Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new tegretol research articles will be listed here shortly after becoming available to us.
Related Sponsors
Medical research on tegretol
Changes in gene expression induced by carbamazepine and phenytoin: testing the danger hypothesis.
J Immunotoxicol. 2008 Apr; 5(2): 107-13
Lu W, Li X, Uetrecht JP
The aromatic anticonvulsants carbamazepine (CBZ) and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that would predict the risk that a drug candidate would cause IDRs it would significantly decrease the risks associated with drug development. The IDRs associated with CBZ and PHN appear to be immune-mediated. The Danger Hypothesis posits that for something to induce an immune response, it must cause some type of cell damage that ultimately causes up-regulation of co-stimulatory molecules on antigen-presenting cells; without this, the response will be immune tolerance. If the Danger Hypothesis is correct, the ability of a drug or its reactive metabolite to induce cell damage or stress may be related to its risk of causing IDRs. In a parallel study reported elsewhere, we found that major metabolites of these two drugs: 3-OH-CBZ and 4-OH-PHN can be oxidized by peroxidases to phenoxyl free radicals, which could cause oxidative stress by redox cycling. In this study using mRNA microarrays, we found that CBZ and PHN treatment induced changes in mRNA expression in mice. Many of the changes were in genes related to Keap1-Nrf2-ARE signaling pathways and enzymes involved in responding to oxidant stressors and reactive metabolites such as glutathione transferase and heat shock proteins. The similar patterns of genes induced by these two drugs are consistent with the clinical observation that those two drugs exhibit cross-sensitivity. These findings are consistent with the induction of cell stress by CBZ and PHN, most likely due to reactive metabolites. Such changes may represent a danger signal and represent a biomarker of the potential that a drug will cause IDRs; however, different drugs likely cause cell stress by different mechanisms and, therefore, the biomarkers for other drugs would likely be different.
Midbrain lesions and paroxysmal dysarthria in multiple sclerosis.
Mult Scler. 2008 Jun; 14(5): 694-7
Blanco Y, Compta Y, Graus F, Saiz A
We describe three patients with relapsing-remitting multiple sclerosis who presented with paroxysmal dysarthria. In one patient, the symptoms were the only manifestation of an acute relapse. In the other two patients, the attacks appeared during the recovery of a brainstem relapse. All three patients had an acute lower midbrain lesion. The location was central in two patients and left paramedian in the other, and probably involving cerebellothalamocortical pathways. Treatment with carbamazepine was effective.
A study on epileptic negative myoclonus in atypical benign partial epilepsy of childhood.
Brain Dev. 2008 Jun 16;
Yang Z, Liu X, Qin J, Zhang Y, Bao X, Chang X, Wang S, Wu Y, Xiong H
Objective. To investigate the clinical and neurophysiological characteristics, particularly therapeutic considerations, of epileptic negative myoclonus (ENM) in atypical benign partial epilepsy (ABPE) of childhood. Methods. From 1998 to 2006, 14/242 patients with benign children epilepsy with centrotemporal spikes (BECTS) were diagnosed as having ABPE with ENM. In all 14 patients, we performed video-EEG monitoring along with tests with the patient's arms outstretched; 6/14 patients were also simultaneously underwent surface electromyogram (EMG). ENM manifestations, electrophysiological features, and responses to antiepileptic drugs were analyzed. Results. In all cases, ENM developed after the onset of epilepsy and during antiepileptic drug therapy, and the appearance of ENM were corresponding to EEG findings of high-amplitude spikes followed by a slow wave in the contralateral motor areas with secondary generalization. This was further confirmed by time-locked silent EMG. During ENM occurrence or recurrence, habitual seizures and interictal discharges were exaggerated. In some patients, the changes in antiepileptic drug regimens in relation to ENM appearance included add-on therapy with carbamazepine, oxcarbazepine, and phenobarbital or withdrawal of valproate. ENM was controlled in most cases by administration of various combinations of valproate, clonazepam, and corticosteroids. Conclusion. The incidence of ENM or ABPE in our center was approximately 5.79%. A combination of video-EEG monitoring with the patient's arms outstretched and EMG is essential to identify ENM. The aggravation of habitual seizures and interictal discharges indicate ENM. Some antiepileptic drugs, such as carbamazepine, oxcarbazepine, and phenobarbital, may be related to ENM occurrence during spontaneous aggravation of ABPE. Various combinations of valproate, benzodiazepines, and corticosteroids are relatively effective for treating ENM that occurs in ABPE.
Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 May 7;
Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, Castro FE, de Leon J
The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age >/=18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.
Epilepsia. 2008 Jun; 49(6): 1108-9
Zimprich F, Stogmann E, Bonelli S, Baumgartner C, Mueller JC, Meitinger T, Zimprich A, Strom TM
Immunity. 2008 Jun; 28(6): 822-32
Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z, Kjer-Nielsen L, Mifsud NA, Tait BD, Holdsworth R, Almeida CA, Nolan D, Macdonald WA, Archbold JK, Kellerher AD, Marriott D, Mallal S, Bharadwaj M, Rossjohn J, McCluskey J
The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.
Intellectual impairment in patients with epilepsy in Ile-Ife, Nigeria.
