OBJECTIVES: To study the effect of prophylactic phenytoin (PHT) or levetiracetam (LEV) on busulfan (BU) blood concentration in children undergoing hematopoietic stem cell transplantation. METHODS: Pediatric patients conditioned with BU plus cyclophosphamide and fludarabine at the First People's Hospital of Chenzhou from September 2023 to February 2025 were retrospectively included. Patients were grouped by prophylactic antiepileptic regimen into PHT (n=24) and LEV (n=26). BU blood concentrations at the end of infusion (0 hour) and at 1, 2, and 4 hours post-infusion were compared between groups. RESULTS: At 0 hour post-infusion, BU blood concentrations did not differ significantly between groups (P>0.05). At 1, 2, and 4 hours post-infusion, BU blood concentrations were higher in the LEV group than in the PHT group (P<0.05). The area under the concentration-time curve from 0 to ∞ (AUC_0-∞) was greater in the LEV group (P<0.001), and the attainment rate of AUC_0-∞ was higher in the LEV group than in the PHT group (73% vs 21%, P<0.001). No significant differences were observed between groups in time to hematopoietic engraftment or in the incidence of BU-related adverse drug reactions (P>0.05). CONCLUSIONS Compared with PHT, LEV prophylaxis is associated with higher BU blood concentration and a higher AUC_0-∞ attainment rate. There is no observed difference in BU efficacy or safety between PHT and LEV.
Humans ; Levetiracetam/therapeutic use* ; Busulfan/pharmacokinetics* ; Hematopoietic Stem Cell Transplantation ; Male ; Female ; Child ; Child, Preschool ; Phenytoin/pharmacology* ; Infant ; Retrospective Studies ; Anticonvulsants/pharmacology* ; Adolescent

Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Synaptic vesicle protein 2A (SV2A) involvement has been reported in the animal models of epilepsy and in human intractable epilepsy. The difference between pharmacosensitive epilepsy and pharmacoresistant epilepsy remains poorly understood. The present study aimed to observe the hippocampus SV2A protein expression in amygdale-kindling pharmacoresistant epileptic rats. The pharmacosensitive epileptic rats served as control. Amygdaloid-kindling model of epilepsy was established in 100 healthy adult male Sprague-Dawley rats. The kindled rat model of epilepsy was used to select pharmacoresistance by testing their seizure response to phenytoin and phenobarbital. The selected pharmacoresistant rats were assigned to a pharmacoresistant epileptic group (PRE group). Another 12 pharmacosensitive epileptic rats (PSE group) served as control. Immunohistochemistry, real-time PCR and Western blotting were used to determine SV2A expression in the hippocampus tissue samples from both the PRE and the PSE rats. Immunohistochemistry staining showed that SV2A was mainly accumulated in the cytoplasm of the neurons, as well as along their dendrites throughout all subfields of the hippocampus. Immunoreactive staining level of SV2A-positive cells was 0.483 ± 0.304 in the PRE group and 0.866 ± 0.090 in the PSE group (P < 0.05). Real-time PCR analysis demonstrated that 2(-ΔΔCt) value of SV2A mRNA was 0.30 ± 0.43 in the PRE group and 0.76 ± 0.18 in the PSE group (P < 0.05). Western blotting analysis obtained the similar findings (0.27 ± 0.21 versus 1.12 ± 0.21, P < 0.05). PRE rats displayed a significant decrease of SV2A in the brain. SV2A may be associated with the pathogenesis of intractable epilepsy of the amygdaloid-kindling rats.
Amygdala ; drug effects ; metabolism ; physiopathology ; Animals ; Anticonvulsants ; pharmacology ; Disease Models, Animal ; Drug Resistance ; Electric Stimulation ; Epilepsy ; drug therapy ; genetics ; metabolism ; pathology ; Gene Expression Regulation ; Hippocampus ; drug effects ; metabolism ; physiopathology ; Kindling, Neurologic ; drug effects ; genetics ; metabolism ; pathology ; Male ; Membrane Glycoproteins ; genetics ; metabolism ; Nerve Tissue Proteins ; genetics ; metabolism ; Phenobarbital ; pharmacology ; Phenytoin ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Synaptic Transmission ; Synaptic Vesicles ; drug effects ; metabolism ; pathology

