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The clinical impact of pharmacogenetics on the treatment of epilepsy.
Epilepsia. 2008 Jul 8;
Löscher W, Klotz U, Zimprich F, Schmidt D
Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.
J Comb Chem. 2008 Jul 16;
Barillaro V, Pescarmona PP, Van Speybroeck M, Thi TD, Van Humbeeck J, Vermant J, Augustijns P, Martens JA, Van Den Mooter G
A high-throughput experimentation method for studying the dissolution of phenytoin, a poorly water soluble drug, was developed and validated. Solid dispersions with 12 excipients (7 polymers and 5 surfactants) were prepared and tested. Each excipient was screened with three drug loadings: 10, 20, and 40% (w/w). Each solid dispersion was prepared in triplicate, for a total of 108 samples. The drug dissolution was studied in simulated gastric fluid without pepsin plus 1% sodium laurylsulfate. This study led to the identification of three improved formulations, exhibiting an extent of dissolution higher than 90% after both 30 and 60 min. The HTE results could be reproduced at a larger scale using a conventional solvent evaporating method, proving the reliability of the HTE protocol.
Phenytoin Metabolite Renal Calculus: An Index Case.
J Endourol. 2008 Jul 11;
Kalorin CM, Bauer R, White MD
Introduction: Drugs and their metabolites are known factors in 1% to 2% of all kidney stones. Certain antiepileptic drugs are known to cause stone formation. Phenytoin is used as a first line antiepileptic therapy for many seizure disorders. We present what we believe to be the first report of a phenytoin metabolite urinary stone. Methods: A 79-year-old woman with a fever and seizure disorder was found to have a right pelvic kidney with hydronephrosis and multiple large calcifications. She had been taking the antiepileptic medication phenytoin for the past 10 years. Average total serum phenytoin level from the year prior was in the normal range. Free phenytoin levels were not routinely monitored, but the one value available was elevated at 5.1 ng/dL. The patient underwent a percutaneous nephrolitomy, ultimately expiring from medical complications after the procedure. Final stone analysis revealed a composition of 35% phenytoin metabolite (5-(para-hydroxyphenyl)-5-phenylhydantoin) and 65% proteinaceous material. An extensive review of literature including PubMed, MedLine, and various internet search engines was performed, searching for any prior reports of urinary calculi formed from phenytoin or its metabolite. Results: No previous reports of phenytoin or phenytoin metabolite urinary stones were found in the medical literature. Phenytoin has many known ill effects on the genitourinary system including acute interstitial nephritis, nephrotic syndrome, acute renal failure, and priapism. Now we can add urinary lithiasis to the list of its potential adverse effects. This article represents the first report of a phenytoin metabolite urinary stone. Conclusion: A metabolite of the commonly used antiepileptic medication phenytoin can cause clinically relevant urolithiasis leading to significant morbidity and even mortality. Clinicians should have an increased level of suspicion for metabolite stone formation in symptomatic patients taking antiepileptic medications. Further studies on phenytoin metabolism and its potential for inducing urinary lithiasis should be performed.
Leukopenia and thrombocytopenia on adding aripiprazole to phenytoin.
World J Biol Psychiatry. 2008 Apr 7; 1-2
Mendhekar D, Duggal H, Andrade C
Biochem Pharmacol. 2008 Jul 5;
Köhle C, Bock KW
Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors suggests that these proteins evolved to an integrated biotransformation system. Two major groups of ligand-activated nuclear receptors/xenosensors evolved: the Ah receptor (activated by aryl hydrocarbons and drugs such as omeprazole) and type 2 steroid receptors such as PXR and CAR, activated by drugs such as rifampicin, carbamazepin and phenytoin. It is increasingly recognized that there is considerable cross-talk between these xenosensors. Therefore, an attempt was made to discuss biotransformation by the Ah receptor together with that of PXR and CAR. Due to considerable species differences the emphasis is on human biotransformation. Agonists coordinately induce biotransformation due to common xenosensor-binding response elements in the regulatory region of target genes. However, whereas different groups of xenobiotics appear to more selectively stimulate CYPs (Phase I), their regulatory control largely converged in modulating Phase II metabolism and transport. Biotransformation appears to be tightly controlled to achieve efficient homeostasis of endobiotics and detoxification of dietary phytochemicals, but nuclear receptor agonists may also lead to potentially harmful drug interactions.
