Administration Of Carbamazepine Research Articles

Correlation between Level of Serum Transaminases and Duration of Antiepileptic Drugs in Epilepsy Children in Sanglah Hospital

BACKGROUND: Some antiepileptic drugs (AEDs), particularly sodium valproate, phenytoin, phenobarbital, and carbamazepine induce and increase production of hepatic enzymes. The adverse metabolic effects of AEDs treatments have become main concern, however data about evaluation of serum transaminases and duration of AEDs in Indonesia still limited. AIM: The aim of the study was to investigate correlation of AEDs and serum transaminases in children with epilepsy. METHODS: This cross-sectional research was conducted in pediatric neurology outpatient clinic in Sanglah Hospital. The target was children with epilepsy who had taken AEDs for at least 6 months. Data were collected from January 2020 to the number of samples were achieved. The exclusion criteria were concomitant liver disease, taking drugs which induce elevated serum transaminase or alcohol abuse. Data including age, gender, nutritional status, type, and duration of AEDs were obtained from medical record. Correlation was analyzed by Pearson’s or Spearman’s correlation, p < 0.05 was considered significant. RESULTS: Total 148 epileptic children enrolled in this study. Aspartate transaminase (AST) and alanine aminotransferase (ALT) level were highest in the group receiving combination therapy (34.37 ± 24.9 U/L and 35.96 ± 23.3 U/L). There was a significant negative correlation between duration of carbamazepine and AST (r = –0.723, p = 0.0001) and ALT (r = –0.457, p = 0.009), as well as duration of valproic acid with AST and ALT (r = –0.689 and –0.677, p = 0.0001). Duration of phenobarbital administration was positively correlated with AST and ALT (r = 0.546 and 0.425, p = 0.0001). Combination therapy also had positive correlation with AST and ALT (r = 0.815 and 0.781, p = 0.0001, respectively). CONCLUSION: Duration administration of carbamazepine and valproic acid had negative correlation with AST and ALT; however, phenobarbital and combination therapy were positively correlated with AST and ALT.

Carbamazepine mitigates parenteral nutrition-associated liver disease in a novel ambulatory piglet model.

Parenteral nutrition (PN) remains a critical therapeutic option in patients who cannot tolerate enteral feeding. However, although lifesaving, PN is associated with significant side effects, including liver injury, the etiology of which is multifactorial. Carbamazepine (CBZ), an antiepileptic medication, is known to modulate hepatic fibrosis and hepatocellular injury in a variety of liver diseases. We hypothesized that CBZ could prevent PN-associated liver disease (PNALD), which we tested by using our novel ambulatory PN piglet model. Piglets were fitted with jugular catheters and infusion pumps for PN and randomized to enteral nutrition (n = 7), PN (n = 6), or PN with parenteral CBZ (n = 6) for 2 weeks. Serum and liver tissue were analyzed via light microscopy, quantification of serum liver injury markers, Ki67 and cytokeratin-7 indexing, and real-time quantitative polymerase chain reaction. PN-fed piglets in our model developed manifestations of PNALD-particularly, increased serum bilirubin, gamma-glutamyltransferase, liver cholestasis, and Ki67 expression compared with that of EN-fed animals (P < 0.03). CBZ therapy in PN-fed animals led to a significant reduction in these markers of injury (P < 0.05). Investigation into the mechanism of these therapeutic effects revealed increased expression of sterol regulatory element-binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor alpha (PPAR-α), and fatty acid binding protein (FABP) in PN-fed animals receiving CBZ (P < 0.03). Further investigation revealed increased LC3 expression and decreased lysosomal-associated membrane protein (LAMP1) expression with CBZ (P < 0.03). CBZ administration mitigates PNALD severity, suggesting a novel therapeutic strategy targeting PN-associated side effects, and may present a paradigm change to current treatment options.

Assessment of hepatic prostaglandin E2 level in carbamazepine induced liver injury.

