytoin. The dose ranged from 12 to 23 mg/kg body weight during 1 to 12 hours. In 20 patients with serial seizures or intolerance to other antiepileptic drugs this treatment was effective. Seizures also stopped in 2 of 4 patients with serial partial motor seizures. These 2 patients required both higher loading dose and faster rate of administration than the other patients. A patient with epilepsia partialis continua failed to respond to the treatment. Patients that received phenytoin through the naso-gastric tube, in respect to oral administration, required higher doses to obtain therapeutic plasma levels of phenytoin. One patient had mild nausea, 3 mild dizziness, and 1 tinitus on the first day of the treatment. There was no correlation between a given dose and the achieved phenytoin plasma levels. In our opinion the therapy with oral loading dose of phenytoin is highly effective in the treatment of serial generalized seizures and rapid antiepileptic drug substitution, and partially effective in the prevention of partial motor seizures. It produces only mild and transient side-effects.

  2. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing

    PubMed Central

    Rettie, A E; Whirl‐Carrillo, M; Smith, L H; Mintzer, S; Lee, M T M; Klein, T E; Callaghan, J T

    2014-01-01

    Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org. Clinical Pharmacology & Therapeutics (2014); 96 5, 542–548. doi:10.1038/clpt.2014.159 PMID:25099164

  3. Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis.

    PubMed

    Khan, Nickalus R; VanLandingham, Matthew A; Fierst, Tamara M; Hymel, Caroline; Hoes, Kathryn; Evans, Linton T; Mayer, Rory; Barker, Fred; Klimo, Paul

    2016-12-01

    Posttraumatic seizure (PTS) is a significant complication of traumatic brain injury (TBI). To perform a systematic review and meta-analysis to compare levetiracetam with phenytoin for seizure prophylaxis in patients diagnosed with severe TBI. An inclusive search of several electronic databases and bibliographies was conducted to identify scientific studies that compared the effect of levetiracetam and phenytoin on PTS. Independent reviewers obtained data and classified the quality of each article that met inclusion criteria. A random effects meta-analysis was then completed. During June and July 2015, a systematic literature search was performed that identified 6097 articles. Of these, 7 met inclusion criteria. A random-effects meta-analysis was performed. A total of 1186 patients were included. The rate of seizure was 35 of 654 (5.4%) in the levetiracetam cohort and 18 of 532 (3.4%) in the phenytoin cohort. Our meta-analysis revealed no change in the rate of early PTS with levetiracetam compared with phenytoin (relative risk, 1.02; 95% confidence interval, 0.53-1.95; P = .96). The lack of evidence on which antiepileptic drug to use in PTS is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI. ADE, adverse drug eventAED, antiepileptic drugCI, confidence intervalOR, odds ratioPTS, posttraumatic seizureTBI, traumatic brain injury.

  4. Potentially Unsafe Herb-drug Interactions Between a Commercial Product of Noni Juice and Phenytoin- A Case Report.

    PubMed

    Kang, Yu-Chan; Chen, Ming-Hong; Lai, Shung-Lon

    2015-06-01

    To report the unsafe herb-drug interactions between a commercial product of noni juice and phenytoin in a human case. A 49-year-old-male has been treated with phenytoin for epilepsy for more than ten years. In spite of his medication adherence, persistent sub-therapeutic phenytoin levels, which were sometimes from low to undetectable, with the result of having poor seizure control were noted as the noni fruit juice was co-administered daily. The possible mechanism is speculated to be due to noni juiceinduced cytochrome P-450 2C9 metabolism of phenytoin. Owing to many beneficial effects of noni juice, the patient was unwilling to accept our advice to quit taking it. Clobazam treatment was added, and with gradually reducing the amount of juice drunk over six months, the patient's epilepsy has been well controlled. Now only auras along with sometimes minor partial seizures occur, but no major attack has been reported for more than one year. Phenytoin had been commonly used for seizure control worldwide and nearly half of patients with epilepsy had received complementary and alternative medicine in Taiwan. Thus, this report is significantly important for clinicians to be aware of the interaction between antiepileptic drugs and some herbs like noni juice. Moreover, as far as we know, this is a rare human case that is reported to disclose this unfavorable herb-drug interaction.

  5. Phenytoin preferentially inhibits L-type calcium currents in whole-cell patch-clamped cardiac and skeletal muscle cells.

    PubMed

    Rivet, M; Bois, P; Cognard, C; Raymond, G

    1990-10-01

    The effect of the anticonvulsant diphenylhydantoin (phenytoin) was tested on the inward calcium currents of whole-cell patch-clamped cells from rat and human muscles and from frog atrium. A concentration of 10 microM phenytoin was required to obtain a threshold inhibitory effect and, even with high concentrations (100 microM), the inhibition was not complete. In skeletal muscle (rat and human cells in culture), phenytoin (30 microM) exerted a more potent effect on the high-threshold calcium current (ICa,L inhibition: 53 +/- 6% mean +/- SDn-1) rather than on the low-threshold one (ICa,T inhibition: 16 +/- 10%). Similar results were obtained on dissociated frog atrial cells. These data are to be contrasted with those previously reported on neuronal cells, where specific inhibition of ICa,T was reported. Thus, the action of phenytoin appears to be different in muscle and nerve so that phenytoin does not appear to be a specific inhibitor of ICa,T.

  6. A randomized, placebo-controlled proof-of-concept, crossover trial of phenytoin for hydrocortisone-induced declarative memory changes

    PubMed Central

    Brown, E. Sherwood; Lu, Hanzhang; Denniston, Daren; Uh, Jinsoo; Thomas, Binu P.; Carmody, Thomas J.; Auchus, Richard J.; Diaz-Arrastia, Ramon; Tamminga, Carol

    2013-01-01

    Background Corticosteroid excess is associated with declarative memory impairment and hippocampal atrophy. These findings are clinically important because approximately 1% of the population receives prescription corticosteroids at any time, and major depressive disorder is associated with elevated cortisol levels and hippocampal atrophy. In animals, hippocampal changes with corticosteroids are blocked by phenytoin. The objective of the current study was to extend these preclinical findings to humans. We examined whether phenytoin attenuated the effects of hydrocortisone on declarative memory. Functional magnetic resonance imaging (fMRI) assessed task-related hippocampal activation. Methods A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in 17 healthy adult volunteers. Participants received hydrocortisone (2.5 days), phenytoin (3.5 days), both medications together, or placebo, with 21-day washouts between conditions. Differences between treatments were estimated using a mixed-effects repeated measures analysis. Results Fifteen participants had data from at least two treatment conditions and were used in the analysis. Basal cortisol levels negatively correlated with fMRI BOLD activation in the para-hippocampus with a similar trend observed in the hippocampus. Decrease in declarative memory with hydrocortisone was blocked with concomitant phenytoin administration. Relative to the placebo condition, a significant decrease in hippocampal BOLD activation was observed with hydrocortisone and phenytoin alone, and the two medications in combination. Declarative memory did not show significant correlations with hippocampal activation. Limitations The modest sample size, which limited our statistical power, was a limitation. Conclusions Findings from this pilot study suggest phenytoin attenuated effects of corticosteroids memory in humans, but potentiated the reduction in hippocampal activation. PMID:23453674

  7. Drug rash with eosinophilia and systemic symptoms syndrome associated with use of phenytoin, divalproex sodium, and phenobarbital.

    PubMed

    Brizendine, Christina E; Naik, Paras J

    2013-03-15

    A probable case of drug reaction with eosinophilia and systemic symptoms (DRESS) associated with consecutive use of three medications for seizure control is reported. A 36-year-old woman was treated at a community hospital for a mild fever (37.9°C) and diffuse raised maculopapular rash with erythema. Three weeks previously, she had been diagnosed with a seizure disorder and initiated on phenytoin (dose unknown) at that time; about two weeks later, she developed a rash, prompting a switch from phenytoin to extended-release divalproex sodium 250 mg orally twice daily. During the week after discontinuation of phenytoin, the rash was improving, but about five days after the initiation of divalproex therapy, she had worsening rash and pruritus requiring urgent treatment; the divalproex was discontinued, and phenobarbital 30 mg three times daily was initiated for continued seizure control. Despite the discontinuation of phenytoin and divalproex, the patient's hepatic function worsened over five days, and phenobarbital therapy was discontinued. With continued deterioration of the patient's condition to fulminant hepatic failure, a transfer to a liver transplant facility was arranged. The use of the adverse reaction probability scale of Naranjo et al. in this case yielded a score of 8, indicating a probable relationship between DRESS and the serial use of phenytoin, divalproex, and phenobarbital. After receiving phenytoin for treatment of seizure disorder, a 36-year-old woman developed a fever and maculopapular rash with erythema. This reaction continued even after drug therapy was switched to extended-release divalproex and then phenobarbital. The patient's liver function deteriorated despite discontinuation of all seizure medications.

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

    PubMed

    Śladowska, Katarzyna; Handzlik, Jadwiga; Kieć-Kononowicz, Katarzyna; Mazur, Lidia

    2016-09-01

    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.

  9. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures.

    PubMed

    Khan, Shahbaz Ali; Bhatti, Sajid Nazir; Khan, Aftab Alam; Khan Afridi, Ehtisham Ahmed; Muhammad, Gul; Gul, Nasim; Zadran, Khalid Khan; Alam, Sudhair; Aurangzeb, Ahsan

    2016-01-01

    The incidence of early post-traumatic seizures after civilian traumatic brain injury ranges 4-25%. The control of early post-traumatic seizure is mandatory because these acute insults may add secondary damage to the already damaged brain with poor outcome. Prophylactic use of anti-epileptic drugs have been found to be have variable efficacy against early post-traumatic seizures. The objective of this study was to compare the efficacy of Phenytion and Levetiracetam in prevention of early post-traumatic seizures in moderate to severe traumatic brain injury. This randomized controlled trial was conducted in department of Neurosurgery, Ayub Medical College, Abbottabad from March, 2012 to March 2013. The patients with moderate to severe head injury were randomly allocated in two groups. Patients in group A were given phenytoin and patients in group B were given Levetiracetam. Patients were followed for one week to detect efficacy of drug in terms of early post traumatic seizures. The 154 patients included in the study were equally divided into two groups. Out of 154 patients 115 (74.7%) were male while 29 (25.3%) were females. Age of patients ranges from 7-48 (24.15±9.56) years. Ninety one (59.1%) patients had moderate head injury while 63 (40.9%) patients had severe head injury. Phenytoin was effective in preventing early post traumatic seizures in 73 (94.8%) patients whereas Levetiracetam effectively controlled seizures in 70 (90.95%) cases (p-value of .348). There is no statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early posttraumatic seizures in cases of moderate to severe traumatic brain injury.

  10. Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation.

    PubMed

    El Massik, M A; Abdallah, O Y; Galal, S; Daabis, N A

    2003-05-01

    Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30 degrees C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.

  11. Assessment of the effect of phenytoin on cutaneous healing from excision of melanocytic nevi on the face and on the back

    PubMed Central

    2010-01-01

    Background Topical phenytoin is a powerful skin wounds healing and it may be useful in clinical practice. The purpose of this study was to evaluate the effect of topical phenytoin 0.5%, by comparing it with cream (control) in wounds resulting from excision of two melanocytic nevi in the same patient. Our purpose was also to assess if phenytoin had better therapeutic and cosmetic outcomes when compared with cream (control). Methods This study evaluated 100 patients with skin wounds from excision of melanocytic nevi. 50 patients with lesions on the face and 50 patients with lesions on the back, totalizing 200 lesions excised with modified punch. The resulting superficial skin wounds had the same diameter and depth, and second intention healing followed. Patients were followed for 60 days. Student's t-test, Mann Whitney nonparametric test, analysis of variance, LSD test, Shapiro-Wilks test and Fisher test were used to analyze the results, depending on the nature of the variables being studied. Results Phenytoin showed better therapeutic and cosmetic results, by healing faster, with more intense epithelization in wounds in comparison with cream (control). Phenytoin showed a statistically significant difference regarding the following parameters (p < 0.05): wounded area and healing time. Phenytoin application resulted in a smaller area and a shorter healing time. Also the intensity of exudates, bleeding, and the epithelization were more intense in phenytoin-treated wounds. Regarding the shape and thickness of the scar, injuries treated with phenytoin had round and flat shaped scars in most of the cases. Considering patient's gender and phototype, female patients presented smaller wounds and scar areas; and phototype I had the largest scar areas. Contact eczema was an adverse reaction in 7 injuries located on the back caused by cream (control) and hypoallergenic tape. Conclusions Phenytoin showed better therapeutic and cosmetic results compared with cream (control

  12. Levetiracetam Versus Phenytoin for Seizure Prophylaxis Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

    PubMed

    Yang, Yong; Zheng, Fangshuo; Xu, Xin; Wang, Xuefeng

    2016-08-01

    Seizure following traumatic brain injury (TBI) constitutes a common complication that requires effective prevention to improve the outcome of TBI. Phenytoin has been the only recommended antiepileptic drug (AED) for seizure prophylaxis; however, several shortcomings have affected its use. Intravenous levetiracetam has been available since 2006 and has been increasingly accepted as a seizure prophylaxis for brain injury, mainly due to its favorable pharmacokinetic features and minimal adverse events profile. However, the efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis following TBI are not well clarified. The aim of this study was to assess the efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis following TBI. We conducted a search of the MEDLINE, EMBASE, and Cochrane library databases to March 2016, and screened original research that included patients with TBI who received levetiracetam. We included randomized controlled trials (RCTs) or controlled observational cohort studies that compared levetiracetam and phenytoin, as well as uncontrolled case series regarding prophylactic levetiracetam following TBI. The outcomes included early or late seizure prophylaxis and safety. The estimates of seizure prophylaxis were pooled using a meta-analysis, and the estimates for the case series were pooled using descriptive statistics. A total of 1614 patients from 11 studies were included in this review, of whom 1285 patients from eight controlled studies (one RCT and seven cohort studies) were included in the meta-analysis. Levetiracetam was not superior to phenytoin with regard to early seizure prophylaxis (risk ratio [RR] 1.10, 95 % confidence interval [CI] 0.64-1.88); the estimate of early seizure incidence was 0.05 (95 % CI 0.02-0.08). Three studies that assessed late seizure did not indicate the superiority of levetiracetam to phenytoin. There were no differences in mortality during hospitalization or after 6

  13. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial.

    PubMed

    Raftopoulos, Rhian; Hickman, Simon J; Toosy, Ahmed; Sharrack, Basil; Mallik, Shahrukh; Paling, David; Altmann, Daniel R; Yiannakas, Marios C; Malladi, Prasad; Sheridan, Rose; Sarrigiannis, Ptolemaios G; Hoggard, Nigel; Koltzenburg, Martin; Gandini Wheeler-Kingshott, Claudia A M; Schmierer, Klaus; Giovannoni, Gavin; Miller, David H; Kapoor, Raju

    2016-03-01

    Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593. We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 μm (SD 16.27) in the phenytoin

  14. Molecular dynamics simulation of the partitioning of benzocaine and phenytoin into a lipid bilayer.

    PubMed

    Martin, Lewis J; Chao, Rebecca; Corry, Ben

    2014-01-01

    Molecular dynamics simulations were used to examine the partitioning behaviour of the local anaesthetic benzocaine and the anti-epileptic phenytoin into lipid bilayers, a factor that is critical to their mode of action. Free energy methods are used to quantify the thermodynamics of drug movement between water and octanol as well as for permeation across a POPC membrane. Both drugs are shown to favourably partition into the lipid bilayer from water and are likely to accumulate just inside the lipid headgroups where they may alter bilayer properties or interact with target proteins. Phenytoin experiences a large barrier to cross the centre of the bilayer due to less favourable energetic interactions in this less dense region of the bilayer. Remarkably, in our simulations both drugs are able to pull water into the bilayer, creating water chains that extend back to bulk, and which may modify the local bilayer properties. We find that the choice of atomic partial charges can have a significant impact on the quantitative results, meaning that careful validation of parameters for new drugs, such as performed here, should be performed prior to their use in biomolecular simulations. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.

    PubMed

    McCormack, Mark; Gui, Hongsheng; Ingason, Andrés; Speed, Doug; Wright, Galen E B; Zhang, Eunice J; Secolin, Rodrigo; Yasuda, Clarissa; Kwok, Maxwell; Wolking, Stefan; Becker, Felicitas; Rau, Sarah; Avbersek, Andreja; Heggeli, Kristin; Leu, Costin; Depondt, Chantal; Sills, Graeme J; Marson, Anthony G; Auce, Pauls; Brodie, Martin J; Francis, Ben; Johnson, Michael R; Koeleman, Bobby P C; Striano, Pasquale; Coppola, Antonietta; Zara, Federico; Kunz, Wolfram S; Sander, Josemir W; Lerche, Holger; Klein, Karl Martin; Weckhuysen, Sarah; Krenn, Martin; Gudmundsson, Lárus J; Stefánsson, Kári; Krause, Roland; Shear, Neil; Ross, Colin J D; Delanty, Norman; Pirmohamed, Munir; Carleton, Bruce C; Cendes, Fernando; Lopes-Cendes, Iscia; Liao, Wei-Ping; O'Brien, Terence J; Sisodiya, Sanjay M; Cherny, Stacey; Kwan, Patrick; Baum, Larry; Cavalleri, Gianpiero L

    2018-01-23

    To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. We report an association between a rare variant in the complement factor H-related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10 -11 ; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  16. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

    PubMed Central

    McCormack, Mark; Gui, Hongsheng; Ingason, Andrés; Speed, Doug; Wright, Galen E.B.; Zhang, Eunice J.; Secolin, Rodrigo; Yasuda, Clarissa; Kwok, Maxwell; Wolking, Stefan; Becker, Felicitas; Rau, Sarah; Avbersek, Andreja; Heggeli, Kristin; Leu, Costin; Depondt, Chantal; Sills, Graeme J.; Marson, Anthony G.; Auce, Pauls; Brodie, Martin J.; Francis, Ben; Johnson, Michael R.; Koeleman, Bobby P.C.; Striano, Pasquale; Coppola, Antonietta; Zara, Federico; Kunz, Wolfram S.; Sander, Josemir W.; Lerche, Holger; Klein, Karl Martin; Weckhuysen, Sarah; Krenn, Martin; Gudmundsson, Lárus J.; Stefánsson, Kári; Krause, Roland; Shear, Neil; Ross, Colin J.D.; Delanty, Norman; Pirmohamed, Munir; Carleton, Bruce C.; Cendes, Fernando; Lopes-Cendes, Iscia; Liao, Wei-ping; O'Brien, Terence J.; Sisodiya, Sanjay M.; Cherny, Stacey; Kwan, Patrick; Baum, Larry

    2018-01-01

    Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients. PMID:29288229

  17. Why we prefer levetiracetam over phenytoin for treatment of status epilepticus.

    PubMed

    Zaccara, G; Giorgi, F S; Amantini, A; Giannasi, G; Campostrini, R; Giovannelli, F; Paganini, M; Nazerian, P

    2018-06-01

    Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Thiopental and Phenytoin as Novel Ionophores for Potentiometric Determination of Lead (II) Ions

    PubMed Central

    Rizk, Nashwa M.H.; Abbas, Samah S.; Hamza, Salem M.; Abd EL-Karem, Yasser M.

    2009-01-01

    Two novel polymeric membrane sensors for the analysis of Pb(II) have been developed based on two therapeutic drugs, thiopental (TP) and phenytoin (PT) as two new ionophores and potassium tetrakis(p-chlorophenyl) borate (KTpClPB) as a lipophilic additive, in plasticized PVC membranes. The sensors show a Nernstian response for Pb(II) ions over the wide concentration ranges of 1×10−2 – 7×10−6 M and 1×10−2 – 8×10−6 M for the sensors based on thiopental and phenytoin, respectively. The proposed sensors have a fast response time and can be used for more than nine weeks without any considerable divergence in potentials. The sensors exhibit comparatively good selectivity with respect to alkaline, alkaline earth and some transition and heavy metal ions. They were employed for direct determination of lead in solder alloys and in galena rocks with a good agreement with the obtained results by atomic absorption spectroscopy. PMID:22573991

  19. Phenytoin mouthwash to treat cancer therapy-induced oral mucositis: A pilot studyPrimary neuroendocrine carcinoma of breast: A rare tumor.

    PubMed

    Baharvand, M; Hamian, M; Moosavizadeh, M A; Mortazavi, A; Ameri, A

    2015-01-01

    Oral mucositis is one of the most common side effects of cancer therapy with no definite treatment. Phenytoin has positive effects on healing of mucosal and dermal wounds. In this study efficacy of 1% phenytoin mouthwash on severity of mucositis (on the basis of WHO scale), pain relief (based on Visual Analogue Scale), and improvement of patients' quality of life (on the basis of EORTC-QLQ-H and N35 questionnaire) was evaluated. In a pilot -double-blind randomized clinical trial, eight patients in study group were given 1% phenytoin mouthwash while eight patients in control group used normal saline. Data analysis was performed by Mann-Whitney and Repeated Measured ANOVA tests. Reduction of mucositis severity was observed, but the difference was not significant. On the other hand, patients on phenytoin therapy had better pain relief (VAS# 6.75 ± 1.58 at the beginning of the study reached to # 3.75 ± 1.16 after 3 weeks in phenytoin group) and improvement in quality of life (score of QOL was 70.63 ± 5.5 that reached to 63.61 ± 6.39 in phenytoin group) than normal saline group significantly (P < 0.05). One percent phenytoin mouthwash caused pain relief and improvement of life quality significantly in patients with mucositis due to cancer therapy, but it did not reduce the severity of mucositis in a statistically significant scale.

  20. Detection of the antiepileptic drug phenytoin using a single free-standing piezoresistive microcantilever for therapeutic drug monitoring.

    PubMed

    Huang, Long-Sun; Pheanpanitporn, Yotsapoom; Yen, Yi-Kuang; Chang, Kai-Fung; Lin, Lung-Yi; Lai, Dar-Ming

    2014-09-15

    Phenytoin, one of the most widely used antiepileptic drugs, suppresses the abnormal brain activity often seen in seizures. In this study, we report the electrical detection of phenytoin as an antiepileptic medication with a narrow therapeutic dosage range to which therapeutic drug monitoring (TDM) is applied. The measurement technique used an electrical detection of a piezoresistive microcantilever biosensor. This label-free, electrically measured microcantilever can be miniaturized in order to be portable for point-of-care, personal diagnosis or for personalized therapeutic drug monitoring. The miniaturized piezoresistive microcantilever was fabricated by micro-electro-mechanical system processes, and was integrated into a microfluidic channel with a system for label-free detection. The microcantilever biosensor was approved for the detection of phenytoin in solutions of deionized water and 100% fetal bovine serum. A linear profile in a drug-concentration range of 10-80 μg/mL was detected, with the signal resolution being about 0.005 Ω. The concentration sensitivity was 2.94×10(-6) (μg/mL)(-1). The binding affinity (KD) was calculated to be 58 μg/mL. The results of the present piezoresistive microcantilever biosensors showed a solid correlation of phenytoin drug detection with that in the clinically used fluorescence polarization immunoassay (FPIA). Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach.

    PubMed

    Boerma, Ragna S; Braun, Kees P; van den Broek, Marcel P H; van de Broek, Maarten P H; van Berkestijn, Frederique M C; Swinkels, Marielle E; Hagebeuk, Eveline O; Lindhout, Dick; van Kempen, Marjan; Boon, Maartje; Nicolai, Joost; de Kovel, Carolien G; Brilstra, Eva H; Koeleman, Bobby P C

    2016-01-01

    Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

  2. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin

    PubMed Central

    Sükrü Aynacioglu, A; Brockmöller, Jürgen; Bauer, Steffen; Sachse, Christoph; Güzelbey, Pinar; Öngen, Zuhal; Nacak, Muradiye; Roots, Ivar

    1999-01-01

    Aims The genetically polymorphic cytochrome P450 enzyme CYP2C9 metabolizes many important drugs. We studied the frequency of the amino acid variants cysteine144 (CYP2C9*2) and leucine359 (CYP2C9*3) in a Turkish population and the correlation between genotype and phenotype using phenytoin as probe drug. Methods CYP2C9 alleles *2 and *3 were measured in 499 unrelated Turkish subjects by PCR and restriction fragment length pattern analysis. Phenotyping was performed in a subgroup of 101 volunteers with a single oral dose of 300 mg phenytoin and concentration analysis in serum drawn 12 h after dosage. Results CYP2C9 allele frequencies in 499 unrelated Turkish subjects were 0.794 for CYP2C9*1, 0.106 for CYP2C9*2 and 0.100 for CYP2C9*3. Mean phenytoin serum concentrations at 12 h after dosage were 4.16 mg l−1 (95% CI 3.86–4.46) in carriers of the genotype CYP2C9*1/1, 5.52 mg l−1 (4.66–6.39) in CYP2C9*1/2, and 5.65 mg l−1 (4.86–6.43) in CYP2C9*1/3. These differences were significant and accounted for 31% of total variability in phenytoin trough levels. Mean 12 h concentration ratios of 5-(para-hydroxyphenyl)-5-phenylhydantoin/phenytoin (p-HPPH/P) were 0.43 (0.39–0.47) for CYP2C9*1/1 compared with 0.26 (0.21–0.31) for CYP2C9*1/2, 0.14 (0.13–0.14) for CYP2C9*2/2, 0.21 (0.18–0.24) for CYP2C9*1/3, and 0.02 for CYP2C9*3/3; all mutant genotypes were significantly different compared with CYP2C9*1/1. Conclusions Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations. A significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes. The 12 h serum concentrations after a single phenytoin dose may be used for routine phenotyping of CYP2C9 mediated metabolic clearance and the p-HPPH/P ratios may be even more sensitive indicators of CYP2C9 activity. PMID:10510154

  3. Therapeutic Drug Monitoring of Phenytoin by Simple, Rapid, Accurate, Highly Sensitive and Novel Method and Its Clinical Applications.

    PubMed

    Shaikh, Abdul S; Guo, Ruichen

    2017-01-01

    Phenytoin has very challenging pharmacokinetic properties. To prevent its toxicity and ensure efficacy, continuous therapeutic monitoring is required. It is hard to get a simple, accurate, rapid, easily available, economical and highly sensitive assay in one method for therapeutic monitoring of phenytoin. The present study is directed towards establishing and validating a simpler, rapid, an accurate, highly sensitive, novel and environment friendly liquid chromatography/mass spectrometry (LC/MS) method for offering rapid and reliable TDM results of phenytoin in epileptic patients to physicians and clinicians for making immediate and rational decision. 27 epileptics patients with uncontrolled seizures or suspected of non-compliance or toxicity of phenytoin were selected and advised for TDM of phenytoin by neurologists of Qilu Hospital Jinan, China. The LC/MS assay was used for performing of therapeutic monitoring of phenytoin. The Agilent 1100 LC/MS system was used for TDM. The mixture of Ammonium acetate 5mM: Methanol at (35: 65 v/v) was used for the composition of mobile phase. The Diamonsil C18 (150mm×4.6mm, 5μm) column was used for the extraction of analytes in plasma. The samples were prepared with one step simple protein precipitation method. The technique was validated with the guidelines of International Conference on Harmonisation (ICH). The calibration curve demonstrated decent linearity within (0.2-20 µg/mL) concentration range with linearity equation, y= 0.0667855 x +0.00241785 and correlation coefficient (R2) of 0.99928. The specificity, recovery, linearity, accuracy, precision and stability results were within the accepted limits. The concentration of 0.2 µg/mL was observed as lower limit of quantitation (LLOQ), which is 12.5 times lower than the currently available enzyme-multiplied immunoassay technique (EMIT) for measurement of phenytoin in epilepsy patients. A rapid, simple, economical, precise, highly sensitive and novel LC/MS assay has been

  4. Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population.

    PubMed

    Tassaneeyakul, Wichittra; Prabmeechai, Napat; Sukasem, Chonlaphat; Kongpan, Thachanan; Konyoung, Parinya; Chumworathayi, Pansu; Tiamkao, Somsak; Khunarkornsiri, Usanee; Kulkantrakorn, Kongkiat; Saksit, Niwat; Nakkam, Nontaya; Satapornpong, Patompong; Vannaprasaht, Suda; Sangviroon, Alisara; Mahasirimongkol, Surakameth; Wichukchinda, Nuanjun; Rerkpattanapipat, Ticha; Tassaneeyakul, Wongwiwat

    2016-05-01

    Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05). Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.

  5. Formation of phenytoin nanoparticles using rapid expansion of supercritical solution with solid cosolvent (RESS-SC) process.

    PubMed

    Thakur, Ranjit; Gupta, Ram B

    2006-02-03

    Nanoparticles are of significant importance in drug delivery. Rapid expansion of supercritical solution (RESS) process can produce pure and high-quality drug particles. However, due to extremely low solubility of polar drugs in supercritical CO(2) (sc CO(2)), RESS has limited commercial applicability. To overcome this major limitation, a modified process rapid expansion of supercritical solution with solid cosolvent (RESS-SC) is proposed which uses a solid cosolvent. Here, the new process is tested for phenytoin drug using menthol solid cosolvent. Phenytoin solubility in pure sc CO(2) is only 3 micromol/mol but when menthol solid cosolvent is used the solubility is enhanced to 1,302 micromol/mol, at 196 bar and 45 degrees C. This 400-fold increase in the solubility can be attributed to the interaction between phenytoin and menthol. Particle agglomeration in expansion zone is another major issue with conventional RESS process. In proposed RESS-SC process solid cosolvent hinders the particle growth resulting in the formation of small nanoparticles. For example, the average particle size of phenytoin in conventional RESS process is 200 nm whereas, with RESS-SC process, the average particle size is 120 nm, at 96 bar and 45 degrees C. Similarly at 196 bar and 45 degrees C, 105 nm average particles were obtained by RESS and 75 nm average particles were obtained in RESS-SC process. The particles obtained were characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS) and differential scanning calorimetery (DSC) analyses. Phenytoin nanoparticle production rate in RESS-SC is about 400-fold more in comparison to that in RESS process.

  6. Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software.

    PubMed

    Batchelor, Hannah; Appleton, Richard; Hawcutt, Daniel B

    2015-12-01

    To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin. A phenytoin pharmacokinetic model was used in the Simcyp population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10 μg/mL), therapeutic in 62/100 (C2h 10-20 μg/mL), and supra-therapeutic in 16/100 (C2h>20 μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 μg/mL, and the mean AUC from 145 to 162 μg/mL/h. A C2h>30 μg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h>40 μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%. Use of PBPK modelling suggests that children receiving the 20 mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  7. Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin

    SciTech Connect

    Delattre, J.Y.; Safai, B.; Posner, J.B.

    1988-02-01

    In 15 months we encountered eight patients with intracranial tumors who developed erythema multiforme (EM) or erythema multiforme bullosa (Stevens-Johnson syndrome). All occurred shortly after use of phenytoin (DPH) and brain radiation therapy (WBRT). The clinical picture differed from the classic form of EM in that the erythema began on the scalp and spread to the extremities, progressing in three cases to extensive bullous formation. There were no cases of EM among patients who received either DPH or radiotherapy alone. The combination of DPH, WBRT, and tapering of steroids seems to predispose to EM. The pathogenesis of the disorder ismore » probably immunologic. In the absence of seizures, anticonvulsants should not be given routinely to patients with brain tumors. When anticonvulsants are necessary in patients scheduled for WBRT, DPH may not be the drug of choice.« less

  8. Phenytoin crystal growth rates in the presence of phosphate and chloride ions

    NASA Astrophysics Data System (ADS)

    Zipp, G. L.; Rodríguez-Hornedo, N.

    1992-09-01

    Phenytoin crystal growth kinetics have been measured as a function of supersaturation in pH 2.2 phosphoric acid and pH 2.2 hydrochloric acid solutions. Two different methods were used for the kinetic analysis. The first involved a zone-sensing device which provided an analysis of the distribution of crystals in a batch crystallizer. Crystal growth rates were calculated from the increase in the size of the distribution with time. In the second method, growth rates were evaluated from the change in size with time of individual crystals observed under an inverted microscope. The results from each method compare favorably. The use of both techniques provides an excellent opportunity to exploit the strengths of each: an average growth rate from a population of crystals from batch crystallization and insight into the effect of growth on the morphology of the crystals from the individual crystal measurements.

  9. Stability of phenytoin in blood collected in vacuum blood collection tubes.

    PubMed

    Parish, R C; Alexander, T

    1990-01-01

    The stability of phenytoin in blood collected in plain and serum separator tubes (SSTs) was investigated under simulated storage and transport conditions. The drug was generally more stable in plain collection tubes than in SSTs. No degradation occurred in plain red-top tubes or in refrigerated SSTs, but clinically significant degradation was present in SSTs stored at room temperature (25 degrees C) and at elevated temperature (32 degrees C) 24 h after collection. The mean loss was 17.9% at 25 degrees C and 25.9% at 32 degrees C. It is recommended that if blood is to be transported or stored in SSTs, the samples be refrigerated unless assay can be performed within 8 h.

  10. Anti-epileptic drugs and bone loss: Phenytoin reduces pro-collagen I and alters the electrophoretic mobility of osteonectin in cultured bone cells.

    PubMed

    Wilson, Emma L; Garton, Mark; Fuller, Heidi R

    2016-05-01

    Phenytoin is an antiepileptic drug used in the management of partial and tonic-clonic seizures. In previous studies we have shown that valproate, another antiepileptic drug, reduced the amount of two key bone proteins, pro-collagen I and osteonectin (SPARC, BM-40), in both skin fibroblasts and cultured osteoblast-like cells. Here we show that phenytoin also reduces pro-collagen I production in osteoblast-like cells, but does not appear to cause a decrease in osteonectin message or protein production. Instead, a 24h exposure to a clinically relevant concentration of phenytoin resulted in a dose-dependent change in electrophoretic mobility of osteonectin, which was suggestive of a change in post-translational modification status. The perturbation of these important bone proteins could be one of the mechanisms to explain the bone loss that has been reported following long-term treatment with phenytoin. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study.

    PubMed

    Gujjar, Arunodaya R; Nandhagopal, Ramachandiran; Jacob, Poovathoor C; Al-Hashim, Abdulhakeem; Al-Amrani, Khalfan; Ganguly, Shyam S; Al-Asmi, Abdullah

    2017-07-01

    Status Epilepticus (SE) is a common medical emergency carrying a high morbidity and mortality. Levetiracetam (LEV) is a novel anticonvulsant effective against varied seizures. Few prospective studies have addressed its use in SE. We aimed to examine the efficacy of intravenous LEV in controlling SE and cluster attacks of seizures (CS), in comparison with IV phenytoin (DPH), using a prospective, randomized study design. Adult patients with SE or CS, following an initial dose of IV benzodiazepine to control ongoing seizure, were randomized to receive either medication. Rates of seizure control over 24h, adverse effects and outcomes were compared. A logistic regression model was used to identify outcome predictors. 52 patients with SE and 63 with CS received either LEV or DPH. In the SE group, LEV was effective in18/22(82%) and DPH in 22/30(73.3%) patients in controlling seizures. Among patients with CS, LEV was effective in 31/38(81.6%) and DPH in 20/25(80%). With the use of LEV, DPH or both, SE and CS were controlled among 92% and 96% of patients respectively. Adverse events included hypotension (in 2 on DPH) and transient agitation (2 on LEV). IV Levetiracetam controls status epilepticus or cluster seizures with an efficacy comparable to that of phenytoin. Use of these two agents consecutively may control >90% of all such conditions without resort to anaesthetic agents. Further studies should explore its efficacy in larger cohorts of epileptic emergencies. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  12. Phenytoin versus Leviteracetam for Seizure Prophylaxis after brain injury – a meta analysis

    PubMed Central

    2012-01-01

    Background Current standard therapy for seizure prophylaxis in Neuro-surgical patients involves the use of Phenytoin (PHY). However, a new drug Levetiracetam (LEV) is emerging as an alternate treatment choice. We aimed to conduct a meta-analysis to compare these two drugs in patients with brain injury. Methods An electronic search was performed in using Pubmed, Embase, and CENTRAL. We included studies that compared the use of LEV vs. PHY for seizure prophylaxis for brain injured patients (Traumatic brain injury, intracranial hemorrhage, intracranial neoplasms, and craniotomy). Data of all eligible studies was extracted on to a standardized abstraction sheet. Data about baseline population characteristics, type of intervention, study design and outcome was extracted. Our primary outcome was seizures. Results The literature search identified 2489 unduplicated papers. Of these 2456 papers were excluded by reading the abstracts and titles. Another 25 papers were excluded after reading their complete text. We selected 8 papers which comprised of 2 RCTs and 6 observational studies. The pooled estimate’s Odds Ratio 1.12 (95% CI = 0.34, 3.64) demonstrated no superiority of either drug at preventing the occurrence of early seizures. In a subset analysis of studies in which follow up for seizures lasted either 3 or 7 days, the effect estimate remained insignificant with an odds ratio of 0.96 (95% CI = 0.34, 2.76). Similarly, 2 trials reporting seizure incidence at 6 months also had insignificant pooled results while comparing drug efficacy. The pooled odds ratio was 0.96 (95% CI = 0.24, 3.79). Conclusions Levetiracetam and Phenytoin demonstrate equal efficacy in seizure prevention after brain injury. However, very few randomized controlled trials (RCTs) on the subject were found. Further evidence through a high quality RCT is highly recommended. PMID:22642837

  13. A Comprehensive Review on the Predictive Performance of the Sheiner-Tozer and Derivative Equations for the Correction of Phenytoin Concentrations.

    PubMed

    Kiang, Tony K L; Ensom, Mary H H

    2016-04-01

    In settings where free phenytoin concentrations are not available, the Sheiner-Tozer equation-Corrected total phenytoin concentration = Observed total phenytoin concentration/[(0.2 × Albumin) + 0.1]; phenytoin in µg/mL, albumin in g/dL-and its derivative equations are commonly used to correct for altered phenytoin binding to albumin. The objective of this article was to provide a comprehensive and updated review on the predictive performance of these equations in various patient populations. A literature search of PubMed, EMBASE, and Google Scholar was conducted using combinations of the following terms: Sheiner-Tozer, Winter-Tozer, phenytoin, predictive equation, precision, bias, free fraction. All English-language articles up to November 2015 (excluding abstracts) were evaluated. This review shows the Sheiner-Tozer equation to be biased and imprecise in various critical care, head trauma, and general neurology patient populations. Factors contributing to bias and imprecision include the following: albumin concentration, free phenytoin assay temperature, experimental conditions (eg, timing of concentration sampling, steady-state dosing conditions), renal function, age, concomitant medications, and patient type. Although derivative equations using varying albumin coefficients have improved accuracy (without much improvement in precision) in intensive care and elderly patients, these equations still require further validation. Further experiments are also needed to yield derivative equations with good predictive performance in all populations as well as to validate the equations' impact on actual patient efficacy and toxicity outcomes. More complex, multivariate predictive equations may be required to capture all variables that can potentially affect phenytoin pharmacokinetics and clinical therapeutic outcomes. © The Author(s) 2016.

  14. Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and alpha-phenyl-N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase

    SciTech Connect

    Wells, P.G.; Zubovits, J.T.; Wong, S.T.

    1989-02-01

    Teratogenicity of the anticonvulsant drug phenytoin is thought to involve its bioactivation by cytochromes P-450 to a reactive arene oxide intermediate. We hypothesized that phenytoin also may be bioactivated to a teratogenic free radical intermediate by another enzymatic system, prostaglandin synthetase. To evaluate the teratogenic contribution of this latter pathway, an irreversible inhibitor of prostaglandin synthetase, acetylsalicylic acid (ASA), 10 mg/kg intraperitoneally (ip), was administered to pregnant CD-1 mice at 9:00 AM on Gestational Days 12 and 13, 2 hr before phenytoin, 65 mg/kg ip. Other groups were pretreated 2 hr prior to phenytoin administration with either the antioxidant caffeicmore » acid or the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). Caffeic acid and PBN were given ip in doses that respectively were up to 1.0 to 0.05 molar equivalents to the dose of phenytoin. Dams were killed on Day 19 and the fetuses were assessed for teratologic anomalies. A similar study evaluated the effect of ASA on the in vivo covalent binding of radiolabeled phenytoin administered on Day 12, in which case dams were killed 24 hr later on Day 13. ASA pretreatment produced a 50% reduction in the incidence of fetal cleft palates induced by phenytoin (p less than 0.05), without significantly altering the incidence of resorptions or mean fetal body weight. Pretreatment with either caffeic acid or PBN resulted in dose-related decreases in the incidence of fetal cleft palates produced by phenytoin, with maximal respective reductions of 71 and 82% at the highest doses of caffeic acid and PBN (p less than 0.05).« less

  15. Incidence of delayed seizures, delayed cerebral ischemia and poor outcome with the use of levetiracetam versus phenytoin after aneurysmal subarachnoid hemorrhage.

    PubMed

    Karamchandani, Rahul Ramesh; Fletcher, Jeffrey James; Pandey, Aditya Swarup; Rajajee, Venkatakrishna

    2014-09-01

    Current guidelines recommend against the use of phenytoin following aneurysmal subarachnoid hemorrhage (aSAH) but consider other anticonvulsants, such as levetiracetam, acceptable. Our objective was to evaluate the risk of poor functional outcomes, delayed cerebral ischemia (DCI) and delayed seizures in aSAH patients treated with levetiracetam versus phenytoin. Medical records of patients with aSAH admitted between 2005-2012 receiving anticonvulsant prophylaxis with phenytoin or levetiracetam for >72 hours were reviewed. The primary outcome measure was poor functional outcome, defined as modified Rankin Scale (mRS) score >3 at first recorded follow-up. Secondary outcomes measures included DCI and the incidence of delayed seizures. The association between the use of levetiracetam and phenytoin and the outcomes of interest was studied using logistic regression. Medical records of 564 aSAH patients were reviewed and 259 included in the analysis after application of inclusion/exclusion criteria. Phenytoin was used exclusively in 43 (17%), levetiracetam exclusively in 132 (51%) while 84 (32%) patients were switched from phenytoin to levetiracetam. Six (2%) patients had delayed seizures, 94 (36%) developed DCI and 63 (24%) had mRS score >3 at follow-up. On multivariate analysis, only modified Fisher grade and seizure before anticonvulsant administration were associated with DCI while age, Hunt-Hess grade and presence of intraparenchymal hematoma were associated with mRS score >3. Choice of anticonvulsant was not associated with any of the outcomes of interest. There was no difference in the rate of delayed seizures, DCI or poor functional outcome in patients receiving phenytoin versus levetiracetam after aSAH. The high rate of crossover from phenytoin suggests that levetiracetam may be better tolerated. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Association analysis of CYP2C9*3 and phenytoin-induced severe cutaneous adverse reactions (SCARs) in Thai epilepsy children.

    PubMed

    Suvichapanich, Supharat; Jittikoon, Jiraphun; Wichukchinda, Nuanjun; Kamchaisatian, Wasu; Visudtibhan, Anannit; Benjapopitak, Suwat; Nakornchai, Somjai; Manuyakorn, Wiparat; Mahasirimongkol, Surakameth

    2015-08-01

    CYP2C9 is the key enzyme in aromatic antiepileptic drugs (AEDs) metabolism. CYP2C9*3 is a loss of function polymorphism. This study was designed to investigate genetic association between CYP2C9*3 and aromatic AED-induced severe cutaneous adverse reactions (SCARs) in Thai children. The 37 aromatic AED-induced SCARs patients (20 phenobarbital and 17 phenytoin) and 35 tolerances (19 phenobarbital and 16 phenytoin) were enrolled. CYP2C9*3 was genotyped by allele-specific PCRs. The association between CYP2C9*3 with phenytoin-induced SCARs and phenobarbital-induced SCARs were analyzed in comparison with tolerances and healthy samples. Significant association between phenytoin-induced SCARs and CYP2C9*3 was discovered (odds ratio=14.52; 95% confidence interval (CI)=1.18-∞, P-value=0.044). CYP2C9*3 was not associated with phenobarbital-induced SCARs. This study is the first report of CYP2C9*3 association to phenytoin-induced SCARs in Thai epileptic children. The CYP2C9*3 is a reasonable predictive genetic marker to anticipate SCARs from phenytoin.

  17. Multiscale Computational Modeling of the Nanostructure of Solid Dispersions of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) and Phenytoin.

    PubMed

    Huang, Wenjun; Mandal, Taraknath; Larson, Ronald G

    2017-10-02

    We recently developed coarse-grained (CG) force fields for hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymers and the model drug molecule phenytoin, and a continuum transport model to study the polymer-drug nanostructures presented during a dissolution test after solvation of solid dispersion particles. We model the polymer-drug interactions that contribute to suppression of drug aggregation, release, and crystal growth during the dissolution process, and we take these as indicators of polymer effectiveness. We find that the size and the intermolecular interaction strength of the functional group and the drug loading concentration are the major factors that impact the effectiveness of the polymeric excipient. The hydroxypropyl acetyl group is the most effective functional group, followed by the acetyl group, while the deprotonated succinyl group is the least effective functional group, except that the deprotonated succinyl group at the 6-position is very effective in slowing down the phenytoin crystal growth. Our simulation results thus suggest HPMCAS with higher acetyl and lower succinyl content is more effective in promoting phenytoin solubility in dissolution media, and polymers become less effective when drug loading becomes high (i.e., 50% of the mass of the polymer/drug solid dispersion), agreeing with previous experimental studies. In addition, our transport model indicates that the drug release time from a solid dispersion particle of 2 μm diameter is less than 10 min, correlating well with the experimental time scale for a typical dissolution profile to reach maximum peak concentration. Our modeling effort, therefore, provides new avenues to understand the dissolution behavior of complex HPMCAS-phenytoin solid dispersions and offers a new design tool to optimize the formulation. Moreover, the systematic and robust approach used in our computational models can be extended to other polymeric excipients and drug candidates.