[Biological effects of phenytoin on cultured human periodontal ligament fibroblasts in vitro]
Hua Xi Kou Qiang Yi Xue Za Zhi. 2008 Apr; 26(2): 215-8
Yu MJ, Yang PS, Ge SH
OBJECTIVE: To study the biological effects of phenytoin (PHT) on cultured human periodontal ligament fibroblasts (hPDLF), and explore the possibility of its accelerating periodontal regeneration. METHODS: Increasing concentrations of PHT (1, 5, 20, 100, 500, 2 500 mg/L) were added into the medium of the fourth passage of cultured hPDLF, respectively. After co-incubated for 3 days, cell proliferation activity, the total amount of protein and alkaline phosphatase (ALP) activity were detected. Mineralized sodium and PHT (20, 100, 500 mg/L) were added into the medium of the fourth passage hPDLF. After co-incubated, the mineralized nodules formation were detected by Von Kossa staining. The third passage hPDLF were stimulated by PHT (20, 100 mg/L), bone morphogenetic protein-2 (BMP-2) concentration was analyzed by enzyme linked immunosorbent sandwich assay (ELISA). RESULTS: At the concentration of 20 or 100 mg/L, PHT significantly enhanced the proliferating activity and ALP activity of hPDLF (P
Lancet Neurol. 2008 Jul 2;
Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott RC
BACKGROUND: Episodes of childhood convulsive status epilepticus (CSE) commonly start in the community. Treatment of CSE aims to minimise the length of seizures, treat the causes, and reduce adverse outcomes; however, there is a paucity of data on the treatment of childhood CSE. We report the findings from a systematic, population-based study on the treatment of community-onset childhood CSE. METHODS: We collected data prospectively on children in north London, UK, who had episodes of CSE (ascertainment 62-84%). The factors associated with seizure termination after first-line and second-line therapies, episodes of CSE lasting for longer than 60 min, and respiratory depression were analysed with logistic regression. Analysis was per protocol, and adjustment was made for repeat episodes in individuals. RESULTS: 182 children of median age 3.24 years (range 0.16-15.98 years) were included in the North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) between May, 2002, and April, 2004. 61% (147) of 240 episodes were treated prehospital, of which 32 (22%) episodes were terminated. Analysis with multivariable models showed that treatment with intravenous lorazepam (n=107) in the accident and emergency department was associated with a 3.7 times (95% CI 1.7-7.9) greater likelihood of seizure termination than was treatment with rectal diazepam (n=80). Treatment with intravenous phenytoin (n=32) as a second-line therapy was associated with a 9 times (95% CI 3-27) greater likelihood of seizure termination than was treatment with rectal paraldehyde (n=42). No treatment prehospital (odds ratio [OR] 2.4, 95% CI 1.2-4.5) and more than two doses of benzodiazepines (OR 3.6, 1.9-6.7) were associated with episodes that lasted for more than 60 min. Treatment with more than two doses of benzodiazepines was associated with respiratory depression (OR 2.9, 1.4-6.1). Children with intermittent CSE arrived at the accident and emergency department later after seizure onset than children with continuous CSE did (median 45 min [range 11-514 min] vs 30 min [5-90 min]; p
Neurology. 2008 Jul 1; 71(1): 38-43
Ahn JE, Cloyd JC, Brundage RC, Marino SE, Conway JM, Ramsay RE, White JR, Musib LC, Rarick JO, Birnbaum AK, Leppik IE
BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients' sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2-3 weeks.
Pharmacological modulation of cortical plasticity following kainic acid lesion in rat barrel cortex.
J Neurosurg. 2008 Jul; 109(1): 108-16
Darbar A, Stevens RT, Siddiqui AH, McCasland JS, Hodge CJ
OBJECT: The brain shows remarkable capacity for plasticity in response to injury. To maximize the benefits of current neurological treatment and to minimize the impact of injury, the authors examined the ability of commonly administered drugs, dextroamphetamine (D-amphetamine) and phenytoin, to positively or negatively affect the functional recovery of the cerebral cortex following excitotoxic injury. METHODS: Previous work from the same laboratory has demonstrated reorganization of whisker functional responses (WFRs) in the rat barrel cortex after excitotoxic lesions were created with kainic acid (KA). In the present study, WFRs were mapped using intrinsic optical signal imaging before and 9 days after creation of the KA lesions. During the post-lesion survival period, animals were either treated with intraperitoneal D-amphetamine, phenytoin, or saline or received no treatment. Following the survival period, WFRs were again measured and compared with prelesion data. RESULTS: The findings suggest that KA lesions cause increases in WFR areas when compared with controls. Treatment with D-amphetamine further increased the WFR area (p < 0.05) while phenytoin-treated rats showed decreases in WFR areas. There was also a statistically significant difference (p < 0.05) between the D-amphetamine and phenytoin groups. CONCLUSIONS: These results show that 2 commonly used drugs, D-amphetamine and phenytoin, have opposite effects in the functional recovery/plasticity of injured cerebral cortex. The authors' findings emphasize the complex nature of the cortical response to injury and have implications for understanding the biology of the effects of different medications on eventual functional brain recovery.
Zhong Yao Cai. 2008 Jan; 31(1): 79-81
Fu SY, Fang RM, Fang GL, Xie YH, Fang YQ
OBJECTIVE: To study effects of beta-asarone on expression of FOS and GAD65 in cortex of epileptic rat induced by penicillin. METHODS: The epileptic animal models were induced by penicillin. The rats were randomly divided into beta-asarone of high (100 mg/kg), medium (50 mg/kg), low (25 mg/kg) dose group, positive control group (Phenytoin sodium), negative control group (matrix). The medicine was administered orally. The effects of beta-asarone on expression of FOS and GAD65 in cortex of epileptic rat were detected by immuohistochemistry method. RESULTS: beta-asarone could raise expression of FOS and reduce expression of GAD65 obviously. There were significant differences between negative control group and beta-asarone group. And it showed significant dose-effect relationship. CONCLUSION: Up-regulation of FOS may be a effective link of anti-epileptic effect of beta-asarone; reduced expression of GAD65 may be a follow-up impact of beta-asarone treatment.