Carbamazepine

Carbamazepine, a sodium channel blocker, is an anticonvulsant drug.

Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings.[Pubmed:28353375]

Hosp Pract (1995). 2017 Apr;45(2):46-50.

OBJECTIVES: Carbamazepine (CBZ) is a commonly used anti-epileptic in rural hospitals in India. These hospitals lack the facilities to measure CBZ concentration; however, in larger hospitals this is performed using high performance liquid chromatography (HPLC). Dried blood spot (DBS) represents a feasible matrix for safe transportation by post/courier. This study was to determine whether the concentration of CBZ in serum can be predicted from that measured in DBS using an inexpensive HPLC method and inexpensive standard filter paper. METHODS: CBZ in serum and DBS from 80 epileptic patients were measured using a validated HPLC assay. The data was then randomly divided into two groups; simple Deming regression was performed with the first group and validation was performed using the second. RESULTS: There was a good correlation between the serum and DBS concentrations (r = 0.932) in the first group. The regression equation obtained was: predicted serum concentration = DBS concentration x 0.83 + 1.09. In the validation group, the correlation between the predicted and actual serum concentrations was also good (r = 0.958), and the mean difference between them was only 0.28 mug/ml (p = 0.8062). The imprecision and bias in both the groups were acceptable. CONCLUSION: Using inexpensive materials, serum CBZ concentrations can be accurately predicted from DBS specimens. This method can be recommended for the therapeutic drug monitoring of CBZ in resource-limited settings.

HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis.[Pubmed:28358139]

Sci Rep. 2017 Mar 30;7:45553.

HLA-B*15:02 screening before Carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action.

Eslicarbazepine acetate as a therapeutic option in a patient with carbamazepine-induced rash and HLA-A*31:01.[Pubmed:28340402]

Seizure. 2017 Apr;47:81-82.

Eslicarbazepine acetate (ESL) is an anticonvulsant drug approved for the treatment of focal epilepsies, and related to oxcarbazepine and Carbamazepine (CBZ), which are also derivatives of the dibenzazepine family. ESL is contraindicated in patients with hypersensitivity reactions to CBZ.We report a patient with frontal lobe epilepsy responding to treatment with ESL without any serious adverse effects after developing a severe skin rash following treatment with CBZ. HLA testing revealed an HLA-A*31:01 haplotype, that increases the risk of CBZ-induced cutaneous reactions.This case study shows that, in clinical practice, ESL may be considered in a patient with the HLA-A*31:01 haplotype and a hypersensitivity reaction to CBZ.

UV/chlorine treatment of carbamazepine: Transformation products and their formation kinetics.[Pubmed:28343060]

Water Res. 2017 Jun 1;116:254-265.

Carbamazepine (CBZ) is one of the pharmaceuticals most frequently detected in the aqueous environment. This study investigated the transformation products when CBZ is degraded by chlorine under ultraviolet (UV) irradiation (the UV/chlorine process). Detailed pathways for the degradation of CBZ were elucidated using ultra-high performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry (QTOF-MS). CBZ is readily degraded by hydroxyl radicals (HO) and chlorine radicals (Cl) in the UV/chlorine process, and 24 transformation products were identified. The products indicate that the 10,11-double bond and aromatic ring in CBZ are the sites most susceptible to attack by HO and Cl. Subsequent reaction produces hydroxylated and chlorinated aromatic ring products. Four specific products were quantified and their evolution was related with the chlorine dose, pH, and natural organic matter concentration. Their yields showed an increase followed by a decreasing trend with prolonged reaction time. CBZ-10,11-epoxide (I), the main quantified transformation product from HO oxidation, was observed with a peak transformation yield of 3-32% depending on the conditions. The more toxic acridine (IV) was formed involving both HO and Cl with peak transformation yields of 0.4-1%. All four quantified products together amounted to a peak transformation yield of 34.5%. The potential toxicity of the transformation products was assayed by evaluating their inhibition of the bioluminescence of the bacterium Vibrio Fischeri. The inhibition increased at first and the decreased at longer reaction times, which was in parallel with the evolution of transformation products.

Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore.[Pubmed:20643904]

Mol Pharmacol. 2010 Oct;78(4):631-8.