  18. Kolaviron and vitamin E ameliorate hematotoxicity and oxidative stress in brains of prepubertal rats treated with an anticonvulsant phenytoin.

    PubMed

    Owoeye, Olatunde; Adedara, Isaac A; Bakare, Oluwafemi S; Adeyemo, Oluwatobi A; Egun, Christa; Farombi, Ebenezer O

    2014-06-01

    Phenytoin (PHT), an anticonvulsant agent, widely used for the treatment of epilepsy has been reported to exhibit toxic side effects. The present study investigated the protective effects of kolaviron and vitamin E on hematotoxicity and neurotoxicity induced by phenytoin, in prepubertal male rats. The animals were treated with PHT (75 mg/kg) separately or in combination with either kolaviron (200 mg/kg) or vitamin E (500 mg/kg) for 14 days. Phenytoin treatment significantly decreased the hemoglobin, white blood cells, lymphocytes and mean corpuscular volume levels without affecting red blood cell, packed cell volume, neutrophils, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration when compared with the control rats. There was a significant increase in lipid peroxidation and hydrogen peroxide levels with marked depletion in antioxidant status in brains of PHT-treated rats when compared with the control. Although PHT treatment had no effect on the granular layer, widest diameter of Purkinje cells and Purkinje layer of the cerebellum, it significantly reduced its molecular layer and the density of Purkinje cell. Administration of PHT significantly reduced the densities of the granule cells of the dentate gyrus and the pyramidal neurons of the cornu ammonis of hippocampus proper. Co-treatment with kolaviron and vitamin E effectively reversed the PHT-mediated alterations in the hematology, brain antioxidant status and histomorphometry when compared to PHT only. Taken together, the present data indicate the abilities of kolaviron and vitamin E to ameliorate phenytoin-induced hematotoxicity and oxidative stress in brains of rats.

  19. Protective effect on phenytoin-induced cognition deficit in pentylenetetrazol kindled mice: A repertoire of Glycyrrhiza glabra flavonoid antioxidants.

    PubMed

    Singh, Paramdeep; Singh, Damanpreet; Goel, Rajesh K

    2016-07-01

    Glycyrrhiza glabra L. (Febaceae) has been widely used in traditional medicine and scientifically explored for its anticonvulsant and memory improving potential. The objective of this study is to investigate the effect of flavonoid rich fraction of G. glabra root extract against phenytoin-induced cognition deficit in pentylenetetrazol (PTZ) kindled mice. The ethyl acetate fraction was initially screened in different in vitro free radical scavenging assays. For in vivo studies, the kindled mice in different groups were given 15 d post-treatment with phenytoin (25 mg/kg; p.o.) per se or in combination with varying doses of the fraction (5, 10, and 15 mg/kg; p.o.). Seizure severity score and cognitive functions were accessed using Racine's scale and passive shock avoidance paradigm, respectively on every 5th d after a PTZ challenge dose (35 mg/kg; i.p.). At the end of study, the animals were scarified for cerebral biochemistry. The fraction showed marked antioxidant activity indicated by low IC50 values in DPPH (20.9 µg/mL), nitric oxide radical scavenging (195.2 µg/mL), and capacity of hydrogen peroxide scavenging (3.4 µg/mL) assays. Treatment with phenytoin per se and along with the flavonoid rich fraction showed significant reduction in seizure severity score as compared to vehicle control. The combined-treated groups also showed improved cognitive functions indicated by reduced number of mistakes and increased step-down latency in passive shock avoidance paradigm. From the results, it can be concluded that the flavonoid rich fraction in combination with phenytoin reduces seizure severity and improve cognitive functions in PTZ-kindled mice.

  20. Region-specific changes in gene expression in rat brain after chronic treatment with levetiracetam or phenytoin

    PubMed Central

    Hassel, Bjørnar; Taubøll, Erik; Shaw, Renee; Gjerstad, Leif; Dingledine, Ray

    2014-01-01

    Summary Purpose It is commonly assumed that antiepileptic drugs (AEDs) act similarly in the various parts of the brain as long as their molecular targets are present. A few experimental studies on metabolic effects of vigabatrin, levetiracetam, valproate, and lamotrigine have shown that these drugs may act differently in different brain regions. We examined effects of chronic treatment with levetiracetam or phenytoin on mRNA levels to detect regional drug effects in a broad, nonbiased manner. Methods mRNA levels were monitored in three brain regions with oligonucleotide-based microarrays. Results Levetiracetam (150 mg/kg for 90 days) changed the expression of 65 genes in pons/medulla oblongata, two in hippocampus, and one in frontal cortex. Phenytoin (75 mg/kg), in contrast, changed the expression of only three genes in pons/medulla oblongata, but 64 genes in hippocampus, and 327 genes in frontal cortex. Very little overlap between regions or drug treatments was observed with respect to effects on gene expression. Discussion We conclude that chronic treatment with levetiracetam or phenytoin causes region-specific and highly differential effects on gene expression in the brain. Regional effects on gene expression could reflect regional differences in molecular targets of AEDs, and they could influence the clinical profiles of AEDs. PMID:20345932

  1. In Vitro Effects of Bromoalkyl Phenytoin Derivatives on Regulated Death, Cell Cycle and Ultrastructure of Leukemia Cells.

    PubMed

    Śladowska, Katarzyna; Opydo-Chanek, Małgorzata; Król, Teodora; Trybus, Wojciech; Trybus, Ewa; Kopacz-Bednarska, Anna; Handzlik, Jadwiga; Kieć-Kononowicz, Katarzyna; Mazur, Lidia

    2017-11-01

    To search for new antileukemic agents, the chemical structure of phenytoin was modified. A possible cytotoxic activity of three bromoalkyl phenytoin analogs, methyl 2-(1-(3-bromopropyl)-2,4-dioxo-5,5-diphenylimidazolidin-3-yl) propanoate (PH2), 1-(3-bromopropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (PH3) and 1-(4-bromobutyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (PH4) on regulated cell death, the cell cycle and cell ultrastructure was assessed. The experiments were performed in vitro on HL-60 and U937 cells, using flow cytometry and electron microscopy methods. Application of PH2, PH3, and PH4 resulted in cell surface exposure of phosphatidylserine and plasma membrane impairment, caspase-8, -9, and -3/7 activation, dissipation of mitochondrial membrane potential, DNA breakage, cell-cycle disturbance and cell ultrastructural changes. In general, PH3 appeared to be the most active against the leukemia cells, and all bromoalkyl hydantoins, PH2-PH4, were more active in HL-60 cells than in U937 cells. The antileukemic activity of the bromoalkyl phenytoin analogs depended on the combination of N-hydantoin substituents and the human cell line used. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Network-specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin.

    PubMed

    Thomas, Evan A; Petrou, Steven

    2013-07-01

    A common notion of the mechanism by which the antiepileptic drugs (AEDs) carbamazepine and phenytoin act is that they block sodium channels by binding preferentially to the inactivated state, thereby allowing normal neuronal firing while blocking ictal activity. However, these drugs have unpredictable efficacy and, in some cases, may exacerbate seizures. Previous studies have suggested that reducing sodium channel availability in the dentate gyrus (DG) paradoxically increases excitability. We used a biophysically detailed computer model of the DG to test the hypothesis that AEDs increase excitability by disproportionately reducing negative feedback mechanisms. We built a Markov model of sodium channel gating that reproduces responses to voltage clamp experiments in the presence of carbamazepine and phenytoin. We incorporated this validated Markov model into a biophysically realistic computer model of DG neurons and networks. Simulated drug concentrations were similar to those measured in cerebral spinal fluid in medicated patients. Single neuron models were stimulated with current injections, and networks were stimulated with perforant path synaptic input. In the network model, environmental effects were studied by introducing mossy fiber sprouting. As expected, drugs reduced sodium channel availability, which in turn reduced action potential amplitude. This had only a small effect on action potential (AP) firing rate during brief (100 msec) current injections. Paradoxically, long current injections (2,500 msec) increased AP firing rates. This was caused by reduced calcium entry and consequently reduced activation of calcium activated potassium channels. It is important to note that the main determinant of drug effect was resting membrane potential (RMP) and not action potential firing rate. Binding of phenytoin and carbamazepine is slow and, thus drug effects are largely determined by the long term state of the RMP. This paradoxical AP firing increase was

  3. Clinical relevance of genetic polymorphism in CYP2C9 gene to pharmacodynamics and pharmacokinetics of phenytoin in epileptic patients: validatory pharmacogenomic approach to pharmacovigilance.

    PubMed

    Kousar, Shazia; Wafai, Zahoor A; Wani, Mushtaq A; Jan, Tariq R; Andrabi, Khurshid I

    2015-07-01

    Variations in drug metabolizing genes are known to have a clinical impact on AED therapy. We genotyped normal and epileptic patient cohorts of monoethnic population of Kashmir valley for CYP2C9 gene and allelic polymorphism and investigated the effect of CYP2C9*2 and *3 polymorphism on the Pharmacokinetic and therapeutic and/or adverse pharmacodynamic responses to Phenytoin in the idiopathic epilepsy patients. PCR-RFLP methods were used for genotyping of 121 normal controls and 92 idiopathic epilepsy patients for CYP2C9*2 and *3 polymorphism, the results were validated by direct sequencing. Phenytoin pharmacokinetic (PK) analysis in idiopathic epilepsy patients was done using a validated EMIT assay technique. Pharmacodynamic analysis was done by evaluating clinical response to phenytoin therapy and ADR monitoring. The respective frequencies of CYP2C9 *1, *2, and *3 alleles were 64%, 6.6%, 29.3%, and 58%, 9.8%, 32.6% in controls and idiopathic epilepsy patients from Kashmir valley. PK analysis revealed that AUC0–4 was a better surrogate biomarker of CYP2C9 metabolizer status compared to C4 and C0 concentrations alone. A comparison of “phenytoin response categories” among CYP2C9 Wild and Heterozygous groups did not reveal any significant difference between the groups (p=0.3800). CYP2C9* 3 was the most frequent mutant allele found in healthy controls and idiopathic epilepsy patients of ethnic Kashmiri population. CYP2C9 genotype based phenytoin therapy is highly relevant in Kashmiri population due to a high incidence of genetic variations associated with therapeutic and adverse responses to phenytoin. Phenytoin AUC0–4 tends to correlate better with genetic polymorphism of CYP2C9.

  4. Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam--Pilot study.

    PubMed

    Mundlamuri, R C; Sinha, S; Subbakrishna, D K; Prathyusha, P V; Nagappa, M; Bindu, P S; Taly, A B; Umamaheswara Rao, G S; Satishchandra, P

    2015-08-01

    This study was conducted to compare the efficacy of phenytoin, valproate and levetiracetam in patients with GCSE. This randomised controlled prospective study was conducted on 150 patients to compare the efficacy of phenytoin (n = 50), valproate (n = 50) and levetiracetam (n = 50) along with lorazepam in patients with GCSE. All recruited patients received i.v. lorazepam (0.1mg/kg) followed by one of the 3 AEDs viz. phenytoin (20 mg/kg), valproate (30 mg/kg), and levetiracetam (25 mg/kg). Those who remained uncontrolled with 1st AED, received the other two AEDs sequentially. Clinical, imaging, EEG, etiological factors were analysed. Predictors of poor seizure control and outcome at discharge and at one month follow-up were assessed. In the phenytoin subgroup, the seizures could be controlled in 34 (68%) with lorazepam+phenytoin infusion. In the valproate subgroup (n = 50), seizures could be controlled in 34 (68%) with lorazepam+valproate infusion. In the levetiracetam subgroup (n = 50), seizures could be controlled in 39 (78%) with lorazepam+levetiracetam infusion. There was no statistically significant difference between the subgroups (p = 0.44). Overall, following lorazepam and 1st AED, 107/150 (71.3%) were controlled; with addition of 2nd AED, 130/150 (86.7%) and by adding 3rd AED, 138/150 (92%) were controlled. Fifteen out of 110 (13.6%) expired within 1 month of SE: phenytoin-6; valproate-4; and levetiracetam-5. Interestingly, 3 patients in the levetiracetam had post-ictal psychosis. Phenytoin, valproate, and levetiracetam are safe and equally efficacious following lorazepam in GCSE. The choice of AEDs could be individualised based on co-morbidities. SE could be controlled in 92% of patients with AEDs only and anaesthetics were not required in them. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort.

    PubMed

    Uribe-San-Martín, Reinaldo; Ciampi, Ethel; Uslar, Wilhelm; Villagra, Silvana; Plaza, Jose; Godoy, Jaime; Mellado, Patricio

    2017-11-01

    Phenytoin (PHT) is an effective and inexpensive antiepileptic drug (AED). However, its use has been limited for fear of adverse drug reactions (ADRs) and is being replaced by newer AED, increasing the costs and causing major budget problems, particularly for developing countries. The objective of this study was to determine ADR frequency, explore, and establish related risk factors. Prospective data were collected from a cohort of inpatients using PHT for the first time. Pharmacovigilance was performed during hospitalization and after one month from the discharge. Clinical variables, plasma levels, and concomitant medications were collected and their association with the occurrence of different ADRs was explored. One hundred patients were included: 59 were women, and mean age was 59±21years. Thirty-three patients presented ADR, all moderate and idiosyncratic. The most frequent were rash (17%), fever (10%), and elevated transaminases (10%). Female gender (85% vs 52%, p=0.029), younger age (mean age: 49 vs 62years, p=0.032), and higher PHT plasmatic levels after IV-PO load (mean plasmatic levels: 18.6 vs 13.9μg/mL, p=0.040) were found to be associated with rash. A higher number of concomitant medications were also found to be associated with the risk for developing any ADR. The multivariate analysis revealed an association between rash and younger age (cut-off: 35years old; relative risk (RR)=11.7; p=0.026), and higher PHT plasmatic levels (cut-off: 16μg/mL; RR=12.5; p=0.021); and increased risk of elevated transaminases with use of PHT inductors (RR=18; p=0.006). A longer hospital stay was found in patients who developed fever (mean: 43days, p<0.0001) and elevated transaminases (mean: 26days, p=0.041) compared with patients without ADR (mean: 17days). Phenytoin is a widely used AED associated with easily detectable ADR through structured pharmacovigilance. The development of ADR is associated with longer hospital stays. Recognition of local risk factors may lead

  6. The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin.

    PubMed

    Barker, Bryan S; Ottolini, Matteo; Wagnon, Jacy L; Hollander, Rachel M; Meisler, Miriam H; Patel, Manoj K

    2016-09-01

    SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav 1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0 and 18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin. The mutation was introduced into the Scn8a cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μm) on mutant and wild-type (WT) channels were compared. Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, whereas inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μm) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use-dependent block of I1327V mutant channels relative to WT. SCN8A - I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain

  7. The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin

    PubMed Central

    Barker, Bryan S.; Ottolini, Matteo; Wagnon, Jacy L.; Hollander, Rachel; Meisler, Miriam H.; Patel, Manoj K.

    2016-01-01

    Objective SCN8A encephalopathy (EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0–18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard anti-epileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin. Methods The mutation was introduced into the Scn8a cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μM) on mutant and wild type (WT) channels were compared. Results Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, while inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μM) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use dependent block of I1327V mutant channels relative to WT. Significance SCN8A – I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain

  8. Applications of molecular physics 'biotechnology' to the rational design of an improved phenytoin analogue.

    PubMed

    Weaver, D F

    1992-12-01

    This study exploits molecular physics, in conjunction with a large scale computing environment, as a tool for understanding the clinical phenomenology of phenytoin (PHT) toxicology at a molecular level and for employing this understanding in an attempt to design improved drugs. The application of molecular physics techniques, such as quantum mechanics and molecular force field calculations, to the process of rational anticonvulsant drug design remains virtually unexplored. A 3-step strategy for applying these techniques to the design of an improved PHT molecule is presented. Step 1 employs quantitative structure-activity relationship calculations on 80 PHT analogues to ascertain the portion of the PHT molecule necessary for bioactivity (i.e. the 'bioactive face' of PHT); the N3-C4(O)-C5-R fragment of PHT was identified as the bioactive face. Step 2 employs molecular modelling studies to determine the portion of the PHT molecule necessary for the teratogenic, mutagenic and connective tissue toxicities of PHT (i.e. the 'biotoxic face'); the C2(O)-N3 fragment of PHT was identified as the biotoxic face. Step 3 experiments design an 'improved' PHT analogue, which maintains the bioactive face while eliminating the integrity of the biotoxic face; 2-deoxy-5,5-diphenylhydantoin was designed and synthesized as the improved PHT analogue. This compound had biological activity equivalent to PHT, but was unable to bind to nucleic acids or to chelate metals involved in connective tissue metabolism.

  9. [Antihyperalgesic activity of chlorimipramine and sodium phenytoin in an induced model of neuropathic pain in rats].

    PubMed

    Guevara-López, Uriah; Gutiérrez-Sougarret, Bernardo; López-Pavón, Lucy; Aldrete, J Antonio; Tamayo-Valenzuela, Antonio

    2004-01-01

    Neuropathic pain results from injury or impairment of the nervous system manifested by pain syndrome. Experimental models have been used to study its effects and how to suppress these. Tricyclic antidepressants (TCA) and anticonvulsant (AC) have been used for treatment. To evaluate the antihyperanalgesic efficiency of intraperitoneal (IP) chlorimipramine (CIP) vs IP phenytoine (DFH) for induced neuropathic pain in an experimental animal model. After making a surgical ligature of the sciatic nerve in the right leg of 18 male rats, the time of withdrawal of both claws immersed in hot (45 degrees C) and cold water (10 degrees C) was measured during a four week period before and after IP CIP, DFH, or placebo administered in a double blind study. Significant statistical differences were observed in the time of withdrawal with CIP as compared with DFH and when both groups were compared with placebo (as tested by the paw immersion in hot water). When the thermal stimulus was cold water, an increase of the time of withdrawal was seen with DFH. These findings suggest that CIP and FS are both effective in the treatment of neuropathic pain in an animal model, as well as for the treatment of secondary hiperalgesia.

  10. Anticonvulsant and psychomotor activity of nitrendipine alone and in combination with phenytoin and valproate in rats.

    PubMed

    Balakrishnan, S; Bhargava, V K; Pandhi, P

    1999-01-01

    The effect of nitrendipine (NTP) alone and in combination with phenytoin (PHT) and valproate (VPA) against maximal electroshock seizures (MES) was studied in rats. In addition, the psychomotor effects of NTP alone and in combination with PHT and VPA were evaluated using the following tests: a) rotarod performance; b) spontaneous motor activity; c) despair behavior; d) righting reflex; e) hole board test; and f) passive avoidance test. ED50 values of PHT, VPA and NTP were 13,255 and 3.6 mg/kg, respectively. When NTP was combined with PHT or VPA, the ED50 values decreased to 0.9 and 226 mg/kg, respectively. In the psychomotor function tests, for the same degree of protection (50%) afforded against MES, PHT or VPA produced a greater impairment in all the parameters compared to NTP alone or a combination of NTP with PHT or VPA. Furthermore, NTP reversed the depression and long-term memory loss induced by PHT and VPA. Thus, NTP was effective against MES in rats, potentiating the anti-electroshock activity of PHT and VPA and producing less impairment of psychomotor activity. Thus, the agent can be considered a potential antiepileptic warranting further studies.

  11. Dried blood spot assay for the quantification of phenytoin using Liquid Chromatography-Mass Spectrometry.

    PubMed

    Villanelli, Fabio; Giocaliere, Elisa; Malvagia, Sabrina; Rosati, Anna; Forni, Giulia; Funghini, Silvia; Shokry, Engy; Ombrone, Daniela; Della Bona, Maria Luisa; Guerrini, Renzo; la Marca, Giancarlo

    2015-02-02

    Phenytoin (PHT) is one of the most commonly used anticonvulsant drugs for the treatment of epilepsy and bipolar disorders. The large amount of plasma required by conventional methods for drug quantification makes mass spectrometry combined with dried blood spot (DBS) sampling crucial for pediatric patients where therapeutic drug monitoring or pharmacokinetic studies may be difficult to realize. DBS represents a new convenient sampling support requiring minimally invasive blood drawing and providing long-term stability of samples and less expensive shipment and storage. The aim of this study was to develop a LC-MS/MS method for the quantification of PHT on DBS. This analytical method was validated and gave good linearity (r(2)=0.999) in the range of 0-100mg/l. LOQ and LOD were 1.0mg/l and 0.3mg/l, respectively. The drug extraction from paper was performed in a few minutes using a mixture composed of organic solvent for 80%. The recovery ranged from 85 to 90%; PHT in DBS showed to be stable at different storage temperatures for one month. A good correlation was also obtained between PHT plasma and DBS concentrations. This method is both precise and accurate and appears to be particularly suitable to monitor treatment with a simple and convenient sample collection procedure. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Effects of withdrawal of phenytoin on cognitive and psychomotor functions in hospitalized epileptic patients on polytherapy.

    PubMed

    May, T W; Bulmahn, A; Wohlhüter, M; Rambeck, B

    1992-08-01

    The effects of the withdrawal of phenytoin (PT) on cognitive and psychomotor functions of long-term patients in an epilepsy centre were studied. The patients had been treated for many years (31.1 +/- 10.8 yrs.) with PT in combination with other antiepileptic drugs. The serum concentration of PT was in the lower to middle therapeutic range (6.8 +/- 3.1 mg/l). Only patients in which the efficacy of PT was questionable were included in the study. PT was withdrawn in 17 patients. The PT dose was not changed in 12 patients (control group). Psychological tests were carried out immediately before the withdrawal of PT and about 10 weeks later. Tests were also carried out with the control group at the same time. A significantly improved performance (using a composite score) was noted after the withdrawal of PT. The statistical evaluation of the different tests showed an significant improvement in one test of concentration and two tests of psychomotor function (tapping and pursuit rotor with the dominant hand). There was no significant change in the frequency of seizures.

  13. Effects of phenytoin on N100 augmenting/reducing and the late positive complex of the event-related potential: a topographic analysis.

    PubMed

    Pritchard, W S; Barratt, E S; Faulk, D M; Brandt, M E; Bryant, S G

    1986-01-01

    The effects of 100 mg of phenytoin on the topographic distribution of augmenting/reducing (amplitude response/nonresponse to increases in stimulus intensity) of the visual N100 component of the event-related potential (ERP) were examined. In normal subjects, visual N100 augmenting is associated with impulsivity and attentional distraction. Effects of phenytoin on the topographic distributions of the P300 and slow-wave cognitive ERP components were also examined. Subjects counted the total number of light flashes presented at two highly discriminable but equiprobable intensities. Results indicated that phenytoin had a significant reducing effect on the intensity response of N100 at the vertex and anterior temporal electrode sites, and approached significance at the frontal pole. That is, at these loci N100 showed less of an increase in amplitude (or, in some subjects, more of a decrease) in going from baseline to drug than in going from baseline to placebo. Results also indicated that phenytoin significantly enhanced the amplitude of the frontal, negative portion of slow wave, but not the posterior, positive portion or the P300 component. These findings are consistent with behavioral evidence that phenytoin reduces impulsivity and improves concentration.

  14. Simultaneous extraction and quantification of lamotrigine, phenobarbital, and phenytoin in human plasma and urine samples using solidified floating organic drop microextraction and high-performance liquid chromatography.

    PubMed

    Asadi, Mohammad; Dadfarnia, Shayessteh; Haji Shabani, Ali Mohammad; Abbasi, Bijan

    2015-07-01

    A novel and simple method based on solidified floating organic drop microextraction followed by high-performance liquid chromatography with ultraviolet detection has been developed for simultaneous preconcentration and determination of phenobarbital, lamotrigine, and phenytoin in human plasma and urine samples. Factors affecting microextraction efficiency such as the type and volume of the extraction solvent, sample pH, extraction time, stirring rate, extraction temperature, ionic strength, and sample volume were optimized. Under the optimum conditions (i.e. extraction solvent, 1-undecanol (40 μL); sample pH, 8.0; temperature, 25°C; stirring rate, 500 rpm; sample volume, 7 mL; potassium chloride concentration, 5% and extraction time, 50 min), the limits of detection for phenobarbital, lamotrigine, and phenytoin were 1.0, 0.1, and 0.3 μg/L, respectively. Also, the calibration curves for phenobarbital, lamotrigine, and phenytoin were linear in the concentration range of 2.0-300.0, 0.3-200.0, and 1.0-200.0 μg/L, respectively. The relative standard deviations for six replicate extractions and determinations of phenobarbital, lamotrigine, and phenytoin at 50 μg/L level were less than 4.6%. The method was successfully applied to determine phenobarbital, lamotrigine, and phenytoin in plasma and urine samples. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy.

    PubMed

    Minaker, K L; Flier, J S; Landsberg, L; Young, J B; Moxley, R T; Kingston, W J; Meneilly, G S; Rowe, J W

    1989-09-01

    Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.

  16. Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review.

    PubMed

    Nolan, Sarah J; Marson, Anthony G; Weston, Jennifer; Tudur Smith, Catrin

    2016-04-28

    Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013. To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types). We searched the Cochrane Epilepsy Group's Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy. This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI. IPD were available for 669 individuals out of 1119 eligible individuals

  17. Comparative behavioral and neurochemical analysis of phenytoin and valproate treatment on epilepsy induced learning and memory deficit: Search for add on therapy.

    PubMed

    Mishra, Awanish; Goel, Rajesh Kumar

    2015-08-01

    Our previous work demonstrated, chronic epilepsy affects learning and memory of rodents along with peculiar neurochemical changes in discrete brain parts. Most commonly used antiepileptic drugs (phenytoin and sodium valproate) also worsen learning and memory in the patients with epilepsy. Therefore this study was designed to carry out comparison of behavioral and neurochemical changes with phenytoin and sodium valproate treatment in pentylenetetrazole-kindling induced learning and memory deficit to devise add on therapy for this menace. For the experimental epilepsy, animals were kindled using PTZ (35 mg/kg; i.p., at 48 ± 2 h intervals) and successful kindled animals were involved in the study. These kindled animals were treated with saline, phenytoin (30 mg/kg/day, i.p.) and sodium valproate (300 mg/kg/day, i.p.) for 20 days. These animals were challenged with PTZ challenging dose (35 mg/kg) on day 5, 10, 15 and 20 to evaluate the effect on seizure severity score on different days. Effect on learning and memory was evaluated using elevated plus maze and passive shock avoidance paradigm. On day 20, after behavioral evaluations, animals were sacrificed to analyze glutamate, GABA, norepinephrine, dopamine, serotonin, total nitrite level and acetylcholinesterase level in cortex and hippocampus. Behavioral evaluations suggested that phenytoin and sodium valproate treatment significantly reduced seizure severity in the kindled animals, while sodium valproate treatment controls seizures with least memory deficit in comparison to phenytoin. Neurochemical findings revealed that elevated cortical acetylcholinesterase level could be one of the responsible factors leading to memory deficit in phenytoin treated animals. However sodium valproate treatment reduced cortical acetylcholinesterase level and had least debilitating consequences on memory deficit. Therefore, attenuation of elevated AChE activity can be one of add-on approach for management of memory deficit

  18. Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

    PubMed Central

    Ku, Lawrence C.; Wu, Huali; Greenberg, Rachel G.; Hill, Kevin D.; Gonzalez, Daniel; Hornik, Christoph P.; Berezny, Alysha; Guptill, Jeffrey T.; Jiang, Wenlei; Zheng, Nan; Cohen-Wolkowiez, Michael; Melloni, Chiara

    2016-01-01

    Background Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Methods Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. Results For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 μg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7–1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. Conclusions This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration–response relationships

  19. Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine.

    PubMed

    Ku, Lawrence C; Wu, Huali; Greenberg, Rachel G; Hill, Kevin D; Gonzalez, Daniel; Hornik, Christoph P; Berezny, Alysha; Guptill, Jeffrey T; Jiang, Wenlei; Zheng, Nan; Cohen-Wolkowiez, Michael; Melloni, Chiara

    2016-12-01

    Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships.

  20. Frequencies of CYP2C9 polymorphisms in North Indian population and their association with drug levels in children on phenytoin monotherapy.

    PubMed

    Chaudhary, Nagendra; Kabra, Madhulika; Gulati, Sheffali; Gupta, Yogendra Kumar; Pandey, Ravindra Mohan; Bhatia, Bal Dev

    2016-05-14

    Phenytoin, mainly metabolized by cytochrome P450 enzyme system, has a narrow therapeutic index and may have adverse effects due to inter-individual variation in the dose requirement and genetic polymorphisms. This cross-sectional study was done to study the prevalence of cytochrome P450 CYP2C9 polymorphisms in Indian epileptic children and to see the effect of polymorphisms on serum levels in epileptic children on phenytoin monotherapy. We studied 89 epileptic children of North Indian population, randomly selected, to see the genotypic and allelic frequency of CYP2C9 and its association with drug levels on phenytoin monotherapy. Analysis was done using STATA 9 Software. The results were analyzed as prevalence at 95 % C.I. (Confidence Interval). The difference in mean phenytoin serum levels between wild and mutant alleles was tested using Student`s T test for independent samples. P value less than 0.05 was considered statistically significant. CYP2C9*1, *2 & *3 allelic frequencies were 85.4, 4.5 and 10.1 % respectively. CYP2C9*3 allelic group showed significantly higher serum phenytoin levels compared to the wild variants (P = 0.009). There was no statistically significant difference in the dose received (P = 0.12) and side effects of CYP2C9*2 and CYP2C9*3 genotypes (P = 0.442 and 0.597 respectively) when compared with wild variant. CYP2C9*3 is more common than *2 in the present study. All the polymorphisms demonstrated in our study were heterozygous with no homozygosity. Serum phenytoin levels are higher in polymorphic groups (*3) which suggest their poor metabolizing nature. Genotyping may help to avoid toxicity and concentration-dependent adverse effects.

  1. Switching between phenytoin generics in patients with epilepsy may lead to increased risk of breakthrough seizure: chart analysis and practice recommendations.

    PubMed

    Shin, Jung-Won; Chu, Kon; Jung, Keun-Hwa; Lee, Soon-Tae; Moon, Jangsup; Lee, Sang Kun

    2014-12-01

    The Food and Drug Administration (FDA) only requires bioequivalence testing of generic substitutions in order for them to be deemed equivalen to the original product. There may be a large difference of bioavailability among the generic drugs that especially have a narrow therapeutic index, and this may affect clinical outcomes. We aimed to determine whether switching from generic-to-generic equivalent anti-epileptic drugs (AEDs) in patients with epilepsy is associated with clinical outcomes. We performed a retrospective study using the electronic medical records of a tertiary hospital. Adults with a history of epilepsy who used a generic phenytoin and whose therapy was switched to another generic phenytoin between January 2012 and June 2013 were included (n = 80). We compared the drug concentration of phenytoin and seizure events before and after the switch. After switching their generic phenytoin, 33 out of 80 patients (41%) suffered from increasing seizure events (pre-interchange period, 0.44 ± 0.97; post-interchange period, 1.24 ± 2.05; p < 0.0001). The number of medical visits for acute seizure significantly increased in the post-interchange period. The phenytoin serum concentration of all the patients was lesser in the post-interchange period than in the pre-interchange period. (pre-interchange period, 12.79 μg/mL; post-interchange period, 6.36 μg/mL; p < 0.0001). Among the patients with drug resistant epilepsy (DRE), 17 patients (84.2%) had increasing seizure events in the post-interchange period. We confirmed that there was a significant difference in bioavailability between generic phenytoin. Therefore, when using or switching generic anti-epileptic drugs, therapeutic drug monitoring must be done, and the patients' condition must be considered.

  2. Two-dimensional high-performance liquid chromatographic method to assay p-hydroxyphenylphenylhydantoin enantiomers in biological fluids and stereoselectivity of enzyme induction in phenytoin metabolism.

    PubMed

    Hsieh, C Y; Huang, J D

    1992-03-13

    A two-dimensional high-performance liquid chromatographic method was developed to assay the enantiomers of a major phenytoin metabolite, p-hydroxyphenylphenylhydantoin (p-HPPH). Racemic p-HPPH was first separated from phenytoin and other interfering peaks by a reversed-phase column and monitored by an ultraviolet detector. At the retention time of p-HPPH, the racemic p-HPPH peak was automatically transferred to a chiral ligand-exchange column to separate R-p-HPPH and S-p-HPPH by a time-programmed column-switching valve. The ratio of enantiomers was measured by a second ultraviolet detector. The method can be used to assay R- and S-p-HPPH enantiomers with reasonable sensitivity and reproducibility. By using this method, the stereoselectivity of enzyme induction and inhibition of phenytoin metabolism was investigated. Male rats were treated with phenobarbital, 3-methylcholanthrene, acetone, Aroclor 1254, pregnenolone-16 alpha-carbonitrile, dexamethasone and isosafrole. Microsomes were prepared from the rat liver and phenytoin hydroxylation was measured. Pretreatment with phenobarbital, pregnenolone-16 alpha-carbonitrile or acetone induced phenytoin metabolism non-stereoselectively. Pretreatment with dexamethasone decreased R-p-HPPH formation without affecting the formation of S-p-HPPH. Liver microsomes from female rats showed a higher S-p-HPPH formation, whereas R-p-HPPH formation remained the same. Various inhibitors were added to inhibit phenytoin metabolism by control microsomes. Sulphaphenazole, ketoconazole, 4,4-di(p-methoxyphenyl)hydantoin, cimetidine and diazepam inhibited the formation of R- and S-p-HPPH. Quinidine, tolbutamide and mephenytoin showed no significant inhibitory activity. None of these inhibitors showed stereoselectivity.

  3. In vitro metabolism of phenytoin in 36 CYP2C9 variants found in the Chinese population.

    PubMed

    Chen, Lian-Guo; Wang, Zhe; Zhu, Yuan; Xiong, Jian-Hua; Sun, Li-Rong; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin

    2016-06-25

    Cytochrome P450 2C9 (CYP2C9) is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Recently, we identified 22 novel alleles (*36 -*56 and N418T) in the Han Chinese population. This study aims to assess the catalytic activities of wild-type (CYP2C9*1) and 36 CYP2C9 allelic variants found in the Chinese population toward phenytoin (PHT) in vitro. Insect microsomes expressing CYP2C9*1 and 36 CYP2C9 variants were incubated with 1-200 μM phenytoin for 30 min at 37 °C. Then, these products were extracted and the signal detection was performed by HPLC-MS/MS. The intrinsic clearance (Vmax/Km) values of all variants, with the exception of CYP2C9*2, CYP2C9*11, CYP2C9*23, CYP2C9*29, CYP2C9*34, CYP2C9*38, CYP2C9*44, CYP2C9*46 and CYP2C9*48, were significantly different from CYP2C9*1. CYP2C9*27, *40, *41, *47, *49, *51, *53, *54, *56 and N418T variant exhibited markedly larger values than CYP2C9*1 (>152.8%), whereas 17 variants exhibited smaller values (from 48.6% to 99.9%) due to larger Km and/or smaller Vmax values than CYP2C9*1. The findings suggest that more attention should be paid on subjects carrying these infrequent CYP2C9 alleles when administering phenytoin in clinic. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Comparative trial of Aloe vera/olive oil combination cream versus phenytoin cream in the treatment of chronic wounds.

    PubMed

    Panahi, Y; Izadi, M; Sayyadi, N; Rezaee, R; Jonaidi-Jafari, N; Beiraghdar, F; Zamani, A; Sahebkar, A

    2015-10-01

    Aloe vera is a medicinal plant that has been traditionally used to accelerate wound healing. Olive oil is also a natural product that may contribute to wound healing owing to its antimicrobial and anti-inflammatory effects. The present study aimed to evaluate the effect of an Aloe vera-olive oil (AVO) combination cream on the healing process of chronic wounds. In this randomised, double-blind, comparator-controlled, parallel-group trial, patients with chronic wounds were treated with either AVO cream or phenytoin cream as the standard treatment for a period of 30 days. Wound healing was evaluated using Bates-Jensen assessment tool and the severity of pain was assessed using a visual analogue scale (VAS). After initial assessment, 60 patients with chronic wounds (41 with pressure ulcer, 13 with diabetic wounds and 6 with venous ulcers), were recruited and randomised into 2 groups of 30. After 30 days of treatment, significant improvements in the wound size, depth, and edges; necrotic tissue type and amount; exudate type and amount; colour of wound surroundings; and peripheral tissue oedema score were observed in the AVO cream group (p<0.001). The total score of wound healing showed significant improvement with both AVO (p<0.001) and phenytoin (p<0.01) creams, although AVO was more efficacious (p<0.001). Likewise, although both treatments reduced the initial VAS score, the efficacy of AVO was significantly greater (p<0.001). AVO cream significantly accelerates biological healing of chronic wounds and helps to reduce pain severity with a higher efficacy compared with phenytoin cream.

  5. Effect of phenytoin on sodium conductances in rat hippocampal CA1 pyramidal neurons

    PubMed Central

    Zeng, Zhen; Hill-Yardin, Elisa L.; Williams, David; O'Brien, Terence; Serelis, Andris

    2016-01-01

    The antiepileptic drug phenytoin (PHT) is thought to reduce the excitability of neural tissue by stabilizing sodium channels (NaV) in inactivated states. It has been suggested the fast-inactivated state (IF) is the main target, although slow inactivation (IS) has also been implicated. Other studies on local anesthetics with similar effects on sodium channels have implicated the NaV voltage sensor interactions. In this study, we reexamined the effect of PHT in both equilibrium and dynamic transitions between fast and slower forms of inactivation in rat hippocampal CA1 pyramidal neurons. The effects of PHT were observed on fast and slow inactivation processes, as well as on another identified “intermediate” inactivation process. The effect of enzymatic removal of IF was also studied, as well as effects on the residual persistent sodium current (INaP). A computational model based on a gating charge interaction was derived that reproduced a range of PHT effects on NaV equilibrium and state transitions. No effect of PHT on IF was observed; rather, PHT appeared to facilitate the occupancy of other closed states, either through enhancement of slow inactivation or through formation of analogous drug-bound states. The overall significance of these observations is that our data are inconsistent with the commonly held view that the archetypal NaV channel inhibitor PHT stabilizes fast inactivation states, and we demonstrate that conventional slow activation “IS” and the more recently identified intermediate-duration inactivation process “II” are the primary functional targets of PHT. In addition, we show that the traditional explanatory frameworks based on the “modulated receptor hypothesis” can be substituted by simple, physiologically plausible interactions with voltage sensors. Additionally, INaP was not preferentially inhibited compared with peak INa at short latencies (50 ms) by PHT. PMID:27489371

  6. Ethosuximide and Phenytoin Dose-Dependently Attenuate Acute Nonconvulsive Seizures after Traumatic Brain Injury in Rats

    PubMed Central

    Shear, Deborah A.; Potter, Brittney; Marcsisin, Sean R.; Sousa, Jason; Melendez, Victor; Tortella, Frank C.; Lu, Xi-Chun M.

    2013-01-01

    Abstract Acute seizures frequently occur following severe traumatic brain injury (TBI) and have been associated with poor patient prognosis. Silent or nonconvulsive seizures (NCS) manifest in the absence of motor convulsion, can only be detected via continuous electroencephalographic (EEG) recordings, and are often unidentified and untreated. Identification of effective anti-epileptic drugs (AED) against post-traumatic NCS remains crucial to improve neurological outcome. Here, we assessed the anti-seizure profile of ethosuximide (ETX, 12.5–187.5 mg/kg) and phenytoin (PHT, 5–30 mg/kg) in a spontaneously occurring NCS model associated with penetrating ballistic-like brain injury (PBBI). Rats were divided between two drug cohorts, PHT or ETX, and randomly assigned to one of four doses or vehicle within each cohort. Following PBBI, NCS were detected by continuous EEG monitoring for 72 h post-injury. Drug efficacy was evaluated on NCS parameters of incidence, frequency, episode duration, total duration, and onset latency. Both PHT and ETX attenuated NCS in a dose-dependent manner. In vehicle-treated animals, 69–73% experienced NCS (averaging 9–10 episodes/rat) with average onset of NCS occurring at 30 h post-injury. Compared with control treatment, the two highest PHT and ETX doses significantly reduced NCS incidence to 13–40%, reduced NCS frequency (1.8–6.2 episodes/rat), and delayed seizure onset: <20% of treated animals exhibited NCS within the first 48 h. NCS durations were also dose-dependently mitigated. For the first time, we demonstrate that ETX and PHT are effective against spontaneously occurring NCS following PBBI, and suggest that these AEDs may be effective at treating post-traumatic NCS. PMID:23822888

  7. Acetanilide and paracetamol pharmacokinetics before and during phenytoin administration: genetic control of induction?

    PubMed Central

    Cunningham, J L; Evans, D A

    1981-01-01

    1 Steady state plasma concentrations (SSPCs) of acetanilide (AA) and its metabolite, paracetamol (PL), were studied in 27 healthy volunteer subjects before and at the end of an 11-day exposure to phenytoin (DPH). Plasma concentrations of DPH were estimated. Plasma concentrations of DPH varied from 5.1 to 20.4 microgram ml-1 (mean +/- s.e.mean 12.2 +/- 0.9). 2 The SSPC of AA before exposure to DPH varied from 0.06 to 0.67 microgram ml-1 (mean +/- s.e.mean 0.24 +/- 0.02), and following exposure from 0.03 to 0.47 microgram ml-1 (mean +/- s.e.mean 0.15 +/- 0.02). 3 The SSPC of PL before exposure to DPH varied from 1.2 to 4.4 microgram ml-1 (mean +/- s.e.mean 2.7 +/- 0.13), and following exposure from 1.1 to 3.8 microgram ml-1 (mean +/- s.e.mean 2.2 +/- 0.13). 4 SSPCs of AA and of PL decreased significantly during DPH administration (P less than 0.01 for AA, P less than 0.001 for PL). 5 Correlations were observed between the SSPCs of the drugs measured, suggesting a common influence on their kinetics. 6 Similarity was observed between the changes in plasma levels of AA and PL following DPH ingestion. There was, however, wide inter-subject variability in this regard. In some subjects no change was observed even though they had DPH demonstrable in their plasma. Consequently it may be speculated that the effects of DPH may be under genetic control. PMID:7272175

  8. 'One-component' ultrathin multilayer films based on poly(vinyl alcohol) as stabilizing coating for phenytoin-loaded liposomes.

    PubMed

    Zasada, Katarzyna; Łukasiewicz-Atanasov, Magdalena; Kłysik, Katarzyna; Lewandowska-Łańcucka, Joanna; Gzyl-Malcher, Barbara; Puciul-Malinowska, Agnieszka; Karewicz, Anna; Nowakowska, Maria

    2015-11-01

    Ultrathin "one-component" multilayer polymeric films for potential biomedical applications were designed based on polyvinyl alcohol,-a non-toxic, fully degradable synthetic polymer. Good uniformity of the obtained film and adequate adsorption properties of the polymeric layers were achieved by functional modification of the polymer, which involved synthesis of cationic and anionic derivatives. Synthesized polymers were characterized by FTIR, NMR spectroscopy, dynamic light scattering measurements and elemental analysis. The layer by layer assembly technique was used to build up a multilayer film and this process was followed using UV-Vis spectroscopy and ellipsometry. The morphology and thickness of the obtained multilayered film material was evaluated by atomic force microscopy (AFM). Preliminary studies on the application of the obtained multilayer film for coating of liposomal nanocarriers containing phenytoin, an antiarrhythmic drug, were performed. The coating effectively stabilizes liposomes and the effect increases with an increasing number of deposited layers until the polymeric film reaches the optimal thickness. The obtained release profiles suggest that bilayer-coated liposomes release phenytoin less rapidly than uncoated ones. The cytotoxicity studies performed for all obtained nanocarriers confirmed that none of them has negative effect on cell viability. All of the performed experiments suggest that liposomes coated with ultrathin film obtained from PVA derivatives can be attractive drug nanocarriers. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Felbamate but not phenytoin or gabapentin reduces glutamate release by blocking presynaptic NMDA receptors in the entorhinal cortex

    PubMed Central

    Yang, Jian; Wetterstrand, Caroline; Jones, Roland S.G.