Objective. Carbamazepine (CBZ), a widely used antiepileptic drug, is one major cause of the idiosyncratic liver injury along with immune reactions. Conversely, prostaglandin E2 (PGE2) demonstrates a hepatoprotective effect by regulating immune reactions and promoting liver repair in various types of liver injury. However, the amount of hepatic PGE2 during CBZ-induced liver injury remains elusive. In this study, we aimed to evaluate the hepatic PGE2 levels during CBZ-induced liver injury using a mouse model. Methods. Mice were orally administered with CBZ at a dose of 400 mg/kg for 4 days, and 800 mg/kg on the 5th day. Results. Plasma alanine transaminase (ALT) level increased in some of mice 24 h after the last CBZ administration. Although median value of hepatic PGE2 amount in the CBZ-treated mice showed same extent as vehicle-treated control mice, it exhibited significant elevated level in mice with severe liver injury presented by a plasma ALT level >1000 IU/L. According to these results, mice had a plasma ALT level >1000 IU/L were defined as responders and the others as non-responders in this study. Even though, the hepatic PGE2 levels increased in responders, the hepatic expression and enzyme activity related to PGE2 production were not upregulated when compared with vehicle-treated control mice. However, the hepatic 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression and activity decreased significantly in responders when compared with control mice. Conclusions. These results indicate that elevated hepatic PGE2 levels can be attributed to the downregulation of 15-PGDH expression under CBZ-induced liver injury.

Inhibition of autophagy with expression of NADPH oxidase subunit p22phox in preneoplastic lesions in a high-fat diet and streptozotocin-related hepatocarcinogenesis rat model

To study the effects of autophagy inducer carbamazepine (CBZ) in a high-fat diet (HFD)/streptozotocin (STZ)-related early hepatocarcinogenesis model, we determined autophagic flux by immunohistochemical analysis of autophagy marker expression in preneoplastic liver foci and compared that with the expression of the NADPH oxidase subunit. Male F344 rats were fed a basal diet or HFD and subjected to two-stage hepatocarcinogenesis; diabetes mellitus was induced via STZ administration. Several STZ-treated, HFD-fed rats were administered CBZ (a total of five doses every one or two days) at week 7 and 8. STZ-treated, HFD-fed rats decreased β cells in the islet of Langerhans and increased adipophilin-positive lipid droplets in the liver; moreover, they had a larger area of glutathione S-transferase placental form-immunopositive preneoplastic liver foci, which was associated with inhibition of autophagy and induction of the NADPH oxidase subunit, as demonstrated by increased immunohistochemical expression of an autophagosome receptor marker microtubule-associated protein light chain 3 (LC3)-binding protein p62, and of an NADPH oxidase subunit p22phox in the preneoplastic foci. An increased trend of an autophagy phagophore marker LC3 in preneoplastic foci was also detected. CBZ administration could induce autophagy and impair p22phox expression, as shown by altered expression of autophagy regulators (Atg5, Atg6, Lamp1, Lamp2, and Lc3), NADPH oxidase subunits (P22phox and P67phox), and antioxidant enzymes Gpx1 and Gpx2. These results suggest that inhibition of autophagy and induction of p22phox might contribute to HFD/STZ-related early hepatocarcinogenesis in rats; however, the effects of CBZ administration on the STZ/HFD-increased preneoplastic foci were marginal in this study.

Liquid Enteral Nutrients Alter the Pharmacokinetics of Orally Administered Carbamazepine in Rats.