The tricyclic anticonvulsant drugs phenytoin, Carbamazepine, and lamotrigine block neuronal voltage-gated Na(+) channels, and their binding sites to domain IV-S6 in the channel's inner pore overlap with those of local anesthetic drugs. These anticonvulsants are neutral, in contrast to the mostly positively charged local anesthetics, but their open/inactivated-state blocking affinities are similar. Using a model of the open pore of the Na(+) channel that we developed by homology with the crystal structures of potassium channels, we have docked these three anticonvulsants with residues identified by mutagenesis as important for their binding energy. The three drugs show a common pharmacophore, including an aromatic ring that has an aromatic-aromatic interaction with Tyr-1771 of Na(V)1.2 and a polar amide or imide that interacts with the aromatic ring of Phe-1764 by a low-energy amino-aromatic hydrogen bond. The second aromatic ring is nearly at a right angle to the pharmacophore and fills the pore lumen, probably interacting with the other S6 segments and physically occluding the inner pore to block Na(+) permeation. Hydrophobic interactions with this second aromatic ring may contribute an important component to binding for anticonvulsants, which compensates energetically for the absence of positive charge in their structures. Voltage dependence of block, their important therapeutic property, results from their interaction with Phe-1764, which connects them to the voltage sensors. Their use dependence is modest and this results from being neutral, with a fast drug off-rate after repolarization, allowing a normal action potential rate in the presence of the drugs.

Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies.[Pubmed:18636076]

Cell Death Differ. 2009 Jan;16(1):46-56.

The formation of intra-neuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease (PD) and polyglutamine disorders, including Huntington's disease (HD). Autophagy is a major clearance pathway for the removal of mutant huntingtin associated with HD, and many other disease-causing, cytoplasmic, aggregate-prone proteins. Autophagy is negatively regulated by the mammalian target of rapamycin (mTOR) and can be induced in all mammalian cell types by the mTOR inhibitor rapamycin. It can also be induced by a recently described cyclical mTOR-independent pathway, which has multiple drug targets, involving links between Ca(2+)-calpain-G(salpha) and cAMP-Epac-PLC-epsilon-IP(3) signalling. Both pathways enhance the clearance of mutant huntingtin fragments and attenuate polyglutamine toxicity in cell and animal models. The protective effects of rapamycin in vivo are autophagy-dependent. In Drosophila models of various diseases, the benefits of rapamycin are lost when the expression of different autophagy genes is reduced, implicating that its effects are not mediated by autophagy-independent processes (like mild translation suppression). Also, the mTOR-independent autophagy enhancers have no effects on mutant protein clearance in autophagy-deficient cells. In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions.

Lamotrigine and carbamazepine affect differently the release of D-[3H]aspartate from mouse cerebral cortex slices: involvement of NO.[Pubmed:10485587]

Neurochem Res. 1999 Sep;24(9):1153-9.

The effects of lamotrigine and Carbamazepine on the release of preloaded D-[3H]aspartate and the involvement of nitric oxide were studied with mouse cerebral cortical slices in a superfusion system. Lamotrigine inhibited the veratridine-evoked release, whereas the K+-stimulated release was attenuated more strongly by Carbamazepine than by lamotrigine. These effects were accentuated by the N-methyl-D-aspartate receptor antagonist L-2-amino-5-phosphonovalerate and the nitric oxide synthase inhibitor L-nitroarginine, but diminished by the nitric oxide donor sodium nitroprusside. The results show that in addition to the blockade of voltage-sensitive Na+ (and Ca2+) channels, NO-mediated mechanisms are probably involved in the anticonvulsant actions of Carbamazepine and, in particular, those of lamotrigine.

Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin.[Pubmed:7603459]

Mol Pharmacol. 1995 Jun;47(6):1189-96.

We report here that Carbamazepine and phenytoin, two widely used antiepileptic drugs, potentiate gamma-aminobutyric acid (GABA)-induced Cl- currents in human embryonic kidney cells transiently expressing the alpha 1 beta 2 gamma 2 subtype of the GABAA receptor and in cultured rat cortical neurons. In cortical neuron recordings, the current induced by 1 microM GABA was enhanced by Carbamazepine and phenytoin with EC50 values of 24.5 nM and 19.6 nM and maximal potentiations of 45.6% and 90%, respectively. The potentiation by these compounds was dependent upon the concentration of GABA, suggesting an allosteric modulation of the receptor, but was not antagonized by the benzodiazepine (omega) modulatory site antagonist flumazenil. Carbamazepine and phenytoin did not modify GABA-induced currents in human embryonic kidney cells transiently expressing binary alpha 1 beta 2 recombinant GABAA receptors. The alpha 1 beta 2 recombinant is known to possess functional barbiturate, steroid, and picrotoxin sites, indicating that these sites are not involved in the modulatory effects of Carbamazepine and phenytoin. When tested in cells containing recombinant alpha 1 beta 2 gamma 2, alpha 3 beta 2 gamma 2, or alpha 5 beta 2 gamma 2 GABAA receptors, Carbamazepine and phenytoin potentiated the GABA-induced current only in those cells expressing the alpha 1 beta 2 gamma 2 receptor subtype. This indicates that the nature of the alpha subunit isoform plays a critical role in determining the Carbamazepine/phenytoin pharmacophore. Our results therefore illustrate the existence of one or more new allosteric regulatory sites for Carbamazepine and phenytoin on the GABAA receptor. These sites could be implicated in the known anticonvulsant properties of these drugs and thus may offer new targets in the search for novel antiepileptic drugs.