    2007-01-01

    Summary We have shown that a number of anticonvulsant drugs can reduce glutamate release at synapses in the rat entorhinal cortex (EC) in vitro. We have also shown that presynaptic NMDA receptors (NMDAr) tonically facilitate glutamate release at these synapses. In the present study we determined whether, phenytoin, gabapentin and felbamate may reduce glutamate release by blocking the presynaptic NMDAr. Whole cell patch clamp recordings of spontaneous excitatory postsynaptic currents (sEPSCs) were used as a monitor of presynaptic glutamate release. Postsynaptic NMDAr were blocked with internal dialysis with an NMDAr channel blocker. The antagonist, 2-AP5, reduced the frequency of sEPSCs by blocking the presynaptic facilitatory NMDAr, but did not occlude a reduction in sEPSC frequency by gabapentin or phenytoin. Felbamate also reduced sEPSC frequency, but this effect was occluded by prior application of 2-AP5. Thus, whilst all three drugs can reduce glutamate release, only the action of felbamate seems to be due to interaction with presynaptic NMDAr. PMID:17980555

  10. Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation.

    PubMed

    Galvez-Contreras, Alma Y; Gonzalez-Castaneda, Rocio E; Campos-Ordonez, Tania; Luquin, Sonia; Gonzalez-Perez, Oscar

    2016-01-01

    Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular-subventricular zone (V-SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V-SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V-SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V-SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V-SVZ, and expanded the population of Olig2-expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V-SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  11. Immunohistochemical Analysis of the Role Connective Tissue Growth Factor in Drug-induced Gingival Overgrowth in Response to Phenytoin, Cyclosporine, and Nifedipine

    PubMed Central

    Anand, A. J.; Gopalakrishnan, Sivaram; Karthikeyan, R.; Mishra, Debasish; Mohapatra, Shreeyam

    2018-01-01

    Objective: To evaluate for the presence of connective tissue growth factor (CTGF) in drug (phenytoin, cyclosporine, and nifedipine)-induced gingival overgrowth (DIGO) and to compare it with healthy controls in the absence of overgrowth. Materials and Methods: Thirty-five patients were chosen for the study and segregated into study (25) and control groups (10). The study group consisted of phenytoin-induced (10), cyclosporine-induced (10), and nifedipine-induced (5) gingival overgrowth. After completing necessary medical evaluations, biopsy was done. The tissue samples were fixed in 10% formalin and then immunohistochemically evaluated for the presence of CTGF. The statistical analysis of the values was done using statistical package SPSS PC+ (Statistical Package for the Social Sciences, version 4.01). Results: The outcome of immunohistochemistry shows that DIGO samples express more CTGF than control group and phenytoin expresses more CTGF followed by nifedipine and cyclosporine. Conclusion: The study shows that there is an increase in the levels of CTGF in patients with DIGO in comparison to the control group without any gingival overgrowth. In the study, we compared the levels of CTGF in DIGO induced by three most commonly used drugs phenytoin, cyclosporine, and nifedipine. By comparing the levels of CTGF, we find that cyclosporine induces the production of least amount of CTGF. Therefore, it might be a more viable drug choice with reduced side effects. PMID:29629324

  12. Is Misonidazole neurotoxicity altered by the use of phenytoin and/or dexamethasone in RTOG 79-18 and RTOG 79-16

    SciTech Connect

    Nelson, D.F.; Gillespie, B.W.; Diener, M.D.

    1984-09-01

    An analysis of Misonidazole (MISO) neurotoxicity in RTOG 79-16 and RTOG 79-18 was undertaken to evaluate the incidence of neurotoxicity relative to dexamethasone dose and phenytoin use. Practically all patients were on dexamethasone, and 240 out of 550 were on phenytoin for seizures. CNS toxicity and ototoxicity rates were no different between treatment groups with overall rates of 2.7 and 1.1%, respectively. Phenytoin did not significantly alter CNS and peripheral neuropathy (PN) toxicity rates. All ototoxicities occurred in patients not on phenytoin. There was no correlation between dexamethasone dose and incidence of neurotoxicity within each study. However, the incidence ofmore » (PN) for the combined studies was 6.4% (35/550) which is lower than 18.9% (85/449) for non-brain Phase III protocols where patients are rarely, if ever, on dexamethasone or other corticosteroids. Four hour and 24 hour plasma MISO levels, and 24 hour/4 hour MISO ratios did not correlate with toxicity.« less

  13. Ranolazine vs phenytoin: greater effect of ranolazine on the transient Na(+) current than on the persistent Na(+) current in central neurons.

    PubMed

    Terragni, Benedetta; Scalmani, Paolo; Colombo, Elisa; Franceschetti, Silvana; Mantegazza, Massimo

    2016-11-01

    Voltage-gated Na(+) channels (NaV) are involved in pathologies and are important targets of drugs (NaV-blockers), e.g. some anti-epileptic drugs (AEDs). Besides the fast inactivating transient Na(+) current (INaT), they generate a slowly inactivating "persistent" current (INaP). Ranolazine, a NaV-blocker approved for treatment of angina pectoris, is considered a preferential inhibitor of INaP and has been proposed as a novel AED. Although it is thought that classic NaV-blockers used as AEDs target mainly INaT, they can also reduce INaP. It is important to disclose specific features of novel NaV-blockers, which could be necessary for their effect as AEDs in drug resistant patients. We have compared the action of ranolazine and of the classic AED phenytoin in transfected cells expressing the neuronal NaV1.1 Na(+) channel and in neurons of neocortical slices. Our results show that the relative block of INaT versus INaP of ranolazine and phenytoin is variable and depends on Na(+) current activation conditions. Strikingly, ranolazine blocks with less efficacy INaP and more efficacy INaT than phenytoin in conditions mimicking pathological states (i.e. high frequency firing and long lasting depolarizations). The effects are consistent with binding of ranolazine to both open/pre-open and inactivated states; larger INaT block at high stimulation frequencies is caused by the induction of a slow inactivated state. Thus, contrary than expected, ranolazine is not a better INaP blocker than phenytoin in central neurons, and phenytoin is not a better INaT blocker than ranolazine. Nevertheless, they show a complementary action and could differentially target specific pathological dysfunctions. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Time-Dependent Decline in Serum Phenytoin Concentration with Heightened Convulsive Seizure Risk by Prolonged Administration of Fosphenytoin in Japanese: A Retrospective Study.

    PubMed

    Ohno, Yuta; Niwa, Takashi; Hirai, Keita; Suzuki, Keiko; Yamada, Yuto; Hayashi, Yuichi; Hayashi, Hideki; Suzuki, Akio; Itoh, Yoshinori

    2018-04-20

    Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days. Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 μg/mL) was calculated from the parameters. Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time-dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/day, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/day). Prolonged use of fosphenytoin for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus time-dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.

  15. Study of the sodium phenytoin effect on the formation of sol-gel SiO 2 nanotubes by TEM

    NASA Astrophysics Data System (ADS)

    López, T.; Asomoza, M.; Picquart, M.; Castillo-Ocampo, P.; Manjarrez, J.; Vázquez, A.; Ascencio, J. A.

    2005-04-01

    Microencapsulation is a versatile technology that allows controlling the release of different active molecules. Recently the sol-gel process has emerged like a promising method to immobilization and stabilization of biologically active compounds like enzymes, antigens, microorganisms and drugs. Porous silica and titanium dioxide materials made by low temperature sol-gel processes are promising host matrixes for encapsulation of biological molecules. The preparation of a low-temperature silica sol followed by gelation to neutral pH with water for injection containing the antiepileptic drug is reported here. The structure is very important so the analysis of the new developed material is also reported. Particularly interesting is the presence of nanotubes and microtubes, produced in the inorganic matrix in the presence of the sodium phenytoin. The use of transmission electron microscopy and quantum mechanics molecular simulation allows determining a micelle-like effect during the synthesis of these materials, which controls the size, structure and stability of them.

  16. Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine

    PubMed Central

    Qiao, Xin; Sun, Guangchun; Clare, Jeffrey J; Werkman, Taco R; Wadman, Wytse J

    2014-01-01

    Background and purpose Voltage-activated Na+ channels contain one distinct α-subunit. In the brain NaV1.1, NaV1.2, NaV1.3 and NaV1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na+ channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine. Experimental approach Na+ currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits. Key results NaV1.2 and NaV1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin. Conclusions and implications The four Na+ channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na+ channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development. PMID:24283699

  17. Phenytoin-Bovine Serum Albumin interactions - modeling plasma protein - drug binding: A multi-spectroscopy and in silico-based correlation

    NASA Astrophysics Data System (ADS)

    Suresh, P. K.; Divya, Naik; Nidhi, Shah; Rajasekaran, R.

    2018-03-01

    The study focused on the analysis of the nature and site of binding of Phenytoin (PHT) -(a model hydrophobic drug) with Bovine Serum Albumin (BSA) (a model protein used as a surrogate for HSA). Interactions with defined amounts of Phenytoin and BSA demonstrated a blue shift (hypsochromic -change in the microenvironment of the tryptophan residue with decrease in the polar environment and more of hydrophobicity) with respect to the albumin protein and a red shift (bathochromic -hydrophobicity and polarity related changes) in the case of the model hydrophobic drug. This shift, albeit lower in magnitude, has been substantiated by a fairly convincing, Phenytoin-mediated quenching of the endogenous fluorophore in BSA. Spectral shifts studied at varying pH, temperatures and incubation periods (at varying concentrations of PHT with a defined/constant BSA concentration) showed no significant differences (data not shown). FTIR analysis provided evidence of the interaction of PHT with BSA with a stretching vibration of 1737.86 cm- 1, apart from the vibrations characteristically associated with the amine and carboxyl groups respectively. Our in vitro findings were extended to molecular docking of BSA with PHT (with the different ionized forms of the drug) and the subsequent LIGPLOT-based analysis. In general, a preponderance of hydrophobic interactions was observed. These hydrophobic interactions corroborate the tryptophan-based spectral shifts and the fluorescence quenching data. These results substantiates our hitherto unreported in vitro/in silico experimental flow and provides a basis for screening other hydrophobic drugs in its class.

  18. Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells.

    PubMed

    Lawrence, Johnathan E; Steele, Christopher J; Rovin, Richard A; Belton, Robert J; Winn, Robert J

    2016-03-01

    Extent of resection of glioblastoma (GBM) correlates with overall survival. Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5-ALA) can improve the extent of resection. Unfortunately not all patients given 5-ALA accumulate sufficient quantities of protoporphyrin IX (PpIX) for successful FGR. In this study, we investigated the effects of dexamethasone, desipramine, phenytoin, valproic acid, and levetiracetam on the production and accumulation of PpIX in U87MG cells. All of these drugs, except levetiracetam, reduce the total amount of PpIX produced by GBM cells (p < 0.05). When dexamethasone is mixed with another drug (desipramine, phenytoin, valproic acid or levetiracetam) the amount of PpIX produced is further decreased (p < 0.01). However, when cells are analyzed for PpIX cellular retention, dexamethasone accumulated significantly more PpIX than the vehicle control (p < 0.05). Cellular retention of PpIX was not different from controls in cells treated with dexamethasone plus desipramine, valproic acid or levetiracetam, but was significantly less for dexamethasone plus phenytoin (p < 0.01). These data suggest that medications given before and during surgery may interfere with PpIX accumulation in malignant cells. At this time, levetiracetam appears to be the best medication in its class (anticonvulsants) for patients undergoing 5-ALA-mediated FGR.

  19. [Comparisons of efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis in patients with brain injury: a meta analysis].

    PubMed

    Li, J N; Chen, Y M

    2016-10-25

    Objective: To systematically review the efficacy, side effects and case-fatality rate of levetiracetam (LEV) versus phenytoin (PHT) for seizure prophylaxis of brain injured patients. Methods: Randomized controlled trials of high quality about LEV versus PHT in seizure prophylaxis of brain injured patients from 2000 to 2016 were collected according to the key word PHT, LEV, brain injury in PubMed, Medline, Ovid, Springer, CNKI, Wanfang data and so on. Valid data were extracted to conduct meta-analysis by RevMan 5.3 software according to inclusion and exclusion criteria. Results: A total of 13 English articles were finally included with 2 529 patients in total.Meta-analysis showed that no significant differences were observed in LEV versus PHT at preventing the occurrence of seizures ( RR =0.88, 95% CI : 0.61-1.27). No superiority of either drug at preventing early seizures ( RR =0.74, 95% CI : 0.42-1.27). As to the occurrence of late seizures, the differences of the two drugs were not statistically significant ( RR =0.71, 95% CI : 0.43-1.20). Number of patients with side effect was not statistically significantly different between the two groups ( RR =0.73, 95% CI : 0.48-1.11). But significant difference was found between LEV and PHT in discontinuation because of side effect ( RR =0.11, 95% CI : 0.06-0.23); no significant differences were noted in the case-fatality rate of patients received pretreatment between the two drugs ( RR =1.57, 95% CI : 0.92-2.67). There were no significant differences between the two groups in the length of stay ( WMD =-1.03, 95% CI : -4.97-2.91). Conclusions: LEV and PHT demonstrate equal efficacy in seizure prevention after brain injury. The differences are insignificant in the side effect, the case-fatality rate and the length of stay between LEV and PH treatment, but adverse drug reactions requiring change in therapy occur more in PHT. Phenytoin remains the first choice for seizure prevention after brain injury based on the existing

  20. Simultaneous analysis method for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin in urine, using C18 poroshell column.

    PubMed

    Anilanmert, Beril; Çavuş, Fatma; Narin, Ibrahim; Cengiz, Salih; Sertler, Şefika; Özdemir, Ali Acar; Açikkol, Münevver

    2016-06-01

    Date-rape drugs have the potential to be used in drug-facilitated sexual assault, organ theft and property theft. Since they are colorless, tasteless and odorless, victims can drink without noticing, when added to the beverages. These drugs must be detected in time, before they are cleared up from the biofluids. A simultaneous extraction and determination method in urine for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin (an anticonvulsant and antiepileptic drug) with LC-MS/MS was developed for the first time with analytically acceptable recoveries and validated. A 4 steps liquid-liquid extraction was applied, using only 1.000mL urine. A new age commercial C18 poroshell column with high column efficiency was used for LC-MS/MS analysis with a fast isocratic elution as 5.5min. A new MS transition were introduced for barbital. 222.7>179.8 with the effect of acetonitrile. Recoveries (%) were between 80.98-99.27 for all analytes, except for GHB which was 71.46. LOD and LOQ values were found in the ranges of 0.59-49.50 and 9.20-80.80ngmL(-1) for all the analytes (except for GHB:3.44 and 6.00μgmL(-1)). HorRat values calculated (between 0.25-1.21), revealed that the inter-day and interanalist precisions (RSD%≤14.54%) acceptable. The simultaneous extraction and determination of these 8 analytes in urine is challenging because of the difficulty arising from the different chemical properties of some. Since the procedure can extract drugs from a wide range of polarity and pKa, it increases the window of detection. Group representatives from barbiturates, z-drugs, ketamine, phenytoin and polar acidic drugs (GHB) have been successfully analyzed in this study with low detection limits. The method is important from the point of determining the combined or single use of these drugs in crimes and finding out the reasons of deaths related to these drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis.

    PubMed

    De, Tanima; Christopher, Rita; Nagaraja, Dindagur

    2014-05-01

    The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT). 476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined. Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p=0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p<0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p=0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p=0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol. This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Locating the route of entry and binding sites of benzocaine and phenytoin in a bacterial voltage gated sodium channel.

    PubMed

    Martin, Lewis J; Corry, Ben

    2014-07-01

    Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites.

  3. In vivo distribution of carbon-11 phenytoin and its major metabolite, and their use in scintigraphic imaging. [Rhesus monkeys

    SciTech Connect

    Stavchansky, S.A.; Tilbury, R.S.; McDonald, J.M.

    1978-08-01

    Curie quantities (0.3 to 1.5 Ci) of H/sup 11/CN were used in the synthesis of C-11-tagged phenytoin (C-11.DPH) and 5-(p-hydroxyphenyl)-5-phenylhydantoin (C-11.HPPH), using a modified Buecherer--Bergs reaction. The H/sup 11/CN was produced from a mixture of 95% nitrogen and 5% hydrogen by a 45-min bombardment with 10-MeV protons at 10 ..mu..A. Following iv infusions of C-11 DPH (13.7 mg/kg at a rate of 29 mg/min) into the left femoral vein of Rhesus monkeys, DPH shows persistent concentration in the brain and liver fields. Extravascular administration shows significant retention at the site of administration. Intravenous bolus injection of (/sup 11/C)-HPPH into amore » Rhesus monkey, at a dose of 6.4 mg/kg, resulted in localization of this compound in the liver, gallbladder, urinary bladder, and intestinal fields. Loss of activity from the liver region, with appearance of this activity in the intestinal field, suggests that (/sup 11/C)-HPPH is secreted into the intestine via the bile. Further investigation is needed to study the potential of (/sup 11/C)-DPH as a brain-scanning agent and (/sup 11/C)-HPPH as a possible cholescintigraphic agent.« less

  4. Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel

    PubMed Central

    Martin, Lewis J.; Corry, Ben

    2014-01-01

    Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites. PMID:24992293

  5. A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients.

    PubMed Central

    McKee, P J; Blacklaw, J; Forrest, G; Gillham, R A; Walker, S M; Connelly, D; Brodie, M J

    1994-01-01

    1. The effect of carbamazepine (CBZ), sodium valproate (VPA) and phenytoin (PHT) on the pharmacokinetics of oxcarbazepine (OXC) was explored in three groups of 12 epileptic patients taking one of these drug as monotherapy. 2. Each patient took a single 600 mg dose of OXC followed 7 days later by 3 weeks' treatment with OXC 300 mg thrice daily and matched placebo in random order. 3. Seven untreated patients, acting as controls, were prescribed the single OXC dose and 3 weeks' active treatment only. 4. In those patients completing the study, the area under the concentration-time curve (AUC) at steady-state for hydroxycarbazepine (OHCZ), the active metabolite of OXC, was significantly lower in the CBZ-treated group than in controls (P < 0.05). 5. No other differences in AUCs or elimination half-lives for OHCZ were found between treated and untreated patients following single or multiple OXC dosing. 6. Median AUCs of CBZ, VPA and PHT during a dosage interval did not differ significantly after treatment with OXC and placebo. 7. Ten patients completing the study complained of side-effects during treatment with OXC compared with one taking placebo (P < 0.01). 8. There were no important changes in cognitive function testing during administration of OXC compared with placebo. 9. Standard doses of OXC can be given as add-on therapy in epileptic patients receiving CBZ, VPA or PHT without producing a clinically relevant pharmacokinetic interaction. PMID:8148215

  6. Effect of anti-tuberculosis therapy on polymorphic drug metabolizing enzyme CYP2C9 using phenytoin as a probe drug

    PubMed Central

    George, Melvin; Shewade, Deepak Gopal; Kumar, Saka Vinod; Adithan, Chandrasekaran

    2012-01-01

    Objectives: Patients on anti-tuberculosis therapy (ATT) are more prone to drug interactions in the presence of coexisting illnesses which warrant drug therapy. Rifampicin is a strong CYP enzyme inducer while isoniazid is a potent CYP inhibitor. The objective of the study was to find the net effect of one month ATT on CYP2C9 enzyme and to correlate it with respect to the CYP2C9 genetic polymorphisms. Materials and Methods: Forty eight newly diagnosed tuberculosis patients were included in the study based on the inclusion-exclusion criteria. Before commencing ATT, they were given a single dose of phenytoin 300 mg as a probe drug for CYP2C9. Blood sample was collected after three hours to carry out CYP2C9 genotyping by PCR-RFLP method. Phenotyping for CYP2C9 enzyme was done by measuring the ratio of phenytoin and its metabolite p-HPPH (para hydroxy phenyl hydantoin) by reverse phase HPLC (high performance liquid chromatography) method before and after one month of ATT. Results: In the CYP2C9*1*1 genotype, the mean plasma concentrations of phenytoin before and after one month of ATT were 5.2 ± 0.3 μg/ml and 3.5 ± 0.4 μg/ml respectively, a reduction by 33% showing significant induction (P < 0.001). There was also significant decrease in the metabolic ratio after one month of ATT from 23.2 ± 4.8 to 10.1 ± 1.9 (P < 0.001). The metabolic ratio was also observed to reduce significantly (P < 0.05) when the CYP2C9*1*2, CYP2C9*1*3, and CYP2C9*3*3 data were pooled together. Conclusion: The presence of polymorphisms in the CYP2C9 gene does not affect the induction potential of ATT. PMID:23087510

  7. Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.

    PubMed

    Brigo, Francesco; Bragazzi, Nicola; Nardone, Raffaele; Trinka, Eugen

    2016-11-01

    The aim of this study was to conduct a meta-analysis of published studies to directly compare intravenous (IV) levetiracetam (LEV) with IV phenytoin (PHT) or IV valproate (VPA) as second-line treatment of status epilepticus (SE), to indirectly compare intravenous IV LEV with IV VPA using common reference-based indirect comparison meta-analysis, and to verify whether results of indirect comparisons are consistent with results of head-to-head randomized controlled trials (RCTs) directly comparing IV LEV with IV VPA. Random-effects Mantel-Haenszel meta-analyses to obtain odds ratios (ORs) for efficacy and safety of LEV versus VPA and LEV or VPA versus PHT were used. Adjusted indirect comparisons between LEV and VPA were used. Two RCTs comparing LEV with PHT (144 episodes of SE) and 3 RCTs comparing VPA with PHT (227 episodes of SE) were included. Direct comparisons showed no difference in clinical seizure cessation, neither between VPA and PHT (OR: 1.07; 95% CI: 0.57 to 2.03) nor between LEV and PHT (OR: 1.18; 95% CI: 0.50 to 2.79). Indirect comparisons showed no difference between LEV and VPA for clinical seizure cessation (OR: 1.16; 95% CI: 0.45 to 2.97). Results of indirect comparisons are consistent with results of a recent RCT directly comparing LEV with VPA. The absence of a statistically significant difference in direct and indirect comparisons is due to the lack of sufficient statistical power to detect a difference. Conducting a RCT that has not enough people to detect a clinically important difference or to estimate an effect with sufficient precision can be regarded a waste of time and resources and may raise several ethical concerns, especially in RCT on SE. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. The effect of lamotrigine and phenytoin on bone turnover and bone strength: A prospective study in Wistar rats.

    PubMed

    Simko, Julius; Karesova, Iva; Kremlacek, Jan; Fekete, Sona; Zimcikova, Eva; Malakova, Jana; Zivna, Helena; Valis, Martin; Palicka, Vladimir

    2016-12-01

    Some data suggest that exposure to lamotrigine (LTG) might be associated with impaired bone health in an orchidectomized rat model. The aim of this study was to determine if LTG poses any significant risk for bone in a gonadally intact animals and to compare the effect of LTG with that of phenytoin (PHT). Twenty-four rats were divided into control and test groups, (n=8 per group). Control rats received a standard laboratory diet (SDL), while rats in the test groups were fed a SLD enriched with LTG or PHT for 12 weeks. Dual energy X-ray absorptiometry was used to measure bone mineral density (BMD). The concentrations of bone turnover markers (BTM) were assayed in bone homogenates. The femurs were measured and biomechanically tested. Treatment with either LTG or PHT had no significant effect on BMD or on the biomechanical strength of the bones. In contrast to the effect of LTG, we did find significant changes in BTM in the PHT group: a highly significant decrease in the osteoprotegerin/receptor activator of nuclear factor kappa B ratio (p<0.01) and highly significant increases in bone alkaline phosphatase and amino-terminal propeptide of procollagen type I (p<0.001, p˂0.01, respectively). In the LTG group, the only significant change was a decrease in sclerostin (p˂0.05). The PHT level was 19.0 (15.6-19.5) μmol/l, which represents the lower end of the therapeutic range used in humans. The level of LTG was 60.7 (58.5-61.8) μmol/l. LTG has no effect on the BMD, BTM or mechanical strength in gonadally intact animals. Although a low dose of PHT was associated with enhanced BTM, it did not affect BMD or the biomechanical properties of the bones, similar to the results observed for LTG. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Carbamazepine-hypersensitivity: assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbazepine.

    PubMed Central

    Pirmohamed, M; Graham, A; Roberts, P; Smith, D; Chadwick, D; Breckenridge, A M; Park, B K

    1991-01-01

    1. Seven patients clinically diagnosed as being hypersensitive to carbamazepine and one patient hypersensitive to both carbamazepine and oxcarbazepine have been identified. They have been compared with a control group (hereafter referred to as 'control subjects') comprising five patients on chronic carbamazepine therapy without adverse effects and 12 healthy volunteers who have never been exposed to anticonvulsants. 2. An in vitro cytotoxicity assay employing mononuclear leucocytes as target cells has been used first, to determine the ability of 10 different human livers to bioactivate carbamazepine to a cytotoxic metabolite, and secondly, to compare the cell defences of carbamazepine-hypersensitive patients and control subjects to oxidative drug metabolites generated by a murine microsomal system, using a blinded protocol. 3. With human liver microsomes, the metabolism-dependent cytotoxicity of carbamazepine increased with increasing microsomal protein concentration. At a protein concentration of 2 mg per incubation, the cytotoxicity of carbamazepine with human liver microsomes (n = 10 livers) increased from 7.2 +/- 0.8% (baseline) to 16.4 +/- 2.1% (with NADPH; P = 0.002). 4. In the presence of phenobarbitone-induced mouse microsomes and NADPH, the mean increase in cytotoxicity above the baseline with carbamazepine was significantly greater (P less than 0.001) for the cells from the carbamazepine-hypersensitive patients (7.9 +/- 0.8%) than from control subjects (2.6 +/- 0.3%). 5. In the presence of phenobarbitone-induced mouse microsomes and NADPH, there was no significant difference in cytotoxicity between the cells from carbamazepine hypersensitive patients and from control subjects in the presence of either phenytoin or oxcarbazepine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1768568

  10. A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.

    PubMed

    Dalziel, Stuart R; Furyk, Jeremy; Bonisch, Megan; Oakley, Ed; Borland, Meredith; Neutze, Jocelyn; Donath, Susan; Sharpe, Cynthia; Harvey, Simon; Davidson, Andrew; Craig, Simon; Phillips, Natalie; George, Shane; Rao, Arjun; Cheng, Nicholas; Zhang, Michael; Sinn, Kam; Kochar, Amit; Brabyn, Christine; Babl, Franz E

    2017-06-22

    Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom

  11. Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial.

    PubMed

    Lyttle, Mark D; Gamble, Carrol; Messahel, Shrouk; Hickey, Helen; Iyer, Anand; Woolfall, Kerry; Humphreys, Amy; Bacon, Naomi E A; Roper, Louise; Babl, Franz E; Dalziel, Stuart R; Ryan, Mary; Appleton, Richard E

    2017-06-19

    Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and

  12. Comprehensive mutation analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1 genes is suggestive of a non- neoplastic nature of phenytoin induced gingival overgrowth.

    PubMed

    Swamikannu, Bhuminathan; Kumar, Kishore S; Jayesh, Raghavendra S; Rajendran, Senthilnathan; Muthupalani, Rajendran Shanmugam; Ramanathan, Arvind

    2013-01-01

    Dilantin sodium (phenytoin) is an antiepileptic drug, which is routinely used to control generalized tonic clonic seizure and partial seizure episodes. A few case reports of oral squamous cell carcinomas arising from regions of phenytoin induced gingival overgrowth (GO), and overexpression of mitogenic factors and p53 have presented this condition as a pathology with potential to transform into malignancy. We recently investigated the genetic status of p53 and H-ras, which are known to be frequently mutated in Indian oral carcinomas in GO tissues and found them to only contain wild type sequences, which suggested a non-neoplastic nature of phenytoin induced GO. However, besides p53 and H-ras, other oncogenes and tumor suppressors such as PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1, are frequently altered in oral squamous cell carcinoma, and hence are required to be analyzed in phenytoin induced GO tissues to be affirmative of its non-neoplastic nature. 100ng of chromosomal DNA isolated from twenty gingival overgrowth tissues were amplified with primers for exons 9 and 20 of PIK3CA, exons 1α, 1β and 2 of p16INK4a and p14ARF, and exon 2 of p21Waf1/Cip1, in independent reactions. PCR amplicons were subsequently gel purified and eluted products were sequenced. Sequencing analysis of the twenty samples of phenytoin induced gingival growth showed no mutations in the analyzed exons of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1. The present data indicate that the mutational alterations of genes, PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1 that are frequently mutated in oral squamous cell carcinomas are rare in phenytoin induced gingival growth. Thus the findings provide further evidence that phenytoin induced gingival overgrowth as a non-neoplastic lesion, which may be considered as clinically significant given the fact that the epileptic patients are routinely administered with phenytoin for the rest of their lives to control seizure episodes.

  13. Clinical Validation and Implications of Dried Blood Spot Sampling of Carbamazepine, Valproic Acid and Phenytoin in Patients with Epilepsy

    PubMed Central

    Kong, Sing Teang; Lim, Shih-Hui; Lee, Wee Beng; Kumar, Pasikanthi Kishore; Wang, Hwee Yi Stella; Ng, Yan Lam Shannon; Wong, Pei Shieen; Ho, Paul C.

    2014-01-01

    To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 12.6.1.0 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r = 0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT−1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs. PMID:25255292

  14. A randomized clinical trial comparing hydrocolloid, phenytoin and simple dressings for the treatment of pressure ulcers [ISRCTN33429693

    PubMed Central

    Hollisaz, Mohammad Taghi; Khedmat, Hossein; Yari, Fatemeh

    2004-01-01

    Background Pressure sores are important and common complications of spinal cord injury. Many preventive and therapeutic approaches have been tried and new trials are evolving. One relatively recent method is application of a hydrocolloid dressing (HD). In this study we compared the therapeutic effects of HD on pressure ulcer healing with two other topical applications, phenytoin cream (PC) and simple dressing (SD). Methods Ninety-one stage I and stage II pressure ulcers of 83 paraplegic male victims of the Iran-Iraq war were randomly allocated to three treatment groups. Mean age and weight of the participants were 36.64 ± 6.04 years and 61.12 ± 5.08 kg, respectively. All the patients were managed in long term care units or in their homes for 8 weeks by a team of general practitioners and nurses, and the ulcer status was recorded as "Complete healing", "Partial healing", "Without improvement" and "Worsening". Results Complete healing of ulcers, regardless of location and stage, was better in the HD group than the PC [23/31(74.19%) vs 12/30(40%); difference: 34.19%, 95% CI = 10.85–57.52, (P < 0.01)] or the SD [23/31(74.19%) vs 8/30(26.66%); difference: 47.53%, 95% CI = 25.45–69.61, (P < 0.005)] groups. Complete healing of stage I ulcers in the HD group [11/13(85%)] was better than in the SD [5/11(45%); difference: 40%, 95% CI = 4.7–75.22, (P < 0.05)] or PC [2/9 (22%); difference: 63%, 95% CI = 29.69–96.3, (P < 0.005)] groups. Complete healing of stage II ulcer in the HD group [12/18 (67%)] was better than in the SD group [3/19(16%); difference: 51%, 95% CI = 23.73–78.26, (P < 0.005)], but not significantly different from the PC group [10/21 (48%); difference: 19%, 95% CI = -11.47–49.47, (P > 0.05)]. We performed a second analysis considering only one ulcer per patient (i.e. 83 ulcers in 83 patients). This "per patient" analysis showed that complete ulcer healing in the HD group was better than in the PC [20/28(71.4%) vs 11/28 (39.3%); difference: 32

  15. Integrating the Forensic Sciences in Wildlife Case Investigations: A Case Report of Pentobarbital and Phenytoin Toxicosis in a Bald Eagle (Haliaeetus leucocephalus).

    PubMed

    Viner, T C; Hamlin, B C; McClure, P J; Yates, B C

    2016-09-01

    The application of medical knowledge to the purpose of law is the foundation of forensic pathology. A forensic postmortem examination often involves the expertise of multiple scientific disciplines to reconstruct the full story surrounding the death of an animal. Wildlife poses additional challenges in forensic investigations due to little or no associated history, and the disruptive effects of decomposition. To illustrate the multidisciplinary nature of wildlife forensic medicine, the authors outline a case of secondary pentobarbital/phenytoin toxicosis in a bald eagle (Haliaeetus leucocephalus). The eagle was the single fatality in a group of 8 birds that fed on euthanized domestic cat remains that had been improperly disposed of in a landfill. Cooperation between responding law enforcement officers, pathologists, and other forensic scientists led to the successful diagnosis and resolution of the case. © The Author(s) 2016.

  16. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms.

    PubMed

    Dorado, P; López-Torres, E; Peñas-Lledó, E M; Martínez-Antón, J; Llerena, A

    2013-08-01

    Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg(-1)), intravenous diazepam (0.3 mg kg(-1)), and intravenous phenytoin with an initial-loading dose of 15 mg kg(-1). However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l(-1); normal range: 10-20 mg l(-1)), and the patient was homozygous for the CYP2C9*2 allele, heterozygous for the CYP2C19*4 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient.

  17. Encapsulation of valproic acid and sodic phenytoin in ordered mesoporous SiO 2 solids for the treatment of temporal lobe epilepsy

    NASA Astrophysics Data System (ADS)

    López, T.; Basaldella, E. I.; Ojeda, M. L.; Manjarrez, J.; Alexander-Katz, R.

    2006-10-01

    Temporal lobe epilepsy is one of the most frequent types of human neurological diseases, and a variety of surgical procedures have been developed for the treatment of intractable cases. An alternative is the use of drug-containing reservoirs based on nanostructured materials of controlled pore sizes in order to deliver the drug without causing secondary effects. Ordered SiO 2 nanostructures were developed as drug reservoirs. The latter were prepared by the sol-gel process using tetraethyl orthosilicate TEOS as precursor to form the "sol" and P123 surfactant as the organic structure-directing agent. In addition to the nontoxic nature of amorphous silica, uniform and tunable pore sizes between 2.5 and 30 nm can be obtained in this way. The aim of this study is to investigate the potential of these materials for the storage and release of drugs in the brain. For that, we loaded valproic acid (VH) and sodic phenytoin (PH) molecules into an ordered mesoporous SiO 2 by impregnation and characterized the drug impregnated SiO 2 by standard physical and spectroscopic techniques to identify the parameters necessary to improve the capacity and quality of the reservoirs. Finally, a study of neurohistopathology of the effects of these reservoirs on brain tissue is presented.

  18. Simultaneous determination of phenytoin, carbamazepine, and 10,11-carbamazepine epoxide in human plasma by high-performance liquid chromatography with ultraviolet detection.

    PubMed

    Bhatti, M M; Hanson, G D; Schultz, L

    1998-03-01

    The Bioanalytical Chemistry Department at the Madison facility of Covance Laboratories, has developed and validated a simple and sensitive method for the simultaneous determination of phenytoin (PHT), carbamazepine (CBZ) and 10,11-carbamazepine epoxide (CBZ-E) in human plasma by high-performance liquid chromatography with 10,11 dihydrocarbamazepine as the internal standard. Acetonitrile was added to plasma samples containing PHT, CBZ and CBZ-E to precipitate the plasma proteins. After centrifugation, the acetonitrile supernatant was transferred to a clean tube and evaporated under N2. The dried sample extract was reconstituted in 0.4 ml of mobile phase and injected for analysis by high-performance liquid chromatography. Separation was achieved on a Spherisorb ODS2 analytical column with a mobile phase of 18:18:70 acetonitrile:methanol:potassium phosphate buffer. Detection was at 210 nm using an ultraviolet detector. The mean retention times of CBZ-E, PHT and CBZ were 5.8, 9.9 and 11.8 min, respectively. Peak height ratios were fit to a least squares linear regression algorithm with a 1/(concentration)2 weighting. The method produces acceptable linearity, precision and accuracy to a minimum concentration of 0.050 micrograms ml-1 in human plasma. It is also simple and convenient, with no observable matrix interferences.

  19. Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

    PubMed

    Ferreira, Anderson O; Polonini, Hudson C; Silva, Sharlene L; Patrício, Fernando B; Brandão, Marcos Antônio F; Raposo, Nádia R B

    2016-01-25

    The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Association of CYP2C9*3 with phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: A systematic review and meta-analysis.

    PubMed

    Wu, X; Liu, W; Zhou, W

    2018-06-01

    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key enzyme in PHT metabolism. The aim of this meta-analysis was to evaluate the association between CYP2C9*3 and PHT-induced SJS/TEN. An extensive search was performed in multiple databases, including the Cochrane Library, EMBASE, PubMed, OVID and EBSCO. Studies exploring the relationship between CYP2C9*3 and PHT-induced SJS and TEN were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for dichotomous data. Data analysis was performed using Review Manager (version 5.3). Four studies, with 117 PHT-induced SJS/TEN cases and 338 matched controls (PHT-tolerant patients) or 4231 population controls (general population), were identified. SJS and TEN were found to be significantly associated with the CYP2C9*3 allele, comparing both matched controls (OR, 8.93; 95% CI, 2.63-30.36; P = .0005) with substantial heterogeneity (I 2  = 46%) and population controls (OR, 8.88; 95% CI, 5.01-15.74; P < .00001). A significant association between CYP2C9*3 and PHT-induced SJS/TEN was identified, especially in a Thai population. CYP2C9*3 is thus a credible predictive genetic marker of PHT-induced SJS/TEN. Further multicenter studies and large prospective observational studies are, however, still required to determine the influence of CYP2C*3 on blood levels of PHT and its metabolites, and their association with SJS/TEN. © 2017 John Wiley & Sons Ltd.

  1. The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex.

    PubMed

    George, Sophie A; Rodriguez-Santiago, Mariana; Riley, John; Rodriguez, Elizabeth; Liberzon, Israel

    2015-01-01

    Post-traumatic stress disorder (PTSD) is a chronic, debilitating disorder. Only two pharmacological agents are approved for PTSD treatment, and they often do not address the full range of symptoms nor are they equally effective in all cases. Animal models of PTSD are critical for understanding the neurobiology involved and for identification of novel therapeutic targets. Using the rodent PTSD model, single prolonged stress (SPS), we have implicated aberrant excitatory neural transmission and glucocorticoid receptor (GR) upregulation in the medial prefrontal cortex (mPFC) and hippocampus (HPC) in fear memory abnormalities associated with PTSD. The objective of this study is to examine the potential protective effect of antiepileptic phenytoin (PHE) administration on SPS-induced extinction retention deficits and GR expression. Forty-eight SPS-treated male Sprague Dawley rats or controls were administered PHE (40, 20 mg/kg, vehicle) for 7 days following SPS stressors; then, fear conditioning, extinction, and extinction retention were tested. Fear conditioning and extinction were unaffected by SPS or PHE, but SPS impaired extinction retention, and both doses of PHE rescued this impairment. Similarly, SPS increased GR expression in the mPFC and dorsal HPC, and PHE prevented SPS-induced GR upregulation in the mPFC. These data demonstrate that PHE administration can prevent the development of extinction retention deficits and upregulation of GR. PHE exerts inhibitory effects on voltage-gated sodium channels and decreases excitatory neural transmission via glutamate antagonism. If glutamate hyperactivity in the days following SPS contributes to SPS-induced deficits, then these data may suggest that the glutamatergic system constitutes a target for secondary prevention.

  2. Effects of Levetiracetam, Carbamazepine, Phenytoin, Valproate, Lamotrigine, Oxcarbazepine, Topiramate, Vinpocetine and Sertraline on Presynaptic Hippocampal Na(+) and Ca(2+) Channels Permeability.

    PubMed

    Sitges, María; Chiu, Luz María; Reed, Ronald C

    2016-04-01

    Ion channels are targets of various antiepileptic drugs. In cerebral presynaptic nerve endings Na(+) and Ca(2+) channels are particularly abundant, as they control neurotransmitter release, including the release of glutamate (Glu), the most concentrated excitatory amino acid neurotransmitter in the brain. Several pre-synaptic channels are implicated in the mechanism of action of the pro-convulsive agent, 4-aminopyridine (4-AP). In the present study the effects of levetiracetam and other established and newer (vinpocetine) anti-epileptic drugs, as well as of the anti-depressant, sertraline on the increase in Ca(2+) induced by 4-AP in hippocampal isolated nerve endings were investigated. Also the effects of some of the anti-seizure drugs on the selective increase in Ca(2+) induced by high K(+), or on the selective increase in Na(+) induced by veratridine were tested. Sertraline and vinpocetine effectively inhibited the rise in Ca(2+) induced by 4-AP, which was dependent on the out-in Na(+) gradient and tetrodotoxin sensitive. Carbamazepine, phenytoin, lamotrigine and oxcarbazepine inhibited the rise in Ca(2+) induced by 4-AP too, but at higher concentrations than sertraline and vinpocetine, whereas levetiracetam, valproic acid and topiramate did not. The three latter antiepileptic drugs also failed in modifying other responses mediated by the activation of brain presynaptic Na(+) or Ca(2+) channels, including Glu release. This indicates that levetiracetam, valproic acid and topiramate mechanisms of action are unrelated with a decrease in presynaptic Na(+) or Ca(2+) channels permeability. It is concluded that depolarized cerebral isolated nerve endings represent a useful tool to unmask potential antiepileptic drugs targeting presynaptic Na(+) and/or Ca(2+) channels in the brain; such as vinpocetine or the anti-depressant sertraline, which high effectiveness to control seizures in the animal in vivo has been demonstrated.

  3. Reversal of P-glycoprotein overexpression by Ginkgo biloba extract in the brains of pentylenetetrazole-kindled and phenytoin-treated mice.

    PubMed

    Zhang, Ce; Fan, Qing; Chen, Shu-Liang; Ma, Hui

    2015-08-01

    The purpose of this study was to investigate the combined effects of Ginkgo biloba extract and phenytoin (PHT) sodium as a dose regimen simulating the clinical treatment of patients with epilepsy, on P-glycoprotein (P-GP) overexpression in a pentylenetetrazole-kindled mouse model of epilepsy. Epilepsy was induced by intraperitoneal administration of pentylenetetrazole (40 mg/kg) for 7 days followed by intragastric administration of PHT (40 mg/kg) for 14 days. Thirty mice that developed seizures were randomly divided into three groups and administered PHT as well as the following treatments: saline (negative control); verapamil (20 mg/kg, positive control); and G. biloba (30 mg/kg). Seizure severity was recorded 30 minutes after treatment on Day 4 of drug administration, after which the mice were euthanized, and their brains isolated. Western blots and immunohistochemistry were performed to analyze the expression of P-GP and caspase-3, respectively, in the brain tissue. High-performance liquid chromatography was used to measure the concentrations of PHT in the brains of the treated mice. After 4 consecutive days of treatment, the seizure severity in the mice in the G. biloba extract group was more significantly reduced than the seizure severity in the saline control group, and a significant difference was observed between the G. biloba extract and verapamil control groups (p < 0.05). P-GP expression in the brain more significantly decreased in the mice treated with G. biloba extract and verapamil than it did in the saline-treated control group (p < 0.05). Compared with the saline-treated control group, the mice treated with G. biloba extract and verapamil showed significantly increased brain PHT concentrations (p < 0.05). Furthermore, caspase-3 expression in the brain tissue of the G. biloba extract group was significantly lower than that in the vehicle control group (p < 0.05); this finding demonstrated the neuroprotective effects of G. biloba. Therefore, this

  4. Modulation of vinblastine cytotoxicity by dilantin (phenytoin) or the protein phosphatase inhibitor okadaic acid involves the potentiation of anti-mitotic effects and induction of apoptosis in human tumour cells.

    PubMed Central

    Kawamura, K. I.; Grabowski, D.; Weizer, K.; Bukowski, R.; Ganapathi, R.

    1996-01-01

    Cellular insensitivity to vinca alkaloids is suggested to be primarily due to drug efflux by P-glycoprotein (P-gp). The anti-epileptic phenytoin (DPH), which does not bind to P-gp, can selectively enhance vincristine (VCR) cytotoxicity in wild-type (WT) or multidrug-resistant (MDR) cells. We now demonstrate that the protein phosphatase inhibitor okadaic acid (OKA) can mimic the effect of DPH by selectively enhancing cytotoxicity of vinblastine (VBL), but not taxol and doxorubicin, in human leukaemia HL-60 cells. Both DPH and OKA potentiate the anti-mitotic effects of VBL by enhanced damage to the mitotic spindle, resulting in prolonged growth arrest. Also, unlike VBL alone, in human leukaemia or non-small-cell lung carcinoma cells treated with VBL plus DPH, recovery from damage to the mitotic spindle is compromised in drug-free medium and cell death by apoptosis in interphase ensues. Since protein phosphatases are involved with the regulation of metaphase to anaphase transit of cells during the mitotic cycle, enhanced VBL cytotoxicity in the presence of DPH or OKA may involve effects during metaphase on the mitotic spindle tubulin leading to growth arrest and apoptosis in interphase. These novel results suggest that DPH or OKA could be powerful tools to study cellular effects of vinca alkaloids and possibly for the development of novel therapeutic strategies. Images Figure 6 PMID:8546904

  5. Development, validation and clinical application of an online-SPE-LC-HRMS/MS for simultaneous quantification of phenobarbital, phenytoin, carbamazepine, and its active metabolite carbamazepine 10,11-epoxide.