Acta Neurol Scand. 2008 Jun 11;
Sunmonu TA, Komolafe MA, Ogunrin AO, Oladimeji BY, Ogunniyi A
Introduction - Epilepsy is the most common non-infectious neurologic disease in developing countries such as Africa, including Nigeria. This study was designed to assess the intellectual performance of patients with epilepsy (PWE) in Nigeria hoping that the result will serve as the basis for educational, vocational, and social counseling. Methods - Forty-one PWE were studied along with 41 age-, sex- and education-matched healthy controls. A questionnaire was developed and applied to all subjects and history was taken from patients and eyewitness. The intellectual function of each subject was assessed with the aid of Wechsler Adult Intelligence Scale adapted for Nigerians. All patients subsequently had electroencephalography (EEG) performed and the EEG findings were noted. SPSS statistical package was used to analyze the data. Result - The PWE performed poorly on the verbal IQ, performance IQ, and full scale IQ scores when compared with controls (P < 0.05) and 20% of PWE had mental retardation. Long duration of epilepsy, long duration of antiepileptic drug therapy, younger age at onset of epilepsy, increased frequency of seizures, and low educational status were found to have negative impacts on intellectual performance in PWE (P < 0.05) while seizure types and type of antiepileptic drugs (carbamazepine or phenytoin) did not influence intellectual performance. Conclusion - This study shows that PWE had significant intellectual impairment when compared with controls. In addition, long duration of epilepsy, long duration of AED therapy, earlier age of onset, increased seizure frequency, and low educational status had a negative impact on intellectual functioning in PWE.
Chem Res Toxicol. 2008 Jun 13;
Ma L, Wen B, Ruan Q, Zhu M
The present study describes a novel integrated approach for rapid analysis of reactive metabolites with a linear ion trap mass spectrometer (LTQ). In this approach, an isotope pattern-dependent scanning method was applied to the data acquisition of glutathione (GSH)-trapped reactive metabolites. Recorded full-scan MS and MS/MS data sets were further processed with neutral loss filtering, product ion filtering, and extracted ion chromatographic analysis to search for protonated molecules and MS/MS spectra of GSH adducts. To evaluate the effectiveness and reliability of the approach, GSH adducts of carbamazepine, diclofenac, 4-ethylphenol, acetaminophen, p-cresol, and omeprazole were analyzed, which were formed in human liver microsome incubations fortified with a mixture of nonlabeled GSH and stable isotope-labeled GSH at a 1:0.8 ratio. Results demonstrate that the combination of the isotope pattern-dependent scanning with the postacquisition data mining was very effective in detecting low levels of GSH adducts, regardless of their fragmentation patterns. As compared to a neutral loss scanning method performed with a triple quadrupole mass spectrometer, the LTQ-based approach had several major advantages, including the superior selectivity and sensitivity in detecting different classes of GSH adducts and the higher throughput capability of the detection and MS/MS spectral acquisition of GSH adducts in a single LC/MS run. Overall, this analytical approach provides a simple and efficient means for screening for reactive metabolites using a linear ion trap LC/MS platform.
Early discharge following liver resection for colorectal metastases.
Scott Med J. 2008 May; 53(2): 22-4
MacKay G, O'Dwyer PJ
OBJECTIVE: Liver resection is currently the recognised treatment for localised colorectal liver metastases. Hospital stay in recently published series is between seven and 12 days for open surgery and five and eight days for laparoscopic resection. Recently there has been interest in the use of 'fast-track' recovery protocols following major abdominal surgery. Our aim was to measure the effect of such a protocol on hospital stay following liver resection. METHODS: Data was collected prospectively from 12 consecutive patients undergoing open liver resection between August 2003 and September 2004. All patients had a large subcostal incision with full mobilisation of the liver. A 'fast-track' protocol was employed consisting of intra venous fluid restriction, patient controlled analgesia and early diet and mobilisation. Data on postoperative complications and hospital stay was recorded. RESULTS: Twelve patients with a median age of 60 (range 43-74) years underwent liver resection. Resection consisted of one hepatic lobectomy, two trisegmentectomies, three bisegmentectomies and six segmentectomies. Median hospital stay was four (range two to seven) days. One epileptic patient developed carbamazepine toxicity delaying their discharge. A further patient developed a collection requiring no intervention. CONCLUSION: Early discharge following major liver resection using a 'fast-track' recovery protocol is both safe and achievable.
Am Fam Physician. 2008 May 1; 77(9): 1291-6
Krafft RM
Trigeminal neuralgia is an uncommon disorder characterized by recurrent attacks of lancinating pain in the trigeminal nerve distribution. Typically, brief attacks are triggered by talking, chewing, teeth brushing, shaving, a light touch, or even a cool breeze. The pain is nearly always unilateral, and it may occur repeatedly throughout the day. The diagnosis is typically determined clinically, although imaging studies or referral for specialized testing may be necessary to rule out other diseases. Accurate and prompt diagnosis is important because the pain of trigeminal neuralgia can be severe. Carbamazepine is the drug of choice for the initial treatment of trigeminal neuralgia; however, baclofen, gabapentin, and other drugs may provide relief in refractory cases. Neurosurgical treatments may help patients in whom medical therapy is unsuccessful or poorly tolerated.