The interaction between enteral nutrients (ENs) and drugs co-administered through a nasogastric (NG) tube reportedly affects the absorption and resultant plasma concentrations of the respective drugs. However, the gastrointestinal absorption of carbamazepine (CBZ), an antiepileptic drug, co-administered with liquid ENs through an NG tube has not been clarified. In this study, we measured the recovery rate (%) of CBZ (Tegretol® powder) passed through an NG tube when co-administered with distilled water or ENs (F2α®, Racol® NF, Ensure Liquid®, and Renalen® LP) of different compositions, frequently used in Japan. We also measured the plasma CBZ level in 26 rats after oral co-administration of CBZ with liquid ENs. The CBZ recovery rate was close to 100% in rats of all EN groups after passage through the NG tube. Furthermore, CBZ area under the plasma concentration-time curve from time zero to 9 h (AUC0→9h) of the Ensure liquid® group decreased compared with that of control group (P < 0.05) and Renalen® LP group (P < 0.01). However, the AUC0→9h of CBZ remained unchanged when co-administered with Ensure liquid® 2 h after initial CBZ administration. In conclusion, the co-administration of CBZ with Ensure Liquid® caused a reduction in the absorption of CBZ from the gastrointestinal tract, without adsorption on the NG tube. The administration of Ensure Liquid® 2 h after CBZ is a way to prevent a decrease in plasma CBZ concentration. Our findings suggest that carefully monitoring the plasma levels of CBZ is necessary in co-administation with Ensure liquid® to prevent the unintended effects of the interaction between CBZ and liquid EN.

Carbamazepine-Induced Symptomatic Bradycardia in a Middle-Aged Female

Carbamazepine is an anticonvulsant drug commonly used to treat seizure disorders and trigeminal neuralgia. Although its hematologi-cal and hepatic side effects are well known, the rare cardiac side effects, mainly bradyarrhythmias, and atrioventricular blocks, are not discussed often in the literature. As per evidence, it has negative chronotropic and dromotropic effects on the cardiac conduction system. This case report discusses the life-threatening cardiac side effects of carbamazepine therapy and the significance of detailed cardiac evaluation before initiating this drug. We report a case of symptomatic bradycardia in a middle-aged female as the consequence of car-bamazepine administration for seizure prophylaxis after meningioma resection.

Effect of long-term administration of clonazepam, carbamazepine, and valproate on cognitive, psychological, and personality changes in adult epilepsy: a case\u2013control study

BackgroundEpilepsy can be treated with antiepileptic drugs (AEDs) which may have psychiatric and behavioral side effects. Additionally, the availability of new AEDs has increased, and our understanding of variability to combinations of several AEDs has evolved. Based on the treatment outcomes of carbamazepine, valproate, and clonazepam, this study aims to compare the cognitive function, personality, and psychological issues associated with these drugs and evaluate seizure-related factors related to them. Only 139 participants were included. Clonazepam was used as an add-on antiepileptic drug. Participants were categorized into five groups: group 1, carbamazepine; group 2, valproate; group 3, carbamazepine and clonazepam; group 4, valproate and clonazepam; and group 5, epileptic patients without AED. All participants were assessed using the Wechsler Adult Intelligence Scale (WAIS), Structured Interview for the Five-Factor Personality Model (SIFFM), Hamilton Anxiety and Depression Rating Scale, and Minnesota Multiphasic Personality Inventory-2 (MMPI-2).ResultsIn the WAIS, group 1 had the worst mean of verbal intelligence quotient (IQ). Moreover, group 3 was more vulnerable in symptomatic response in all subscales of MMPI-2 except the masculinity–femininity subscale and a high percentage in moderate severity of anxiety and depression in the Hamilton scales.ConclusionsThe use of clonazepam and carbamazepine might increase the incidence of behavioral problems especially increased severity of anxiety and depression and decreased performance IQ compared with either clonazepam or carbamazepine alone. Moreover, patients with carbamazepine treatment might have more personality changes and lowered verbal IQ than others.

Effects of concurrent and staggered dosing of semi-solid enteral nutrients on pharmacokinetic behavior of antiepileptic drugs after oral administration in rats.