    PubMed

    Qu, Lihua; Fan, Yuanjie; Wang, Wenjun; Ma, Kai; Yin, Zheng

    2016-09-01

    A simple and efficient bioanalytical method for simultaneous determination of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and its active metabolite carbamazepine 10,11-epoxide (CBZE) in human plasma using online solid phase extraction (SPE)-liquid chromatography (LC) coupled with high resolution mass spectrum (HRMS) under targeted MS/MS (t-MS(2)) analysis mode has been developed. The procedure integrated an automated sample clean-up of human plasma by Oasis®HLB SPE cartridge, a separation by ZORBAX SB-C18 analysis column, and a quantification by Q-Exactive Hybrid Quadrupole-Orbitrap. The total running time was 13min. The lower limit of quantification (LLOQ) of PB, PHT, CBZ, and CBZE were 0.008, 0.008, 0.0016 and 0.0016μgmL(-1) respectively and the linearities were in the range of 0.008-2.500, 0.008-2.500, 0.0016-0.500 and 0.0016-0.500μgmL(-1) respectively. The mean recovery was between 91.82% and 108.27% and the matrix effect was between 93.29% and 102.09%. The relative standard deviations of interday and intraday were less than 6.41%. The method has been successfully applied in therapeutic drug monitoring (TDM) of four Chinese epilepsy patients. This fully automated, simple, sensitive and reliable online-SPE-LC-HRMS/MS method serves well for TDM of PB, PHT, CBZ and CBZE at clinics for either single or combination treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Liquid chromatographic assay based on microextraction by packed sorbent for therapeutic drug monitoring of carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin and the active metabolites carbamazepine-10,11-epoxide and licarbazepine.

    PubMed

    Ferreira, Ana; Rodrigues, Márcio; Oliveira, Paula; Francisco, Joana; Fortuna, Ana; Rosado, Luísa; Rosado, Pedro; Falcão, Amílcar; Alves, Gilberto

    2014-11-15

    A new, sensitive and fast high-performance liquid chromatography-diode-array detection assay based on microextraction by packed sorbent (MEPS/HPLC-DAD) is herein reported, for the first time, to simultaneously quantify carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), and the active metabolites carbamazepine-10,11-epoxide (CBZ-E) and licarbazepine (LIC) in human plasma. Chromatographic separation of analytes and ketoprofen, used as internal standard (IS), was achieved in less than 15min on a C18-column, at 35°C, using acetonitrile (6%) and a mixture (94%) of water-methanol-triethylamine (73.2:26.5:0.3, v/v/v; pH 6.5) pumped at 1mL/min. The analytes and IS were detected at 215, 237 or 280nm. The method showed to be selective, accurate [bias ±14.8% (or ±17.8% in the lower limit of quantification)], precise [coefficient variation ≤9.7% (or ≤17.7% in the lower limit of quantification)] and linear (r(2)≥0.9946) over the concentration ranges of 0.1-15μg/mL for CBZ; 0.1-20μg/mL for LTG; 0.1-5μg/mL for OXC and CBZ-E; 0.2-40μg/mL for PB; 0.3-30μg/mL for PHT; and 0.4-40μg/mL for LIC. The absolute extraction recovery of the analytes ranged from 57.8 to 98.1% and their stability was demonstrated in the studied conditions. This MEPS/HPLC-DAD assay was successfully applied to real plasma samples from patients, revealing to be a cost-effective tool for routine therapeutic drug monitoring of CBZ, LTG, OXC, PB and/or PHT. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. EFFECT OF PHENYTOIN ON GENE EXPRESSION, OXIDATIVE DAMAGE AND CELL VIABILITY OF CULTURED HUMAN FETAL LIVER SLICES. (R827441)

    EPA Science Inventory

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  8. Evidence for an arene oxide-NIH shift pathway in the metabolic conversion of phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin in the rat and in man

    SciTech Connect

    Claesen, M.; Moustafa, M.A.; Adline, J.

    To determine whether the hydroxylation of 5,5-diphenylhydantoin (DPH) to 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) occurs by an arene oxide-NIH shift process, racemic 5-(4-deuteriophenyl)-5-phenylhydantoin (p-2H-DPH) was subjected to in vivo metabolic experiments in the rat and in man. After enzymatic hydrolysis of the urine, para-hydroxylated metabolites were separated by HPLC. Deuterium retention in the isolated metabolites determined by gas chromatography-mass spectrometry, was 68-72%. The results are interpreted as the predominance of an arene oxide-NIH shift pathway in those two metabolic systems. Induction of rats with phenobarbital or 3-methylcholanthrene showed no effect on the value of deuterium retention.

  9. An Analysis of the Effects of Phenytoin in Treating Motion Sickness and the Effects of Motion Sickness on the Human Electroencephalogram

    DTIC Science & Technology

    1990-12-01

    ears ( tinnitus ) and/or a reduced auditory acuity resulted from the dosing. These side effects have been shown to 29 occur in some subjects as a result of...examinations. 5. Complete blood count (CBC). 6. Blood biochemistry screen (Chem 18 including liver function tests). 7. Blood cholesterol and lipids . 8. Chest X...blood lipids and cholesterol, chest X-ray, urinalysis, visual acuity test, vestibular evaluation and liver function studies. Subjects will then take

  10. Fosphenytoin. Pharmacoeconomic implications of therapy.

    PubMed

    Holliday, S M; Benfield, P; Plosker, G L

    1998-12-01

    Advantages and disadvantages of Fosphenytoin. Advantages. More rapid intravenous administration than phenytoin and no need for an in-line filter. May be administered by intramuscular injection. Lower potential for local tissue and cardiac toxicity than phenytoin. Associated with less pain and phlebitis at the injection site, fewer reductions in infusion rate and fewer changes of administration site because of injection site complications than phenytoin. Benefits in terms of ease of administration and improved tolerability vs phenytoin have pharmacoeconomic implications which may translate into an overall cost advantage. Disadvantages. Approximately 10-fold higher acquisition cost vs phenytoin. Fosphenytoin is a parenterally administered prodrug of phenytoin, used in the treatment of patients with seizures. Advantages of fosphenytoin over phenytoin include more rapid intravenous administration, no need for an intravenous filter, and a lower potential for local tissue and cardiac toxicity. Unlike phenytoin, fosphenytoin may also be administered by intramuscular injection. Pharmacoeconomic data from a small study of patients with acute seizures in a US emergency department showed an overall cost advantage of fosphenytoin over phenytoin, despite a considerably greater acquisition cost of fosphenytoin. The main cost drivers for phenytoin therapy were treatment costs associated with adverse events. In view of the limited pharmacoeconomic data currently available, it is in the interests of individual institutions to conduct their own formal pharmacoeconomic studies applying local cost data and patterns of clinical practise to determine whether fosphenytoin should replace phenytoin on their formularly list.

  11. Preventing Epilepsy after Traumatic Brain Injury

    DTIC Science & Technology

    2007-02-01

    the standard of care ( phenytoin ). A secondary objective is to obtain the data necessary to design a randomized clinical trial to determine if TPM can...than the current standard of care ( phenytoin ). A secondary objective is to obtain the data necessary to design a randomized clinical trial to...dose of phenytoin within several hours of being admitted to the trauma/neurosurgical unit, as part of the standard of care for such individuals. The

  12. Preventing Epilepsy After Traumatic Brain Injury

    DTIC Science & Technology

    2008-02-01

    early seizures to the standard of care ( phenytoin ). A secondary objective is to obtain the data necessary to design a randomized clinical trial to...protocol was revised to eliminate several major obstacles. We have enrolled 5 subjects into the study; two in the phenytoin arm, one in the short term...prevent early seizures better than the current standard of care ( phenytoin ). A secondary objective is to obtain the data necessary to design a randomized

  13. Preventing Epilepsy After Traumatic Brain Injury

    DTIC Science & Technology

    2009-02-01

    treatment of early seizures following TBI, and to compare the efficacy of topiramate to prevent early seizures to the standard of care ( phenytoin ). A...injury (TBI), to determine if topiramate could prevent early seizures better than the current standard of care ( phenytoin ) and to develop a...receive topiramate for three months, and the third, control, arm would receive phenytoin for seven days (current standard of care). EEGs were to

  14. Medial Prefrontal Cortex and HPA Axis Roles in Generation of PTSD-Like Symptoms in SPS Model

    DTIC Science & Technology

    2010-09-01

    phenytoin , 5) SPS alters locus coeruleus (LC) activity. The research conducted to date has compelled us to change some of our hypotheses and/or the...antikindling drug Phenytoin can reverse these effects. This experiment was proposed in specific aim #4 (hypothesis #4b). SPS enhanced fear renewal without...affecting fear conditioning or extinction. Systemic administration of phenytoin reversed this effect. This is shown in Figure 7. 5) SPS sensitizes LC

  15. The Role of High Pressure and Inert Gases in the Production and Reversal of the High Pressure Neurological Syndrome.

    DTIC Science & Technology

    1982-08-06

    mine, and phenytoin . All except the latter and/3-chloralose caused marked decreases in order. The bilayer/buffer partition coefficients of...phenobarbital, phenytoin , and urethane were measured. The change-in-order parameter as a function of total anesthetic concen- tration varied widely but when the...BY GENERAL ANESTHETICS 85 to disorder egg phosphatidylcholine:cholesterol (2:1) bi- Partition coefficients of phenobarbital and phenytoin layers. This

  16. Preanesthetic Assessment of Herbal and Dietary Supplement Use

    DTIC Science & Technology

    2000-12-06

    effectiveness of anticonvulsants such as carbamazepine, phenytoin , and phenobarbital by lowering the seizure threshold (Miller, 1998). Ginseng has been...DeSmet & D’Arcy, 1996). Vitamin B6 can nullify the effects of L-dopa in patients with Parkinson disease. Intraoperative Parkinsonism has been...Hall, 1996). Folic acid has been associated with decreased levels of phenytoin . Patients on phenytoin for control of seizures that are taking large

  17. The antiepileptic drug diphenylhydantoin affects the structure of the human erythrocyte membrane.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Villena, Fernando; Cuevas, Francisco; Sotomayor, Carlos P

    2004-01-01

    Phenytoin (diphenylhydantoin) is an antiepileptic agent effective against all types of partial and tonic-clonic seizures. Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord neurons maintained in vitro. This effect is mediated by a slowing of the rate of recovery of voltage activated Na+ channels from inactivation. For this reasons it was thought of interest to study the binding affinities of phenytoin with cell membranes and their perturbing effects upon membrane structures. The effects of phenytoin on the human erythrocyte membrane and molecular models have been investigated in the present work. This report presents the following evidence that phenytoin interacts with cell membranes: a) X-ray diffraction and fluorescence spectroscopy of phospholipid bilayers showed that phenytoin perturbed a class of lipids found in the outer moiety of cell membranes; b) in isolated unsealed human erythrocyte membranes (IUM) the drug induced a disordering effect on the polar head groups and acyl chains of the erythrocyte membrane lipid bilayer; c) in scanning electron microscopy (SEM) studies on human erythrocytes the formation of echinocytes was observed, due to the insertion of phenytoin in the outer monolayer of the red cell membrane. This is the first time that an effect of phenytoin on the red cell shape is described. However, the effects of the drug were observed at concentrations higher than those currently found in plasma when phenytoin is therapeutically administered.

  18. Oxazepam

    MedlinePlus

    ... in Sinemet, in Stalevo); medication for depression, seizures, Parkinson's disease, asthma, colds, or allergies; muscle relaxants; oral contraceptives; phenytoin (Dilantin, Phenytek); probenecid (Probalan, in Col-Probenecid); rifampin ( ...

  19. Trifluoperazine

    MedlinePlus

    ... anxiety, irritable bowel disease, mental illness, motion sickness, Parkinson's disease, ulcers, or urinary problems; medications for seizures such as phenytoin (Dilantin); narcotic medications for pain; propranolol (Inderal); sedatives; ...

  20. Anticonvulsants and thyroid function.

    PubMed Central

    Yeo, P P; Bates, D; Howe, J G; Ratcliffe, W A; Schardt, C W; Heath, A; Evered, D C

    1978-01-01

    Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3. PMID:656820

  1. Dapsone Topical

    MedlinePlus

    ... as phenytoin (Dilantin, Phenytek); antimalarial medications such as chloroquine (Aralen), primaquine, and quinine (Qualaquin); dapsone (by mouth); ... and the laboratory.Do not let anyone else use your medication. Ask your pharmacist any questions you ...

  2. Folate deficiency

    MedlinePlus

    ... as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole) Eating an unhealthy diet that does not include enough fruits and vegetables Kidney dialysis Symptoms Folic acid deficiency may cause: Fatigue, irritability, or diarrhea Poor growth Smooth and ...

  3. Swollen lymph nodes

    MedlinePlus

    ... lymph nodes, including: Seizure medicines such as phenytoin Typhoid immunization Which lymph nodes are swollen depends on ... hard, irregular, or fixed in place. You have fever, night sweats, or unexplained weight loss. Any node ...

  4. Sorafenib Combined With Transarterial Chemoembolization in Treating HBV-infected Patients With Intermediate Hepatocellular Carcinoma

    ClinicalTrials.gov

    2012-04-24

    PHENYTOIN/SORAFENIB [VA Drug Interaction]; Liver Neoplasms; Carcinoma, Hepatocellular; Digestive System Neoplasms; Neoplasms by Site; Liver Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; DOXORUBICIN/TRASTUZUMAB [VA Drug Interaction]; HBV

  5. Tardive dyskinesia

    MedlinePlus

    ... as levodopa Antiseizure drugs such as phenobarbital and phenytoin Symptoms Symptoms of TD may include: Facial grimacing ... ncbi.nlm.nih.gov/pubmed/23897874 . Jankovic J. Parkinson disease and other movement disorders. In: Daroff RB, ...

  6. Dysarthria

    MedlinePlus

    ... on the central nervous system, such as narcotics, phenytoin, or carbamazepine Symptoms Depending on its cause, dysarthria ... lose the ability to speak. Some people with Parkinson disease or multiple sclerosis lose the ability to ...

  7. Pimavanserin

    MedlinePlus

    ... hallucinations and delusions in people with psychosis from Parkinson's disease (PD; a disorder of the nervous system ... Nuedexta), and sotalol (Betapace, Sorine, Sotylize); moxifloxacin (Avelox); phenytoin (Dilantin, Phenytek); rifampin (Rifadin, Rimactane, in Rifamate, in ...

  8. Drug Interactions with Clinafloxacin

    PubMed Central

    Randinitis, Edward J.; Alvey, Christine W.; Koup, Jeffery R.; Rausch, George; Abel, Robert; Bron, Nicola J.; Hounslow, Neil J.; Vassos, Artemios B.; Sedman, Allen J.

    2001-01-01

    Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration. PMID:11502527

  9. Defining Platelet Function During Polytrauma

    DTIC Science & Technology

    2014-04-01

    Haloperidol Midaz. Ca+ gluc. cefazolin clinda. someprazol fent. gent. glucose peg. Insulin Mg+ phenobarb.someprazol gent. cefalozin clinda. propofol...Phenytoin Senna Thiamine Haloperidol 0 0 Etom Roc 0 Amiodaro Midaz. Fent. Nafcillin T. Dap 0 0 fent. midaz. 0 0 Lido Midaz 1500 Phenytoin Fent. Propofol...odium bicarodium phos mannitol Ca+Cl- docusate Cefepime someprazolonduparinuLevofloxacin Mg+ Mannitol MVI K+ Haloperidol Midaz. henylephrine peg

  10. Stability of nitroglycerin in intravenous admixtures.

    PubMed

    Klamerus, K J; Ueda, C T; Newton, D W

    1984-02-01

    The stability of nitroglycerin in intravenous admixtures was studied. Admixtures containing nitroglycerin 400 micrograms/ml and each of seven injectable drugs in concentrations used clinically were prepared in triplicate in 5% dextrose and 0.9% sodium chloride injections. Admixtures were stored in glass bottles at room temperature for 24 hours in the upright position and then for 24 hours in the inverted position to ensure contact of the solution with the rubber stopper of the container. At 0, 24, and 48 hours, samples of each admixture were assayed by high-performance liquid chromatography for nitroglycerin concentration. The pH of one randomly chosen bottle of each admixture was measured at 0, 24, and 48 hours. A significant loss of nitroglycerin potency at 48 hours was observed only in admixtures containing phenytoin; in these solutions, a 9% decrease in initial nitroglycerin concentration was noted. Phenytoin crystallization was present in all phenytoin admixtures by 24 hours. Compared with initial values, no significant differences in the pH values of any admixture samples assayed at 24 and 48 hours were noted; however, admixtures containing phenytoin had the most alkaline pH values. Under the conditions studied, nitroglycerin concentrations remained above 90% of their initial values for 48 hours in all tested admixtures; however, phenytoin crystallization limits the stability of phenytoin admixtures.

  11. Fiber Optic Immunochemical Sensors For Continuous Monitoring Of Hapten Concentrations

    NASA Astrophysics Data System (ADS)

    Miller, W. Greg; Anderson, F. Philip

    1989-06-01

    We describe a fiber optic sensor based on a homogeneous fluorescence energy transfer immunoassay which operates in a continuous, reversible manner to quantitate the anticonvulsant drug phenytoin. B-phycoerythrin-phenytoin and Texas Red labeled anti-phenytoin antibody were sealed inside a short length of cellulose dialysis tubing which was cemented to the distal end of an optical fiber. When the sensor was placed into a solution of phenytoin, the drug crossed the dialysis membrane, displaced a fraction of the B-phycoerythrin-phenytoin from the antibody, and produced a change in fluorescence signal which was measured with a fiber optic fluorometer. The sensor had a concentration response of 5 to 500μmo1/L phenytoin with a response time of 5 to 15 min and precision of <2.5% CV. The chemical kinetics of the antibody-hapten indicator reaction were modeled mathematically and simulation showed that response time in the minutes range can be achieved when the dissociation rate constant is greater than approximately 10-3 sec-1. The dissociation rate constant influences the time to reach equilibrium and the unbound P* concentration range available for instrumental measurement. The ratio of the labeled and unlabeled hapten dissociation rate constants influences the analyte concentration range to which the sensor will respond.

  12. Studies on the effects of acetylcholine and antiepileptic drugs on /sup 32/P incorporation into phospholipids of rat brain synaptosomes

    SciTech Connect

    Aly, M.I.; Abdel-Latif, A.A.

    1982-02-01

    Studies were conducted on the effects of antiepileptic drugs on the acetylcholine-stimulated /sup 32/P labeling of phospholipids in rat brain synaptosomes. Of the four antiepileptic drugs investigated in the present study, namely phenytoin, carbamazepine, phenobarbital, and valproate, only phenytoin blocked the acetylcholine-stimulated /sup 32/P labeling of phosphatidylinositol and phosphatidic acid, and the acetylcholine-stimulated breakdown of polyphosphoinositides. Phenytoin alone, like atropine alone, had no effect on the /sup 32/P labeling of phospholipids nor on the specific radioactivity of (/sup 32/P)ATP. Omission of Na/sup +/ drastically reduced both the /sup 32/P labeling of synaptosomal phospholipids and the specific radioactivity of (/sup 32/P)ATPmore » and furthermore it significantly decreased the phosphoinositide effect. It was concluded that certain antiepileptic drugs, such as phenytoin, could exert their pharmacological actions through their antimuscarinic effects. In addition the finding that phenytoin, which acts to regulate NA/sup +/ and Ca/sup 2 +/ permeability of neuronal membranes, also inhibited the phosphoinositide effects in synaptosomes, support the conclusions that Ca2+ and Na+ are probably involved in the molecular mechanism underlying this phenomenon in excitable tissues.« less

  13. The effect of some anti-epilepsy drugs on enhancement of the monoamine-mediated behavioural responses following the administration of electroconvulsive shocks to rats.

    PubMed

    Bhavsar, V H; Dhumal, V R; Kelkar, V V

    1981-09-11

    Daily administration of electroconvulsive shocks (ECS) to rats for 10 days resulted in enhanced 5-hydroxytryptamine (5-HT), dopamine (DA) and noradrenaline (NA)-mediated behavioural responses. 5-HT and NA-mediated responses were still enhanced after 21 shock-free days. The three types of behavioural responses were also studied in rats given phenytoin sodium, carbamazepine and diazepam every day, alone, or 1 h after ECS administration. Phenytoin did not alter the ECS-induced enhancement of any of the three behaviours. Carbamazepine and diazepam significantly retarded the enhancement in 5-HT and DA-mediated behaviours, although they did not alter the enhancement in NA-mediated behaviour.

  14. Serum and plasma for total and free anticonvulsant drug analyses: effects on EMIT assays and ultrafiltration devices.

    PubMed

    Godolphin, W; Trepanier, J; Farrell, K

    1983-01-01

    The suitability of serum and plasma anticoagulated with heparin, EDTA, citrate, or oxalate was assessed for analysis of free and total phenytoin, carbamazepine, and valproic acid. The free fraction was isolated by ultrafiltration through FreeLevel devices (Syva, Palo Alto, CA). Serum, heparin, and EDTA plasma were satisfactory for both free and total phenytoin and carbamazepine. EDTA could not be used for EMIT (Syva) analysis of valproate. Citrate and, to a lesser degree, oxalate cause a significant negative interference in the concentration of these three drugs as measured both by EMIT and gas-liquid chromatography.

  15. Characterization of nanoscale spatial distribution of small molecules in amorphous polymer matrices

    NASA Astrophysics Data System (ADS)

    Ricarte, Ralm; Hillmyer, Marc; Lodge, Timothy

    Hydroxypropyl methylcellulose acetate succinate (HPMCAS) can significantly enhance the efficacy of active pharmaceutical ingredients (APIs). Yet, the interactions between species in HPMCAS-API blends are not understood. Elucidating these interactions is difficult because the spatial distributions of HPMCAS and API in the blends are ambiguous; the polymer and drug may be molecularly mixed or the species may form phase separated domains. As these phase separated domains may be less than 100 nm in size, traditional characterization techniques may not accurately evaluate the spatial distribution. To address this challenge, we explore the use of electron energy-loss spectroscopy (EELS) for detecting the model API phenytoin in an HPMCAS-phenytoin blend. Using EELS, we directly measured with high accuracy and precision the phenytoin concentrations in several blends. We present evidence that suggests phase separation occurs in blends that have a phenytoin loading of approximately 50 wt percent. Finally, we demonstrate that this technique achieves a sub-100 nm spatial resolution and can detect several other APIs.

  16. The Temporal Relationship Between Intrafamilial Violence, Deployment, and Serious Mental Illness in US Army Service Members

    DTIC Science & Technology

    2013-03-01

    PROPOXYPHENE (DARVON) - TRAMADOL (ULTRAM) ANTI SEIZURE MEDICATION (USED FOR CHRONIC PAIN ) - PHENYTOIN (DILANTIN) NSAIDS - ASPIRIN - IBUPROFEN...ESZOPICLONE) g. Prazosin - PRAZOSIN HCL (MINIPRESS) h. Other relevant Medications: Pain medications OPIODS - CODEINE - FENTANYL... pain : - AMITRIPTYLINE HCL/CHLORDIAZEPOXIDE (LIMBITROL) - AMITRIPTYLINE HCL/PERPHENAZINE (TRIAVIL, ETRAFON) - DESIPRAMINE HCL (PERTOFRANE, NORPRAMIN

  17. Influence of organic surface coatings on the sorption of anticonvulsants on mineral surfaces.

    PubMed

    Qu, Shen; Cwiertny, David M

    2013-10-01

    Here, we explore the role that sorption to mineral surfaces plays in the fate of two commonly encountered effluent-derived pharmaceuticals, the anticonvulsants phenytoin and carbamazepine. Adsorption isotherms and pH-edge experiments are consistent with electrostatics governing anticonvulsant uptake on metal oxides typically found in soil and aquifer material (e.g., Si, Al, Fe, Mn, and Ti). Appreciable, albeit limited, adsorption was observed only for phenytoin, which is anionic above pH 8.3, on the iron oxides hematite and ferrihydrite. Adsorption increased substantially in the presence of cationic and anionic surfactants, species also commonly encountered in wastewater effluent. For carbamazepine, we propose the enhanced uptake results entirely from hydrophobic interactions with apolar tails of surfactant surface coatings. For phenytoin, adsorption also arises from the ability of surfactants to alter the net charge of the mineral surface and thereby further enhance favorable electrostatic interactions with its anionic form. Collectively, our results demonstrate that although pristine mineral surfaces are likely not major sinks for phenytoin and carbamazepine in the environment, their alteration with organic matter, particularly surfactants, can considerably increase their ability to retain these emerging pollutants in subsurface systems.

  18. [Effect of Environmental Factors on the Ecotoxicity of Pharmaceuticals and Personal Care Products].

    PubMed

    Sugihara, Kazumi

    2018-01-01

     In recent years, pharmaceuticals and personal care products (PPCPs) have emerged as significant pollutants of aquatic environments and have been detected at levels in the range of ng/L to μg/L. The source of PPCPs is humans and livestock that have been administered pharmaceuticals and subsequently excreted them via urine and feces. Unlike agricultural chemicals, the environmental dynamics of PPCPs is not examined and they would undergo structural transformation by environmental factors, e.g., sunlight, microorganisms and treatments in sewage treatment plants (STPs). Processing at STPs can remove various PPCPs; however, they are not removed completely and some persist in the effluents. In this study, we examined the degradation of 9 pharmaceuticals (acetaminophen, amiodarone, dapsone, dexamethasone, indomethacin, raloxifene, phenytoin, naproxen, and sulindac) by sunlight or UV, and investigated the ecotoxicological variation of degradation products. Sunlight (UVA and UVB) degraded most pharmaceuticals, except acetaminophen and phenytoin. Similar results were obtained with UVB and UVA. All the pharmaceuticals were photodegraded by UVC, which is used for sterilization in STPs. Ecotoxicity assay using the luminescent bacteria test (ISO11348) indicated that UVC irradiation increased the toxicity of acetaminophen and phenytoin significantly. The photodegraded product of acetaminophen was identified as 1-(2-amino-5-hydroxyphenyl)ethanone and that of phenytoin as benzophenone, and the authentic compounds showed high toxicity. Photodegraded products of PPCPs are a concern in ecotoxicology.

  19. An update in the initial management of paediatric status epilepticus.

    PubMed

    Lawton, Ben; Davis, Tessa; Goldstein, Henry; Tagg, Andrew

    2018-06-01

    Over the last 2 years, algorithms for the optimal management of status epilepticus have changed, as the medical community has recognized the need to terminate seizures in status in a timely manner. Recent research has evaluated the different choices of benzodiazepine and has given consideration to second-line treatment options. There has been a move to examine alternatives to phenytoin (such as levetiracetam and lacosamide) as second-line agents. Valproate should be used cautiously in view of the potential side effects. Three ongoing trials [Established Staus Epilepticus Treatment Trial (ESETT), Convulsive Status Epilepticus Paediatric Trial (ConSEPT), and emergency treatment with levetiracetam or phenytoin in status epilepticus in children (EcLiPSE)] are comparing the efficacy of levetiracetam and phenytoin. Benzodiazepines remain the first-line agent of choice, although there is ongoing discussion about the mode of administration and the best drug to choose. The results of ESETT, ConSEPT, and EcLiPSE will affect our future management of status, as we give consideration to levetiracetam as an alternative to phenytoin. Other medications such as lacosamide may emerge in future algorithms too.

  20. Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs

    PubMed Central

    Herrera, José A.; Ward, Christopher S.; Pitcher, Meagan R.; Percy, Alan K.; Skinner, Steven; Kaufmann, Walter E.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

    2015-01-01

    One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na+ channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na+ channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na+ channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na+ channel blocker antiepileptic therapies. Thus, Na+ channel blockers should be considered for the clinical management of LQT in individuals with RTT. PMID:25713300

  1. Physiologic, Behavioral, and Histologic Responses to Various Euthanasia Methods in C57BL/6NTac Male Mice.

    PubMed

    Boivin, Gregory P; Bottomley, Michael A; Schiml, Patricia A; Goss, Lori; Grobe, Nadja

    2017-01-01

    Rodent euthanasia using exposure to increasing concentrations of CO2 has come under scrutiny due to concerns of potential pain during the euthanasia process. Alternatives to CO2, such as isoflurane and barbiturates, have been proposed as more humane methods of euthanasia. In this study, we examined 3 commonly used euthanasia methods in mice: intraperitoneal injection of pentobarbital-phenytoin solution, CO2 inhalation, and isoflurane anesthesia followed by CO2 inhalation. We hypothesized that pentobarbital-phenytoin euthanasia would cause fewer alterations in cardiovascular response, result in less behavioral evidence of pain or stress, and produce lower elevations in ACTH than would the isoflurane and CO2 methods, which we hypothesized would not differ in regard to these parameters. ACTH data suggested that pentobarbital-phenytoin euthanasia may be less stressful to mice than are isoflurane and CO2 euthanasia. Cardiovascular, behavioral, and activity data did not consistently or significantly support isoflurane or pentobarbital-phenytoin euthanasia as less stressful methods than CO2. Euthanasia with CO2 was the fastest method of the 3 techniques. Therefore, we conclude that using CO2 with or without isoflurane is an acceptable euthanasia method. Pathologic alterations in the lungs were most severe with CO2 euthanasia, and alternative euthanasia techniques likely are better suited for studies that rely on analysis of the lungs.

  2. A Clinical Evaluation of Gingival Overgrowth in Children on Antiepileptic Drug Therapy.

    PubMed

    Suneja, Bharat; Chopra, Saroj; Thomas, Abi M; Pandian, Jeyraj

    2016-01-01

    Gingival overgrowth, a well-known side effect of chronic phenytoin therapy has also been known to be caused by other anti epileptic drugs (AED's). Various factors like plaque, gingival inflammation, and periodontal health have been postulated to effect gingival overgrowth. To identify the AED having an effect on gingival overgrowth and to study the factors affecting it. Three groups of 30 children each on monotherapy of phenytoin, sodium valproate, and carbamazepine were longitudinally followed for six months. Their oral and epileptic health status was assessed and were monitored for change in plaque levels, gingival inflammation, probing depth and the status of gingival overgrowth at baseline, at the end of 3 months and finally at the end of 6 months. The data was recorded and statistically analysed. Phenytoin caused gingival overgrowth in a significant number of children (53.6%) within 3 months. Sodium valproate also led to gingival overgrowth, but not upto statistically significant levels. Patients on carbamazepine did not show any signs of gingival overgrowth. Gingival overgrowth is seen more on buccal side, in the anterior segment and in the lower arch. No correlation could be found between, either plaque level, or gingival inflammation with gingival overgrowth. Probing depth could be positively correlated with gingival overgrowth. Phenytoin is the drug, which can be chiefly implicated for causing gingival overgrowth. Sodium valproate carries the potential for gingival overgrowth, although only up to clinically insignificant levels in 6 months. Carbamazepine can be considered a safe drug in children in relation to gingival overgrowth.

  3. 2, 5-Disubstituted phthalimides: design, synthesis and anticonvulsant activity in scPTZ and MES models.

    PubMed

    Saadabadi, Atefeh; Kohen, Babak; Irandoust, Maryam; Shafaroudi, Hamed; Mohammadpour, Tara; Rezayat, Mahdi; Davood, Asghar

    2018-05-15

    In this study, fifteenth new 2,5-disubstituted analgouges of phthalimide were designed and synthesized using the appropriate synthetic route to evaluate anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) compare to phenytoin as a positive control. The structures of the synthesized compounds were confirmed by FT-IR, H-NMR, C-NMR and MASS spectroscopy. All the tested compounds were found to be effective in the PTZ model at the dose of 60 mg/kg and most of the compounds showed protection against MES test indicative of their ability to inhibit the seizure spread at the all dose ranges. Compound 3 has illustrated the best efficacy among all compounds and showed more potency than phenytoin in clonic seizure and was potent as phenytoin in tonic seizure. Using a model of the Na channel, these derivatives were docked in the active site. Docking studies displayed that all synthesized compounds have more negative binding energy compare to reference drug and inhibition-constant less than phenytoin that means they can block the receptor more efficiently and usually form hydrophobic interactions or hydrogen binding interaction frequently with the domains I, II, III and rarely with domain IV. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Physiologic, Behavioral, and Histologic Responses to Various Euthanasia Methods in C57BL/6NTac Male Mice

    PubMed Central

    Boivin, Gregory P; Bottomley, Michael A; Schiml, Patricia A; Goss, Lori; Grobe, Nadja

    2017-01-01

    Rodent euthanasia using exposure to increasing concentrations of CO2 has come under scrutiny due to concerns of potential pain during the euthanasia process. Alternatives to CO2, such as isoflurane and barbiturates, have been proposed as more humane methods of euthanasia. In this study, we examined 3 commonly used euthanasia methods in mice: intraperitoneal injection of pentobarbital–phenytoin solution, CO2 inhalation, and isoflurane anesthesia followed by CO2 inhalation. We hypothesized that pentobarbital–phenytoin euthanasia would cause fewer alterations in cardiovascular response, result in less behavioral evidence of pain or stress, and produce lower elevations in ACTH than would the isoflurane and CO2 methods, which we hypothesized would not differ in regard to these parameters. ACTH data suggested that pentobarbital–phenytoin euthanasia may be less stressful to mice than are isoflurane and CO2 euthanasia. Cardiovascular, behavioral, and activity data did not consistently or significantly support isoflurane or pentobarbital–phenytoin euthanasia as less stressful methods than CO2. Euthanasia with CO2 was the fastest method of the 3 techniques. Therefore, we conclude that using CO2 with or without isoflurane is an acceptable euthanasia method. Pathologic alterations in the lungs were most severe with CO2 euthanasia, and alternative euthanasia techniques likely are better suited for studies that rely on analysis of the lungs. PMID:28905718

  5. Fosphenytoin: Current Place in Therapy

    PubMed Central

    Mueller, Eric W.; Boucher, Bradley A.

    2004-01-01

    Fosphenytoin is a parenteral phosphate ester prodrug of phenytoin developed to overcome the limitations associated with parenteral administration of phenytoin. Despite potential clinical advantages, pharmacoeconomic concerns have prevented widespread substitution of parenteral phenytoin with fosphenytoin. The purposes of this descriptive review are to (1) highlight recent clinical and pharmacoeconomic data regarding the therapeutic decision to use phenytoin or fosphenytoin for the parenteral management of acute seizures, and (2) discuss the implications of fosphenytoin use in neonatal and pediatric patients. Supporting recent, multidisciplinary, consensus guidelines, it is our opinion that each patient should be evaluated individually to identify those who will benefit most from fosphenytoin. Such patients may include those without intravenous or enteral access, those requiring parenteral therapy with tenuous peripheral intravenous access, and pediatric and neonatal patients. Additionally, institution-specific cost analyses should be done to assure the most appropriate agent is being used, while being sensitive to the potential disparate risk profiles between patient populations. Until the issues of safety relative to cost are objectively ameliorated, individual clinicians will likely use their own experience to dictate the place of fosphenytoin in their respective practices. PMID:23118706

  6. Nano-extrusion: a promising tool for continuous manufacturing of solid nano-formulations.

    PubMed

    Baumgartner, Ramona; Eitzlmayr, Andreas; Matsko, Nadejda; Tetyczka, Carolin; Khinast, Johannes; Roblegg, Eva

    2014-12-30

    Since more than 40% of today's drugs have low stability, poor solubility and/or limited ability to cross certain biological barriers, new platform technologies are required to address these challenges. This paper describes a novel continuous process that converts a stabilized aqueous nano-suspension into a solid oral formulation in a single step (i.e., the NANEX process) in order to improve the solubility of a model drug (phenytoin). Phenytoin nano-suspensions were prepared via media milling using different stabilizers. A stable nano-suspension was obtained using Tween(®) 80 as a stabilizer. The matrix material (Soluplus(®)) was gravimetrically fed into the hot melt extruder. The suspension was introduced through a side feeding device and mixed with the molten polymer to immediately devolatilize the water in the nano-suspension. Phenytoin nano-crystals were dispersed and embedded in the molten polymer. Investigation of the nano-extrudates via transmission electron microscopy and atomic force microscopy showed that the nano-crystals were embedded de-aggregated in the extrudates. Furthermore, no changes in the crystallinity (due to the mechanical and thermal stress) occurred. The dissolution studies confirmed that the prepared nano-extrudates increased the solubility of nano-crystalline phenytoin, regardless of the polymer. Our work demonstrates that NANEX represents a promising new platform technology in the design of novel drug delivery systems to improve drug performance. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Improving effect of mild foot electrical stimulation on pentylenetetrazole-induced impairment of learning and memory.

    PubMed

    Abasi-Moghadam, Monir; Ghasemi-Dehno, Arefe; Sadegh, Mehdi; Palizvan, Mohammad Reza

    2018-05-10

    Epilepsy is a common neurological disorder that affects learning and memory. Recently it has been shown that mild foot electrical stimulation (MFES) can increase learning and memory in normal rats. Pentylenetetrazole (PTZ) kindling is a model of human epilepsy. As with human epilepsy, PTZ kindling impairs learning and memory in rats. The purpose of this study was to investigate the effect MFES on kindling-induced learning and memory deficits in rats. Forty-nine male Wistar rats weighting 200 to 250 g were divided into the following seven groups: PTZ only, phenytoin only, MFES only, PTZ plus phenytoin, PTZ plus MFES, phenytoin plus MFES, and saline (control), with the treatments administered for 26 days. Forty-eight hours after the last injection, the animals performed the Morris water maze (MWM) task, and spatial learning and memory were measured. The results indicated that although chronic administration of phenytoin inhibited the development of PTZ kindling, it did not exert a protective effect against kindling-induced spatial learning and memory impairment in rats. On the other hand, pretreatment of PTZ-kindled animals with MFES significantly improved spatial working and reference memory. The results point to potential novel beneficial effects of MFES on learning and memory impairment induced by PTZ kindling in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. A Study into the Possible Link between Anti-Epileptic Drugs and the Risk of Fractures in Muckamore Abbey Hospital.

    ERIC Educational Resources Information Center

    Tohill, Carmel

    1997-01-01

    A study investigated whether the effects of anti-epileptic drugs were (carbamazepine, phenobarbitone, and phenytoin) related, to the incidence of fractures in 85 Irish patients. If patients were only on one antiepileptic drug, there appeared to be no correlation; however, if patients were taking a combination of three drugs, they were more likely…

  9. Chronic Glucocorticoids Increase Hippocampal Vulnerability to Neurotoxicity under Conditions That Produce CA3 Dendritic Retraction But Fail to Impair Spatial Recognition Memory

    PubMed Central

    Conrad, Cheryl D.; McLaughlin, Katie J.; Harman, James S.; Foltz, Cainan; Wieczorek, Lindsay; Lightner, Elizabeth; Wright, Ryan L.

    2007-01-01

    We previously found that chronic stress conditions producing CA3 dendritic retraction and spatial memory deficits make the hippocampus vulnerable to the neurotoxin ibotenic acid (IBO). The purpose of this study was to determine whether exposure to chronic corticosterone (CORT) under conditions that produce CA3 dendritic retraction would enhance CA3 susceptibility to IBO. Male Sprague Dawley rats were chronically treated for 21 d with CORT in drinking water (400 μg/ml), and half were given daily injections of phenytoin (40 mg/kg), an antiepileptic drug that prevents CA3 dendritic retraction. Three days after treatments stopped, IBO was infused into the CA3 region. Conditions producing CA3 dendritic retraction (CORT and vehicle) exacerbated IBO-induced CA3 damage compared with conditions in which CA3 dendritic retraction was not observed (vehicle and vehicle, vehicle and phenytoin, CORT and phenytoin). Additionally, spatial recognition memory was assessed using the Y-maze, revealing that conditions producing CA3 dendritic retraction failed to impair spatial recognition memory. Furthermore, CORT levels in response to a potentially mild stressor (injection and Y-maze exposure) stayed at basal levels and failed to differ among key groups (vehicle and vehicle, CORT and vehicle, CORT and phenytoin), supporting the interpretations that CORT levels were unlikely to have been elevated during IBO infusion and that the neuroprotective actions of phenytoin were not through CORT alterations. These data are the first to show that conditions with prolonged glucocorticoid elevations leading to structural changes in hippocampal dendritic arbors can make the hippocampus vulnerable to neurotoxic challenges. These findings have significance for many disorders with elevated glucocorticoids that include depression, schizophrenia, Alzheimer’s disease, and Cushing’s disease. PMID:17670974

  10. Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta‐analysis

    PubMed Central

    Tsaousi, Georgia; Apostolidou, Eirini; Karakoulas, Konstantinos; Kouvelas, Dimitrios; Amaniti, Ekaterini

    2016-01-01

    Aims The aim of this study was to perform an up‐to‐date systematic review and meta‐analysis on the efficacy and safety of prophylactic administration of levetiracetam in brain tumour patients. Method A systematic review of studies published until April 2015 was conducted using Scopus/Elsevier, EMBASE and MEDLINE. The search was limited to articles reporting results from adult patients, suffering from brain tumour, undergoing supratentorial craniotomy for tumour resection or biopsy and administered levetiracetam in the perioperative period for seizure prophylaxis. Outcomes included the efficacy and safety of levetiracetam, as well as the tolerability of the specific regimen, defined by the discontinuation of the treatment due to side effects. Results The systematic review included 1148 patients from 12 studies comparing levetiracetam with no treatment, phenytoin and valproate, while only 243 patients from three studies, comparing levetiracetam vs phenytoin efficacy and safety, were included in the meta‐analysis. The combined results from the meta‐analysis showed that levetiracetam administration was followed by significantly fewer seizures than treatment with phenytoin (OR = 0.12 [0.03–0.42]: χ2 = 1.76: I2 = 0%). Analysis also showed significantly fewer side effects in patients receiving levetiracetam, compared to other groups (P < 0.05). The combined results showed fewer side effects in the levetiracetam group compared to the phenytoin group (OR = 0.65 [0.14–2.99]: χ2 = 8.79: I2 = 77%). Conclusions The efficacy of prophylaxis with levetiracetam seems to be superior to that with phenytoin and valproate administration. Moreover, levetiracetam use demonstrates fewer side effects in brain tumour patients. Nevertheless, high risk of bias and moderate methodological quality must be taken into account when considering these results. PMID:26945547

  11. Hippocampal volume in healthy controls given 3-day stress doses of hydrocortisone.

    PubMed

    Brown, E Sherwood; Jeon-Slaughter, Haekyung; Lu, Hanzhang; Jamadar, Rhoda; Issac, Sruthy; Shad, Mujeeb; Denniston, Daren; Tamminga, Carol; Nakamura, Alyson; Thomas, Binu P

    2015-03-13

    In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing's syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=-0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.

  12. Hippocampal Volume in Healthy Controls Given 3-Day Stress Doses of Hydrocortisone

    PubMed Central

    Brown, E Sherwood; Jeon-Slaughter, Haekyung; Lu, Hanzhang; Jamadar, Rhoda; Issac, Sruthy; Shad, Mujeeb; Denniston, Daren; Tamminga, Carol; Nakamura, Alyson; Thomas, Binu P

    2015-01-01

    In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing's syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=−0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids. PMID:25409592

  13. Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity

    PubMed Central

    Hirashima, Rika; Michimae, Hirofumi; Takemoto, Hiroaki; Sasaki, Aya; Kobayashi, Yoshinori; Itoh, Tomoo; Tukey, Robert H.

    2016-01-01

    Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3′,5′-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)—an enzyme involved in the metabolism of T4—by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile–treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels. PMID:27413119

  14. Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity.

    PubMed

    Hirashima, Rika; Michimae, Hirofumi; Takemoto, Hiroaki; Sasaki, Aya; Kobayashi, Yoshinori; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2016-09-01

    Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3',5'-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)-an enzyme involved in the metabolism of T4-by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile-treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  15. Patch testing and cross sensitivity study of adverse cutaneous drug reactions due to anticonvulsants: A preliminary report.

    PubMed

    Shiny, T N; Mahajan, Vikram K; Mehta, Karaninder S; Chauhan, Pushpinder S; Rawat, Ritu; Sharma, Rajni

    2017-03-26

    To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions (ACDR) from common anticonvulsants. Twenty-four (M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. Clinical patterns were exanthematous drug rash with or without systemic involvement (DRESS) in 18 (75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis (SJS/TEN) overlap and TEN in 2 (8.3%) patients each, SJS and lichenoid drug eruption in 1 (4.2%) patient each, respectively. The implicated drugs were phenytoin in 14 (58.3%), carbamazepine in 9 (37.5%), phenobarbitone in 2 (8.3%), and lamotrigine in 1 (4.7%) patients, respectively. Twelve (50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6 (50%), phenytoin alone in 4 (33.3%), phenobarbitone alone in 1 (8.3%), and both phenytoin and phenobarbitone in 1 (8.33%) patients, respectively. Cross-reactions occurred in 11 (92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three (75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically.