This study is to investigate the effects of phenytoin sodium, lidocaine (sodium channel blockers), propranolol (beta-adrenergic receptor antagonist), amiodarone (drugs prolonging the action potential duration) and verapamil (calcium channel blockers) on arrhythmia of mice induced by Bufonis Venenum (Chansu) and isolated mouse hearts lethal dose of Chansu. Arrhythmia of mice were induced by Chansu and then electrocardiograms (ECGs) were recorded. The changes of P-R interval, QRS complex, Q-T interval, T wave amplitude, heart rate (HR) were observed. Moreover, arrhythmia rate, survival rate and arrhythmia score were counted. Isolated mouse hearts were prefused, and the lethal dose of Chansu was recorded. Compared with control group, after pretreatment with phenytoin sodium, broadening of QRS complex and HR were inhibited, and the incidence of ventricular arrhythmia was reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with lidocaine, the prolongation of P-R interval and broadening of QRS complex were inhibited, and the incidences of ventricular arrhythmia were reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with propranolol, prolongation of P-R interval, broadening of QRS complex, prolongation of Q-T interval and HR were inhibited, and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically, while survival rate was improved. After pretreatment with amiodarone, HR was inhibited, the incidences of ventricular tachycardia were reduced dramatically. Lastly, after pretreatment with verapamil, the prolongation of P-R interval and Q-T interval were inhibited and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically; the isolated mouse hearts lethal dose of Chansu was reduced significantly. In in vivo experiments, phenytoin sodium was most effective against the mice arrhythmias induced by Chansu while cautious use of verapamil for Chansu inducing arrhythmia should be noted. It is also concluded that mice ventricular arrhythmias induced by Chansu might be most closely related to sodium channel, supraventricular arrhythmias might be related to beta-adrenergic receptor, and calcium channel plays an important role in conduction block. In in vitro experiments, phenytoin sodium was most effective, followed by lidocaine and propranolol, and amiodarone had no obvious effect and verapamil reduced the lethal dose of Chansu.
Amiodarone ; pharmacology ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; Bufanolides ; toxicity ; Electrocardiography ; drug effects ; Female ; Heart Rate ; drug effects ; In Vitro Techniques ; Lethal Dose 50 ; Lidocaine ; pharmacology ; Male ; Mice ; Phenytoin ; pharmacology ; Propranolol ; pharmacology ; Verapamil ; pharmacology

OBJECTIVETo study the anticonvulsive action of scorpion alcoholic extraction (SAE) on phenytoin-resistant convulsive rats made by direct cortical electrical stimulation in order to investigate the mechanism of antagonizing drug-resistance of SAE.

METHODUsing the method of implanting microelectrodes in the cortical motor area of the brains of rats where the brain tissue was stimulated frequently by electricity through microelectrodes until igniting and then PHT (0.154 g x kg(-1) x d(-1)) ig for 7 days, We established phenytoin-resistant convulsive rat model. Total 6 groups were set up in the experiment: Normal control group, convulsion model control group (CMCG), phenytoin-resistant convulsion control group (PRCG), verapamil positive control group (VPCG, 0.0385 g x kg(-1)), scorpion alcohol extraction (SAE1, 6.5 g x kg(-1)) and scorpion alcohol extraction (SAE2, 13.0 g x kg(-1)). After ig both doses of SAE (6.5, 13.0 g x kg(-1)), the effects of SAE on the changes of convulsion threshold of phenytoin-resistant convulsive rats were observed. The method of RT-polymerase chain reaction (RT-PCR) was used to detect the changes of mdrl gene expression and the method of immunohistochemistry (SABC) was adopted to determine the changes of P-gp expression.

RESULTBoth doses of SAE and verapamil (Ver) ig all raised the convulsant threshold of phenytoin-resistant rats (480.38 +/- 18.48) microA, there were statistical differences (P < 0.05) compared to themselves before drugs-treated. PHT was administrated, and mdrl mRNA and P-gp expression in PRCG was much higher than that in CMCG, with significantly statistical difference (P < 0.01); ig both doses of SAE and Ver all decreased mdrl mRNA and P-gp expression compared to PRCG respectively (P < 0.01).

CONCLUSIONSAE and Ver ig all produce antagonizing action on phenytoin-resistant convulsive rat model. The machanism is related with inhabiting the mdrl mRNA expression and further decreasing the product P-gp.

ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Animals ; Brain ; drug effects ; metabolism ; Disease Models, Animal ; Ethanol ; chemistry ; Female ; Gene Expression ; drug effects ; Humans ; Phenytoin ; pharmacology ; Rats ; Rats, Wistar ; Scorpions ; chemistry ; Seizures ; drug therapy ; genetics ; metabolism

The present study was performed in order to test the effects of diphenylhydantoin (DPH) and two central nervous system (CNS) stimulants, intermittent light stimulation(ILS) and pentylenetetrazol (Metrazol) on body temperature (Tb) during cold exposure in the bat DHP delayed the onset of entry into hibernation in both the oriental discoloured bats and the little brown bats and formed long and prominent plateaus that were not found in the normal and the controls. The responses of body temperature to the ILS were sensitive and the body temperature fell dramatically in the big brown bats. Metrazol effects on body temperature were obvious but; seemed dose-dependent. The experimental results further support the hypothesis that hibernation is an epileptic fit as suggested by serveral researchers.
Animal ; Body Temperature/drug effects ; Body Temperature Regulation ; Chiroptera/physiology* ; Female ; Hibernation* ; Light ; Male ; Pentylenetetrazole/pharmacology ; Phenytoin/pharmacology