BackgroundThe use of enteral nutrients plays a highly important role in accurate nutrition management, but limited information is currently available on the cautionary points of semi-solid enteral nutrients.AimIn this study, we examined whether the pharmacokinetic profiles of sodium valproate (SVA), levetiracetam (LEV), and carbamazepine (CBZ) are affected by altering the dosing time of RACOL®-NF Semi Solid for Enteral Use (RASS), a prescribed semi-solid formula. We also investigated whether the pharmacokinetic interaction observed in this study can be avoided by staggered dosing of the chemical drug and semi-solid enteral nutrient.MethodsThe plasma concentration of SVA, LEV and CBZ after oral administration was measured by LC-MS/MS method.ResultsThere was no difference in pharmacokinetic characteristics of SVA and LEV when the dosing time of RASS was altered. On the other hand, the plasma concentration of CBZ after oral administration at all sampling points decreased with the extension of the dosing time of RASS, which was consistent with the Cmax and AUC. However, no significant difference was observed in the pharmacokinetic profiles or parameters of CBZ between the short-term and long-term RASS dosing groups by prolonging the administered interval of CBZ and RASS for 2 hr.ConclusionWe concluded that the pharmacokinetic profiles of CBZ, but not SVA and LEV, after its oral administration are affected by the dosing time of RASS, but staggered administration of CBZ and RASS prevented their interaction.

The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly-inherited ataxia worldwide and is characterised by the accumulation of mutant ataxin-3 (mutATXN3) in different brain regions, leading to neurodegeneration. Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology. The autophagy-enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD-associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients. We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up-regulated autophagy through activation of AMPK, which was dependent on the myo-inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study. Our data support the autophagy-enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.

Carbamazepine-induced immune thrombocytopenia confirmed by modified MASPAT test

A 76-year-old man suffering post-herpetic neuralgia developed severe thrombocytopenia 15 days after the administration of carbamazepine. Carbamazepine-dependent platelet antibodies were proved to be present in the patient’s serum by a modified Monoclonal Antibody Solid-phase Platelet Antibody Test (MASPAT), and the diagnosis of carbamazepine-induced immune thrombocytopenia was confirmed. For the patient, carbamazepine should be advised to be avoided permanently. The present report advocated the application of a modified MASPAT test for the detection of carbamazepine-dependent platelet antibodies.

Cost-effectiveness analysis of genotyping for HLA-B*15:02 in Indonesian patients with epilepsy using a generic model.

Carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are strongly associated with the HLA-B*15:02 allele. Screening HLA-B*15:02 before CBZ administration might prevent CBZ-induced SJS/TEN by enabling clinicians to prescribe alternative therapy for positive patients. Similar to other Southeastern Asian countries, HLA-B*15:02 is highly prevalent in Indonesia. Therefore, we assessed the economic value of HLA-B*15:02 screening before CBZ prescription to patients with epilepsy in Indonesia. A generic cost-effectiveness model and decision support tool, developed to enable users to perform an initial cost-effectiveness analysis from a healthcare provider/payer perspective, were used to assess the value of HLA-B*15:02 genotyping. The incremental cost-effectiveness ratio of adopting universal HLA-B*15:02 screening was 656,444,671 Indonesian Rupiah (IDR)/quality-adjusted life year (QALY) gained for patients compared with 2,634,975,574 IDR/QALY gained for providing valproic acid (alternative drug) without screening. Thus, neither HLA-B*15:02 screening nor substitution with VPA meets the Indonesian threshold for cost effectiveness. However, the improved outcomes with this test in other Asian countries may inform the desirability of implementation in Indonesia even with suboptimal cost-effectiveness.