  16. Patch testing and cross sensitivity study of adverse cutaneous drug reactions due to anticonvulsants: A preliminary report

    PubMed Central

    Shiny, T N; Mahajan, Vikram K; Mehta, Karaninder S; Chauhan, Pushpinder S; Rawat, Ritu; Sharma, Rajni

    2017-01-01

    AIM To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions (ACDR) from common anticonvulsants. METHODS Twenty-four (M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. RESULTS Clinical patterns were exanthematous drug rash with or without systemic involvement (DRESS) in 18 (75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis (SJS/TEN) overlap and TEN in 2 (8.3%) patients each, SJS and lichenoid drug eruption in 1 (4.2%) patient each, respectively. The implicated drugs were phenytoin in 14 (58.3%), carbamazepine in 9 (37.5%), phenobarbitone in 2 (8.3%), and lamotrigine in 1 (4.7%) patients, respectively. Twelve (50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6 (50%), phenytoin alone in 4 (33.3%), phenobarbitone alone in 1 (8.3%), and both phenytoin and phenobarbitone in 1 (8.33%) patients, respectively. Cross-reactions occurred in 11 (92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three (75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. CONCLUSION Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically. PMID:28396847

  17. Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.

    PubMed Central

    Riley, R J; Kitteringham, N R; Park, B K

    1989-01-01

    The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism-dependent toxicity of the latter is potentiated by pre-treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase. PMID:2590607

  18. Automated homogeneous liposome immunoassay systems for anticonvulsant drugs.

    PubMed

    Kubotsu, K; Goto, S; Fujita, M; Tuchiya, H; Kida, M; Takano, S; Matsuura, S; Sakurabayashi, I

    1992-06-01

    We developed automated homogeneous immunoassays, based on immunolysis of liposomes, for measuring phenytoin, phenobarbital, and carbamazepine from serum. Liposome lysis was detected spectrophotometrically from entrapped glucose-6-phosphate dehydrogenase activity. The procedure was fully automated on a routine automated clinical analyzer. Within-run, between-run, dilution, and recovery tests showed good accuracies and reproducibilities. Bilirubin, hemoglobin, triglycerides, and Intrafat did not affect assay results. The results obtained by liposome immunoassays for phenytoin, phenobarbital, and carbamazepine correlated well with those obtained by enzyme-multiplied immunoassay (Syva EMIT) kits (r = 0.995, 0.986, and 0.988, respectively) and fluorescence polarization immunoassay (Abbott TDx) kits (r = 0.990, 0.991, and 0.975, respectively). The proposed method should be useful for monitoring anticonvulsant drug concentrations in blood.

  19. DRESS syndrome: A case of cross-reactivity with lacosamide?

    PubMed

    Fong, Man Kei; Sheng, Bun

    2017-06-01

    A 42-year-old patient with epilepsy was admitted to the hospital for fever and generalized skin rash. He has known allergy to phenytoin. Valproate was started in 2012, but failed to control his seizure despite gradual increase in dosage. Phenobarbitone was added 16 days before admission and was stopped on admission. He was treated with beta-lactam antibiotics. The rash subsided gradually after the cessation of phenobarbitone. Lacosamide was subsequently added for seizure control. Unfortunately, he developed drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome soon after introduction of lacosamide that required the use of systemic steroid for acute hepatitis. A cross-reactivity with lacosamide was suspected in view of the rapid onset of DRESS syndrome after the initial rash resolution and soon after the introduction of lacosamide. We postulated that the rapid onset of DRESS syndrome may be related to the aromatic ring that is in common among phenytoin, phenobarbitone, and lacosamide.

  20. Assessing the Efficacy of Poly(N-isopropylacrylamide) for Drug Delivery Applications Using Molecular Dynamics Simulations.

    PubMed

    Moghadam, Soroush; Larson, Ronald G

    2017-02-06

    All-atom molecular dynamic simulations (AA-MD) are performed for aqueous solutions of hydrophobic drug molecules (phenytoin) with model polymer excipients, namely, (1) N-isopropylacrylamide, (pNIPAAm), (2) pNIPAAm-co-acrylamide (Am), and (3) pNIPAAm-co-dimethylacrylamide (DMA). After validating the force field parameters using the well-known lower critical solution behavior of pNIPAAm, we simulate the polymer-drug complex in water and its behavior at temperatures below (295 K) and above the LCST (310 K). Using radial distribution functions, we find that there is an optimum comonomer molar fraction of around 20-30% DMA at which interaction with phenytoin drug molecules is strongest, consistent with recent experimental findings. The results provide evidence that molecular simulations are able to provide guidance in the optimization of novel polymer excipients for drug release.

  1. Intraperitoneal Administration of Ethanol as a Means of Euthanasia for Neonatal Mice (Mus musculus).

    PubMed

    de Souza Dyer, Cecilia; Brice, Angela K; Marx, James O

    2017-05-01

    The humane euthanasia of animals in research is of paramount importance. Neonatal mice frequently respond differently to euthanasia agents when compared with adults. The AVMA's Guidelines for the Euthanasia of Animals includes intraperitoneal injection of ethanol as "acceptable with conditions," and recent work confirmed that this method is appropriate for euthanizing adult mice, but neonatal mice have not been tested. To explore this method in neonatal mice, mouse pups (C57BL/6 and CD1, 162 total) were injected with 100% ethanol, a pentobarbital-phenytoin combination, or saline at 7, 14, 21, 28, or 35 d of age. Electrocardiograms, respiratory rates, and times to loss of righting reflex and death were recorded. Time to death (TTD) differed significantly between ethanol and pentobarbital-phenytoin at 7, 14, and 21 d and between ethanol groups at 7, 14, and 21 d compared with 35 d. The average TTD (± 1 SD) for ethanol-injected mice were: 7 d, 70.3 ± 39.8 min; 14 d, 51.7 ± 30.5 min; 21 d, 32.3 ± 20.8 min, 28 d, 14.0 ± 15.2; and 35 d, 4.9 ± 1.4. Mean TTD in pentobarbital-phenytoin-injected mice were: 7 d, 2.8 ± 0.4 min; 14 d, 2.9 ± 0.5 min; 21 d, 3.9 ± 1.2 min; 28 d, 3.9 ± 0.7 min; and 35 d, 4.4 ± 0.5. Although TTD did not differ between ethanol and pentobarbital-phenytoin at 28 d of age, the TTD in 3 of 12 mice was longer than 15 min after ethanol administration at this age. Therefore, ethanol should not be used as a method of euthanasia for mice younger than 35 d, because the criteria for humane euthanasia were met only in mice 35 d or older.

  2. Acne and anticonvulsants.

    PubMed Central

    Greenwood, R; Fenwick, P B; Cunliffe, W J

    1983-01-01

    The severity of acne and rate of excretion of sebum were assessed in 243 patients with epilepsy taking various anticonvulsants who were in hospital long term and in matched controls derived from a normal population of 2176 people. Neither the prevalence of acne nor the sebum excretion rate significantly increased in the patients compared with the controls or in patients taking phenytoin compared with those not. It is concluded that anticonvulsant treatment does not cause acne. PMID:6227369

  3. Preanesthetic Assessment of Herbal and Dietary Supplement Use

    DTIC Science & Technology

    2000-10-01

    anticoagulant therapy. Ginkgo has been reported to diminish the effectiveness of anticonvulsants such as carbamazepine, phenytoin , and phenobarbital by lowering...been implicated in drug interactions (DeSmet & D Arcy, 1996). Vitamin B6 can nullify the effects of L-dopa in patients with Parkinson disease...Intraoperative Parkinsonism has been associated with a neuroleptic malignant- like syndrome potentially creating unnecessary and inappropriate delay in

  4. Design of porous microparticles with single-micron size by novel spray freeze-drying technique using four-fluid nozzle.

    PubMed

    Niwa, Toshiyuki; Shimabara, Hiroko; Kondo, Masahiro; Danjo, Kazumi

    2009-12-01

    Spray freeze-drying (SFD) process, which is a novel particle design technique previously developed by authors, has been improved by using four-fluid nozzle (4N) instead of conventional two-fluid nozzle (2N) to expand its application in pharmaceutical industry. Aqueous spray solutions of the drug and the polymeric carrier were separately supplied into 4N, and atomized while colliding with each other at the tip of nozzle. The droplets of mixed solutions were directly immersed into liquid nitrogen and immediately frozen to form a suspension. Then, the iced droplets were lyophilized by freeze-dryer to prepare the composite particles of the drug and carrier. This process has been used in the present study to modify and enhance the dissolution profiles of poorly water-soluble drug, phenytoin. Water-soluble and enteric polymeric carriers in pharmaceutical use were used as a dissolution modifier. The SFD composite particles prepared by using 4N were fully characterized compared to those using 2N from morphological and physicochemical perspectives. It was found that the particles have fine porous structure producing vast specific surface area. Further, phenytoin was completely dispersed as amorphous state in the polymeric matrix with higher carrier ratio than phenytoin:carrier = 1:3. The dissolution of phenytoin from the water-soluble carrier-based particles was greatly enhanced because of large effective surface area and disappearance of crystalline. On the other hand, the release profiles from enteric carrier-based particles showed the typical enteric patterns, that is, delayed in acidic medium and accelerated in neutral pH. The results demonstrated that SFD technique using 4N has potential to develop the novel solubilized formulation for poorly water-soluble APIs.

  5. Cavitary pulmonary nodules in atypical collagen disease and lupoid drug reaction. Report of two cases.

    PubMed

    Muren, C; Strandberg, O

    1989-01-01

    The case histories of two patients with cavitary pulmonary nodules and the findings at chest radiography are reviewed. The first patient had a connective tissue disease with features common to systematic lupus erythematosus and Wegener's granulomatosis. In the second patient the lung changes developed as part of a drug reaction to carbamezapine and/or phenytoin. The common denominator of the cavitating nodules is probably the presence of granulomas, developing as a sequela of pulmonary vasculitis.

  6. A Clinical Evaluation of Gingival Overgrowth in Children on Antiepileptic Drug Therapy

    PubMed Central

    Chopra, Saroj; Thomas, Abi M; Pandian, Jeyraj

    2016-01-01

    Introduction Gingival overgrowth, a well-known side effect of chronic phenytoin therapy has also been known to be caused by other anti epileptic drugs (AED’s). Various factors like plaque, gingival inflammation, and periodontal health have been postulated to effect gingival overgrowth. Aim To identify the AED having an effect on gingival overgrowth and to study the factors affecting it. Materials and Methods Three groups of 30 children each on monotherapy of phenytoin, sodium valproate, and carbamazepine were longitudinally followed for six months. Their oral and epileptic health status was assessed and were monitored for change in plaque levels, gingival inflammation, probing depth and the status of gingival overgrowth at baseline, at the end of 3 months and finally at the end of 6 months. The data was recorded and statistically analysed. Results Phenytoin caused gingival overgrowth in a significant number of children (53.6%) within 3 months. Sodium valproate also led to gingival overgrowth, but not upto statistically significant levels. Patients on carbamazepine did not show any signs of gingival overgrowth. Gingival overgrowth is seen more on buccal side, in the anterior segment and in the lower arch. No correlation could be found between, either plaque level, or gingival inflammation with gingival overgrowth. Probing depth could be positively correlated with gingival overgrowth. Conclusion Phenytoin is the drug, which can be chiefly implicated for causing gingival overgrowth. Sodium valproate carries the potential for gingival overgrowth, although only up to clinically insignificant levels in 6 months. Carbamazepine can be considered a safe drug in children in relation to gingival overgrowth. PMID:26894172

  7. [Pharmacology of a 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), a new sleep-inducer (III). Behavioral study on interactions of 450191-S and other drugs in mice].

    PubMed

    Ibii, N; Horiuchi, M; Yamamoto, K

    1984-08-01

    Interactions between 450191-S and other representative drugs which might be clinically used with 450191-S were behaviorally investigated in mice, and compared with the cases of nitrazepam, estazolam and triazolam. The potencies of 450191-S and nitrazepam in preventing pentetrazol convulsions were markedly decreased by aminopyrine, whereas that of estazolam was remarkably increased by phenytoin. Administration of nitrazepam with other drugs, except aminopyrine, or of estazolam together with haloperidol exhibited an anticonvulsive pattern different from the case of dosing with either drug alone. Only the effect of triazolam was not influenced by any drugs used. The potency of haloperidol against apomorphine-induced climbing behavior was significantly reduced by nitrazepam, and the pattern of the haloperidol effect was changed by treatment together with 450191-S or estazolam. However, triazolam had no influence on the effect of haloperidol. The antagonistic activity of imipramine to reserpine-induced hypothermia was slightly decreased by 450191-S, estazolam and triazolam, but little affected by nitrazepam. In the protection from maximal electroshock convulsions (MEC), the potency of phenytoin was significantly decreased by 450191-S and triazolam. Moreover, the anti-MES pattern of phenytoin was altered by nitrazepam. Estazolam exerted no significant influence on the effect of phenytoin. Analgesic activities of morphine and/or aminopyrine were potentiated by pretreatment with sleep-inducers, but not 450191-S. Thus, judging from the potency and stability of the anti-pentetrazol effect, 450191-S seems to be inferior to triazolam, but superior to nitrazepam and estazolam. Also, 450191-S may be differentiated from other sleep-inducers by the fact that only 450191-S did not potentiate the analgesic activities of morphine and aminopyrine.

  8. Mapping the availability, price, and affordability of antiepileptic drugs in 46 countries.

    PubMed

    Cameron, Alexandra; Bansal, Amit; Dua, Tarun; Hill, Suzanne R; Moshe, Solomon L; Mantel-Teeuwisse, Aukje K; Saxena, Shekhar

    2012-06-01

    In low- and middle-income countries (LMICs), a large proportion of people with epilepsy do not receive treatment. An analysis of the availability, price, and affordability of antiepileptic drugs (AEDs) was conducted to evaluate whether these factors contribute to the treatment gap. Data for five AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, and diazepam) were obtained from facility-based surveys conducted in 46 countries using the World Health Organization/Health Action International (WHO/HAI) methodology. Outcome measures were percentage availability, ratios of local prices to international reference prices, and number of days' wages needed by the lowest-paid unskilled government worker to purchase treatment. Prices were adjusted for inflation/deflation and purchasing power parity. The average availability of generic AEDs in the public sector was <50% for all medicines except diazepam injection. Private sector availability of generic oral AEDs ranged from 42.2% for phenytoin to 69.6% for phenobarbital. Public sector patient prices for generic carbamazepine and phenytoin were 4.95 and 17.50 times higher than international reference prices, respectively, whereas private sector patient prices were 11.27 and 24.77 times higher, respectively. For both medicines, originator brand prices were about 30 times higher. The highest prices were observed in the lowest income countries. The lowest-paid government worker would need wages from 1-2.6 days' to purchase a month's supply of phenytoin, whereas carbamazepine would cost 2.7-16.2 days' wages. Despite its widespread use in LMICs, WHO/HAI survey data for phenobarbital was only available from a small number of countries. In LMICs, availability and affordability of AEDs are poor and may be acting as a barrier to accessing treatment for epilepsy. Ensuring a consistent supply of AEDs at an affordable price should be a priority. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

  9. Coarse-grained modeling of crystal growth and polymorphism of a model pharmaceutical molecule.

    PubMed

    Mandal, Taraknath; Marson, Ryan L; Larson, Ronald G

    2016-10-04

    We describe a systematic coarse-graining method to study crystallization and predict possible polymorphs of small organic molecules. In this method, a coarse-grained (CG) force field is obtained by inverse-Boltzmann iteration from the radial distribution function of atomistic simulations of the known crystal. With the force field obtained by this method, we show that CG simulations of the drug phenytoin predict growth of a crystalline slab from a melt of phenytoin, allowing determination of the fastest-growing surface, as well as giving the correct lattice parameters and crystal morphology. By applying meta-dynamics to the coarse-grained model, a new crystalline form of phenytoin (monoclinic, space group P2 1 ) was predicted which is different from the experimentally known crystal structure (orthorhombic, space group Pna2 1 ). Atomistic simulations and quantum calculations then showed the polymorph to be meta-stable at ambient temperature and pressure, and thermodynamically more stable than the conventional orthorhombic crystal at high pressure. The results suggest an efficient route to study crystal growth of small organic molecules that could also be useful for identification of possible polymorphs as well.

  10. Site of anticonvulsant action on sodium channels: autoradiographic and electrophysiological studies in rat brain

    SciTech Connect

    Worley, P.F.; Baraban, J.M.

    1987-05-01

    The anticonvulsants phenytoin and carbamazepine interact allosterically with the batrachotoxin binding site of sodium channels. In the present study, we demonstrate an autoradiographic technique to localize the batrachotoxin binding site on sodium channels in rat brain using (/sup 3/H)batrachotoxinin-A 20-alpha-benzoate (BTX-B). Binding of (/sup 3/H)BTX-B to brain sections is dependent on potentiating allosteric interactions with scorpion venom and is displaced by BTX-B (Kd approximately 200 nM), aconitine, veratridine, and phenytoin with the same rank order of potencies as described in brain synaptosomes. The maximum number of (/sup 3/H)BTX-B binding sites in forebrain sections also agrees with biochemical determinations. Autoradiographic localizationsmore » indicate that (/sup 3/H)BTX-B binding sites are not restricted to cell bodies and axons but are present in synaptic zones throughout the brain. For example, a particularly dense concentration of these sites in the substantia nigra is associated with afferent terminals of the striatonigral projection. By contrast, myelinated structures possess much lower densities of binding sites. In addition, we present electrophysiological evidence that synaptic transmission, as opposed to axonal conduction, is preferentially sensitive to the action of aconitine and veratridine. Finally, the synaptic block produced by these sodium channel activators is inhibited by phenytoin and carbamazepine at therapeutic anticonvulsant concentrations.« less

  11. Preventing Small Molecule Nucleation and Crystallization by Sequestering in a Micelle Corona

    NASA Astrophysics Data System (ADS)

    Li, Ziang; Johnson, Lindsay; Ricarte, Ralm; Yao, Letitia; Hillmyer, Marc; Bates, Frank; Lodge, Timothy

    We exploited a blend of hydroxypropyl methylcellulose acetate succinate and poly(N-isopropylacrylamide) (PNIPAm) to improve the solubility and dissolution of a rapidly crystallizing model drug molecule phenytoin and observed synergistic effect in vitro at constant drug loading by varying the blending ratio. Dynamic and static light scattering experiments showed that PNIPAm self-assembled into micelles in aqueous solution. We believe that adding these PNIPAm micelles inhibited both nucleation and crystal growth of phenytoin based on the polarized light micrographs taken from the dissolution media. The drug-polymer intermolecular interaction was revealed by nuclear Overhauser effect spectroscopy and further quantified by diffusion ordered spectroscopy. We found that the phenytoin molecules were sequestered in aqueous solution by partitioning into the corona of the micelle. The blend strategy through the use of self-assembled micelles showcased in this study offers a new platform for designing advanced excipients for oral drug delivery. This study was funded by The Dow Chemical Company through Agreement 224249AT with the University of Minnesota.

  12. Periodontal and oral manifestations of marijuana use.

    PubMed

    Rawal, Swati Y; Tatakis, Dimitris N; Tipton, David A

    2012-01-01

    Marijuana, prepared from the plant Cannabis sativa, is the most widely used illicit drug in the United States. Marijuana use has been associated with adverse psychosocial and health effects, including effects on oral tissues. Periodontal literature has limited references to the periodontal effects of cannabis use. In this report, we present two cases of marijuana-associated gingival enlargement and review the literature on oral complications of marijuana use. Two asymptomatic males, aged 23 and 42 years, presented independently for oral prophylaxis. Both had an unremarkable medical history and related a history of significant marijuana use of 2-16 years duration. Common findings following oral and periodontal examination were nicotinic stomatitis-like lesions, uvulitis and gingival enlargement. Marginal and papillary gingiva of the anterior dentition were the areas primarily affected by gingival enlargement, while some of these areas exhibited a nodular or "pebbly" appearance. Marijuana-associated gingival enlargement was diagnosed in the reported cases. A review of the literature revealed two other reports of marijuana-associated gingival enlargement, all in young adult males with chronic (2 or more years) cannabis use. These authors reported a resemblance to phenytoin-induced enlargement. Biochemical similarities between phenytoin and cannabis active compounds suggest possible common pathogenetic mechanisms. Uvulitis and nicotinic stomatitis appear to be the two most common of the several oral manifestations of marijuana use. Chronic marijuana use may result in gingival enlargement with clinical characteristics similar to phenytoin-induced enlargement.

  13. Classical Michaelis-Menten and system theory approach to modeling metabolite formation kinetics.

    PubMed

    Popović, Jovan

    2004-01-01

    When single doses of drug are administered and kinetics are linear, techniques, which are based on the compartment approach and the linear system theory approach, in modeling the formation of the metabolite from the parent drug are proposed. Unlike the purpose-specific compartment approach, the methodical, conceptual and computational uniformity in modeling various linear biomedical systems is the dominant characteristic of the linear system approach technology. Saturation of the metabolic reaction results in nonlinear kinetics according to the Michaelis-Menten equation. The two compartment open model with Michaelis-Menten elimination kinetics is theorethicaly basic when single doses of drug are administered. To simulate data or to fit real data using this model, one must resort to numerical integration. A biomathematical model for multiple dosage regimen calculations of nonlinear metabolic systems in steady-state and a working example with phenytoin are presented. High correlation between phenytoin steady-state serum levels calculated from individual Km and Vmax values in the 15 adult epileptic outpatients and the observed levels at the third adjustment of phenytoin daily dose (r=0.961, p<0.01) were found.

  14. Enzyme induction in neonates after fetal exposure to antiepileptic drugs

    SciTech Connect

    Rating, D.; Jaeger-Roman, E.; Nau, H.

    1983-01-01

    The /sup 13/C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to /sup 13/C-AP breath tests, neonates have a very low capacity to eliminate /sup 13/CO/sub 2/, which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs /sup 13/C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerablymore » stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, /sup 13/C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by /sup 13/C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between /sup 13/C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the /sup 13/C breath test data will transport very different informations about enzyme induction in these neonates.« less

  15. Quantitative Analysis of the Area of the Apical Ectodermal Ridge in Chick Appendages Using Image-J.

    PubMed

    Syed, Hamd Binte Shahab; Khan, Muhammad Yunus

    2018-06-01

    To determine the effect of sodium phenytoin on the apical ectodermal ridges (AER) of chick wing buds by using the software program Image-J. An experimental study. Department of Anatomy, Regional Center, College of Physicians and Surgeons Pakistan (CPSP), Islamabad, from January 2014 to January 2015. Sixty fertilised chicken eggs of 'Egyptian fayoumi' breed were selected and separated into experimental (B) and control (A) groups, each having 30 eggs. A single dose of 3.5 mg sodium phenytoin was injected into each egg of the experimental group. The controls were injected with the same volume of normal saline. Developing embryos were extracted 96 hours (day 4) after incubation and histological sections were cut at 5 μm thickness. These sections were stained with Feulgen Nuclear and Light Green. The area of apical ectodermal ridges of chick wing buds was calculated by employing Image-J and subjected to statistical analysis. The difference between the mean values of the area of apical ectodermal ridges of experimental and control groups, as calculated by Image-J, was found to be statistically insignificant. Change in the area of the apical ectodermal ridges in experimental chicks, following phenytoin exposure, was insignificant as proven on the basis of quantification by Image-J.

  16. Valerenic acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish).

    PubMed

    Torres-Hernández, Bianca A; Del Valle-Mojica, Lisa M; Ortíz, José G

    2015-07-14

    Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis. Our aims were to examine the anticonvulsant properties of valerenic acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs. All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, valerenic acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with valerenic acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p < 0.05 level of significance. All treatments were compared with the untreated animals and with the other pretreatments. After exposure to pentylenetetrazole, zebrafish exhibited a series of stereotypical behaviors prior to the appearance of clonic-like movements--convulsions. Both valerenic acid and valerian extracts (aqueous and ethanolic) significantly extended the latency period to the onset of seizure (convulsion) in adult zebrafish. The ethanolic valerian extract was a more potent anticonvulsant than the aqueous extract. Valerenic acid and both valerian extracts interacted synergistically with clonazepam to extended the

  17. Effect of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of classical antiepileptic drugs against maximal electroshock-induced seizures in mice.

    PubMed

    Zagaja, Miroslaw; Pyrka, Daniel; Skalicka-Wozniak, Krystyna; Glowniak, Kazimierz; Florek-Luszczki, Magdalena; Glensk, Michał; Luszczki, Jarogniew J

    2015-09-01

    The effects of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Results indicate that xanthotoxin (50 and 100 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures (P<0.05 and P<0.001, respectively). Similarly, xanthotoxin (100 mg/kg, i.p.) markedly enhanced the anticonvulsant action of valproate in the maximal electroshock seizure test (P<0.001). In contrast, xanthotoxin (100 mg/kg, i.p.) did not affect the protective action of phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Moreover, xanthotoxin (100 mg/kg, i.p.) significantly increased total brain concentrations of carbamazepine (P<0.001) and valproate (P<0.05), but not those of phenytoin and phenobarbital, indicating pharmacokinetic nature of interactions between drugs. In conclusion, the combinations of xanthotoxin with carbamazepine and valproate, despite their beneficial effects in terms of seizure suppression in mice, were probably due to a pharmacokinetic increase in total brain concentrations of these antiepileptic drugs in experimental animals. Copyright © 2015. Published by Elsevier B.V.

  18. Valproate overdose: a comparative cohort study of self poisonings

    PubMed Central

    Isbister, Geoffrey K; Balit, Corrine R; Whyte, Ian M; Dawson, Andrew

    2003-01-01

    Aims Based on individual case reports of massive overdoses, valproate is often regarded as having significant toxicity. This study aimed to describe the epidemiology of valproate poisoning and the spectrum of its clinical effects. Methods Consecutive valproate poisonings were identified and compared with other anticonvulsant overdoses and all other poisonings, from a prospective database of poisoning admissions presenting to a regional toxicology service. National prescription data for the same period were obtained. Results There were 79 patients with valproate poisoning from January 1991 to November 2001, 15 cases with valproate alone. Of the 15 cases, drowsiness occurred in two patients (both taking>200 mg kg−1), vomiting occurred in four and tachycardia in five. In patients co-ingesting other medications, moderate to severe effects were consistent with the co-ingestants. There was one death not directly related to valproate. One patient had metabolic acidosis and thrombocytopaenia consistent with severe valproate toxicity. Comparison of valproate, carbamazepine, phenytoin and control groups showed that length of stay for both phenytoin and carbamazepine was significantly longer than for valproate (P < 0.0001), and there was a significantly increased risk of intensive care unit admission for carbamazepine vs valproate (OR 2.73; 95% CI 1.22, 6.28; P = 0.015). Although valproate prescriptions increased over the 10 years, there was relatively greater increase in the incidence of valproate poisoning. The odds of a valproate overdose in 1992 compared with carbamazepine were 0.29 (95% CI 0.07, 1.28; P = 0.141), but in 2001 were 2.73 (95% CI 1.38, 5.39; P = 0.004). Conclusions Valproate causes mild toxicity in the majority of cases. Massive overdoses of greater than 400 mg kg−1 can cause severe toxicity, but these are uncommon. The older anticonvulsants phenytoin and carbamazepine remain a greater problem than valproate in overdose. PMID:12680889

  19. Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes

    PubMed Central

    Harden, C. L.; Meador, K. J.; Pennell, P. B.; Hauser, W. A.; Gronseth, G. S.; French, J. A.; Wiebe, S.; Thurman, D.; Koppel, B. S.; Kaplan, P. W.; Robinson, J. N.; Hopp, J.; Ting, T. Y.; Gidal, B.; Hovinga, C. A.; Wilner, A. N.; Vazquez, B.; Holmes, L.; Krumholz, A.; Finnell, R.; Hirtz, D.; Le Guen, C.

    2009-01-01

    Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. Methods: Systematic review of relevant articles published between January 1985 and June 2007. Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. Recommendations: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C). PMID:19398681

  20. Pain management strategies for neuropathic pain in Fabry disease--a systematic review.

    PubMed

    Schuller, Y; Linthorst, G E; Hollak, C E M; Van Schaik, I N; Biegstraaten, M

    2016-02-24

    Neuropathic pain is one of the key features of (classical) Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies. PubMed and Embase were searched up to September 2014 for relevant articles on treatment of neuropathic pain in FD. Seven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8. Carbamazepine appeared most beneficial: complete pain relief in 5/25, partial relief in 17/25, and no benefit in 3/25 patients. Phenytoin resulted in complete relief in 1/27, partial relief in 12/27 and no benefit in 6/27 patients. In 8 patients a significant reduction in the frequency of pain attacks was described. Gabapentin caused partial relief in 6/7 and no relief in 1/7 patients. Little evidence was reported for SSNRI's or treatment combinations. Adverse-effects were reported in all treatment strategies. Only for carbamazepine, phenytoin and gabapentin there is evidence of effectiveness in neuropathic pain due to FD, but comparison of effectiveness between these drugs is lacking. In routine clinical practice adverse-effects may discourage use of carbamazepine and phenytoin in favor of second-generation antiepileptic drugs, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies.

  1. Drug-Induced Gingival Overgrowth: The Genetic Dimension

    PubMed Central

    Charles, Noronha Shyam Curtis; Chavan, Rahul; Moon, Ninad Joshirao; Nalla, Srinivas; Mali, Jaydeepchandra; Prajapati, Anchal

    2014-01-01

    Background: Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Phenytoin, one of the common drugs implicated in gingival enlargement, is metabolized mainly by cytochrome P450 (CYP)2C9 and partly by CYP2C19. The CYP2C9 and CYP2C19 genes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. Aims: The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 variant genotypes on phenytoin hydroxylation in subjects diagnosed with epilepsy from South India, thus establishing the genetic polymorphisms leading to its defective hydroxylation process. Materials and Methods: Fifteen epileptic subjects, age 9 to 60 years were included in the study. Among the study subjects, 8 were males and 7 were females. Genomic DNA was extracted from patients’ blood using Phenol-chloroform method and genotyping was done for CYP2C9 using customized TaqMan genotyping assays on a real time thermocycler, by allelic discrimination method. The genetic polymorphisms *1, *2 and *3 on CYP2C9 were selected based on their function and respective allele frequencies in Asian subcontinent among the Asian populations. Results: CYP2C9*1*2 and CYP2C9*3/*3 were identified with equal frequency in the study population. There were seven subjects with CYP2C9*1/*2 genotype (heterozygous mutant), one subject with CYP2C9*1/*1 (wild type) and seven study subjects with CYP2C9*3/*3 (homozygous mutant). Conclusion: The results obtained in the present study will be helpful in the medical prescription purposes of phenytoin, and a more personalized patient approach with its administration can be advocated. PMID:25317394

  2. Drug-induced gingival overgrowth: the genetic dimension.

    PubMed

    Charles, Noronha Shyam Curtis; Chavan, Rahul; Moon, Ninad Joshirao; Nalla, Srinivas; Mali, Jaydeepchandra; Prajapati, Anchal

    2014-09-01

    Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Phenytoin, one of the common drugs implicated in gingival enlargement, is metabolized mainly by cytochrome P450 (CYP)2C9 and partly by CYP2C19. The CYP2C9 and CYP2C19 genes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 variant genotypes on phenytoin hydroxylation in subjects diagnosed with epilepsy from South India, thus establishing the genetic polymorphisms leading to its defective hydroxylation process. Fifteen epileptic subjects, age 9 to 60 years were included in the study. Among the study subjects, 8 were males and 7 were females. Genomic DNA was extracted from patients' blood using Phenol-chloroform method and genotyping was done for CYP2C9 using customized TaqMan genotyping assays on a real time thermocycler, by allelic discrimination method. The genetic polymorphisms *1, *2 and *3 on CYP2C9 were selected based on their function and respective allele frequencies in Asian subcontinent among the Asian populations. CYP2C9*1*2 and CYP2C9*3/*3 were identified with equal frequency in the study population. There were seven subjects with CYP2C9*1/*2 genotype (heterozygous mutant), one subject with CYP2C9*1/*1 (wild type) and seven study subjects with CYP2C9*3/*3 (homozygous mutant). The results obtained in the present study will be helpful in the medical prescription purposes of phenytoin, and a more personalized patient approach with its administration can be advocated.

  3. A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice.

    PubMed

    Aiyer, Rohit; Mehta, Neel; Gungor, Semih; Gulati, Amitabh

    2018-05-01

    To investigate the efficacy of N-methyl-D-aspartate receptor (NMDAR) antagonists for neuropathic pain (NeuP) and review literature to determine if specific pharmacologic agents provide adequate NeuP relief. Literature was reviewed on PubMed using a variety of key words for 8 NMDAR antagonists. These key words include: "Ketamine and Neuropathy," "Ketamine and Neuropathic Pain," "Methadone and Neuropathy," "Methadone and Neuropathic Pain," "Memantine and Neuropathic pain," "Memantine and Neuropathy," "Amantadine and Neuropathic Pain," "Amantadine and Neuropathy," "Dextromethorphan and Neuropathic Pain," "Dextromethorphan and Neuropathy," "Carbamazepine and Neuropathic Pain," "Carbamazepine and Neuropathy," "Valproic Acid and Neuropathy," "Valproic Acid and Neuropathic Pain," "Phenytoin and Neuropathy," and "Phenytoin and Neuropathic Pain." With the results, the papers were reviewed using the PRISMA (Preferred Reporting in Systematic and Meta-Analyses) guideline. A total of 58 randomized controlled trials were reviewed among 8 pharmacologic agents, which are organized by date and alphabetical order. Of the trials for ketamine, 15 showed some benefit for analgesia. Methadone had 3 positive trials, while amantadine and memantine each only had 2 trials showing NeuP analgesic properties. Dextromethorphan and valproic acid both had 4 randomized controlled trials that showed some NeuP treatment benefit while carbamazepine had over 8 trials showing efficacy. Finally, phenytoin only had 1 trial that showed clinical response in treatment. There are a variety of NMDAR antagonist agents that should be considered for treatment of NeuP. Nevertheless, continued and further investigation of the 8 pharmacologic agents is needed to continue to evaluate their efficacy for treatment of NeuP.

  4. Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

    PubMed

    Šíma, M; Pokorná, P; Hronová, K; Slanař, O

    2015-01-01

    Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

  5. Solubilization and characterization of haloperidol-sensitive (+)-( sup 3 H)SKF-10,047 binding sites (sigma sites) from rat liver membranes

    SciTech Connect

    McCann, D.J.; Su, T.P.

    1991-05-01

    The zwitterionic detergent 3-((3-cholamidopropyl)dimethylamino)-1-propanesulfonate (CHAPS) produced optimal solubilization of (+)-({sup 3}H)SKF-10,047 binding sites from rat liver membranes at a concentration of 0.2%, well below the critical micellular concentration of the detergent. The pharmacological selectivity of the liver (+)-({sup 3}H)SKF-10,047 binding sites corresponds to that of sigma sites from rat and guinea pig brain. When the affinities of 18 different drugs at (+)-({sup 3}H)SKF-10,047 binding sites in membranes and solubilized preparations were compared, a correlation coefficient of 0.99 and a slope of 1.03 were obtained, indicating that the pharmacological selectivity of rat liver sigma sites is retained after solubilization. In addition,more » the binding of 20 nM ({sup 3}H)progesterone to solubilized rat liver preparations was found to exhibit a pharmacological selectivity appropriate for sigma sites. A stimulatory effect of phenytoin on (+)-({sup 3}H)SKF-10,047 binding to sigma sites persisted after solubilization. When the solubilized preparation was subjected to molecular sizing chromatography, a single peak exhibiting specific (+)-({sup 3}H)SKF-10,047 binding was obtained. The binding activity of this peak was stimulated symmetrically when assays were performed in the presence of 300 microM phenytoin. The molecular weight of the CHAPS-solubilized sigma site complex was estimated to be 450,000 daltons. After solubilization with CHAPS, rat liver sigma sites were enriched to 12 pmol/mg of protein. The present results demonstrate a successful solubilization of sigma sites from rat liver membranes and provide direct evidence that the gonadal steroid progesterone binds to sigma sites. The results also suggest that the anticonvulsant phenytoin binds to an associated allosteric site on the sigma site complex.« less

  6. Real-world cost-effectiveness of pharmacogenetic screening for epilepsy treatment.

    PubMed

    Chen, Zhibin; Liew, Danny; Kwan, Patrick

    2016-03-22

    To assess the cost-effectiveness of the HLA-B*15:02 screening policy for the treatment of epilepsy in Hong Kong. From all public hospitals and clinics in Hong Kong, 13,231 patients with epilepsy who started their first antiepileptic drug (AED) between September 16, 2005, and September 15, 2011 (3 years before and 3 years after policy implementation on September 16, 2015), were identified retrospectively. A decision tree model was constructed to incorporate the real-world data on AED prescription patterns, incidences of AED-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), costs of AED treatments, SJS/TEN treatment, and HLA-B*15:02 testing, and quality of life. Cost-effectiveness of the screening policy was analyzed for 3 scenarios: (1) current real-world situation, (2) "ideal" situation assuming full policy adherence and preferable testing practices, and (3) "extended" situation simulating the extension of HLA-B*15:02 screening to phenytoin in ideal practice. The current screening policy was associated with an incremental cost-effectiveness ratio of US $85,697 per quality-adjusted life year (QALY) compared with no screening. The incremental cost-effectiveness ratio was estimated to be US $11,090/QALY in the ideal situation and US $197,158/QALY in the extended situation. The HLA-B*15:02 screening policy, as currently practiced, is not cost-effective. Its cost-effectiveness may be improved by enhancing policy adherence and by low-cost point-of-care genotyping. Extending the screening to phenytoin would not be cost-effective because of the low incidence of phenytoin-SJS/TEN among HLA-B*15:02 carriers. © 2016 American Academy of Neurology.

  7. Antinociceptive activity of novel amide derivatives of imidazolidine-2,4-dione in a mouse model of acute pain.

    PubMed

    Czopek, Anna; Sałat, Kinga; Byrtus, Hanna; Rychtyk, Joanna; Pawłowski, Maciej; Siwek, Agata; Soluch, Joanna; Mureddu, Valentina; Filipek, Barbara

    2016-06-01

    Antiepileptic drugs are commonly used in non-epileptic disorders. For example, phenytoin and levetiracetam demonstrate analgesic properties in rodent models of pain. In order to enhance their antinociceptive activity, structural features of phenytoin and levetiracetam, such as imidazolidine-2,4-dione and amide bond in alkyl chain, were combined in one molecule. Furthermore, in preliminary studies, methoxyphenylpiperazinpropyl derivatives of imidazolidine-2,4-dione acted as antinociceptive agents in several rodent models of acute pain. The final compounds and the reference drugs - levetiracetam and phenytoin were evaluated in the hot plate test to assess their antinociceptive activity in this acute pain model. Furthermore, for the analgesic active compounds the impact on animals' locomotor activity and motor performance were estimated and the affinity to serotonergic (5-HT1A, 5-HT7) and adrenergic (α1) receptors was determined. Three of the tested compounds: 7, 15 and 18 showed statistically significant antinociceptive properties at the dose of 30mg/kg. Among them, compound 18, 1-methyl-3-[1-(morpholin-4-yl)-1-oxobutan-2-yl]imidazolidine-2,4-dione, exhibited the most significant and long-lasting antinociceptive activity. Noteworthy, this activity was not associated with a negative effect on animals' motor functions. Serotonergic or adrenergic neurotransmission is not involved in this antinociceptive effect. Some amide derivatives of imidazolidine-2,4-diones possess antinociceptive properties in mice but further studies are needed to explain their mechanism of action and assess their toxicity. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Use of anti-epileptic drugs in a tertiary care hospital of Eastern India with emphasis on epilepsy due to neurocysticercosis.

    PubMed

    Sil, Amrita; Das, Kamalesh; Das, Nilay K; Chakraborty, Dibyendu; Mazumdar, Goutameswar; Tripathi, Santanu K

    2012-01-01

    Epilepsy is a chronic disease and neurocysticercosis is an important cause of secondary seizures. Its therapy is modified by a number of parameters and thus the pattern of anti-epileptic drugs used varies in different clinical settings. It was our objective to evaluate clinico-demographic and treatment profile of epilepsy patients attending neurology outpatient department, efficacy and side-effect profile of anti-epileptic drugs with special emphasis on epilepsy resulting from neurocysticercosis. This was a cross-sectional descriptive study of epilepsy patients over four months in neurology outpatient department. Clinico-biological data were obtained by interrogating patients and from recorded data using standard case-report form. 79 patients were studied with 54.43% having primary etiology, 40.51% having seizures secondary to neurocysticercosis. 81% had generalized tonic-clonic seizure, 17.7% partial and 1.3% myoclonic seizures. Phenytoin (86.08%), valproate (30.38%), clobazam (26.58%) and carbamazepine (10.13%) were used either alone or in combination, with no use of anthelmintics even in cases of neurocysticercosis. Control of seizure was obtained in 79.7% with significant decrease in seizure frequency from 2.92 to 0.51 (P < 0.0001). Weight loss, nausea, decreased appetite, increased sleep, drowsiness, tremors were found to be significantly associated (P < 0.05) with phenytoin use. Phenytoin is the primary antiepileptic in spite of its side effects; though addition of other anti-epileptic drugs (valproate, clobazam) was required for better seizure control. Cases of neurocysticercosis respond to anti-epileptic drugs without addition of anthelmintics. Side effects observed were mostly neurological in nature.

  9. Effect of cannabidiol on human gingival fibroblast extracellular matrix metabolism: MMP production and activity, and production of fibronectin and transforming growth factor β.

    PubMed

    Rawal, S Y; Dabbous, M Kh; Tipton, D A

    2012-06-01

    Marijuana (Cannabis sativa) use may be associated with gingival enlargement, resembling that caused by phenytoin. Cannabidiol (CBD), a nonpsychotropic Cannabis derivative, is structurally similar to phenytoin. While there are many reports on effects of phenytoin on human gingival fibroblasts, there is no information on effects of Cannabis components on these cells. The objective of this study was to determine effects of CBD on human gingival fibroblast fibrogenic and matrix-degrading activities. Fibroblasts were incubated with CBD in serum-free medium for 1-6 d. The effect of CBD on cell viability was determined by measuring activity of a mitochondrial enzyme. The fibrogenic molecule transforming growth factor β and the extracellular matrix molecule fibronectin were measured by ELISA. Pro-MMP-1 and total MMP-2 were measured by ELISA. Activity of MMP-2 was determined via a colorimetric assay in which a detection enzyme is activated by active MMP-2. Data were analysed using ANOVA and Scheffe's F procedure for post hoc comparisons. Cannabidiol had little or no significant effect on cell viability. Low CBD concentrations increased transforming growth factor β production by as much as 40% (p < 0.001), while higher concentrations decreased it by as much as 40% (p < 0.0001). Cannabidiol increased fibronectin production by as much as approximately 100% (p < 0.001). Lower CBD concentrations increased MMP production, but the highest concentrations decreased production of both MMPs (p < 0.05) and decreased MMP-2 activity (p < 0.02). The data suggest that the CBD may promote fibrotic gingival enlargement by increasing gingival fibroblast production of transforming growth factor β and fibronectin, while decreasing MMP production and activity. © 2011 John Wiley & Sons A/S.

  10. Hallucination: A rare complication of levetiracetam theraphy.

    PubMed

    Erdogan, Seher; Bosnak, Mehmet

    2017-01-01

    Levetiracetam is a new antiepileptic drug. In addition to epilepsy, it is also used for treating anxiety disorders and dystonia as well as tardive dyskinesia associated with the use of levodopa and neuroleptic drugs. Phenytoin therapy in a 10-year-old boy with convulsions was discontinued following cardiac rhythm impairment. The patient was then started on levetiracetam. However, visual and auditory hallucinations were observed on the 1st day of levetiracetam therapy. Levetiracetam was discontinued and replaced with sodium valproate, and the hallucinations resolved. The purpose of this report was to remind physicians that hallucinations are one of the rare complications of levetiracetam.

