1. Levetiracetam, lamotrigine and carbamazepine: which monotherapy during pregnancy?
Luisa Mari, et al. Neurol Sci. 2022 Mar;43(3):1993-2001. doi: 10.1007/s10072-021-05542-2. Epub 2021 Sep 1.
Objective: Epilepsy treatment during pregnancy is still challenging. The study is aimed at comparing the efficacy and safety of carbamazepine (CBZ), lamotrigine (LTG) and levetiracetam (LEV) monotherapies during pregnancy in women with focal (FE) or generalized (GE) epilepsy. Methods: A multicentre retrospective study was conducted to evaluate seizures frequency and seizure freedom (SF) rate during 3 months before pregnancy, each trimester of gestation and post-partum period in women on monotherapy with CBZ, LTG and LEV. Results: Fifty-seven pregnancies (45 FE, 12 GE) on monotherapy (29 CBZ, 11 LTG, 17 LEV) were included. A significant reduction of seizure frequency was found in the first trimester of pregnancy as compared with that one before pregnancy (p = 0.004), more evident in GE (p = 0.003) and in LEV group (p = 0.004). The SF rate significantly increased in the first trimester in comparison to that one before pregnancy and persisted in the post-partum period in the whole sample (p < 0.001) and in women on LEV (p = 0.004). Besides, 88.57% of SF women before pregnancy remained unchanged during gestation and the post-partum period. One major heart malformation in CBZ and no major malformations in LTG and LEV groups were found. Conclusions: A better clinical outcome during pregnancy emerged since the first trimester in comparison to the before-pregnancy period, mostly evident in women with GE and LEV therapy, reinforcing the hypothesis of a protective role of pregnancy versus seizures. SF before pregnancy represents a significant predictive factor of good clinical outcome during gestation and the post-partum period. Compared to CBZ, LTG and LEV showed a better safety profile.
2. Ellagic acid enhances the antinociceptive action of carbamazepine in the acetic acid writhing test with mice
Bahareh Naghizadeh, Mohammad Taghi Mansouri, Behnam Ghorbanzadeh Pharm Biol. 2016;54(1):157-61. doi: 10.3109/13880209.2015.1025288. Epub 2015 Apr 21.
Context: Ellagic acid (EA) produced antinociceptive and anti-inflammatory effects through the central and peripheral sites of action. Objective: The objective of the current study was to examine the functional interaction between ellagic acid and carbamazepine (CBZ) on pain. Materials and methods: Fourteen groups of mice (8-10 each) were used in this study. Pain was induced by intraperitoneal acetic acid in mice (writhing test) and the functional interaction was analyzed using the isobolographic method. EA at doses 0.3, 1, 3, and 10 mg/kg and carbamazepine at doses 3, 10, 20, and 30 mg/kg, alone and also in combination (1/2, 1/4, and 1/8 of the drug's ED50) were intraperitoneally administered 30 min before acetic acid (0.6% v/v). Then, the abdominal writhes were counted during a 25-min period. Results: EA (0.3-10 mg/kg, i.p.) and CBZ (3-30 mg/kg, i.p.) inhibited the writhing response evoked by acetic acid. Fifty percent effective dose (ED50) values against this tonic pain were 1.02 mg/kg and 6.40 mg/kg for EA and CBZ, respectively. The antinociception induced by EA showed higher potency than that of carbamazepine. Co-administration of increasing fractional increments of ED50 values of EA and CBZ produced additive interaction against writhing responses, as revealed by isobolographic analysis. Discussion and conclusion: These results suggest that a combination of carbamazepine and ellagic acid may be a new strategy for the management of neuropathic pain such as what occurs in trigeminal neuralgia, since the use of carbamazepine is often limited by its adverse effects and by reduction of its analgesic effect through microsomal enzyme induction.
3. Antiepileptic drug mechanisms of action
R L Macdonald, K M Kelly Epilepsia. 1995;36 Suppl 2:S2-12. doi: 10.1111/j.1528-1157.1995.tb05996.x.
Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.