Effect and Mechanism of Carbamazepine on SCN1A Expression in Temporal Lobe Epilepsy Rats

To investigate the effect of carbamazepine treatment on the expression of SCN1A in temporal lobe epilepsy and its mechanism of action. 90 male Wistar rats were randomly divided into 30 rats each in the carbamazepine group, model group and blank control group, in which the temporal lobe epilepsy rat model was established using lithium-pilocarpine in the carbamazepine and model groups. After successful modeling, the carbamazepine group was given carbamazepine solution at a concentration of 16 mg/ml in a dose of 2 ml once/d; the model group was not given any drug treatment, and distilled water was given 2 ml/ time/d. The normal control group was fed routinely without any special treatment. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction and Western blot assay were used to detect the changes of SCN1A expression level in each group. Polymerase chain reaction results showed that the expression of SCN1A messenger ribonucleic acid in the model group was significantly higher than that in the control group and the carbamazepine group, and the difference was statistically significant (p 0.05). The level of SCN1A protein product Nav1.1 in the model group was significantly higher than that in the control group and the carbamazepine group, and the difference was statistically significant, although the level of SCN1A protein product Nav1.1 in the carbamazepine group was higher than that in the control group, but the difference was not statistically significant, indicating that the administration of carbamazepine could reduce the expression of CN1A protein product Nav1.1 level. Immuno-histochemical results showed that SCN1A was more expressed in the temporal cortex and CA1 and CA3 regions of the hippocampus in normal rats. Compared with the control group, the expression of SCN1A immuno positive cells in the hippocampal CA1 and CA3 regions and temporal cortex of the model group was increased, with highly significant difference (p 0.05) was found in the carbamazepine group. Carbamazepine could better control the abnormally elevated expression of SCN1A in temporal lobe epileptic rats and return its expression level to normal, which may be related to the restoration of the impaired inward rectification by reducing the expression of Nav1.1 channel protein and thus buffering the extracellular sodium load to some extent. Maintaining resting membrane potential reduces neuronal excitability ultimately may reduce the generation of epileptiform discharges.

A case of marked thrombocytopenia during carbamazepine administration

A case of marked thrombocytopenia during carbamazepine administration

Quantitative and qualitative application of a novel capillary microsampling device, Microsampling Wing™ (MSW), using antiepileptic drugs in rats

A novel microsampling device, namely, the Microsampling Wing™ (MSW), was evaluated using three anti-epileptic drugs (AEDs): carbamazepine, lamotrigine, and phenytoin. A simultaneous assay method of the three AEDs was developed and qualified via liquid chromatography with tandem mass spectrometry. Using 2.8 μL plasma, the three AEDs were quantifiable from 1 or 2 ng/mL. According to the intra-assay reproducibility assessment and additional validation parameters, the established method is reproducible. To apply the device to a pharmacokinetic (PK) study in rats, a cocktail of the three AEDs was orally administered to rats. Whole blood samples were serially collected using the MSW device and a glass capillary from the tail vein, and plasma samples (each 2.8 μL) from each device were assayed to compare PK parameters. The PK parameters of the three AEDs were similar between the two devices. A metabolite identification study was also conducted after oral administration of carbamazepine to rats. At least seven metabolites were detected in plasma, and the major metabolite was carbamazepine 10,11-epoxide, which is in accordance with the reported results. These findings suggest that the MSW device is a useful microsampling device for PK and metabolite identification studies.

Carbamazepine evoked reproductive toxicity in male Wistar rats: protective properties of Moringa oleifera leaves methanolic extract

Carbamazepine is an effective chemotherapeutic agent used to manage individual with epilepsy and trigeminal neuralgia. Chronic use of carbamazepine has been incriminated to cause reproductive disorders. The present study investigates the protective property of Moringa oleifera leaves methanolic extract on chronic carbamazepine-evoked reproductive toxicity in male Wistar rats. Forty male Wistar rats (150–260 g) were randomly separated into four groups with 10 rats, given distilled water (2 ml/kg), M. oleifera (200 mg/kg), carbamazepine (20 mg/kg) and M. oleifera accompanied with carbamazepine, after 30 min. The treatments were administered once in a day for 15 weeks via gavage. The pituitary and testis were evaluated for parameters measuring oxidative challenge, sperm characteristics and histological changes. Sex hormone concentrations were also evaluated from sera samples. The result of the phytochemical analysis shows that M. oleifera leaves extract contain total phenolics (7.8%) and flavonoids (22.23%), which are considered higher in the plant. The results also revealed that exposure to M. oleifera leaves mitigates the disruption in oxidative stress parameters, sex hormone concentration, sperm characteristics and histological changes. This study revealed that chronic carbamazepine administration evokes oxidative stress, partly involved in the alterations of concentration of sex hormones, sperm characteristics and histoarchitecture of pituitary gland and testes. Treatment with leaf extract of M. oleifera protects against the adverse reproductive consequences of long-term exposure to CBZ, due to its antioxidant property.

The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats.

Carbamazepine (CBZ) is mainly metabolized by CYP3A4 into carbamazepine-10,11-epoxide (CBZE). Cannabidiol (CBD) is a potent inhibitor of the CYP3A family. The aim of this study is to determine the effect of acute and chronic administration of CBD on the pharmacokinetics of CBZ and CBZE. Male SD rats were assigned into four acute and four chronic groups: control (CBZ only), positive control (ketoconazole), low-dose cannabidiol (l-CBD), and high-dose cannabidiol (h-CBD). Acute CBD groups were administered a single dose of CBD, while chronic CBD groups were given multiple doses of CBD for 14days (q.d.) before CBZ administration. Plasma samples had been collected and analyzed for CBZ and CBZE, then their noncompartmental pharmacokinetic parameters before and after CBD administration were determined. The co-administration of a single l-CBD has significantly increased CBZ's [Formula: see text] by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in Cmax by 31.8%. Acute h-CBD caused similar effects on CBZ's [Formula: see text] with 40.4% significant decrease in CBZE's Cmax, when compared to the control. Chronic h-CBD caused a significant decrease in CBZ's Cmax and [Formula: see text] by 75.3% and 65.7%, respectively. Besides, [Formula: see text] and Cmax of CBZE significantly decreased by 75.3% and 78.3%, respectively. These results demonstrated that the pharmacokinetics of CBZ and CBZE had been significantly affected by CBD. When CBD has been administered as a single dose, the effect is believed to be mainly caused by the inhibition of CBZ metabolism through CYP3A. The effect of chronic administration of CBD probably includes kinetic pathways other than the inhibition of CYP3A-dependent pathways. Graphical abstract.

Early Chronic Carbamazepine-in-Food Administration to MAM/Pilocarpine Rats Does Not Affect Convulsive Motor Seizures.

Antiepileptic drug-resistance is a major health problem in patients with cortical dysplasia (CD). Whether drug-resistant epilepsy is associated with progressive brain damage is still debated. We previously generated a rat model of acquired CD, the methylazoxymethanol-pilocarpine (MP) rat, in which the occurrence of status epilepticus and subsequent spontaneous seizures induce progressive brain damage (Nobili et al., 2015). The present study tested the outcome of early-chronic carbamazepine (CBZ) administration on both seizure activity and brain damage in MP rats. We took advantage of the non-invasive CBZ-in-food administration protocol, established by Ali (2012), which proved effective in suppressing generalized convulsive seizures in kainic acid rat model of epilepsy. MP rats were treated immediately after the onset of the first spontaneous seizure with 300 mg/kg/day CBZ formulated in pellets for a two-months-trial. CBZ-treated rats were continuously video-monitored to detect seizure activity and were compared with untreated epileptic MP rats. Despite CBZ serum levels in treated rats were within the suggested therapeutic range for humans, CBZ affected spontaneous convulsive seizures in 2 out of 10 treated rats (responders), whereas the remaining animals (non-responders) did not show any difference when compared to untreated MP rats. Histological analysis revealed cortical thinning paralleled by robust staining of Fluoro-Jade+ (FJ+) degenerating neurons and diffuse tissue necrosis in CBZ-non-responder vs CBZ-responder rats. Data reported here suggest that MP rat model represents suitable experimental setting where to investigate mechanisms of CD-related drug-resistant epilepsy and to verify if modulation of seizures, with appropriate treatment, may reduce seizure-induced brain damage.

Activation of adenosine receptors modulates the efflux transporters in brain capillaries and restores the anticonvulsant effect of carbamazepine in carbamazepine resistant rats developed by window-pentylenetetrazole kindling

Up-regulation of efflux transporters in brain capillaries may lead to the decreased therapeutic efficacy of antiepileptic drugs in patients with Drug Resistant Epilepsy. Adenosine receptor activation in brain capillaries can modulate blood-brain barrier permeability by decreasing the protein levels and function of efflux transporters. Therefore, we aimed to investigate whether the activation of adenosine receptors improves convulsions outcome in carbamazepine (CBZ) resistant animals and modulates the protein levels of efflux transporters (P-GP, MRP1, MRP2) in brain capillaries. We employed the window-pentylenetetrazol (PTZ) kindling model to develop CBZ resistant rats by CBZ administration during the post-kindling phase, and tested if these animals displayed subsequent resistance to other antiepileptic drugs. Crucially, we investigated if the administration of a broad-spectrum adenosine agonist (NECA) improves convulsions control in CBZ resistant rats. Of potential therapeutic relevance, in CBZ resistant rats NECA restored the anticonvulsant effect of CBZ. We also evaluated how the resistance to CBZ and the activation of adenosine receptors with NECA affect protein levels of efflux transporters in brain capillaries, as quantified by western blot. While CBZ resistance was associated with the up-regulation of both P-GP/MRP2 in brain capillaries, with the administration of NECA in CBZ resistant rats, we observed a decrease of P-GP and an increase of MRP2 levels, in brain capillaries. Since the activation of adenosine receptors improves the outcome of convulsions probably through the modulation of the efflux transporters protein levels in brain capillaries, adenosine agonists could be useful as an adjunct therapy for the control of Drug Resistant Epilepsy.

Electrophysiological and Neurochemical Assessment of Selenium Alone or Combined with Carbamazepine in an Animal Model of Epilepsy

The present study aims to evaluate the efficacy of selenium (Se) alone or combined with carbamazepine (CBZ) against the adverse effects induced by the chemoconvulsant pentylenetetrazole (PTZ) in the cortex of adult male rats. Electrocorticogram (ECoG) and oxidative stress markers were implemented to evaluate the differences between treated and untreated animals. Animals were divided into five groups: control group that received i.p. saline injection, PTZ-treated group that received a single i.p. injection of PTZ (60mg/kg) for induction of seizures followed by a daily i.p. injection of saline, Se-treated group that received an i.p. injection of sodium selenite (0.3mg/kg/day) after PTZ administration, CBZ-treated group that received orally CBZ (80mg/kg/day) after PTZ administration, and combination (Se plus CBZ)-treated group that received an oral administration of CBZ (80mg/kg/day) followed by an i.p. injection of sodium selenite (0.3mg/kg/day) after PTZ administration. Quantitative analyses of the ECoG indices and the neurochemical parameters revealed that Se and CBZ have mitigated the adverse effects induced by PTZ. The main results were decrease in the number of epileptic spikes, restoring the normal distribution of slow and fast ECoG frequencies and attenuation of most of the oxidative stress markers. However, there was an increase in lipid perioxidation marker in combined treatment of CBZ and Se. The electrophysiological and neurochemical data proved the potential of these techniques in evaluating the treatment's efficiency and suggest that supplementation of Se with antiepileptic drugs (AEDs) may be beneficial in ameliorating most of the alterations induced in the brain as a result of seizure insults and could be recommended as an adjunct therapy with AEDs.

Identification of drug-specific public TCR driving severe cutaneous adverse reactions

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.