  11. Anticonvulsant properties of methanol leaf extract of Laggera Aurita Linn. F. (Asteraceae) in laboratory animals.

    PubMed

    Malami, S; Kyari, H; Danjuma, N M; Ya'u, J; Hussaini, I M

    2016-09-15

    Preparation of Laggera aurita Linn. (Asteraceae) is widely used in traditional medicine to treat various kinds of diseases such as epilepsy, malaria, fever, pain and asthma. Its efficacy is widely acclaimed among communities in Northern Nigeria. The present study is aimed at establishing the possible anticonvulsant effects of the methanol leaf extract of Laggera aurita using acute and chronic anticonvulsant models. Median lethal dose (LD50) was determined in mice and rats via oral and intraperitoneal routes. Anticonvulsant screening of the extract was performed using maximal electroshock-induced seizure test in day-old chicks; pentylenetetrazole-, strychnine- and picrotoxin- induced seizure models in mice. Similarly; its effects on pentylenetetrazole-induce kindling in rats as well as when co-administered with fluphenamic and cyproheptadine in mice, were evaluated. Median lethal dose (LD50) values were found to be >5000mg/kg, p.o. and 2154mg/kg, i.p., each for both rats and mice. The extract showed dose dependent protection against tonic hind limb extension (THLE) and significantly (p<0.05) decreased the mean recovery from seizure in the maximal electroshock-induced seizure. In the pentylenetetrazole-induced seizure model, the extract offered 50% protection at 600mg/kg and also increased the mean onset of seizure at all doses with significant (p<0.05) increase at the highest dose (600mg/kg). Similarly the extract produced significant (p<0.05) increase in the onset of seizures in both strychnine- and picrotoxin- induced seizure models, at all the doses except at 150mg/kg for the picrotoxin model. Co-administration of fluphenamic acid (FFA) (5mg/kg) and the extract (600mg/kg) showed an enhanced effect with percentage protection of 70% while co-administration of FFA (5mg/kg) and phenytoin (5mg/kg) as well phenytoin (5mg/kg) and the extract (600mg/kg) produced an additive effect. Administration of the extract (600mg/kg), phenytoin (20mg/kg) and cyproheptadine (4mg

  12. Daytime encopresis associated with gland mal epileptic seizures: case report.

    PubMed

    Oyatsi, D P

    2005-08-01

    Sphincteric incontinence of stool and urine are not unusual features of generalised epileptic seizures. Isolated secondary encopresis as a manifestation of an epileptic seizure is unusual. This report is of, a four year old boy, with daytime secondary non-retentive encopresis. The onset of encopresis was preceded by several episodes of nocturnal generalised tonic clonic epileptic seizures. An electroencephalogram showed features consistent with complex partial seizures. He was commenced on anti-epileptic treatment with phenytoin sodium, and by the third day of treatment, the patient had achieved stool control.

  13. Lethal obesity associated with sodium valproate in a brain-injured patient.

    PubMed

    Black, Deborah N; Althoff, Robert R; Daye, Kathleen; Pelletier, Corinne A

    2005-06-01

    A 34-year-old man developed posttraumatic epilepsy and a disinhibited orbitofrontal syndrome following severe head trauma at age 22. After an 11-year prison term marked by repeated impulsive aggression, he was transferred to a state psychiatric hospital. Replacement of phenytoin by valproic acid resulted in a 100-lb weight gain, exacerbation of sleep apnea, and right heart failure. Despite replacement of valproate with topiramate, he died of a cardiorespiratory arrest during a seizure. This case illustrates the potential risks associated with valproate therapy in the obese brain-damaged population.

  14. New pharmacokinetic methods. III. Two simple test for deep pool effect

    SciTech Connect

    Browne, T.R.; Greenblatt, D.J.; Schumacher, G.E.

    1990-08-01

    If a portion of administered drug is distributed into a deep peripheral compartment, the drug's actual elimination half-life during the terminal exponential phase of elimination may be longer than determined by a single dose study or a tracer dose study (deep pool effect). Two simple methods of testing for deep pool effect applicable to drugs with either linear or nonlinear pharmacokinetic properties are described. The methods are illustrated with stable isotope labeled (13C15N2) tracer dose studies of phenytoin. No significant (P less than .05) deep pool effect was detected.

  15. Cambridge glioma trial of misonidazole and radiation therapy with associated pharmacokinetic studies

    SciTech Connect

    Bleehen, N.M.

    Fifty-five patients with grade 3 and 4 supratentorial astrocytomas, were randomized into a three-limb study. At 9 months after the last treatment there were no differences in survival between the treatment groups. No cases of peripheral neuropathy were seen. Investigations into the possible cause of this are presented. It is thought that microsomal enzyme induction by the anticonvulsants phenobarbitone and phenytoin resulted in increased 0-demethylation of the misonidazole. Clinical data to confirm this view are presented. Current MRC protocols of misonidazole studies on gliomas and carcinomas of the cervix and head and neck are summarized.

  16. Short-term Vision Loss Following Whipple Surgery: A Case Report.

    PubMed

    Gollapalli, Lakshman; Kumar, Aashish J; Sood, Kunal; Muppuri, Rudram

    2017-04-15

    Occipital seizures may result in visual deficits and may be an ictal or postictal phenomenon. A 71-year-old woman underwent pancreatoduodenectomy (Whipple procedure). During recovery in the postanesthesia care unit, the patient complained of blindness. Upon transfer to the intensive care unit, an electroencephalogram indicated bilateral occipital and hemispheric seizure activity. The patient was treated with antiseizure medication, and vision normalized within 3 days. Subtherapeutic concentration of free phenytoin was confirmed. Our experience suggests that electroencephalogram evaluation should be considered in the workup of postoperative patients who present with acute-onset blindness and in whom the cause remains ambiguous even in the absence of obvious clinical signs of seizures.

  17. Prescription Drugs: HCFA’s Proposed Drug Utilization Review System Ignores Quality of Care Issues

    DTIC Science & Technology

    1989-07-13

    Parkinsonism , 32,000 with hip fractures attributable to dOfg-induced falls, 163,000 with drug-induced memory loss or impaired thinking, and 243,000...year there are approximately 61,000 older adults with drug-induced Parkinsonism , 32,000 with hip fractures attributable to drug-induced falls, 163,000...particu- larly phenytoin and warfarin). A drug in one category may interact with a drug in another category to raise the concentration of the drugs in the

  18. Intraperitoneal Administration of Ethanol as a Means of Euthanasia for Neonatal Mice (Mus musculus)

    PubMed Central

    Dyer, Cecilia de Souza; Brice, Angela K; Marx, James O

    2017-01-01

    The humane euthanasia of animals in research is of paramount importance. Neonatal mice frequently respond differently to euthanasia agents when compared with adults. The AVMA's Guidelines for the Euthanasia of Animals includes intraperitoneal injection of ethanol as “acceptable with conditions,” and recent work confirmed that this method is appropriate for euthanizing adult mice, but neonatal mice have not been tested. To explore this method in neonatal mice, mouse pups (C57BL/6 and CD1, 162 total) were injected with 100% ethanol, a pentobarbital–phenytoin combination, or saline at 7, 14, 21, 28, or 35 d of age. Electrocardiograms, respiratory rates, and times to loss of righting reflex and death were recorded. Time to death (TTD) differed significantly between ethanol and pentobarbital–phenytoin at 7, 14, and 21 d and between ethanol groups at 7, 14, and 21 d compared with 35 d. The average TTD (± 1 SD) for ethanol-injected mice were: 7 d, 70.3 ± 39.8 min; 14 d, 51.7 ± 30.5 min; 21 d, 32.3 ± 20.8 min, 28 d, 14.0 ± 15.2; and 35 d, 4.9 ± 1.4. Mean TTD in pentobarbital–phenytoin-injected mice were: 7 d, 2.8 ± 0.4 min; 14 d, 2.9 ± 0.5 min; 21 d, 3.9 ± 1.2 min; 28 d, 3.9 ± 0.7 min; and 35 d, 4.4 ± 0.5. Although TTD did not differ between ethanol and pentobarbital–phenytoin at 28 d of age, the TTD in 3 of 12 mice was longer than 15 min after ethanol administration at this age. Therefore, ethanol should not be used as a method of euthanasia for mice younger than 35 d, because the criteria for humane euthanasia were met only in mice 35 d or older. PMID:28535865

  19. Hallucination: A rare complication of levetiracetam theraphy

    PubMed Central

    Erdogan, Seher; Bosnak, Mehmet

    2017-01-01

    Levetiracetam is a new antiepileptic drug. In addition to epilepsy, it is also used for treating anxiety disorders and dystonia as well as tardive dyskinesia associated with the use of levodopa and neuroleptic drugs. Phenytoin therapy in a 10-year-old boy with convulsions was discontinued following cardiac rhythm impairment. The patient was then started on levetiracetam. However, visual and auditory hallucinations were observed on the 1st day of levetiracetam therapy. Levetiracetam was discontinued and replaced with sodium valproate, and the hallucinations resolved. The purpose of this report was to remind physicians that hallucinations are one of the rare complications of levetiracetam. PMID:29270577

  20. Comparative persistence of antiepileptic drugs in patients with epilepsy: A STROBE-compliant retrospective cohort study

    PubMed Central

    Lai, Edward Chia-Cheng; Hsieh, Cheng-Yang; Su, Chien-Chou; Yang, Yea-Huei Kao; Huang, Chin-Wei; Lin, Swu-Jane; Setoguchi, Soko

    2016-01-01

    Abstract We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy. A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs. Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74–0.83), valproic acid (0.88; 0.85–0.92), lamotrigine (0.72; 0.65–0.81), and topiramate (0.90; 0.82–0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06–1.13), while gabapentin users (1.03; 0.98–1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58–0.74) and lamotrigine (0.46; 0.35–0.62) users had lower risk, while phenytoin (1.35; 1.26–1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses. The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine. PMID:27583857

  1. Effect of enzyme induction on nephrotoxicity of halothane-related compounds.

    PubMed Central

    Hitt, B A; Mazze, R I

    1977-01-01

    Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent. PMID:612443

  2. Misoprostol for tinnitus.

    PubMed

    Crinnion, C L; McCart, G M

    1995-01-01

    Practitioners should realize that further study of misoprostol in larger patient populations must be undertaken to determine its efficacy and safety in the treatment of tinnitus. Previous approaches to treating tinnitus have included carbamazepine, phenytoin, lidocaine, tocainide, flecainide acetate, alprazolam, and nortriptyline. Studies using lidocaine, nortriptyline, or alprazolam have shown encouraging results. The relative contribution of misoprostol remains to be seen; however, it may offer a new treatment option to patients who have experienced adverse effects or have contraindications to the pharmacologic agents currently available.

  3. Evaluation and Refinement of Euthanasia Methods for Xenopus laevis

    PubMed Central

    Torreilles, Stéphanie L; McClure, Diane E; Green, Sherril L

    2009-01-01

    The most common method of euthanasia for Xenopus species is by immersion in tricaine methane sulfonate solution (MS222). A wide range of doses of MS222 (0.5 to 5 g/L) have been recommended, but few reports describe dose–response testing, the time to loss of consciousness, or the reliability of euthanasia. The objective of this study is to evaluate the efficacy of immersing individual and groups of frogs in MS222 at concentrations ranging from 1 to 5 g/L for euthanasia and of 3 less-common methods: intracoelomic injection of MS222, intracoelomic injection of sodium pentobarbital with phenytoin, and ventral cutaneous application of benzocaine gel. Our results indicate that immersion for at least 1 h in a 5-g/L buffered solution of MS222, intracoelomic injection of 1100 mg/kg sodium pentobarbital with sodium phenytoin (equivalent to 0.3 mL solution per frog), or ventral cutaneous application of 182 mg/kg benzocaine (equivalent to a 2 cm × 1 mm of 20% benzocaine gel) is necessary to euthanize adult X. laevis and ensure complete cessation of the heartbeat without recovery. These doses are considerably higher than those previously recommended for this species. PMID:19807972

  4. Severe propylene glycol toxicity secondary to use of anti-epileptics.

    PubMed

    Pillai, Unnikrishnan; Hothi, Jatinder C; Bhat, Zeenat Y

    2014-01-01

    Propylene glycol toxicity presenting as high anion gap metabolic acidosis and osmolar gap has been extensively reported in literature, and most of them are secondary to intravenous lorazepam infusion. However, propylene glycol is used as a solvent in a number of medications that are frequently utilized in critical care setting, and hence one should be aware that the toxicity is possible from a variety of medication. Phenobarbital and phenytoin are one of those, and we hereby report a novel case of propylene glycol toxicity secondary to phenobarbital and phenytoin infusion in a patient with refractory status epilepticus. Furthermore, our patient had end-stage renal disease, which we think could have been an important precipitating factor for the toxicity. Because most of the symptoms from propylene glycol toxicity can mimic sepsis-which is very common in critical care unit patients-this life threatening scenario could be easily missed. Regular monitoring of osmolar gap is an easily available intervention in the at risk patients.

  5. Refractory status epilepticus

    PubMed Central

    Singh, Sanjay P; Agarwal, Shubhi; Faulkner, M

    2014-01-01

    Refractory status epilepticus is a potentially life-threatening medical emergency. It requires early diagnosis and treatment. There is a lack of consensus upon its semantic definition of whether it is status epilepticus that continues despite treatment with benzodiazepine and one antiepileptic medication (AED), i.e., Lorazepam + phenytoin. Others regard refractory status epilepticus as failure of benzodiazepine and 2 antiepileptic medications, i.e., Lorazepam + phenytoin + phenobarb. Up to 30% patients in SE fail to respond to two antiepileptic drugs (AEDs) and 15% continue to have seizure activity despite use of three drugs. Mechanisms that have made the treatment even more challenging are GABA-R that is internalized during status epilepticus and upregulation of multidrug transporter proteins. All patients of refractory status epilepticus require continuous EEG monitoring. There are three main agents used in the treatment of RSE. These include pentobarbital or thiopental, midazolam and propofol. RSE was shown to result in mortality in 35% cases, 39.13% of patients were left with severe neurological deficits, while another 13% had mild neurological deficits. PMID:24791086

  6. Effect of particle size of parenteral suspensions on in vitro muscle damage.

    PubMed

    Brazeau, Gayle; Sauberan, Shauna L; Gatlin, Larry; Wisniecki, Peter; Shah, Jaymin

    2011-01-01

    Suspension particle size plays a key role in the release and stability of drugs for oral and parenteral formulations. However, the role of particle size in suspension formulations on tissue damage (myotoxicity) following intramuscular (IM) injection has not been systematically investigated. Myotoxicity was assessed by the release of cumulative creatine kinase (CCK) from the isolated extensor digitorium longus (EDL) and soleus (SOL) rat muscles for selected suspensions of phenytoin, bupivicane and diazepam. Particle size effects on myotoxicity, independent of any specific drug, were also investigated using characterized non-dissolving polystyrene beads. Myotoxicity was quantitated by the cumulative release of creatine kinase (CCK) from these isolated muscles over 90 or 120 min. The relationship between particle size and myotoxicity was dependent upon the drug in these suspensions. Diazepam and phenytoin suspensions were found to be less myotoxic than bupivicaine. Using unmodified and carboxy modified polystyrene beads, an optimal particle size for reduced myotoxicity following IM injection ranges from approx. 500 nm to 1 µM. The relationship between myotoxicity of IM suspensions and particle size is dependent upon the particular drug and suspension particle size.

  7. A framework for multi-scale simulation of crystal growth in the presence of polymers.

    PubMed

    Mandal, Taraknath; Huang, Wenjun; Mecca, Jodi M; Getchell, Ashley; Porter, William W; Larson, Ronald G

    2017-03-01

    We present a multi-scale simulation method for modeling crystal growth in the presence of polymer excipients. The method includes a coarse-grained (CG) model for small molecules of known crystal structure whose force field is obtained using structural properties from atomistic simulations. This CG model is capable of stabilizing the molecular crystal structure and capturing the crystal growth from the melt for a wide range of small organic molecules, as demonstrated by application of our method to the molecules isoniazid, urea, sulfamethoxazole, prilocaine, oxcarbazepine, and phenytoin. This CG model can also be used to study the effect of additives, such as polymers, on the inhibition of crystal growth by polymers, as exemplified by our simulation of suppression of the rate of crystal growth of phenytoin, an active pharmaceutical ingredient (API), by a cellulose excipient, functionalized with acetate (Ac), hydroxy-propyl (Hp) and succinate (Su) groups. We show that the efficacy of the cellulosic polymers in slowing crystal growth of small molecules strongly depends on the functional group substitution on the cellulose backbone, with the acetate substituent group slowing crystal growth more than does the deprotonated succinate group, which we confirm by experimental drug supersaturation studies.

  8. [Generic drugs in the treatment of epilepsy].

    PubMed

    González de Dios, J; Ochoa-Sangrador, C; Sempere, A P

    We discuss some controversial aspects with prescription of generic drugs (GD) and the problems concerning bioequivalence, mainly in the case of drugs with non-linear pharmacokinetics and/or narrow therapeutic rank, like the antiepileptic drugs (AED). There is considerable debate about GD in the treatment of epilepsy, with clearly advantages (cost saving) and disadvantages (loss of seizure control or drug toxicity) in prescribing generics anticonvulsants. We make a systematic review of the literature in primary (PubMed) and secondary (Tripdatabase and Cochrane Library) bibliographic databases in relation to GD and AED. The main information is about classical AED (phenytoin, carbamazepine, valproic acid and primidone) and we don't found studies in this area about the new AED. The level of evidence is, generally, weak, based on case-series and expert opinion without explicit critical appraisal (except in phenytoin with level of evidence moderate, based on some analytical studies). In Spain, at this moment, there are only two generic AED, one-classical (carbamazepine) and one-new (gabapentin). The American Academy of Neurology and Epilepsy Foundation maintains that the individual and physician should be notified and give their consent before a switch in antiepileptic medications is made, whether it involves generic substitution for brand name products, or generic to generic substitutions.

  9. Effects of anticonvulsants on soman-induced epileptiform activity in the guinea-pig in vitro hippocampus.

    PubMed

    Harrison, Patrick K; Sheridan, Robert D; Green, A Chris; Tattersall, John E H

    2005-08-22

    Seizures arising from acetylcholinesterase inhibition are a feature of organophosphate anticholinesterase intoxication. Although benzodiazepines are effective against these seizures, alternative anticonvulsant drugs may possess greater efficacy and fewer side-effects. We have investigated in the guinea-pig hippocampal slice preparation the ability of a series of anticonvulsants to suppress epileptiform bursting induced by the irreversible organophosphate anticholinesterase, soman (100 nM). Carbamazepine (300 microM), phenytoin (100 microM), topiramate (100-300 microM) and retigabine (1-30 microM) reduced the frequency of bursting but only carbamazepine and phenytoin induced a concurrent reduction in burst duration. Felbamate (100-500 microM) and clomethiazole (100-300 microM) had no effect on burst frequency but decreased burst duration. Clozapine (3-30 microM) reduced the frequency but did not influence burst duration. Levetiracetam (100-300 microM) and gabapentin (100-300 microM) were without effect. These data suggest that several compounds, in particular clomethiazole, clozapine, felbamate, topiramate and retigabine, merit further evaluation as possible treatments for organophosphate poisoning.

  10. Optimal prevention of seizures induced by high-dose busulfan.

    PubMed

    Eberly, Andrea L; Anderson, Gail D; Bubalo, Joseph S; McCune, Jeannine S

    2008-12-01

    High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.

  11. Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

    PubMed Central

    Todorovic, Slobodan M; Rastogi, A J; Jevtovic-Todorovic, Vesna

    2003-01-01

    Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics. PMID:12970103

  12. An audit of therapeutic drug monitoring of anticonvulsants.

    PubMed Central

    Sharpe, P. C.; Morrow, J.; Trimble, E. R.

    1995-01-01

    An audit of therapeutic drug monitoring (TDM) of anticonvulsants was performed to assess both its use and misuse in the management of patients with epilepsy. Over a four week period all samples received for phenytoin, carbamazepine, sodium valproate and phenobarbitone assays were included in the audit. The aims were to establish the source of the specimens, the reasons for the requests and to ascertain what action, if any, would be taken when the result of the assay was provided. A total of 163 separate assays were performed over the four week period (43 phenytoin, 74 carbamazepine, 41 valproate, 5 phenobarbitone). Only 18.7% of all requests originated from the adult neurology department. The vast majority of tests had been ordered by junior medical staff (only 10% by consultants) and approximately 50% were 'routine' with no satisfactory clinical reason for the request offered. There was a tendency to manipulate prescribed doses on the basis of drug levels alone without taking the clinical picture into consideration. These results demonstrate a general ignorance, especially amongst junior medical staff, of the value of TDM of anticonvulsants, and reinforce the need for both an educative and interpretive service to be provided by the Chemical Pathology Department. PMID:8533181

  13. Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy.

    PubMed

    Yamamoto, Yoshiaki; Takahashi, Yukitoshi; Imai, Katsumi; Ikeda, Hiroko; Takahashi, Masaaki; Nakai, Masahiko; Inoue, Yushi; Kagawa, Yoshiyuki

    2015-06-01

    This study evaluated the influence of concomitant antiepileptic drugs (AEDs) on the plasma concentration of lamotrigine (LTG) in pediatric patients with epilepsy. We retrospectively reviewed 1653 plasma samples from 709 patients (aged 6 months to 16 years) and compared the concentration-to-dose ratio (CD ratio) of LTG among different AED regimens. The median CD ratio of patients receiving LTG monotherapy was 1.25 μg/mL/mg/kg. In patients receiving LTG plus VPA, the CD ratio was increased by about 140%. The CD ratio was elevated from a low VPA concentration (<40 μg/mL) and the increase was VPA concentration-dependent. In contrast, the median CD ratio of patients treated with LTG plus the inducers phenytoin, phenobarbital, and carbamazepine was 0.42, 0.63, and 0.66, respectively, and phenytoin significantly reduced the CD ratio in comparison with phenobarbital or carbamazepine (p < 0.001). Pediatric patients of all ages beyond infancy showed similar susceptibility to VPA or inducers, but infants had higher CD ratios compared with the other age groups. Among other AEDs, topiramate, ethosuximide, and rufinamide reduced the CD ratio. These findings should be useful for estimating interactions between LTG and concomitant AEDs. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  14. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk.

    PubMed Central

    Shear, N H; Spielberg, S P

    1988-01-01

    Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis of a hypersensitivity reaction was corroborated by in vitro rechallenge for each drug (phenytoin, n = 34; phenobarbital, n = 22; carbamazepine, n = 25) when cytotoxicity (% dead cells) exceeded 3 SD above the mean result for controls. Cross-reactivity among the drugs was noted. 7 out of 10 patients who had received all three anticonvulsants had adverse reactions to each. 40 out of 50 patients tested to all three drugs in vitro were positive to each. Adverse reactions were indistinguishable among anti-convulsants. Skin rash (87%), fever (94%), hepatitis (51%), and hematologic abnormalities (51%) were common clinical features of each drug. 62% of reactions involved more than two organs. Cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients. In vitro testing can help diagnose hypersensitivity to anticonvulsants. Cells from patients may also be used for prospective individualization of therapy to decrease risk of adverse reaction. Cross-reactivity among the major anticonvulsants is common and should be considered before deciding on alternative therapy. Images PMID:3198757

  15. An unusual case of relay pentobarbital toxicosis in a dog.

    PubMed

    Bischoff, Karyn; Jaeger, Robin; Ebel, Joseph G

    2011-09-01

    Sodium pentobarbital and phenytoin are common constituents of veterinary euthanasia solutions in the United States. Relay, or secondary, barbiturate toxicosis has been reported in carnivorous animals that have fed from the carcasses of euthanized livestock. This case report presents barbiturate toxicosis in a dog. A 2-year-old female spayed Australian shepherd presented comatose 2 h after ingesting an unknown substance on the beach. The material was retrieved from the stomach by gastric lavage and visually identified as fish or other animal tissue. The dog recovered with symptomatic and supportive therapy and was released on the third day of hospitalization. Tissue found on the beach near where the dog walked and a urine sample from the dog were analyzed by gas chromatography/mass spectrometry. Both samples were positive for pentobarbital and phenytoin. The tissue was consistent with mammalian blubber based on gross and histological examination. Three weeks previously, a juvenile humpback whale had stranded on the beach where the dog had ingested the unknown substance. The whale had been euthanized with a barbiturate solution, necropsied, and removed from the beach. It was not definitively determined that the pentobarbital-containing blubber ingested by the dog was from the euthanized whale, but that was the most likely source. Although attempts were made to remove the whale's remains from the beach, practical considerations made complete removal challenging, if not impossible.

  16. A "Neurological Emergency Trolley" reduces turnaround time for high-risk medications in a general intensive care unit.

    PubMed

    Ajzenberg, Henry; Newman, Paula; Harris, Gail-Anne; Cranston, Marnie; Boyd, J Gordon

    2018-02-01

    To reduce medication turnaround times during neurological emergencies, a multidisciplinary team developed a neurological emergency crash trolley in our intensive care unit. This trolley includes phenytoin, hypertonic saline and mannitol, as well as other equipment. The aim of this study was to assess whether the cart reduced turnaround times for these medications. In this retrospective cohort study, medication delivery times for two year epochs before and after its implementation were compared. Eligible patients were identified from our intensive care unit screening log. Adults who required emergent use of phenytoin, hypertonic saline or mannitol while in the intensive care unit were included. Groups were compared with nonparametric analyses. 33-bed general medical-surgical intensive care unit in an academic teaching hospital. Time to medication administration. In the pre-intervention group, there were 43 patients with 66 events. In the post-intervention group, there were 45 patients with 80 events. The median medication turnaround time was significantly reduced after implementation of the neurological emergency trolley (25 vs. 10minutes, p=0.003). There was no statistically significant difference in intensive care or 30-day survival between the two cohorts. The implementation of a novel neurological emergency crash trolley in our intensive care unit reduced medication turnaround times. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Optimizing therapy of seizures in neurosurgery.

    PubMed

    Michelucci, Roberto

    2006-12-26

    The use of antiepileptic drugs (AEDs) in the neurosurgical setting has a number of implications, including their possible role in the prevention of seizures after acute cerebral insults or brain tumors and the potential for toxicity and interactions when these agents are administered in association with radiotherapy or chemotherapy. This review discusses these controversial issues and draws the following conclusions. 1) AEDs should be prescribed on a short-term basis to prevent seizures occurring within the first week after a cerebral insult (trauma, neurosurgical procedure) but are ineffective to avoid true post-traumatic epilepsy or first seizures in patients with primary or secondary cerebral neoplasms. 2) The use of phenytoin and, to a lesser extent, phenobarbital and carbamazepine during cranial irradiation is associated with an increased risk for severe, potentially fatal, mucocutaneous reactions. In this context, new AEDs with a very low potential for allergic cutaneous reactions should be preferred. 3) Enzyme-inducing AEDs, such as phenytoin, phenobarbital, and carbamazepine, may increase the clearance and reduce the clinical efficacy of corticosteroids and anticancer agents that are also metabolized by the cytochrome P450 system. The newly developed AEDs that are devoid of hepatic metabolism, such as levetiracetam and gabapentin, are now recommended because of good results in preliminary studies and because they do not show interactions with anticancer agents.

  18. Influence of sedation on onset and quality of euthanasia in sheep.

    PubMed

    Barletta, Michele; Hofmeister, Erik H; Peroni, John F; Thoresen, Merrilee; Scharf, Alexandra M; Quandt, Jane E

    2018-04-01

    The purpose of this study was to determine if dexmedetomidine administered IV prior to euthanasia in sheep affected the speed or quality of euthanasia. Twenty clinically healthy Dorset-cross adult ewes between 1 and 3years of age were enrolled in a randomized blinded experimental trial. The subjects were randomly assigned to receive dexmedetomidine 5μg/kg IV or an equivalent volume of saline. Five minutes later, euthanasia was accomplished with a pentobarbital/phenytoin overdose given IV. The time to apnea, asystole, cessation of audible heartbeat, and absence of corneal reflex were recorded by two blinded investigators. If any muscle spasms, contractions, vocalization, and/or dysrhythmias were noted, the time was recorded and type of ECG abnormality was described. An overall score of the euthanasia event was assigned using a numeric rating scale (NRS) after the animal was declared dead. The time to loss of corneal reflex was significantly longer in sheep given dexmedetomidine compared with those who received saline (P=0.03). Although vocalization was observed only in some animals premedicated with dexmedetomidine, no significance was found for this event and no other significant differences between groups were noted. Dexmedetomidine at 5μg/kg IV 5min prior to injection of pentobarbital/phenytoin for euthanasia did not substantially affect the progress of euthanasia. Dexmedetomidine may be given to sedate sheep prior to euthanasia without concern for it adversely affecting the progress of euthanasia, however vocalization may occur. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Antiepileptic drugs as prophylaxis for postcraniotomy seizures.

    PubMed

    Greenhalgh, Janette; Weston, Jennifer; Dundar, Yenal; Nevitt, Sarah J; Marson, Anthony G

    2018-05-23

    , we did not combine data from the included trials in a meta-analysis; we presented the findings of the review in narrative format. Visual comparisons of outcomes are presented in forest plots. We included 10 RCTs (N = 1815), which were published between 1983 and 2015. Three trials compared a single AED (phenytoin) with placebo or no treatment. One three-armed trial compared two AEDs (phenytoin, carbamazepine) with no treatment. A second three-armed trial compared phenytoin, phenobarbital with no treatment. Of these five trials comparing AEDs with placebo or no treatment, two trials reported a statistically significant advantage for AED treatment compared to controls for early seizure occurrence; all other comparisons showed no clear or statistically significant differences between AEDs and control treatment. None of the trials that were head-to-head comparisons of AEDs (phenytoin versus sodium valproate, phenytoin versus phenobarbital, levetiracetam versus phenytoin, zonisamide versus phenobarbital) reported any statistically significant differences between treatments for either early or late seizure occurrence.Incidences of death were reported in only five trials. One trial reported statistically significantly fewer deaths in the carbamazepine and no-treatment groups compared with the phenytoin group after 24 months of treatment, but not after six months of treatment. Incidences of adverse effects of treatment were poorly reported; however, three trials did show that significantly more adverse events occurred on phenytoin compared to valproate, placebo, or no treatment. No trials reported any results relating to functional outcomes such as disability.We considered the evidence to be of low quality for all reported outcomes due to methodological issues and variability of comparisons made in the trials. There is limited, low-quality evidence to suggest that AED treatment administered prophylactically is either effective or not effective in the prevention of

  20. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    PubMed

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

  1. Vitamin B6 deficiency: a potential cause of refractory seizures in adults.

    PubMed

    Gerlach, Anthony T; Thomas, Sheela; Stawicki, Stanislaw P; Whitmill, Melissa L; Steinberg, Steven M; Cook, Charles H

    2011-03-01

    In children, vitamin B(6) (pyridoxine) deficiency has been described as a cause of seizures that are refractory to conventional antiepileptic medications. We describe the clinical presentation of 3 adults with refractory seizures (later diagnosed with vitamin B(6) deficiency) that resolved after pyridoxine treatment. Case series. Tertiary care surgical intensive care unit. In the first case, a 54-year-old male with history of alcoholic cirrhosis developed new-onset seizures refractory to phenytoin and levetiracetam 8 days after liver transplantation. In the second case, a 59-year-old male with hepatitis C infection developed intracranial hemorrhage and new-onset seizures refractory to phenytoin, levetiracetam, and pentobarbital. The third patient is a 78-year-old male with a history of alcohol dependence who was admitted for an intraventricular bleed and developed new onset of refractory seizures. Intravenous pyridoxine followed by oral pyridoxine. In all 3 cases, seizures persisted despite escalation of conventional antiepileptic medications but resolved within 2 days of pyridoxine supplementation. In each case, low serum pyridoxal 5'-phosphate concentrations normalized with pyroxidine administration. Although refractory seizures caused by vitamin B(6) deficiency are rare in adults, it should be considered in critically ill adult patients with refractory seizures.

  2. Delayed seizure associated with paclitaxel-Cremophor el in a patient with early-stage breast cancer.

    PubMed

    O'Connor, Tracey L; Kossoff, Ellen

    2009-08-01

    Paclitaxel, a microtubule stabilizer, is an effective agent for treating cancer of the breast, ovary, head and neck, and lung. Because paclitaxel is insoluble in water, it is formulated with the micelle-forming Cremophor EL. Neurologic toxicity is well described with both the drug and this carrier, with most toxicities manifesting as peripheral neuropathy, motor neuropathy, autonomic neuropathy, and myopathy. Toxic effects on the central nervous system, such as seizures or encephalopathy, have been rarely reported; however, the seizures reported were closely related to the time of infusion. We describe a 41-year-old woman with no history of seizures who was treated with paclitaxel for breast cancer. Four days after the drug was infused, she developed a generalized tonic-clonic seizure that could not be attributed to other causes. The patient was treated with phenytoin and was able to complete her adjuvant chemotherapy with nab-paclitaxel without further events. Her condition was neurologically stable without phenytoin for the next 6 months. Use of the Naranjo adverse drug reaction probability scale indicated a possible association (score of 3) between the delayed seizure and paclitaxel or its solvent, Cremophor EL. Clinicians should be aware of the potential for seizure activity in patients who receive paclitaxel formulated with Cremophor EL.

  3. Short-term outcomes and major barriers in the management of convulsive status epilepticus in children: a study in Georgia.

    PubMed

    Shatirishvili, Teona; Kipiani, Tamar; Lomidze, Giorgi; Gabunia, Maia; Tatishvili, Nino

    2015-09-01

    Convulsive status epilepticus is the most common childhood neurological emergency in developing countries, where poor healthcare organisation could play a negative role in the management of the condition. Unavailability of second-line injectable anticonvulsants is an additional hindering factor in Georgia. This report reflects the results of the first study aimed at evaluating the epidemiological features of convulsive status epilepticus, as well as identifying obstacles influencing the management of patients with convulsive status epilepticus in Georgia. A prospective, hospital-based study was performed. Paediatric patients with convulsive status epilepticus, admitted to the emergency department of a referral academic hospital from 2007 to 2012, were included in the study. Forty-eight paediatric patients admitted to hospital met the criteria for convulsive status epilepticus. Seizure duration was significantly shorter among the group with adequate and timely pre-hospital intervention. Moreover, patients with appropriate pre-hospital treatment less frequently required mechanical ventilation (p=0.039). Four deaths were detected during the follow-up period, thus the case fatality rate was 8%. Only 31% of patients received treatment with intravenous phenytoin. The study results show that adequate and timely intervention could improve outcome of convulsive status epilepticus and decrease the need for mechanical ventilation. Mortality parameters were comparable to the results from other resource-limited countries. More than one third of patients did not receive appropriate treatment due to unavailability of phenytoin.

  4. Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs

    PubMed Central

    Koltai, Tomas

    2015-01-01

    Objective: To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties. Material and methods: A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings. Results: The following pharmaceuticals that fulfill the above mentioned effects, were found: phenytoin, carbamazepine, valproate, lamotrigine, ranolazine, resveratrol, ropivacaine, lidocaine, mexiletine, flunarizine, and riluzole. Each of them are independently described and analyzed. Conclusions: The above mentioned pharmaceuticals have shown anti-metastatic and anti-invasion activity and many of them deserve to be tested in well-planned clinical trials as adjunct therapies for solid tumors and as anti-metastatic agents. Antiepileptic drugs like phenytoin, carbamazepine and valproate and the vasodilator flunarizine emerged as particularly useful for anti-metastatic purposes. PMID:27408684

  5. Genetic risk factors for antiepileptic drug-induced hypersensitivity reactions in Israeli populations.

    PubMed

    Israel, Shoshana; Maggio, Nicola; Ekstein, Dana; Zaid, Huda; Firer, Maria; Bederovsky, Yana; Noyman, Iris; Gandelman-Marton, Revital; Blatt, Ilan; Brautbar, Chaim; Marom, Eli; Nahlieli Dil, Dorit; Berman, Erez; Sabag, David; Ingber, Arieh; Eyal, Sara

    2016-10-01

    The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  6. Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

    PubMed Central

    Saruwatari, Junji; Ishitsu, Takateru; Nakagawa, Kazuko

    2010-01-01

    Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed. PMID:27713373

  7. Concentration Gradient Immunoassay I. A Rapid Immunoassay Based on Interdiffusion and Surface Binding in a Microchannel

    PubMed Central

    Nelson, Kjell E.; Foley, Jennifer O.; Yager, Paul

    2008-01-01

    We describe a novel microfluidic immunoassay method based on the diffusion of a small molecule analyte into a parallel-flowing stream containing cognate antibody. This interdiffusion results in a steady-state gradient of antibody binding site occupancy transverse to convective flow. In contrast to the diffusion immunoassay (Hatch et al. Nature Biotechnology,19:461−465 (2001)), this antibody occupancy gradient is interrogated by a sensor surface coated with a functional analog of the analyte. Antibodies with at least one unoccupied binding site may specifically bind to this functionalized surface, leading to a quantifiable change in surface coverage by the antibody. SPR imaging is used to probe the spatial distribution of antibody binding to the surface and, therefore, the outcome of the assay. We show that the pattern of antibody binding to the SPR sensing surface correlates with the concentration of a model analyte (phenytoin) in the sample stream. Using an inexpensive disposable microfluidic device, we demonstrate assays for phenytoin ranging in concentration from 75 to 1000 nM in phosphate buffer. At a total volumetric flow rate of 90 nL/sec, the assays are complete within 10 minutes. Inclusion of an additional flow stream on the side of the antibody stream opposite to that of the sample enables simultaneous calibration of the assay. This assay method is suitable for rapid quantitative detection of low-molecular weight analytes for point-of-care diagnostic instrumentation. PMID:17437332

  8. Antiepileptics for aggression and associated impulsivity

    PubMed Central

    Huband, Nick; Ferriter, Michael; Nathan, Rajan; Jones, Hannah

    2014-01-01

    Background Aggression is a major public health issue and is integral to several mental health disorders. Antiepileptic drugs may reduce aggression by acting on the central nervous system to reduce neuronal hyper-excitability associated with aggression. Objectives To evaluate the efficacy of antiepileptic drugs in reducing aggression and associated impulsivity. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, metaRegister of Controlled Trials (mRCT) and ClinicalTrials.gov to April 2009. We also searched Cochrane Schizophrenia Group’s register of trials on aggression, National Research Record and handsearched for studies. Selection criteria Prospective, placebo-controlled trials of antiepileptic drugs taken regularly by individuals with recurrent aggression to reduce the frequency or intensity of aggressive outbursts. Data collection and analysis Three authors independently selected studies and two authors independently extracted data. We calculated standardised mean differences (SMDs), with odds ratios (ORs) for dichotomous data. Main results Fourteen studies with data from 672 participants met the inclusion criteria. Five different antiepileptic drugs were examined. Sodium valproate/divalproex was superior to placebo for outpatient men with recurrent impulsive aggression, for impulsively aggressive adults with cluster B personality disorders, and for youths with conduct disorder, but not for children and adolescents with pervasive developmental disorder. Carbamazepine was superior to placebo in reducing acts of self-directed aggression in women with borderline personality disorder, but not in children with conduct disorder. Oxcarbazepine was superior to placebo for verbal aggression and aggression against objects in adult outpatients. Phenytoin was superior to placebo on the frequency of aggressive acts in male prisoners and in outpatient men including those with personality disorder, but not on the frequency of ‘behavioral incidents’ in

  9. Treatment of Convulsive Status Epilepticus.

    PubMed

    Grover, Eric H; Nazzal, Yara; Hirsch, Lawrence J

    2016-03-01

    Convulsive status epilepticus (CSE) is a medical emergency with an associated high mortality and morbidity. It is defined as a convulsive seizure lasting more than 5 min or consecutive seizures without recovery of consciousness. Successful management of CSE depends on rapid administration of adequate doses of anti-epileptic drugs (AEDs). The exact choice of AED is less important than rapid treatment and early consideration of reversible etiologies. Current guidelines recommend the use of benzodiazepines (BNZ) as first-line treatment in CSE. Midazolam is effective and safe in the pre-hospital or home setting when administered intramuscularly (best evidence), buccally, or nasally (the latter two possibly faster acting than intramuscular (IM) but with lower levels of evidence). Regular use of home rescue medications such as nasal/buccal midazolam by patients and caregivers for prolonged seizures and seizure clusters may prevent SE, prevent emergency room visits, improve quality of life, and lower health care costs. Traditionally, phenytoin is the preferred second-line agent in treating CSE, but it is limited by hypotension, potential arrhythmias, allergies, drug interactions, and problems from extravasation. Intravenous valproate is an effective and safe alternative to phenytoin. Valproate is loaded intravenously rapidly and more safely than phenytoin, has broad-spectrum efficacy, and fewer acute side effects. Levetiracetam and lacosamide are well tolerated intravenous (IV) AEDs with fewer interactions, allergies, and contraindications, making them potentially attractive as second- or third-line agents in treating CSE. However, data are limited on their efficacy in CSE. Ketamine is probably effective in treating refractory CSE (RCSE), and may warrant earlier use; this requires further study. CSE should be treated aggressively and quickly, with confirmation of treatment success with epileptiform electroencephalographic (EEG), as a transition to non-convulsive status

  10. An Update on Maternal Use of Antiepileptic Medications in Pregnancy and Neurodevelopment Outcomes

    PubMed Central

    Gerard, Elizabeth E.; Meador, Kimford J.

    2015-01-01

    Antiepileptic drugs (AEDs) are prescribed commonly to women of childbearing age. In utero exposure to some AEDs can have significant cognitive and behavioral consequences for the unborn child. Recently, prospective studies of women taking AEDs during pregnancy have added significantly to our understanding of cognitive and behavioral teratogenic risks posed by fetal AED exposure. Valproate is clearly associated with impaired cognitive development as well as an increased risk of disorders such as autism and autism spectrum disorder. Exposure to carbamazepine, lamotrigine, levetiracetam, or phenytoin monotherapy is associated with more favorable cognitive and behavioral outcomes than valproate, but more data are required to clarify if these AEDs have more subtle effects on cognition and behavior. There are insufficient data on the developmental effects of other AEDs in humans. Further, the underlying mechanisms of cognitive teratogenesis are poorly understood, including the genetic factors that affect susceptibility to AEDs. PMID:27617120

  11. (Biphenyl-4-yl)methylammonium chlorides: potent anticonvulsants that modulate Na+ currents.

    PubMed

    Lee, Hyosung; Park, Ki Duk; Yang, Xiao-Fang; Dustrude, Erik T; Wilson, Sarah M; Khanna, Rajesh; Kohn, Harold

    2013-07-25

    We have reported that compounds containing a biaryl linked unit (Ar-X-Ar') modulated Na(+) currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na(+) currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models, and in the maximal electroshock seizure test the activity of (3'-trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A-differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na(+) currents.

  12. Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes.

    PubMed Central

    Miller, J. A.; Richter, J. A.

    1985-01-01

    The effects of several anticonvulsant drugs on sodium-dependent high affinity choline uptake (HACU) in mouse hippocampal synaptosomes was investigated. HACU was measured in vitro after in vivo administration of the drug to mice. HACU was inhibited by drugs which have in common the ability to facilitate gamma-aminobutyric acid (GABA) transmission, pentobarbitone, phenobarbitone, barbitone, diazepam, chloridiazepoxide, and valproic acid. Dose-response relationships were determined for these drugs and the drugs' potencies at inhibiting HACU correlated well with their anticonvulsant potencies. Clonazepam, ethosuximide, carbamazepine, and barbituric acid had no effect on HACU in the doses used while phenytoin and trimethadione stimulated HACU. These results suggest that certain anticonvulsants may elicit a part of their anticonvulsant activity by modulating cholinergic neurones. This effect may be mediated through a GABA mechanism. PMID:3978310

  13. Anti-epileptic drugs in pediatric traumatic brain injury.

    PubMed

    Tanaka, Tomoko; Litofsky, N Scott

    2016-10-01

    Pediatric post-traumatic epilepsy incidence varies depending on reporting mechanism and injury severity; anti-epileptic drug (AEDs) use also varies with lack of quality evidence-based data. Adverse AED effects are not negligible; some may negatively affect functional outcome. This review focuses on clarifying available data. This review discusses seizures associated with traumatic brain injury in children, including seizure incidence, relationship to severity of injury, potential detrimental effects of seizures, potential benefits of AED, adverse effects of AED, new developments in preventing epileptogenesis, and suggested recommendations for patient management. English language papers were identified from PubMed using search terms including but not excluding the following: adverse drug effects, anti-epileptic drugs, children, electroencephalogram, epilepsy, epileptogenesis, head injury, levetiracetam, pediatrics, phenytoin, post-traumatic epilepsy, prevention, prophylaxis, seizures, and traumatic brain injury. Expert commentary: Identification of high-risk patients for post-traumatic seizures is a key goal. Levetiracetam may prevent epileptogenesis, as may other developments.

  14. Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation

    PubMed Central

    Chang, Shang-Hung; Chou, I-Jun; Yeh, Yung-Hsin; Chiou, Meng-Jiun; Wen, Ming-Shien; Kuo, Chi-Tai; See, Lai-Chu

    2017-01-01

    Importance Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. Objective To assess the association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. Design, Setting, and Participants Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. Exposures NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. Main Outcomes and Measures Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. Results Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years [SD, 10.8]; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole

  15. Camphor: an herbal medicine causing grand mal seizures

    PubMed Central

    MacKinney, Theodore G; Soti, Kamal Raj; Shrestha, Poojan; Basnyat, Buddha

    2015-01-01

    Camphor is usually used in the USA to repel insects, but it is widely used in other countries as an herb. We report the case of a 52-year-old previously healthy Nepali man who ingested approximately 10 g of pure camphor with therapeutic intention. He developed grand mal seizures, and was evaluated in an emergency room. He failed to recall the camphor ingestion initially, and was treated with phenytoin for new-onset idiopathic seizures. Examining physicians only later found out about his camphor ingestion. Finding the cause of new-onset seizures is often challenging for emergency room physicians, internists and neurologists. In addition to other well-reported causes of secondary seizures, herbal medications and supplements must also be explored. PMID:26065546

  16. Refractory status epilepticus complicated by drug-induced involuntary movements.

    PubMed

    Nair, Pradeep Pankajakshan; Wadwekar, Vaibhav; Murgai, Aditya; Narayan, Sunil K

    2014-02-11

    New onset refractory status epilepticus (NORSE) is a neurological emergency and difficult to treat condition. We report a case of involuntary movements resulting from thiopentone sodium infusion during the management of refractory status epilepticus. A young woman was admitted with fever and NORSE in the neurology intensive care unit. In addition to supportive measures, she was treated with intravenous lorazepam, phenytoin sodium, sodium valproate, midazolam and thiopentone sodium. While on thiopentone sodium, she developed involuntary twitches involving her upper limbs and face with EEG showing no evidence of ongoing status epilepticus. Because of the temporal relationship with thiopentone infusion, we tapered the dose of thiopentone sodium, which resulted in the disappearance of the movements. The patient recovered well with no recurrence of the seizures during the hospital stay.

