Preliminarily Analysis of Carbamazepine (CBZ) C0 in Patients Visited Isfahan Epileptic Clinics

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Abstract

Background:

Carbamazepine (CBZ) is mostly considered as the first line of effective treatment against simple or complex partial seizure and primary-secondary generalization. To prevent side-effects related to higher amount of CBZ minimum concentration (C ₀) in body fluid or seizure attacks associated to lower amount of CBZ-C ₀, the suggested minimum therapeutic concentrations range from 4 to 12 ng/ml (according to previous publications). The aim of this preliminarily study was to investigate the scope of discrepancy associated to the C ₀of CBZ in patients visited Isfahan Epileptic Clinic.

Methods:

A cross-sectional study of 22 patients located in neurology ward of Isfahan Neurosciences Research Centre (INRC) was carried out between April 1, 2012 and December 31, 2012. Female ( n = 9) and male subjects ( n = 13) with a mean age of 27.4 years (range; 16-38 years) were studied. Pharmacological (CBZ-C ₀) and demographical variables were recorded and processed in excel.

Results:

The results of CBZ-C ₀ showed wide inter-individual variability. The mean value of CBZ-C ₀ was 7.2 ng/ml. In 10 out of 22 patients, CBZ-C ₀ were lower than the suggested therapeutic window (4-12 ng/ml). CBZ-C ₀ in nine patients was non-detectable and in one patient was 0.5 ng/ml (45% < 4 ng/ml). In 55% of the patients, CBZ-C ₀ ranged from 4.8 to 12 ng/ml.

Conclusions:

A schedule therapeutic drug monitoring based on measurement of CBZ-C ₀for individual patient could be a practical marker to achieve therapeutic objectives. Further study related to correlating of CBZC ₀to clinical events in Iranian Epileptic population seems to be valuable.

Related collections

Most cited references 28

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Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I.

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For decades, carbamazepine (CBZ) has served as a model compound for groups engaged in the study of crystal polymorphism. Despite considerable effort, crystal structures for only three of its four anhydrous forms have previously been determined. Herein, we report the first single crystal X-ray structure of the high temperature modification of CBZ (form I). Form I crystallizes in a triclinic cell (P-1) having four inequivalent molecules with the following lattice parameters: a = 5.1705(6), b = 20.574(2), c = 22.245(2) A, alpha = 84.12(4), beta = 88.01(4), and gamma = 85.19(4) degrees. Furthermore, we compare the physical properties of the four anhydrous polymorphs of CBZ, including the first comprehensive characterization of form IV. Substantial differences are seen among these forms by powder X-ray diffraction, infrared spectroscopy, thermomicroscopy, and differential scanning calorimetry. These data are correlated to their respective crystal structures for the first time. We have found that all polymorphs possess identical strong hydrogen bonding patterns, similar molecular conformations, and stabilities that are within 0.7 kcal/mol of each other. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2260-2271, 2003

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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.

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One of the major differences between the older antiepileptic drugs (AEDs) and the newer AEDs is the potential of the older AEDs for significant interactions with other medications. Many of the drug-drug interactions involving the older AEDs are reciprocal, i.e., both drugs affect each other. In contrast, the newer AEDs have either no or limited drug interaction potential. Despite our extensive understanding of and our ability to predict drug-drug interactions, serious drug interactions still occur. More than 30% of all new seizures occur in the elderly, and because this population may be taking a variety of other medications the addition of an AED can have profound impact on these other therapies. In women, the use of enzyme-inducing AEDs can cause significant alterations of sex hormones and can decrease the efficacy of oral contraceptives. In children and adults, the use of enzyme inducers may result in long-term endocrine effects, including bone loss and lipid, thyroid, and sex hormone abnormalities. Phenytoin and phenobarbital are metabolized by cytochrome P450 isozymes, with activity dependent on genetic polymorphism (CYP2C9, CYP2C19). The dosing of the newer AEDs is not affected by genetic polymorphism. The decreased induction and inhibition effects and the lack of significant genetic polymorphism of the newer AEDs allow increased ease of use and perhaps greater safety, especially for patients taking multiple medications.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Prev Med

Journal ID (iso-abbrev): Int J Prev Med

Journal ID (publisher-id): IJPVM

Title: International Journal of Preventive Medicine

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 2008-7802

ISSN (Electronic): 2008-8213

Publication date (Print): May 2013

Volume: 4

Issue: Suppl 2 , 8th Iranian Neurology Congress

Pages: S343-S346

Affiliations

[1]Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

[1 ]Department of Neurology, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Author notes

Correspondence to: Dr. Zahra Tolou Ghamari, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail: toloeghamari@ 123456pharm.mui.ac.ir

Article

Publisher ID: IJPVM-4-343

PMC ID: 3678243

PubMed ID: 23776749

SO-VID: a1fe97c4-66ef-41a4-93c4-dc50ffc7e0aa

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.