  17. Transient bradycardia induced by thiopentone sodium: a unique challenge in the management of refractory status epilepticus.

    PubMed

    Sharma, Sushma; Nair, Pradeep P; Murgai, Aditya; Selvaraj, Raja J

    2013-10-15

    Thiopentone sodium is one of the important drugs in the armamentarium for terminating refractory status epilepticus, a neurological emergency. We report a case of thiopentone-related bradycardia during the management of the new onset refractory status epilepticus in a young man, which was circumvented by prophylactic insertion of temporary pacemaker while thiopentone infusion was continued. A systematic approach was employed to manage the status epilepticus, including infusion of thiamine and glucose followed by antiepileptic drugs. The patient was ventilated and infused with lorazepam, phenytoin, sodium valproate, levetiracetam and midazolam followed by thiopentone sodium. With the introduction of thiopentone the seizures could be controlled but the patient developed severe bradycardia and junctional rhythm. The bradycardia disappeared when thiopentone was withdrawn and reappeared when the drug was reintroduced. Propofol infusion was tried with no respite in seizures. Later thiopentone sodium was reintroduced after inserting temporary cardiac pacemaker. Seizure was controlled and patient was weaned off the ventilator.

  18. The use of phenobarbital and other anti-seizure drugs in newborns.

    PubMed

    El-Dib, Mohamed; Soul, Janet S

    2017-10-01

    Neonatal seizures constitute the most frequent presenting neurologic sign encountered in the neonatal intensive care unit. Despite limited efficacy and safety data, phenobarbital continues to be used near-universally as the first-line anti-seizure drug (ASD) in neonates. The choice of second-line ASDs varies by provider and institution, and is still not supported by sufficient scientific evidence. In this review, we discuss the available evidence supporting the efficacy, mechanism of action, potential adverse effects, key pharmacokinetic characteristics such as interaction with therapeutic hypothermia, logistical issues, and rationale for use of neonatal ASDs. We describe the widely used neonatal ASDs, namely phenobarbital, phenytoin, midazolam, and levetiracetam, in addition to potential ASDs, including lidocaine, topiramate, and bumetanide. Copyright © 2017. Published by Elsevier Ltd.

  19. Early adventures in drug metabolism. 1. Role of the Bratton-Marshall reagent

    SciTech Connect

    Glazko, A.J.

    1987-01-01

    The Bratton-Marshall reagent is one of the real land-marks in the development of drug metabolism and pharmacokinetics, coming at a time when highly sensitive and specific analytical procedures were desperately needed for the measurement of drug concentrations in the body. Examples of its applications are taken from early work in the mid-40's and 50's in the Parke-Davis Research Laboratories, extending from primary aromatic amines (e.g., sulfonamides), to p-nitrophenyl compounds that must first be reduced to amines (e.g., chloramphenicol), and to phenyl derivatives that must be nitrated on a microgram scale and then reduced to aryl amines (e.g., phenytoin). The developmentmore » and use of separation techniques such as liquid/liquid counter-current partition and paper chromatography is described. Emphasis is placed upon continued, progressive improvement in the basic assay procedures over long periods of time.« less

  20. Drug inhibition of first-stage radioemesis. Interim report, 5 November 1975--31 December 1976

    SciTech Connect

    Gralla, E.J.; Krupp, J.H.; Mattsson, J.L.

    1977-06-01

    An animal model of irradiation-induced emesis was developed which involved exposing young male beagle dogs to 800 rads in the abdominal area. This caused a 100% incidence of emesis within 8 hr and a second wave of emesis and hemorrhagic diarrhea approximately 48 hr later. Seven drugs and one combination of two drugs were examined for effects against these responses. Chlorpromazine proved to be the most potent antagonist of first-stage emesis while dimenhydrinate and diphenhydramine HC1 showed the same activity but to a lesser degree. Inactive drugs were phenytoin sodium, perphenazine (at a low dose), WR2721, and the combination ofmore » amphetamine plus scopolamine. Acetylsalicylic acid intensified the emetic responses. (Author)« less

  1. Evidence for involvement of the astrocytic benzodiazepine receptor in the mechanism of action of convulsant and anticonvulsant drugs

    SciTech Connect

    Bender, A.S.; Hertz, L.

    1988-01-01

    The anticonvulsant drugs carbamazepine, phenobarbital, trimethadione, valproic acid and ethosuximide at pharmacologically relevant concentrations inhibit (/sup 3/H)diazepam binding to astrocytes in primary cultures but have much less effect on a corresponding preparation of neurons. Phenytoin as well as pentobarbital (which is not used chronically as an anticonvulsant) are equipotent in the two cell types. The convulsants picrotoxinin and pentylenetetrazol, the convulsant benzodiazepine RO 5-3663 and the two convulsant barbiturates DMBB and CHEB similarly inhibit diazepam binding to astrocytes but have little effect on neurons. On the basis of these findings it is suggested that these convulsants and anticonvulsants owe atmore » least part of their effect to an interaction with the astrocytic benzodiazepine receptor, perhaps by interference with a calcium channel.« less

  2. A micromethod for the determination of the new antiepileptic drug levetiracetam (ucb LO59) in serum or plasma by high performance liquid chromatography.

    PubMed

    Ratnaraj, N; Doheny, H C; Patsalos, P N

    1996-04-01

    An isocratic high performance liquid chromatographic micromethod is described for the quantitation of levetiracetam (ucb L059) in plasma or serum of patients. The chromatography is performed on a 250 x 4 mm I.D. LiChrospher 60 RP-select B, 5-micron column, eluted with an acetonitrile/50 mM phosphate buffer (15:85 vol/vol, pH 5.6) mobile phase, and levetiracetam detected using ultraviolet absorbance at 220 nm. The limit of quantitation was 5 mumol/L and the within-batch and between-batch coefficients of variation were < 7%. No interference from commonly prescribed antiepileptic drugs (carbamazepine and its metabolite carbamazepine epoxide, ethosuximide, gabapentin, lamotrigine, phenobarbitone, phenytoin, primidone, valproic acid, and vigabatrin) was observed, and thus the method can be used to monitor levetiracetam in patients on polytherapy antiepileptic drug regimens.

  3. Transient bradycardia induced by thiopentone sodium: a unique challenge in the management of refractory status epilepticus

    PubMed Central

    Sharma, Sushma; Nair, Pradeep P; Murgai, Aditya; Selvaraj, Raja J

    2013-01-01

    Thiopentone sodium is one of the important drugs in the armamentarium for terminating refractory status epilepticus, a neurological emergency. We report a case of thiopentone-related bradycardia during the management of the new onset refractory status epilepticus in a young man, which was circumvented by prophylactic insertion of temporary pacemaker while thiopentone infusion was continued. A systematic approach was employed to manage the status epilepticus, including infusion of thiamine and glucose followed by antiepileptic drugs. The patient was ventilated and infused with lorazepam, phenytoin, sodium valproate, levetiracetam and midazolam followed by thiopentone sodium. With the introduction of thiopentone the seizures could be controlled but the patient developed severe bradycardia and junctional rhythm. The bradycardia disappeared when thiopentone was withdrawn and reappeared when the drug was reintroduced. Propofol infusion was tried with no respite in seizures. Later thiopentone sodium was reintroduced after inserting temporary cardiac pacemaker. Seizure was controlled and patient was weaned off the ventilator. PMID:24130206

  4. Pharmacogenomic Testing for Neuropsychiatric Drugs: Current Status of Drug Labeling, Guidelines for Using Genetic Information, and Test Options

    PubMed Central

    Drozda, Katarzyna; Müller, Daniel J.; Bishop, Jeffrey R.

    2014-01-01

    Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to help guide pharmacotherapy used to treat neuropsychiatric conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for assessing the starting and target doses, as well as drug interaction potential, for a number of other medications used to treat psychiatric and neurological conditions. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients. PMID:24523097

  5. Paroxysmal Kinesigenic Dyskinesia.

    PubMed

    Mallik, Ritwika; Nandi, Sitansu Sekhar

    2016-04-01

    We present a case of paroxysmal kinesigenic dyskinesia (PKD) in a 21 year old girl, with no family history of similar episodes. The episodes were short (lasting less than a minute), frequent, occurring 5 to 10 times a day, self-limiting dystonia of her right upper limb precipitated by sudden movement. She also had a past history of partial seizures with secondary generalization in her childhood. She responded to phenytoin, with cessation of events after 1 month of treatment. This case impresses upon the hypothesis stating the association between seizure activity and PKD probably due to a common foci of origin. Awareness of this condition is required as it is easily treatable but frequently misdiagnosed. © Journal of the Association of Physicians of India 2011.

  6. Antiepileptic drug therapy: clinical laboratory significance.

    PubMed

    Naradzay, J F; Olshaker, J S

    1996-01-01

    When evaluating a patient who is taking an antiepileptic medication, it is important for the emergency physician to correlate the clinical presentation with the antiepileptic drug level. Therapeutic ranges have been suggested for most antiepileptic medications, but these must be interpreted in light of clinical efficacy and patient tolerance. When considering the efficacy of anti-epileptic medications, it is necessary to consider the patient's unique metabolism, side-effect tolerance, and overall response to therapy. Suggested therapeutic ranges should be the first reference for the emergency physician. The purpose of this report is to discuss the laboratory values of commonly prescribed antiepileptic medications. Therapeutic ranges, side-effects, and common medication interactions are discussed concerning phenytoin, phenobarbital, carbamezapine, and valproic acid.

  7. Synthesis of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives and evaluation of their in vivo anticonvulsant activity.

    PubMed

    Harish, Kikkeri P; Mohana, Kikkeri N; Mallesha, Lingappa; Prasanna Kumar, Basavapatna N

    2013-07-01

    A series of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives 8(a-o) were synthesized and characterized by elemental analyses, (1)H NMR, (13)C NMR and mass spectral studies. The newly synthesized compounds were screened for their anticonvulsant activity against maximal electroshock seizure (MES) model in male wistar rats and compared with the standard drug phenytoin. The neurotoxic effects were determined by rotorod test by using mice. Compounds 8d, 8e, 8f and 8h were found to be most potent of this series. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). The efforts were also made to establish the structure activity relationships among synthesized compounds. The pharmacophore model was used to validate the anticonvulsant activity of the synthesized molecules. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  8. Highly accurate nephelometric titrimetry.

    PubMed

    Zhan, Xiancheng; Li, Chengrong; Li, Zhiyi; Yang, Xiucen; Zhong, Shuguang; Yi, Tao

    2004-02-01

    A method that accurately indicates the end-point of precipitation reactions by the measurement of the relative intensity of the scattered light in the titrate is presented. A new nephelometric titrator with an internal nephelometric sensor has been devised. The work of the titrator including the sensor and change in the turbidity of the titrate and intensity of the scattered light are described. The accuracy of the nephelometric titrimetry is discussed theoretically. The titration of NaCl with AgNO(3) serves as a model. A relative error as well as deviation is within 0.2% under the experimental conditions. The applicability of the titrimetry in pharmaceutical analyses, for example, phenytoin sodium and procaine hydrochloride, is generally illustrated. Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association

  9. Effect of selected drugs on first-stage radioemesis in beagle dogs. [Following x irradiation of abdomen

    SciTech Connect

    Gralla, E.J.; Sabo, J.P.; Hayden, D.W.

    1979-05-01

    An animal model of irradiation-induced emesis was developed by exposing the abdominal area of young beagle dogs to 800 rad. A 100% incidence of emesis occurred within 2 hr followed by a second wave of emesis, anorexia, and hemorrhagic diarrhea aproximately 48 hr later. Seven individual drugs and one combination of two drugs were examined for antagonistic effects against the first-stage emesis. Chlorpromazine proved to be the most potent antagonist, while dimenhydrinate and diphenhydramine showed the same activity but to a lesser degree. Inactive drugs were phenytoin sodium, perphenazine (at a low dose), WR2721, and the combination of amphetamine plusmore » scopolamine. Acetylsalicyclic acid adversely intensified the emesis. These results suggest that CNS-active agents are potentially more effective in counteracting first-stage emesis.« less

  10. Anticonvulsant hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro.

    PubMed

    Karande, Sunil; Gogtay, Nithya J; Kanchan, Sandeep; Kshirsagar, Nilima A

    2006-02-01

    Anticonvulsant hypersensitivity syndrome (AHS) developing to lamotrigine, a non-aromatic anticonvulsant, has rarely been reported. We present a two-year-old boy with refractory epilepsy on valproic acid and lamotrigine therapy who developed fever and a maculopapular itchy rash. Blood investigations detected lymphocytosis and thrombocytopenia. With a presumptive diagnosis of AHS, lamotrigine was discontinued. The fever and rash resolved over the next three days and the child was discharged on valproic acid and clobazam. The diagnosis was confirmed by in vitro lymphocyte toxicity assay, which not only demonstrated increased cell death following exposure to lamotrigine, but also to the three first-line aromatic anticonvulsants: phenytoin, phenobarbital and carbamazepine. The potential of first-line aromatic anticonvulsants to cause AHS should be remembered in a patient who has developed AHS on exposure to lamotrigine. Timely recognition of this rare but potentially fatal drug reaction is important.

  11. Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs.

    PubMed

    Hamed, Sherifa A

    2016-01-01

    Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.

  12. New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice.

    PubMed

    Enrique, Andrea; Goicoechea, Sofía; Castaño, Rocío; Taborda, Facundo; Rocha, Luisa; Orozco, Sandra; Girardi, Elena; Bruno Blanch, Luis

    2017-01-01

    About 30% of the patients with epilepsy do not respond to clinically established anticonvulsants, despite having effective concentrations of the antiepileptic drug in plasma. Therefore, new preclinical models of epilepsy are needed to identify more efficacious treatments. We describe here a new drug-resistant seizure model in mice to be used at the early stages of pre-clinical trials. This model consists in inducing daily generalized seizures for 23 consecutive days by administration of 3-mercaptopropionic acid (MP). As a result, 100% of animals become resistant to phenytoin and 80% to phenobarbital. Such resistance is strongly associated with the overexpression of P-glycoprotein (Pgp), observed in cerebral cortex, hippocampus and striatum while resistance to Pgp nonsubstrate drugs such as carbamazepine, diazepam and levetiracetam is not observed. This model could be useful for screening novel anticonvulsant drugs with a potential effect on pharmacoresistant seizures treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Encephalopathy with status epilepticus during sleep (ESES) induced by oxcarbazepine in idiopathic focal epilepsy in childhood

    PubMed Central

    Pavlidis, Elena; Rubboli, Guido; Nikanorova, Marina; Kölmel, Margarethe Sophie; Gardella, Elena

    2015-01-01

    Summary Encephalopathy with status epilepticus during sleep (ESES) is an age-related disorder characterized by neuropsychological regression, epilepsy and a typical EEG pattern of continuous epileptiform activity (> 85%) during NREM sleep. Cases of worsening or induction of ESES with phenytoin, carbamazepine and phenobarbital have been reported. We describe a child with benign epilepsy with centrotemporal spikes (BECTS) in whom treatment with oxcarbazepine (OXC) induced ESES. The patient was studied through repeated clinical-neuropsychological evaluations and 24-hour EEG recordings. He was treated with OXC two months after epilepsy onset. One month after starting OXC, he developed an abrupt and severe cognitive deterioration. A 24-hour EEG and neuropsychological tests showed an electro-clinical picture compatible with ESES. Withdrawal of OXC and introduction of other drugs were followed by a prompt improvement. Five months after ESES onset, a 24-hour EEG was normal. Our report indicates that OXC can induce ESES in BECTS. PMID:26415787

  14. Sodium valproate induced gingival enlargement with pre-existing chronic periodontitis.

    PubMed

    Joshipura, Vaibhavi

    2012-04-01

    Gingival enlargement is a common clinical feature of gingival and periodontal diseases. Currently, more than 20 prescription medications are associated with gingival enlargement. Although the mechanisms of action may be different, the clinical and microscopic appearance of drug-induced gingival enlargement is similar with any drug. Gingival enlargement produces esthetic changes, and clinical symptoms including pain, tenderness, bleeding, speech disturbances, abnormal tooth movement, dental occlusion problems, enhancement of caries development and periodontal disorders. Sodium valproate is considered to produce gingival enlargement, but very rarely. This case report features sodium valproate induced gingival enlargement in a patient with pre-existing chronic periodontitis, who came to the Dental Department, Chinmaya Mission Hospital, Bangalore. The case is special as the patient did not develop the enlargement in spite of taking phenytoin for 1 year and developed enlargement with sodium valproate within 6 months.

  15. Interaction of injectable neurotropic drugs with the red cell membrane.

    PubMed

    Reinhart, Walter H; Lubszky, Szabina; Thöny, Sandra; Schulzki, Thomas

    2014-10-01

    The normal red blood cell (RBC) shape is a biconcave discocyte. An intercalation of a drug in the outer half of the membrane lipid bilayer leads to echinocytosis, an intercalation in the inner half to stomatocytosis. We have used the shape transforming capacity of RBCs as a model to analyse the membrane interaction potential of various neurotropic drugs. Chlorpromazine, clomipramine, citalopram, clonazepam, and diazepam induced a reversible stomatocytosis, phenytoin induced echinocytosis, while the anticonvulsants levetiracetam, valproic acid and phenobarbital had no effect. This diversity of RBC shape transformations suggests that the pharmacological action is not linked to the membrane interaction. We conclude that this simple RBC shape transformation assay could be a useful tool to screen for potential drug interactions with cell membranes. Copyright © 2014. Published by Elsevier Ltd.

  16. Recent advances in drug therapy for epilepsy.

    PubMed Central

    Bruni, J.

    1979-01-01

    Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug's bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects. PMID:371777

  17. Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions.

    PubMed

    Thommes, Markus; Ely, David R; Carvajal, M Teresa; Pinal, Rodolfo

    2011-06-06

    We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

  18. Practical synthesis, anticonvulsant, and antimicrobial activity of N-allyl and N-propargyl di(indolyl)indolin-2-ones.

    PubMed

    Praveen, Chandrasekaran; Ayyanar, Asairajan; Perumal, Paramasivan Thirumalai

    2011-07-01

    An operation friendly protocol for the synthesis of novel di(indolyl)indolin-2-ones via Cu(OTf)(2) catalyzed bis-addition of N-allyl and N-propargyl indole with isatin was developed. This methodology allowed us to achieve the products in excellent yields without requiring purification technique like column chromatography. All the synthesized compounds were evaluated for their in vivo anticonvulsant activity against maximal electroshock test. Six compounds showed maximum activity compared to the standard drug phenytoin. The scope of the new molecules as antimicrobial agents were tested against two bacterial strains (Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans). Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Wound healing property of milk in full thickness wound model of rabbit.

    PubMed

    Hemmati, Ali Asghar; Larki-Harchegani, Amir; Shabib, Somayeh; Jalali, Amir; Rezaei, Anahita; Housmand, Gholamreza

    2018-04-22

    Wound healing consists of several continuous phases in which various cells and chemical intermediates are involved. Milk as a rich source of nutritional elements has proved to have potential benefits for treatment of various diseases. The present study was designed to investigate the healing effect of low-fat cow's milk on an open skin wound model in the rabbit. The 2%, 5%, and 10% (w/w) ointments of lyophilized powder of low-fat milk were prepared in the eucerin base and were applied twice daily in the treatment groups. Phenytoin 1% ointment was used as a standard control. The healing effect of the milk ointment (MO) was evaluated through the measurement of wound surface area, the extent of tissue tension, and the content of hydroxyproline. Histological evaluation of skin tissue specimens was also performed using hematoxylin and eosin staining. The results showed that the healing rate in the treatment group was significantly higher than that of untreated group and eucerin group (p < 0.01). The best healing effect was seen in 5% milk ointment with the shortest healing time (15 days) and the highest tissue tension in comparison to other groups. Although the tissue hydroxyproline content in this group was slightly lower than that of the phenytoin group, this difference was not significant. Histologic, findings indicated increased collagen fibers, increased fibroblasts and an evident decrease in inflammatory cells in that group. It can, therefore, be concluded that low-fat cow's milk has significant beneficial effects on skin wound healing. Therefore, it may be used as a healing agent in different types of the wound in humans after certain clinical trials. Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  20. QTc prolongation after brain surgery.

    PubMed

    Capparelli, Federico J; Abello, Mauricio; Patricio Maskin, L; Arista, Eugenia; Hlavnicka, Alejandro; Diaz, Maria Fernanda; Varela, Daniel; Wainsztein, Nestor A

    2013-03-01

    Abnormalities observed in the electrocardiogram (ECG) after acute central nervous system (CNS) events have been reported. Our objective was to assess the incidence of heart rate-corrected QT interval (QTc) prolongation in patients admitted to the intensive care unit (ICU) after brain surgery. Admission standard 12-lead ECGs were analyzed blinded to patient data. The QT interval was measured and Bazzett's formula was used to obtain QTc. Prolonged QTc was defined as ≧450 ms. We included 114 patients in the study. The mean age was 49±17 years. Brain neoplasm was the surgical indication in 90% of the patients. The mean QTc was 470±42 ms. Prolonged QTc was found in 71% patients. The heart rate-corrected QT interval was between 450 ms and 500 ms in 52% and >500 ms in 19% of the patients. The heart rate and concentration of serum glucose were higher in the prolonged QTc group. Only 7·5% of all patients had hypokalemia (≤3 mEq/l). In the prolonged QTc group 9·2% had hypokalemia compared to 3·2% in normal QTc patients (P = 0·406). There were no significant associations between categories of QTc and the serum levels of creatinine, magnesium, calcium, sodium, or pH. Phenytoin and metoclopramide were not frequently used in patients with prolonged QTc. This study supports our hypothesis that prolonged QTc is frequently observed after a brain surgery. Hypokalemia, hypocalcaemia, and drugs such as metoclopramide or phenytoin could not explain the high incidence of prolonged QTc. Brain injury during a surgical procedure may be one of the primary causes of QTc prolongation after neurosurgery.

  1. SCN2A encephalopathy

    PubMed Central

    Howell, Katherine B.; McMahon, Jacinta M.; Carvill, Gemma L.; Tambunan, Dimira; Mackay, Mark T.; Rodriguez-Casero, Victoria; Webster, Richard; Clark, Damian; Freeman, Jeremy L.; Calvert, Sophie; Olson, Heather E.; Mandelstam, Simone; Poduri, Annapurna; Mefford, Heather C.; Harvey, A. Simon

    2015-01-01

    Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1–4 in 8, week 2–6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one. Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile–onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control. PMID:26291284

  2. Validation of a patch clamp screening protocol that simultaneously measures compound activity in multiple states of the voltage-gated sodium channel Nav1.2.

    PubMed

    Liu, Yi; Beck, Edward J; Flores, Christopher M

    2011-12-01

    Hyperactivity of voltage-gated sodium channels underlies, at least in part, a range of pathological states, including pain and epilepsy. Selective blockers of these channels may offer effective treatment of such disorders. Currently employed methods to screen for sodium channel blockers, however, are inadequate to rationally identify mechanistically diverse blockers, limiting the potential range of indications that may be treated by such agents. Here, we describe an improved patch clamp screening assay that increases the mechanistic diversity of sodium channel blockers being identified. Using QPatch HT, a medium-throughput, automated patch clamp system, we tested three common sodium channel blockers (phenytoin, lidocaine, and tetrodotoxin) with distinct mechanistic profiles at Nav1.2. The single-voltage protocol employed in this assay simultaneously measured the compound activity in multiple states, including the slow inactivated state, of the channel. A long compound incubation period (10 s) was introduced during channel inactivation to increase the probability of identifying "slow binders." As such, phenytoin, which preferentially binds with slow kinetics to the fast inactivated state, exhibited significantly higher potency than that obtained from a brief exposure (100 ms) used in typical assays. This assay also successfully detected the use-dependent block of tetrodotoxin, a well-documented property of this molecule yet unobserved in typical patch clamp protocols. These results indicate that the assay described here can increase the likelihood of identification and mechanistic diversity of sodium channel blockers from a primary screen. It can also be used to efficiently guide the in vitro optimization of leads that retain the desired mechanistic properties. © MARY ANN LIEBERT, INC.

  3. 'MacDope': a simulation of drug disposition in the human body: applications in clinical pharmacokinetics.

    PubMed Central

    Bloch, R; Sweeney, G; Ahmed, K; Dickinson, C J; Ingram, D

    1980-01-01

    1 We have described a novel approach to absorption, distribution, metabolism and elimination of drugs in which the patient is described using 23 Patient Factors and drugs by up to 50 Drug Factors. Kinetic behavior of a drug results from the interaction of patient and drug factors according to equations describing an eight compartment model. In this model non-linear processes (protein binding, hepatic drug metabolism and renal tubular transport) are handled by derivations of the law of mass action which have been generalised to permit the consequences of multiple drugs interacting at single macromolecular sites to be correctly calculated. 2 The mathematical description of this model is provided in a companion paper and solution of the equations is only possible using a digital computer. The computer programme is provided with an interactional format which makes operation independent of mathematical skills. Patients are defined by age, sex, height and weight with, or without, organ dysfunction; the programme then generates appropriate factors. Drug enters the system when a prescription is type on the keyboard and required Drug Factors are then retrieved from the disc flies. Drug concentrations in plasma or body fluids are given as simple graphs as a function of time, or in tabular form. 3 Any of the Patient or Drug Factors may be altered before, or during a run and up to three drugs may be simulated at one time thus permitting certain kinetic interactions to be examined. The scope of the simulator is illustrated using aspirin: pH dependent gastric absorption, first-order conversion of aspirin to salicylate, partly first order and partly saturable hepatic metabolism of salicylate, and the complex renal handling of this drug are all represented. Interaction of phenytoin with salicylate has been examined quantitatively to suggest limited clinical relevance for the observed displacement of phenytoin from serum albumin. The use of the simulator in a short course of

  4. Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: Report of RTOG trial 89-05

    SciTech Connect

    Phillips, T.L.; Scott, C.B.; Leibel, S.A.

    1995-09-30

    The purpose of this trial was to determine if the addition of bromodeoxyuridine (BrdUrd) to radiotherapy prolongs survival when compared to radiotherapy alone in patients with brain metastases. Seventy-two patients with brain metastases were randomized to 37.5 Gy in 15 fractions of 2.5 Gy or to the same dose with BrdUrd 0.8 g/m{sup 2} per day for 4 days of each of 3 weeks. Patients were stratified by primary site (breast, lung or other), number of metastases (single or multiple) and age (<60 vs. >60). There was no significant difference between the two treatment arms (p = 0.904). The studymore » was open from October 1989 to March 1993 and accrued 72 patients. Only one patient in the RT only arm remains alive. The two treatment arms were balanced with respect to all stratification variables. Toxicity due to radiotherapy was similar in both arms. BrdUrd caused significant Grade 4 and 5 hematologic and skin toxicity in five patients. Two patients died due to hematologic toxicity and one from a Stevens-Johnson type skin reaction. Phenytoin played a role in the skin reactions and ranitidine was associated with the hematologic deaths. Ranitidine was eliminated, BrdUrd was discontinued after any hematologic toxicity, and no further Grade 4 or 5 toxicities were seen. The median survival was 6.12 months in the radiotherapy group and 4.3 in the BrdUrd group (p = 0.904). Patients with solitary brain metastases had significantly better survival (p = 0.031). BrdUrd did not enhance the efficacy of the radiotherapy regiment tested, in spite of the fact that brain metastases have shown high labeling indices. The toxicity of this schedule of BrdUrd administration was apparently increased by ranitidine and phenytoin. 16 refs., 4 figs., 13 tabs.« less

  5. Effects of Antiepileptic Drugs on Spontaneous Recurrent Seizures in a Novel Model of Extended Hippocampal Kindling in Mice.

    PubMed

    Song, Hongmei; Tufa, Uilki; Chow, Jonathan; Sivanenthiran, Nila; Cheng, Chloe; Lim, Stellar; Wu, Chiping; Feng, Jiachun; Eubanks, James H; Zhang, Liang

    2018-01-01

    Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures and comorbidities. Kindling has long been used to model epileptogenic mechanisms and to assess antiepileptic drugs. In particular, extended kindling can induce spontaneous recurrent seizures without gross brain lesions, as seen clinically. To date, the development of spontaneous recurrent seizures following extended kindling, and the effect of the antiepileptic drugs on these seizures are not well understood. In the present study we aim to develop a mouse model of extended hippocampal kindling for the first time. Once established, we plan to evaluate the effect of three different antiepileptic drugs on the development of the extended-hippocampal-kindled-induced spontaneous recurrent seizures. Male C57 black mice were used for chronic hippocampal stimulations or handling manipulations (twice daily for up to 70 days). Subsequently, animals underwent continuous video/EEG monitoring for seizure detection. Spontaneous recurrent seizures were consistently observed in extended kindled mice but no seizures were detected in the control animals. The aforementioned seizures were generalized events characterized by hippocampal ictal discharges and concurrent motor seizures. Incidence and severity of the seizures was relatively stable while monitored over a few months after termination of the hippocampal stimulation. Three antiepileptic drugs with distinct action mechanisms were tested: phenytoin, lorazepam and levetiracetam. They were applied via intra-peritoneal injections at anticonvulsive doses and their effects on the spontaneous recurrent seizures were analyzed 10-12 h post-injection. Phenytoin (25 mg/kg) and levetiracetam (400 mg/kg) abolished the spontaneous recurrent seizures. Lorazepam (1.5 mg/kg) decreased motor seizure severity but did not reduce the incidence and duration of corresponding hippocampal discharges, implicating its inhibitory effects on

  6. Reliability of the Roussel Uclaf Causality Assessment Method for Assessing Causality in Drug-Induced Liver Injury*

    PubMed Central

    Rochon, James; Protiva, Petr; Seeff, Leonard B.; Fontana, Robert J.; Liangpunsakul, Suthat; Watkins, Paul B.; Davern, Timothy; McHutchison, John G.

    2013-01-01

    The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally. Conclusion The mediocre reliability of the RUCAM is problematic for future studies of drug-induced liver injury. Alternative methods, including modifying the RUCAM, developing drug-specific instruments, or causality assessment based on

  7. Synergistic Effect of Honey and Propolis on Cutaneous Wound Healing in Rats.

    PubMed

    Takzaree, Nasrin; Hadjiakhondi, Abbas; Hassanzadeh, Gholamreza; Rouini, Mohammad Reza; Manayi, Azadeh

    2016-04-01

    Accelerating wound healing is now considered as a principle clinical treatment and increasing the quality and speed of healing which has always been emphasized by the scientists. Propolis and honey are natural bee products with wide range of biological and medicinal properties. This study was aimed to determine the synergistic effect of honey and propolis in wound healing of rat skin. A total of 75 Wistar rats weighing 200-250 gr were placed under general anesthesia and sterile conditions. Then a square shape wound with 1.5*1.5 mm dimension was made on the back of the neck. Animals were randomly divided into control, honey, propolis, combined honey propolis and phenytoin 1% groups, respectively. Rats were randomly divided into the following groups: 4th, 7th and, 14th days of treatment in each period of study. Wound area in the experimental group was covered once daily with a fixed amount of thyme honey, propolis, propolis and honey and phenytoin cream (1%), the control group did not receive any treatment. For histological studies, during the fourth, seventh and fourteenth day's rats were sacrificed and samples were taken from the wound and adjacent skin. After histological staining fibroblast, neutrophils, macrophages and vascular sections were counted in the wound bed. The macroscopic and microscopic evaluations showed that the percentage of wound healing on different days in the experimental and control groups were significant (P<0.05). The macroscopic and microscopic evaluation showed that the percentage of wound healing on different days in combined propolis and honey experimental group was significantly different from the control group (Multivariate ANOVA test) (P<0.05). Combined application of propolis and honey on the open wound healing in rats has a synergistic effect.

  8. Detection of 22 antiepileptic drugs by ultra-performance liquid chromatography coupled with tandem mass spectrometry applicable to routine therapeutic drug monitoring.

    PubMed

    Shibata, Mai; Hashi, Sachiyo; Nakanishi, Haruka; Masuda, Satohiro; Katsura, Toshiya; Yano, Ikuko

    2012-12-01

    The purpose of this study was to develop an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method of 22 antiepileptics for routine therapeutic monitoring. The antiepileptics used in the analyses were carbamazepine, carbamazepine-10,11-epoxide, clobazam, N-desmethylclobazam, clonazepam, diazepam, N-desmethyldiazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, N-desmethylmesuximide, nitrazepam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide. After protein precipitation of 50 μL plasma with methanol, the supernatant was diluted with water or was evaporated to dryness and reconstituted with mobile phase in the case of benzodiazepines. Separation was achieved on an Acquity UPLC BEH C₁₈ column with a gradient mobile phase of 10 mm ammonium acetate containing 0.1% formic acid and methanol at a flow rate of 0.4 mL/min. An Acquity TQD instrument in multiple reaction monitoring mode with ion mode switching was used for detection. All antiepileptics were detected and quantified within 10 min, with no endogenous interference. All the calibration curves showed good linearity in the therapeutic range (r²  < 0.99). The precision and accuracy values for intra- and inter-assays were within ±15% except for phenobarbital and tiagabine. A good correlation was observed between the concentration of clinical samples measured by the new method described here and the conventional methods. The values of carbamazepine and phenytoin by UPLC-MS/MS were lower than those detected by the immunoassays, which might be caused by the cross-reaction of antibodies with their metabolites. In conclusion, we developed a simple and selective UPLC-MS/MS method suitable for routine therapeutic monitoring of antiepileptics. Copyright © 2012 John Wiley & Sons, Ltd.

  9. Pharmacokinetics of combined treatment with praziquantel and albendazole in neurocysticercosis

    PubMed Central

    Garcia, Hector H; Lescano, Andres G; Lanchote, Vera L; Pretell, E Javier; Gonzales, Isidro; Bustos, Javier A; Takayanagui, Osvaldo M; Bonato, Pierina S; Horton, John; Saavedra, Herbert; Gonzalez, Armando E; Gilman, Robert H

    2011-01-01

    AIMS Neurocysticercosis is the most common cause of acquired epilepsy in the world. Antiparasitic treatment of viable brain cysts is of clinical benefit, but current antiparasitic regimes provide incomplete parasiticidal efficacy. Combined use of two antiparasitic drugs may improve clearance of brain parasites. Albendazole (ABZ) has been used together with praziquantel (PZQ) before for geohelminths, echinococcosis and cysticercosis, but their combined use is not yet formally recommended and only scarce, discrepant data exist on their pharmacokinetics when given together. We assessed the pharmacokinetics of their combined use for the treatment of neurocysticercosis. METHODS A randomized, double-blind, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ and PZQ in 32 patients with neurocysticercosis was carried out. Patients received their usual concomitant medications including an antiepileptic drug, dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug (phenytoin or carbamazepine). Subjects had sequential blood samples taken after the first dose of antiparasitic drugs and again after 9 days of treatment, and were followed for 3 months after dosing. RESULTS Twenty-one men and 11 women, aged 16 to 55 (mean age 28) years were included. Albendazole sulfoxide concentrations were increased in the combination group compared with the ABZ alone group, both in patients taking phenytoin and patients taking carbamazepine. PZQ concentrations were also increased by the end of therapy. There were no significant side effects in this study group. CONCLUSIONS Combined ABZ + PZQ is associated with increased albendazole sulfoxide plasma concentrations. These increased concentrations could independently contribute to increased cysticidal efficacy by themselves or in addition to a possible synergistic effect. PMID:21332573

  10. Curcumin inhibits TGF-β1-induced connective tissue growth factor expression through the interruption of Smad2 signaling in human gingival fibroblasts.

    PubMed

    Chen, Jung-Tsu; Wang, Chen-Ying; Chen, Min-Huey

    2018-01-13

    Many fibrotic processes are associated with an increased level of transforming growth factor-β1 (TGF-β1). TGF-β1 can increase synthesis of matrix proteins and enhance secretion of protease inhibitors, resulting in matrix accumulation. Connective tissue growth factor (CTGF) is a downstream profibrotic effector of TGF-β1 and is associated with the fibrosis in several human organs. Curcumin has been applied to reduce matrix accumulation in fibrotic diseases. This study was aimed to evaluate whether curcumin could suppress TGF-β1-induced CTGF expression and its related signaling pathway involving in this inhibitory action in primary human gingival fibroblasts. The differences in CTGF expression among three types of gingival overgrowth and normal gingival tissues were assessed by immunohistochemistry. Gingival fibroblast viability in cultured media with different concentrations of curcumin was studied by MTT assay. The effect of curcumin on TGF-β1-induced CTGF expression in primary human gingival fibroblasts was examined by immunoblotting. Moreover, the proteins involved in TGF-β1 signaling pathways including TGF-β1 receptors and Smad2 were also analyzed by immunoblotting. CTGF was highly expressed in fibroblasts, epithelial cells and some of endothelial cells, smooth muscle cells, and inflammatory cells in phenytoin-induced gingival overgrowth tissues rather than in those of hereditary and inflammatory gingival overgrowth tissues. Moreover, CTGF expression in the epithelial and connective tissue layers was higher in phenytoin-induced gingival overgrowth tissues than in normal gingival tissues. Curcumin was nontoxic and could reduce TGF-β1-induced CTGF expression by attenuating the phosphorylation and nuclear translocation of Smad2. Curcumin can suppress TGF-β1-induced CTGF expression through the interruption of Smad2 signaling. Copyright © 2018. Published by Elsevier B.V.

  11. Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome

    PubMed Central

    McCauley, Mark D.; Wang, Tiannan; Mike, Elise; Herrera, Jose; Beavers, David L.; Huang, Teng-Wei; Ward, Christopher S.; Skinner, Steven; Percy, Alan K.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

    2013-01-01

    Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in Methyl-CpG-Binding Protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms (ECGs) in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), indicating a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally-mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current in order to prevent lethal cardiac arrhythmias. PMID:22174313

  12. Challenges in the treatment of convulsive status epilepticus.

    PubMed

    Zaccara, Gaetano; Giannasi, Gianfranco; Oggioni, Roberto; Rosati, Eleonora; Tramacere, Luciana; Palumbo, Pasquale

    2017-04-01

    Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. The most recent definition of CSE is a convulsive seizure lasting more than 5min or consecutive seizures without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam, lorazepam or midazolam are the most common treatments, although the choice of agent seems less important than rapid treatment. Midazolam, when administered intramuscularly (best evidence), buccally, or nasally, is effective and safe in the pre-hospital setting. The antiepileptic drugs, phenytoin, valproate, levetiracetam and, more recently lacosamide, are used in CSE that persists after first-line treatments (established CSE). Phenytoin is more difficult to administer and is less well tolerated. Evidence of the efficacy of lacosamide is scarce. Anaesthetics are the drugs of choice for the treatment of refractory CSE (not responding to second-line drugs). Midazolam seems to be the best tolerated and is the most often used drug, followed by propofol and thiopental (pentobarbital in the USA). A few studies indicate that ketamine is effective with the possible advantage that it can be co-administered with other anaesthetics, such as midazolam or propofol. CSE becomes super-refractory after more than 24h of appropriate treatments and may last weeks. Several anaesthetics have been proposed but evidence is scarce. Autoimmune refractory CSE has been recently identified, and early treatment with immuno-modulatory agents (corticosteroids and IV immunoglobulins and also second-line agents such as cyclophosphamide and rituximab followed by chronic immunosuppressive treatment) is now recommended by many experts. Copyright © 2017. Published by Elsevier Ltd.

  13. Canine status epilepticus treated with fosphenytoin: A proof of principle study.

    PubMed

    Patterson, Edward E; Leppik, Ilo E; Coles, Lisa D; Podell, Michael; Vite, Charles H; Bush, William; Cloyd, James C

    2015-06-01

    There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available to treat status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs, with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people. A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or who had additional seizures after enrolling received intravenous (i.v.) benzodiazepine (BZD) followed immediately by intravenous infusion of 15 mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured. Consent was obtained for 50 dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 h responder rate, with 63% in the FOS group versus 22% in the placebo group (p = 0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 min were within the therapeutic concentrations for people (1-2 μg/ml) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 min of FOS administration and none of the placebo group (0/9) (p = 0.064). This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Furthermore, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds. © 2015 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against

  14. The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

    PubMed Central

    Okkerse, Pieter; van Amerongen, Guido; de Kam, Marieke L.; Stevens, Jasper; Butt, Richard P.; Gurrell, Rachel; Dahan, Albert; van Gerven, Joop M.; Hay, Justin L.

    2017-01-01

    Aim The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. Methods The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)‐pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg–1, phenytoin 300 mg, (S)‐ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post‐dose. Endpoints were analysed using a mixed model analysis of variance. Results Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)‐ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)‐ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. Conclusion This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. PMID:27862179

  15. The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study.

    PubMed

    Okkerse, Pieter; van Amerongen, Guido; de Kam, Marieke L; Stevens, Jasper; Butt, Richard P; Gurrell, Rachel; Dahan, Albert; van Gerven, Joop M; Hay, Justin L; Groeneveld, Geert Jan

    2017-05-01

    The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg -1 , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post-dose. Endpoints were analysed using a mixed model analysis of variance. Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)-ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)-ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. © 2016 The British Pharmacological Society.

  16. Intravenous Infiltration Risk by Catheter Dwell Time Among Hospitalized Children.

    PubMed

    Jeong, Ihn Sook; Jeon, Gey Rok; Lee, Man Seop; Shin, Bum Joo; Kim, Yong-Jin; Park, Soon Mi; Hyun, Sookyung

    This study was aimed to examine the cumulative risk for infiltration over IV catheter dwell time by general or catheterization-specific characteristics of pediatric patients with IV therapy. This secondary data analysis was done with the data of 1596 children who received peripheral IV therapy at least once during their hospital stay between August 1st and October 30th, 2011 and in June, 2013 in an academic medical center, Yangsan, Republic of Korea. The survival functions of infiltration were determined by using the Kaplan-Meier analysis. The cumulative risk for infiltration had rapidly increased from 1.5% after 24 hours of catheter dwell time to 17.3% after 96 hours. The survival functions were significantly different in the medical than in the surgical department (p=.005), lower extremities than upper ones (p=.001), and use of 10% dextrose (p=.001), ampicillin/sulbactam (p<.001), vancomycin (p=.024), high-concentration electrolytes (p=.001), and phenytoin (p<.001). When catheter dwell times are similar, the cumulative risk for infiltration was higher in cases wherein the patient had a risk factor. The cumulative risk for infiltration has rapidly increased after 24 hours in patients who have 10% dextrose, high-concentration electrolytes, and phenytoin. The results suggest that nurses are required to assess the IV site every hour after 24 hours of catheter dwell time for the infusion of irritants for a safer practice of IV therapy. However, this monitoring time may be modified by the age of child, previous IV complications, and/or hemodynamic issues which may impact IV integrity. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Pharmacological treatments for preventing epilepsy following traumatic head injury.

    PubMed

    Thompson, Kara; Pohlmann-Eden, Bernhard; Campbell, Leslie A; Abel, Hannah

    2015-08-10

    Head injury is a common event and can cause a spectrum of motor and cognition disabilities. A frequent complication is seizures. Antiepileptic drugs (AED) such as phenytoin are often used in clinical practice with the hopes of preventing post-traumatic epilepsy. Whether immediate medical intervention following head trauma with either AEDs or neuroprotective drugs can alter the process of epileptogenesis and lead to a more favorable outcome is currently unknown. This review attempted to address the effectiveness of these treatment interventions. This review updates and expands on the earlier Cochrane review. To compare the efficacy of antiepileptic drugs and neuroprotective agents with placebo, usual care or other pharmacologic agents for the prevention of post-traumatic epilepsy in people diagnosed with any severity of traumatic brain injury. We searched The Cochrane Epilepsy Group's specialized register, CENTRAL, MEDLINE, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP) in January 2015. We searched EMBASE, Biological Abstracts and National Research Register in September 2014 and SCOPUS in December 2013. The Cochrane Epilepsy Group performed handsearches of relevant journals. We included randomized controlled trials (RCTs) that include AEDs or neuroprotective agents compared with placebo, another pharmacologic agent or a usual care group. The outcomes measured included a seizure occurring within one week of trauma (early seizure), seizure occurring later than one week post-trauma (late seizure), mortality and any adverse events. Two review authors independently assessed study quality and extracted the data. We calculated risk ratios (RR) and 95% confidence intervals (CI) for each outcome. We used random-effects models in the meta-analyses and performed pre-defined subgroup and sensitivity analyses. This review included 10 RCTs (reported in 12 articles) consisting of 2326 participants The methodological quality

  18. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.

    PubMed

    Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio; Craig, John; Lindhout, Dick; Perucca, Emilio; Sabers, Anne; Thomas, Sanjeev V; Vajda, Frank

    2018-06-01

    Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable

  19. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society

    PubMed Central

    Shinnar, Shlomo; Gloss, David; Alldredge, Brian; Arya, Ravindra; Bainbridge, Jacquelyn; Bare, Mary; Bleck, Thomas; Dodson, W. Edwin; Garrity, Lisa; Jagoda, Andy; Lowenstein, Daniel; Pellock, John; Riviello, James; Sloan, Edward; Treiman, David M.

    2016-01-01

    associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline. PMID:26900382

  20. Antiepileptic Drug Titration and Related Health Care Resource Use and Costs.

    PubMed

    Fishman, Jesse; Kalilani, Linda; Song, Yan; Swallow, Elyse; Wild, Imane

    2018-02-27

    Unexpected breakthrough seizures resulting from suboptimal antiepileptic drug (AED) dosing during the titration period, as well as adverse events resulting from rapid AED titration, may influence the titration schedule and significantly increase health care resource use (HRU) and health care costs. To assess the relationship between AEDs, HRU, and costs during AED titration and maintenance. Practicing neurologists were recruited from a nationwide panel to provide up to 3 patient records each for this retrospective medical chart review. Patients with epilepsy who were aged ≥ 18 years and had initiated an AED between January 1, 2014, and January 1, 2016, were followed for 6 months from AED initiation. Titration duration was the time from AED initiation to the beginning of treatment maintenance as determined by the physician. Outcomes were epilepsy-specific HRU (hospitalizations, emergency department visits, outpatient visits, physician referral, laboratory testing/diagnostic imaging, and phone calls) and related costs that occurred during the titration or maintenance treatment periods. Of 811 patients, 156, 128, 125, 120, 114, 107, and 61 initiated the following AEDs: levetiracetam, lamotrigine, lacosamide, valproate, topiramate, carbamazepine, and phenytoin, respectively. Most patients (619/803 [77.1%] with complete AED data) received monotherapy. Baseline characteristics were similar across AEDs (mean [SD] age, 36.6 [14.4] years; 59.0% male). Kaplan-Meier estimates of titration duration ranged from 3.3 weeks (phenytoin) to 8.1 weeks (lamotrigine). From titration to maintenance, the overall incidence of HRU per person-month decreased 54.5%-89.3% for each HRU measure except outpatient visits (24.6% decrease). Total epilepsy-related costs decreased from $80.48 to $42.77 per person-month, or 46.9% from titration to maintenance. AED titration periods had higher HRU rates and costs than AED maintenance, suggesting that use of AEDs with shorter titration requirements

  1. Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored Data.

    PubMed

    Takeuchi, Masato; Yano, Ikuko; Ito, Satoko; Sugimoto, Mitsuhiro; Yamamoto, Shota; Yonezawa, Atsushi; Ikeda, Akio; Matsubara, Kazuo

    2017-04-01

    Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum

  2. Intramuscular and rectal therapies of acute seizures.

    PubMed

    Leppik, Ilo E; Patel, Sima I

    2015-08-01

    The intramuscular (IM) and rectal routes are alternative routes of delivery for antiepileptic drugs (AEDs) when the intravenous route is not practical or possible. For treatment of acute seizures, the AED used should have a short time to maximum concentration (Tmax). Some AEDs have preparations that may be given intramuscularly. These include the benzodiazepines (diazepam, lorazepam, and midazolam) and others (fosphenytoin, levetiracetam). Although phenytoin and valproate have parenteral preparations, these should not be given intramuscularly. A recent study of prehospital treatment of status epilepticus evaluated a midazolam (MDZ) autoinjector delivering IM drug compared to IV lorazepam (LZP). Seizures were absent on arrival to the emergency department in 73.4% of the IM MDZ compared to a 63.4% response in LZP-treated subjects (p < 0.001 for superiority). Almost all AEDs have been evaluated for rectal administration as solutions, gels, and suppositories. In a placebo-controlled study, diazepam (DZP) was administered at home by caregivers in doses that ranged from 0.2 to 0.5 mg/kg. Diazepam was superior to placebo in reduced seizure frequency in children (p < 0.001) and in adults (p = 0.02) and time to recurrent seizures after an initial treatment (p < 0.001). Thus, at this time, only MZD given intramuscularly and DZP given rectally appear to have the properties required for rapid enough absorption to be useful when intravenous routes are not possible. Some drugs cannot be administered rectally owing to factors such as poor absorption or poor solubility in aqueous solutions. The relative rectal bioavailability of gabapentin, oxcarbazepine, and phenytoin is so low that the current formulations are not considered to be suitable for administration by this route. When administered as a solution, diazepam is rapidly absorbed rectally, reaching the Tmax within 5-20 min in children. By contrast, rectal administration of lorazepam is relatively slow, with a Tmax of 1-2h

  3. Effects of Antiepileptic Drugs on Spontaneous Recurrent Seizures in a Novel Model of Extended Hippocampal Kindling in Mice

    PubMed Central

    Song, Hongmei; Tufa, Uilki; Chow, Jonathan; Sivanenthiran, Nila; Cheng, Chloe; Lim, Stellar; Wu, Chiping; Feng, Jiachun; Eubanks, James H.; Zhang, Liang

    2018-01-01

    Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures and comorbidities. Kindling has long been used to model epileptogenic mechanisms and to assess antiepileptic drugs. In particular, extended kindling can induce spontaneous recurrent seizures without gross brain lesions, as seen clinically. To date, the development of spontaneous recurrent seizures following extended kindling, and the effect of the antiepileptic drugs on these seizures are not well understood. In the present study we aim to develop a mouse model of extended hippocampal kindling for the first time. Once established, we plan to evaluate the effect of three different antiepileptic drugs on the development of the extended-hippocampal-kindled-induced spontaneous recurrent seizures. Male C57 black mice were used for chronic hippocampal stimulations or handling manipulations (twice daily for up to 70 days). Subsequently, animals underwent continuous video/EEG monitoring for seizure detection. Spontaneous recurrent seizures were consistently observed in extended kindled mice but no seizures were detected in the control animals. The aforementioned seizures were generalized events characterized by hippocampal ictal discharges and concurrent motor seizures. Incidence and severity of the seizures was relatively stable while monitored over a few months after termination of the hippocampal stimulation. Three antiepileptic drugs with distinct action mechanisms were tested: phenytoin, lorazepam and levetiracetam. They were applied via intra-peritoneal injections at anticonvulsive doses and their effects on the spontaneous recurrent seizures were analyzed 10–12 h post-injection. Phenytoin (25 mg/kg) and levetiracetam (400 mg/kg) abolished the spontaneous recurrent seizures. Lorazepam (1.5 mg/kg) decreased motor seizure severity but did not reduce the incidence and duration of corresponding hippocampal discharges, implicating its inhibitory effects on

  4. Lacosamide improves outcome in a murine model of traumatic brain injury.

    PubMed

    Wang, Bo; Dawson, Hana; Wang, Haichen; Kernagis, Dawn; Kolls, Brad J; Yao, Lucy; Laskowitz, Daniel T

    2013-08-01

    Use of antiepileptic drugs (AED's) is common in the neurocritical care setting. However, there remains a great deal of controversy regarding the optimal agent. Studies associating the prophylactic use of AED's with poor outcomes are heavily biased by the prevalent use of phenytoin, an agent highly associated with deleterious effects. In the current study, we evaluate lacosamide for neuroprotective properties in a murine model of closed head injury. Mice were subjected to moderate closed head injury using a pneumatic impactor, and then treated with either low-dose (6 mg/kg) or high-dose (30 mg/kg) lacosamide or vehicle at 30 min post-injury, and twice daily for 3 days after injury. Motor and cognitive functional assessments were performed following injury using rotarod and Morris Water Maze, respectively. Neuronal injury and microglial activation were measured by flourojade-B, NeuN, and F4/80 staining at 1 and 7 days post-injury. Timm's staining was also performed to assess lacosamide effects on mossy fiber axonal sprouting. To evaluate possible mechanisms of lacosamide effects on the inflammatory response to injury, an RNA expression array was used to evaluate for alterations in differential gene expression patterns in injured mice following lacosamide or vehicle treatments. High-dose lacosamide was associated with improved functional outcome on both the rotarod and Morris Water Maze. High-dose lacosamide was also associated with a reduction of neuronal injury at 24 h post-injury. However, the reduction in neuronal loss observed early did not result in greater neuronal density at 31 days post-injury based on unbiased stereology of NeuN staining. High-dose lacosamide was also associated with a significant reduction in microglial activation at 7 days post-injury. The therapeutic effects of lacosamide are associated with a delay in injury-related changes in RNA expression of a subset of inflammatory mediator genes typically seen at 24 h post-injury. Administration of

  5. Lacosamide and concomitant use of antiepileptic and other medications in a US population - A retrospective cohort study.

    PubMed

    Kalilani, Linda; Lu, Chao; Pierre-Louis, Bosny; Gold, Michael

    2017-07-01

    Information on the use of lacosamide and concomitant antiepileptic and non-antiepileptic drugs (non-AEDs) is available from clinical trials and observational studies with small sample sizes. This retrospective cohort study was conducted to gain insight into the use of lacosamide in a large number of patients with epilepsy in real-life clinical practice with less restrictive selection criteria compared with clinical trial participants. The Truven Health MarketScan (Commercial Claims and Medicare Supplemental) database was used to identify patients with a prior diagnosis of epilepsy with at least one prescription claim for lacosamide between June 2009 and September 2013 and continuous health insurance enrolment with medical and pharmacy coverage during the 1-year pre-index baseline period. A total of 8859 eligible patients were identified, of whom, at index (lacosamide initiation), 16.8% received lacosamide as monotherapy and 54.0% as polytherapy. The median prescription duration was 196days (Interquartile range 69-476days). Levetiracetam was the most frequently prescribed concomitant AED across all age groups, followed by phenytoin among older (>65years) and lamotrigine among younger patients. Older patients who had LCM monotherapy at initiation, were prescribed fewer concomitant AEDs, but more non-AEDs. The most common non-AED medications were prescribed for pain, psychiatric conditions, hyperlipidemia and gastrointestinal diseases across all age groups. Overall, results suggest that the lacosamide use is driven predominantly by age and that there is substantial use of lacosamide monotherapy (16.8%), despite lack of indication at the time of the study. Results also reveal substantial use of concomitant non-AEDs; 90.4% among patients >65years of age and 54.3% among those ≤17years, confirming the high prevalence of comorbidities among patients with epilepsy across all ages. Despite the availability of numerous newer AEDs, older AEDs are still being frequently

  6. pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH methods.

    PubMed

    Avdeef, A; Berger, C M; Brownell, C

    2000-01-01

    The objective of this study was to compare the results of a normal saturation shake-flask method to a new potentiometric acid-base titration method for determining the intrinsic solubility and the solubility-pH profiles of ionizable molecules, and to report the solubility constants determined by the latter technique. The solubility-pH profiles of twelve generic drugs (atenolol, diclofenac.Na, famotidine, flurbiprofen, furosemide, hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, and propranolol.HCl), with solubilities spanning over six orders of magnitude, were determined both by the new pH-metric method and by a traditional approach (24 hr shaking of saturated solutions, followed by filtration, then HPLC assaying with UV detection). The 212 separate saturation shake-flask solubility measurements and those derived from 65 potentiometric titrations agreed well. The analysis produced the correlation equation: log(1/S)titration = -0.063(+/- 0.032) + 1.025(+/- 0.011) log(1/S)shake-flask, s = 0.20, r2 = 0.978. The potentiometrically-derived intrinsic solubilities of the drugs were: atenolol 13.5 mg/mL, diclofenac.Na 0.82 microg/mL, famotidine 1.1 mg/ mL, flurbiprofen 10.6 microg/mL, furosemide 5.9 microg/mL, hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 microg/mL, ketoprofen 118 microg/mL, labetolol.HCl 128 microg/mL, naproxen 14 microg/mL, phenytoin 19 microg/mL, and propranolol.HCl 70 microg/mL. The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drug substances. Its speed compared to conventional equilibrium measurements, its sound theoretical basis, its ability to generate the full solubility-pH profile from a single titration, and its dynamic range (currently estimated to be seven orders of magnitude) make the new pH-metric method an attractive addition to traditional approaches used by preformulation and development scientists. It may be useful even to discovery

  7. Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine.

    PubMed

    Martinez Ferri, M; Peña Mayor, P; Perez López-Fraile, I; Escartin Siquier, A; Martin Moro, M; Forcadas Berdusan, M

    2018-03-01

    The prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. After signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015) RESULTS: We compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. The prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV

  8. Antiepileptic drugs affect neuronal androgen signaling via a cytochrome P450-dependent pathway.

    PubMed

    Gehlhaus, Marcel; Schmitt, Nina; Volk, Benedikt; Meyer, Ralf P

    2007-08-01

    Recent data imply an important role for brain cytochrome P450 (P450) in endocrine signaling. In epileptic patients, treatment with P450 inducers led to reproductive disorders; in mouse hippocampus, phenytoin treatment caused concomitant up-regulation of CYP3A11 and androgen receptor (AR). In the present study, we established specific in vitro models to examine whether CYP3A isoforms cause enhanced AR expression and activation. Murine Hepa1c1c7 cells and neuronal-type rat PC-12 cells were used to investigate P450 regulation and its effects on AR after phenytoin and phenobarbital administration. In both cell lines, treatment with antiepileptic drugs (AEDs) led to concomitant up-regulation of CYP3A (CYP3A11 in Hepa1c1c7 and CYP3A2 in PC-12) and AR mRNA and protein. Inhibition of CYP3A expression and activity by the CYP3A inhibitor ketoconazole or by CYP3A11-specific short interfering RNA molecules reduced AR expression to basal levels. The initial up-regulation of AR signal transduction, measured by an androgen-responsive element chloramphenicol-acetyltransferase reporter gene assay, was completely reversed after specific inhibition of CYP3A11. Withdrawal of the CYP3A11 substrate testosterone prevented AR activation, whereas AR mRNA expression remained up-regulated. In addition, recombinant CYP3A11 was expressed heterologously in PC-12 cells, thereby eliminating any direct drug influence on the AR. Again, the initial up-regulation of AR mRNA and activity was reduced to basal levels after silencing of CYP3A11. In conclusion, we show here that CYP3A2 and CYP3A11 are crucial mediators of AR expression and signaling after AED application. These findings point to an important and novel function of P450 in regulation of steroid hormones and their receptors in endocrine tissues such as liver and brain.

  9. Anticonvulsant prescription patterns in patients covered by the Colombian Health System.

    PubMed

    Morales-Plaza, C D; Machado-Alba, J E

    Epilepsy is a group of long-term neurological disorders characterised by seizures that may respond to pharmacological treatment. Determine the prescribing patterns of anticonvulsants for patients covered by the healthcare system in Colombia. Cross-sectional study using a database containing 6.5 million people. From among residents in 88 Colombian cities, we selected patients of both sexes and all ages who were treated continuously with anticonvulsants between June and August 2012. We designed a drug consumption database and performed multivariate analysis for combination treatment and co-medication using SPSS 20.0. A total of 13,793 patients with mean age of 48.9±22.0 years were studied; 52.9% of the participants were women. Of the patient total, 74.4% were treated in monotherapy and 25.6% received two or more anticonvulsants. Globally, 72.9% of the patients were initially treated with classic anticonvulsants and 27.1% with new drugs. The most frequently used drugs were valproic acid (33.3%), carbamazepine (30.2%), clonazepam (15.7%), pregabalin (10.3%), phenytoin (10.0%) and levetiracetam (7.9%). Most agents were used in higher doses than recommended. The most common combinations were valproic acid+clonazepam (10.9%), valproic acid+carbamazepine (10.0%), carbamazepine+clonazepam (5.6%), valproic acid+phenytoin (4.4%). The most frequently prescribed co-medications were antihypertensives (61.0%), lipid-lowering drugs (45.8%), antidepressants (36.7%), antipsychotics (20.1%), anxiolytics (7.9%), and lithium (1.8%). Doctors predominantly prescribe drugs with a high therapeutic value and favour anticonvulsant monotherapy. Most agents were used in higher doses than recommended. This underlines the need to design educational strategies addressing these prescribing habits, and to undertake research on the effectiveness of treatment. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.

    PubMed

    Baker, Erin M; Thompson, Christopher H; Hawkins, Nicole A; Wagnon, Jacy L; Wengert, Eric R; Patel, Manoj K; George, Alfred L; Meisler, Miriam H; Kearney, Jennifer A

    2018-06-01

    De novo mutations of SCN8A, encoding the voltage-gated sodium channel Na V 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential for toxicity. Functional characterization of several SCN8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases. The novel sodium channel modulator GS967 has greater preference for persistent as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8a N1768D/+ mouse model carrying an SCN8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8a N1768D/+ mice. GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8a N1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock-induced seizures in Scn8a N1768D/+ and wild-type mice. Chronic treatment of Scn8a N1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8a N1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A

  11. Photodegradation of pharmaceuticals in the aquatic environment by sunlight and UV-A, -B and -C irradiation.

    PubMed

    Kawabata, Kohei; Sugihara, Kazumi; Sanoh, Seigo; Kitamura, Shigeyuki; Ohta, Shigeru

    2013-01-01

    In order to investigate the effect of sunlight on the persistence and ecotoxicity of pharmaceuticals contaminating the aquatic environment, we exposed nine pharmaceuticals (acetaminophen (AA), amiodarone (AM), dapsone (DP), dexamethasone (DX), indomethacin (IM), naproxen (NP), phenytoin (PH), raloxifene (RL), and sulindac (SL)) in aqueous media to sunlight and to ultraviolet (UV) irradiation at 254, 302 or 365 nm (UV-C, UV-B or UV-A, respectively). Degradation of the pharmaceuticals was monitored by means of high-performance liquid chromatography (HPLC). Sunlight completely degraded AM, DP and DX within 6 hr, and partly degraded the other pharmaceuticals, except AA and PH, which were not degraded. Similar results were obtained with UV-B, while UV-A was less effective (both UV-A and -B are components of sunlight). All the pharmaceuticals were photodegraded by UV-C, which is used for sterilization in sewage treatment plants. Thus, the photodegradation rates of pharmaceuticals are dependent on both chemical structure and the wavelength of UV exposure. Toxicity assay using the luminescent bacteria test (ISO11348) indicated that UV irradiation reduced the toxicity of some pharmaceuticals to aquatic organisms by decreasing their amount (photodegradation) and increased the toxicity of others by generating toxic photoproduct(s). These results indicate the importance of investigating not only parent compounds, but also photoproducts in the risk assessment of pharmaceuticals in aquatic environments.

  12. Trigeminal Neuralgia

    PubMed Central

    Yadav, Yad Ram; Nishtha, Yadav; Sonjjay, Pande; Vijay, Parihar; Shailendra, Ratre; Yatin, Khare

    2017-01-01

    Trigeminal neuralgia (TN) is a sudden, severe, brief, stabbing, and recurrent pain within one or more branches of the trigeminal nerve. Type 1 as intermittent and Type 2 as constant pain represent distinct clinical, pathological, and prognostic entities. Although multiple mechanism involving peripheral pathologies at root (compression or traction), and dysfunctions of brain stem, basal ganglion, and cortical pain modulatory mechanisms could have role, neurovascular conflict is the most accepted theory. Diagnosis is essentially clinically; magnetic resonance imaging is useful to rule out secondary causes, detect pathological changes in affected root and neurovascular compression (NVC). Carbamazepine is the drug of choice; oxcarbazepine, baclofen, lamotrigine, phenytoin, and topiramate are also useful. Multidrug regimens and multidisciplinary approaches are useful in selected patients. Microvascular decompression is surgical treatment of choice in TN resistant to medical management. Patients with significant medical comorbidities, without NVC and multiple sclerosis are generally recommended to undergo gamma knife radiosurgery, percutaneous balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation procedures. Partial sensory root sectioning is indicated in negative vessel explorations during surgery and large intraneural vein. Endoscopic technique can be used alone for vascular decompression or as an adjuvant to microscope. It allows better visualization of vascular conflict and entire root from pons to ganglion including ventral aspect. The effectiveness and completeness of decompression can be assessed and new vascular conflicts that may be missed by microscope can be identified. It requires less brain retraction. PMID:29114270

  13. Design, synthesis and anticonvulsant activity of some new 6,8-halo-substituted-2h-[1,2,4]triazino[5,6-b]indole-3(5h)-one/-thione and 6,8-halo-substituted 5-methyl-2h-[1,2,4]triazino[5,6-b]indol-3(5h)-one/-thione

    PubMed Central

    Kumar, Rajeev; Singh, Tejendra; Singh, Hariram; Jain, Sandeep; Roy, R. K.

    2014-01-01

    A new series of 6,8-halo-substituted-2H-[1,2,4]triazino[5,6-b]indole-3(5H)-one/-thione and 6,8-halo-substituted 5-methyl-2H-[1,2,4]triazino[5,6-b]indol-3(5H)-one/-thione (5a-5l) were designed and synthesized keeping in view of the structural requirement of pharmacophore. The above compounds were characterized by thin layer chromatography and spectral analysis. Anticonvulsant activity of the synthesized compounds was evaluated by the maximal electroshock (MES) test. Neurotoxicity and CNS depressant effects were evaluated by the rotarod motor impairment and Porsolt’s force swim tests, respectively. A computational study was carried out, for calculation of pharmacophore pattern, prediction of pharmacokinetic properties and toxicity properties. The above study revealed that the compounds 8-chloro-2H-[1,2,4]triazino[5,6-b]indol-3(5H)-one (5e), 6,8-dibromo-2H-[1,2,4]triazino[5,6-b]indol-3(5H)-one (5i) and 6,8-dibromo-5-methyl-2H-[1,2,4]triazino[5,6-b]indol-3(5H)-one (5k) possess excellent anticonvulsant activity in the series with little CNS depressant effect and no neurotoxicity as compared to standard drugs phenytoin and carbamazepine. PMID:26417257

  14. Hippocampal low-frequency stimulation inhibits afterdischarge and increases GABA (A) receptor expression in amygdala-kindled pharmacoresistant epileptic rats.

    PubMed

    Wu, Guofeng; Wang, Likun; Hong, Zhen; Ren, Siying; Zhou, Feng

    2017-08-01

    The purpose of the present study was to observe the effects of hippocampal low-frequency stimulation (Hip-LFS) on amygdala afterdischarge and GABA (A) receptor expression in pharmacoresistant epileptic (PRE) rats. A total of 110 healthy adult male Wistar rats were used to generate a model of epilepsy by chronic stimulation of the amygdala. Sixteen PRE rats were selected from 70 amygdala-kindled rats by testing their response to Phenytoin and Phenobarbital, and they were randomly assigned to a pharmacoresistant stimulation group (PRS group, 8 rats) or a pharmacoresistant control group (PRC group, 8 rats). A stimulation electrode was implanted into the hippocampus of all of the rats. Hip-LFS was administered twice per day in the PRS group for two weeks. Simultaneously, amygdala stimulus-induced seizures and afterdischarge were recorded. After the hippocampal stimulation was terminated, the brain tissues were obtained to determine the GABA (A) receptors by a method of immumohistochemistry and a real-time polymerase chain reaction. The stages and duration of the amygdala stimulus-induced epileptic seizures were decreased in the PRS group. The afterdischarge threshold was increased and the duration as well as the afterdischarge frequency was decreased. Simultaneously, the GABA (A) expression was significantly increased in the PRS group. Hip-LFS may inhibit amygdala stimulus-induced epileptic seizures and up-regulate GABA (A) receptor expression in PRE rats. The antiepileptic effects of hippocampal stimulation may be partly achieved by increasing the GABA (A) receptor.

  15. Antihypoxic activities of Eryngium caucasicum and Urtica dioica.

    PubMed

    Khalili, M; Dehdar, T; Hamedi, F; Ebrahimzadeh, M A; Karami, M

    2015-09-01

    Urtica dioica and Eryngium spp. have been used in traditional medicine for many years. In spite of many works, nothing is known about their protective effect against hypoxia-induced lethality. Protective effects of U. dioica (UD) aerial parts and E. caucasicum (EC) inflorescence against hypoxia-induced lethality in mice were evaluated by three experimental models of hypoxia, asphyctic, haemic and circulatory. Statistically significant protective activities were established in some doses of extracts in three models. Antihypoxic activity was especially pronounced in polyphenol fractions in asphyctic model. EC polyphenol fraction at 400 mg/kg prolonged survival time (48.80 ± 4.86, p < 0.001) which was comparable with that of phenytoin (p > 0.05). It was the most effective extract in circulatory model, too. It prolonged survival time significantly respect to control group (p < 0.001). UD extracts protected the mice but the response was not dose-dependent. In haemic model, extracts of EP significantly and dose dependently prolonged survival time as compared to control group (p < 0.001). At 600 mg/kg, EP was the most effective one, being capable of keeping the mice alive for 12.71 ± 0.75 min. Only the concentration of 300 mg/kg of UD was effective (p < 0.001). Extracts showed remarkable antihypoxic effects. Pharmacological effects may be attributed to the presence of polyphenols in the extracts.

  16. Herb-drug interactions.

    PubMed

    Fugh-Berman, A

    2000-01-08

    Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

  17. The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders

    PubMed Central

    Munshi, Kaizad R.; Oken, Tanya; Guild, Danielle J.; Trivedi, Harsh K.; Wang, Betty C.; Ducharme, Peter; Gonzalez-Heydrich, Joseph

    2010-01-01

    Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs—valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine—in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective. PMID:27713387

  18. The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders.

    PubMed

    Munshi, Kaizad R; Oken, Tanya; Guild, Danielle J; Trivedi, Harsh K; Wang, Betty C; Ducharme, Peter; Gonzalez-Heydrich, Joseph

    2010-09-10

    Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs - valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine - in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective.

  19. In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs.

    PubMed

    Tahara, Kohei; Nishikawa, Masahiro; Matsui, Ko; Hisazumi, Koji; Onodera, Risako; Tozuka, Yuichi; Takeuchi, Hirofumi

    2016-09-01

    The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC). Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo. The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size. PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.

  20. The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth

    PubMed Central

    Alitheen, Noorjahan Banu

    2013-01-01

    Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF), endothelin-1 (ET-1), angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-β, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth. PMID:23690667

  1. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth

    PubMed Central

    Ponnaiyan, Deepa; Jegadeesan, Visakan

    2015-01-01

    Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities. PMID:26759584

  2. Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel

    PubMed Central

    Boiteux, Céline; Vorobyov, Igor; French, Robert J.; French, Christopher; Yarov-Yarovoy, Vladimir; Allen, Toby W.

    2014-01-01

    Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the “hinged lid”-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water–protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors. PMID:25136136

  3. Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats.

    PubMed

    Shannon, Harlan E; Love, Patrick L

    2007-02-01

    Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously demonstrated that a number of AEDs can impair working memory and attention. The purpose of the present study was to evaluate the effects of AEDs on learning as measured by a repeated acquisition of response sequences task in nonepileptic rats. The GABA-related AEDs phenobarbital and chlordiazepoxide significantly disrupted performance by shifting the learning curve to the right and increasing errors, whereas tiagabine and valproate did not. The sodium channel blockers carbamazepine and phenytoin suppressed responding at higher doses, whereas lamotrigine shifted the learning curve to the right and increased errors, and topiramate was without significant effect. Levetiracetam also shifted the learning curve to the right and increased errors. The disruptions produced by triazolam, chlordiazepoxide, lamotrigine, and levetiracetam were qualitatively similar to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can impair learning, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function and some that block sodium channels producing the most consistent impairment of learning.

  4. Effects of antiepileptic drugs on attention as assessed by a five-choice serial reaction time task in rats.

    PubMed

    Shannon, Harlan E; Love, Patrick L

    2005-12-01

    Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously evaluated a number of AEDs with respect to their effects on working memory. The purpose of the present study was to evaluate the effects of AEDs on attention as measured by five-choice serial reaction time behavior in nonepileptic rats. The GABA-related AEDs triazolam, phenobarbital, and chlordiazepoxide significantly disrupted performance by increasing errors of omission, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blocker carbamazepine increased errors of omission at relatively high doses, whereas the sodium channel blockers phenytoin, topiramate, and lamotrigine were without significant effect. Levetiracetam had no effect on attention. The disruptions produced by triazolam, phenobarbital, chlordiazepoxide, and carbamazepine were similar in magnitude to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can disrupt attention, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function producing the most consistent disruption of attention.

  5. Quality assessment of internet pharmaceutical products using traditional and non-traditional analytical techniques.

    PubMed

    Westenberger, Benjamin J; Ellison, Christopher D; Fussner, Andrew S; Jenney, Susan; Kolinski, Richard E; Lipe, Terra G; Lyon, Robbe C; Moore, Terry W; Revelle, Larry K; Smith, Anjanette P; Spencer, John A; Story, Kimberly D; Toler, Duckhee Y; Wokovich, Anna M; Buhse, Lucinda F

    2005-12-08

    This work investigated the use of non-traditional analytical methods to evaluate the quality of a variety of pharmaceutical products purchased via internet sites from foreign sources and compared the results with those obtained from conventional quality assurance methods. Traditional analytical techniques employing HPLC for potency, content uniformity, chromatographic purity and drug release profiles were used to evaluate the quality of five selected drug products (fluoxetine hydrochloride, levothyroxine sodium, metformin hydrochloride, phenytoin sodium, and warfarin sodium). Non-traditional techniques, such as near infrared spectroscopy (NIR), NIR imaging and thermogravimetric analysis (TGA), were employed to verify the results and investigate their potential as alternative testing methods. Two of 20 samples failed USP monographs for quality attributes. The additional analytical methods found 11 of 20 samples had different formulations when compared to the U.S. product. Seven of the 20 samples arrived in questionable containers, and 19 of 20 had incomplete labeling. Only 1 of the 20 samples had final packaging similar to the U.S. products. The non-traditional techniques complemented the traditional techniques used and highlighted additional quality issues for the products tested. For example, these methods detected suspect manufacturing issues (such as blending), which were not evident from traditional testing alone.

  6. Treatment of Established Status Epilepticus

    PubMed Central

    Falco-Walter, Jessica J.; Bleck, Thomas

    2016-01-01

    Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE. PMID:27120626

  7. Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis

    PubMed Central

    Lin, Kuang-Lin; Lin, Jainn-Jim; Hsia, Shao-Hsuan; Chou, Min-Liang; Hung, Po-Cheng; Wang, Huei-Shyong

    2015-01-01

    Background Encephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy. Patients and Methods Cases of acute pediatric encephalitis between January 2000 and December 2010 were reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of antiepileptic drugs, and prognosis were analyzed. Results During the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had intractable seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects. Conclusions Children with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy. PMID:26444013

  8. Identification of Risk Factors for Intravenous Infiltration among Hospitalized Children: A Retrospective Study

    PubMed Central

    2016-01-01

    This retrospective study was aimed to identify risk factors of intravenous (IV) infiltration for hospitalized children. The participants were 1,174 children admitted to a general hospital, who received peripheral intravenous injection therapy at least once, and had complete records. Data were analyzed with frequency and percentage or mean and standard deviation were calculated, and odds ratio (OR) from univariate and multiple logistic regressions. The number and % of infiltrations were 92 and 7.8%, respectively. IV infiltration risk factors were lower limb (OR = 1.72), phenytoin (OR = 11.03), 10% dextrose (OR = 6.55), steroids (OR = 6.21), vancomycin (OR = 4.10), high-concentration electrolytes (OR = 3.49), and ampicillin/sulbactam combination (OR = 3.37). Nurses working at children’s hospitals should consider the risk of IV infiltration for children receiving IV infusion therapy and make a preventive effort to identify IV infiltration in high-risk children at an early stage. PMID:27351488

  9. The effects of ethosuximide on aversive instrumental learning in adult rats.

    PubMed

    Orczyk, John J; Garraghty, Preston E

    2018-05-03

    Antiepileptic medications are the frontline treatment for seizure conditions but are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin-, carbamazepine-, valproic acid-, and felbamate-treated rats. In this experiment, the effects found in ethosuximide (ETH)-treated rats have been compared with those in water-treated controls (controls) using the same instrumental training tasks. Rats treated with ETH did not display any performance deficits in any of the conditions tested relative to controls. These animals showed more rapid acquisition of the avoidance response than the control animals but only when they had prior experience in the appetitive condition. Of the drugs tested to date with these learning paradigms, ETH is the only one that did not impair performance relative to controls in any condition tested. Moreover, in comparison with rats treated with valproic acid, the only other available compound commonly recommended for the treatment of absence seizures, ETH-treated rats show substantially higher performance. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Neurologist knowledge about interactions between antiepileptic drugs and contraceptive methods.

    PubMed

    Suto, Hilda S; Braga, Giordana C; Scarpellini, Giuliano R; Takeuchi, Leandro I; Martins, Ana P; Leite, João P; Vieira, Carolina S

    2016-09-01

    To evaluate neurologists' knowledge of contraceptive counseling for women receiving antiepileptic drugs (AEDs). An interview-based survey was conducted from February 2 to June 30, 2015, among neurologists working in Ribeirão Preto, Brazil. Direct interviews were conducted using a questionnaire that assessed knowledge of the pharmacological interactions between various contraceptive methods and six AEDs (carbamazepine, phenobarbital, topiramate, phenytoin, lamotrigine, and valproate) on the basis of WHO medical eligibility criteria for contraceptive use. Among 42 neurologists who participated, 32 (76%) stated that they treated women with epilepsy and provided them with counseling for family planning. Overall, 34 (81%) recommended the use of a copper intrauterine device irrespective of the AED used, and 26 (60%) stated that they co-prescribed AEDs and hormonal contraceptives. Although 39 (93%) neurologists had knowledge that AEDs might contraindicate the use of some contraceptives, their knowledge regarding the specific drug interactions was lacking. Furthermore, 34 (81%) had no knowledge of WHO medical eligibility criteria for contraceptive use. Although most neurologists interviewed had knowledge of interactions between AEDs and hormonal contraceptives, they did not know which specific AEDs interacted with these agents. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  11. Management of seizures in the elderly: a survey of UK geriatricians.

    PubMed Central

    Stolarek, I H; Brodie, A F; Brodie, M J

    1995-01-01

    The incidence and prevalence of epilepsy increase substantially with old age. Despite this, the investigation and management of this patient population remains a grey area. Four hundred and eleven (53%) consultant geriatricians responded to a questionnaire exploring their approach to seizures in the elderly in order to establish an overview of current clinical practice. Between one and five patients presenting with seizures, predominantly aged between 75-85 years, were reviewed monthly. Seventy per cent of geriatricians undertook to investigate the patients themselves with biochemical and haematological profiles performed by most. Electroencephalography and computerized tomographic scanning were routinely requested by a quarter of responders. Only 58% would themselves initiate therapy with antiepileptic drugs, with 16% of consultants starting treatment following the first seizure, 59% after a second and 5% after a third. Phenytoin was first choice for generalized tonic-clonic seizures with carbamazepine preferred for partial seizures. If good control was not obtained, 67% would substitute another first line drug, while 27% would add in a second. Less than 3% would use the new anticonvulsants lamotrigine or vigabatrin. Sixty per cent monitored anticonvulsant concentrations in patients with poor control or suspected toxicity. A wide variability was seen in the current approach to seizures in the elderly, which reflects a lack of established practice. Epilepsy clinics for the elderly would encourage structured research into the many unanswered questions affecting the care of older people with seizures. PMID:8786590

  12. Molecular-level elucidation of saccharin-assisted rapid dissolution and high supersaturation level of drug from Eudragit® E solid dispersion.

    PubMed

    Ueda, Keisuke; Kanaya, Harunobu; Higashi, Kenjirou; Yamamoto, Keiji; Moribe, Kunikazu

    2018-03-01

    In this work, the effect of saccharin (SAC) addition on the dissolution and supersaturation level of phenytoin (PHT)/Eudragit® E (EUD-E) solid dispersion (SD) at neutral pH was examined. The PHT/EUD-E SD showed a much slower dissolution of PHT compared to the PHT/EUD-E/SAC SD. EUD-E formed a gel layer after the dispersion of the PHT/EUD-E SD into an aqueous medium, resulting in a slow dissolution of PHT. Pre-dissolving SAC in the aqueous medium significantly improved the dissolution of the PHT/EUD-E SD. Solid-state 13 C NMR measurements showed an ionic interaction between the tertiary amino group of EUD-E and the amide group of SAC in the EUD-E gel layer. Consequently, the ionized EUD-E could easily dissolve from the gel layer, promoting PHT dissolution. Solution-state 1 H NMR measurements revealed the presence of ionic interactions between SAC and the amino group of EUD-E in the PHT/EUD-E/SAC solution. In contrast, interactions between PHT and the hydrophobic group of EUD-E strongly inhibited the crystallization of the former from its supersaturated solution. The PHT supersaturated solution was formed from the PHT/EUD-E/SAC SD by the fast dissolution of PHT and the strong crystallization inhibition effect of EUD-E after aqueous dissolution. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth.

    PubMed

    Ponnaiyan, Deepa; Jegadeesan, Visakan

    2015-01-01

    Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities.

  14. Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice.

    PubMed

    Zagaja, Mirosław; Andres-Mach, Marta; Skalicka-Woźniak, Krystyna; Rękas, Anna R; Kondrat-Wróbel, Maria W; Gleńsk, Michał; Łuszczki, Jarogniew J

    2015-01-01

    The aim of this study was to determine the effects of umbelliferone (7-hydroxycoumarin; UMB) on the anticonvulsant potency of four classical antiepileptic drugs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproate (VPA)) in the mouse maximal electroshock-induced seizure (MES) model. UMB administered systemically intraperitoneally (ip) in a dose of 150 mg/kg significantly elevated the threshold for maximal electroconvulsions (p < 0.05) in mice. Moreover, UMB (150 mg/kg) co-administered with PB and VPA significantly enhanced the anticonvulsant potency of these drugs by reducing their median effective doses (ED50 values) from 35.39 to 21.78 mg/kg (p < 0.01) for PB, and from 281.4 to 215.5 mg/kg (p < 0.01) for VPA. In contrast, UMB (150 mg/kg, ip) had no significant effect on the antiseizure activity of CBZ and PHT in the mouse MES model. Neither total brain PB, nor total brain VPA concentrations were altered after ip administration of UMB, indicating a pharmacodynamic nature of interactions between the tested drugs. The selective potentiation of the anticonvulsant potency of PB and VPA by UMB, and lack of any pharmacokinetic interactions between drugs, make the combinations of UMB with PB or VPA worthy of consideration for epileptic patients who are refractory to standard antiepileptic treatment. © 2015 S. Karger AG, Basel.

  15. The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients.

    PubMed

    Eldin, Essam Eldin Mohamed Nour; Elshebiny, Hosam Abdel-Fattah; Mohamed, Tarek Mostafa; Abdel-Aziz, Mohamed Abdel-Azim; El-Readi, Mahmoud Zaki

    2016-01-01

    Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with mono- or poly-therapy of carbamazepine, valproic acid, or phenytoin. The treated epileptic patients were divided into 2 main groups according to the seizure frequency: controlled seizure patients GII (n = 30) and uncontrolled seizure patients GIII (n = 30). GII included the GIIA subgroup (n = 15) which had been seizure free for more than 12 months and the GIIB subgroup (n = 15) which had been seizure free for a period from 6 to12 months. GIII included GIIIA (n = 15) and GIIIB (n = 15) for patients which had a seizure frequency of less than and more than four times/month, respectively. In comparison to the control group (GI), the levels of nitric oxide (NO) and malondialdehyde/creatinine ratio were significantly increased in GIIB, GIIIA, and GIIIB, while vitamins A and E levels were significantly decreased in GIIIB. Serum NO levels had significant negative correlations with serum vitamin E in the GIIA and GIIB groups, and with vitamin A in the GIIIA and GIIIB groups. However, serum NO had positive correlation with urinary MDA/Cr ratio. The imbalance between free radical generation and antioxidant system in epileptic patients may be a factor in seizure frequency.

  16. Zebrafish (Danio rerio) embryos as a model for testing proteratogens.

    PubMed

    Weigt, Stefan; Huebler, Nicole; Strecker, Ruben; Braunbeck, Thomas; Broschard, Thomas H

    2011-03-15

    Zebrafish embryos have been shown to be a useful model for the detection of direct acting teratogens. This communication presents a protocol for a 3-day in vitro zebrafish embryo teratogenicity assay and describes results obtained for 10 proteratogens: 2-acetylaminofluorene, benzo[a]pyrene, aflatoxin B(1), carbamazepine, phenytoin, trimethadione, cyclophosphamide, ifosfamide, tegafur and thio-TEPA. The selection of the test substances accounts for differences in structure, origin, metabolism and water solubility. Apart from 2-acetylaminofluorene, which mainly produces lethal effects, all proteratogens tested were teratogenic in zebrafish embryos exposed for 3 days. The test substances and/or the substance class produced characteristic patterns of fingerprint endpoints. Several substances produced effects that could be identified already at 1 dpf (days post fertilization), whereas the effects of others could only be identified unambiguously after hatching at ≥ 3 dpf. The LC₅₀ and EC₅₀ values were used to calculate the teratogenicity index (TI) for the different substances, and the EC₂₀ values were related to human plasma concentrations. Results lead to the conclusion that zebrafish embryos are able to activate proteratogenic substances without addition of an exogenous metabolic activation system. Moreover, the teratogenic effects were observed at concentrations relevant to human exposure data. Along with other findings, our results indicate that zebrafish embryos are a useful alternative method for traditional teratogenicity testing with mammalian species. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  17. Survey of Prophylactic Antiseizure Drug Use for Nontraumatic Intracerebral Hemorrhage

    PubMed Central

    Jensen, Matthew B.; Sattar, Ahsan; Sherbini, Khalid Al

    2013-01-01

    Objective Prophylactic antiseizure drugs (PAD) are commonly prescribed for nontraumatic intracerebral hemorrhage (ICH) despite limited evidence for this indication. We sought to determine the current prescribing patterns of the use of a PAD for ICH. Methods A 36-item survey was distributed to physicians that manage ICH patients soliciting details of PAD prescription in their practice. Results A total of 199 physicians responded to the survey, all of who manage between one and 50 or more ICH patients per year. The respondents were neurologists (32%), neurosurgeons (11%), and intensivists (57%) in academia (69%) and private practice (31%). PAD prescriptions were used: never (33%), 1–33% (35%), 34–66% (14%), 67–99% (9%) of the time, or always (9%). Most respondents performed electroencephalographic and serum level monitoring in at least some patients. Levetiracetam was used most often (60%), followed by fos/phenytoin (37%), for a usual duration of days (36%), weeks (47%), or months (17%). PAD prescription varied by patient characteristics and physician specialty. Perception of physician community consensus regarding PAD use for ICH among respondents ranged from strongly (7%) or weakly (23%) against the practice, to a fairly equal division of opinion (41%), to weakly (27%) or strongly (4%) in favor of the practice. Conclusions We found variability of multiple aspects of the current prescribing patterns and opinions regarding the use of a PAD for ICH. This variability is likely secondary to insufficient data. Clinical equipoise exists for this issue, and controlled trials would be both justified and useful. PMID:23582711

  18. Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs.

    PubMed

    Wychowski, Thomas; Wang, Hongyue; Buniak, Liana; Henry, J Craig; Mohile, Nimish

    2013-11-01

    To identify risk factors for the development of tumor-associated epilepsy (TAE) and potential benefit of newer generation AEDs in seizure prevention. We performed an IRB approved retrospective study of newly diagnosed GBM patients at the University of Rochester between 1/1/05 and 5/13/11. Records were reviewed to describe demographics, seizure incidence, occurrence of status epilepticus, and AED use and toxicity. 172 patients with newly diagnosed GBM were included in the study. 53.4% developed TAE. 31.4% had seizure prior to diagnosis. 118 patients were seizure-free at diagnosis: 32.2% developed post-diagnosis TIE (PostTAE) and 60.2% remained seizure-free. 70 seizure-free patients received an AED peri-operatively. 36 were weaned off AEDs and 31 were continued. Incidence of PostTAE and time to first seizure were comparable in AED-treated and untreated patients. 4 PostTAE patients presented with status epilepticus (SE), all were not AED treated. AEDs were withdrawn in 10 patients due to toxicity: 9 from phenytoin and 1 from levetiracetam. There is a high incidence of PostTAE in GBM. Prophylactic AED therapy did not reduce PostTAE but may have prevented SE. Minimal toxicity was observed on 2nd generation AEDs. The high burden of epilepsy in this population and tolerability of newer AEDS suggest that AAN guidelines should be revisited. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Lactation studies of anticonvulsants: a quality review

    PubMed Central

    van der Meer, Douwe H; Wieringa, Andre; Wegner, Ilse; Wilffert, Bob; ter Horst, Peter G J

    2015-01-01

    AIM The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. METHODS We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). RESULTS Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. CONCLUSION The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed. PMID:25291358

  20. Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharm