The effects of COVID-19 measures on the hospitalization of patients with epilepsy and status epilepticus in Thailand: An interrupted time series analysis.

OBJECTIVE: To investigate the effect of Coronavirus disease 2019 (COVID-19) measures on the hospitalization of patients with epilepsy and status epilepticus (SE). METHODS: This interrupted time series design included data from the Thai Universal Coverage Scheme electronic database between January 2017 and September 2020. The monthly hospitalization rate of epilepsy and SE was calculated by the number of hospitalizations divided by the midyear population. Segmented regression fitted by ordinary least squares (OLS) was used to detect the immediate and overtime effects of COVID-19 measures on the hospitalization rate. RESULTS: During January 2017 and September 2020, the numbers of epilepsy and SE patients admitted to the hospital were 129 402 and 15 547 episodes, respectively. The monthly trend of the hospitalization rate in epilepsy decreased immediately after the COVID-19 measure (0.739 per 100 000 population [95% CI: 0.219 to 1.260]). In particular, the number of children declined to 1.178 per 100 000 population, and the number of elderly individuals dropped to 0.467 per 100 000 population, while there was a nonstatistically significant change in SE. SIGNIFICANCE: COVID-19 measures reduced the hospital rate in epilepsy, particularly in children and adults. However, there was no change in SE patients.

The Efficacy and Safety Profile of Generic Intravenous Levetiracetam in a Real-World Setting.

BACKGROUND: There are 3 main epileptic conditions in hospital settings that may require intravenous antiepileptic treatment: status epilepticus, acute repetitive convulsive seizures, and postoperative seizures. Generic intravenous levetiracetam (IV LEV) (Focale; Great Eastern Drug Co, Bangkok, Thailand), has been reported to have comparable efficacy to original IV LEV for treating status epilepticus and acute repetitive convulsive seizures in a randomized controlled trial. At present, there are limited data on the efficacy and tolerability of generic intravenous LEV in real-world situations. OBJECTIVE: This study aimed to evaluate the clinical outcomes of generic IV LEV in a real-world setting. METHODS: A retrospective study and analyses were conducted. All adult patients who used IV LEV at University Hospital, Khon Kaen University, Thailand from June 1, 2019, until February 15, 2020, were included. Data were analyzed and reported in terms of the efficacy and tolerability of generic IV LEV. RESULTS: Ninety-three patients received IV LEV by 3 indications: status epilepticus, acute repetitive convulsive seizures, and postoperative seizures. The proportions of these 3 indications were 41.94% (39 patients), 9.67% (9 patients), and 48.39% (45 patients), respectively. The average seizure control rate at 24 hours was 89.25%. The seizure control rate was significantly higher in the acute repetitive convulsive seizures and postoperative seizure groups than in the status epilepticus group when generic IV LEV was given as the first-line treatment (75.00%; 88.37% vs 50.00%; P 0.035). The average length of hospital stay was 18.24 (25.40) days. There was no significant discharge status among the 3 groups (P = 0.348). Moreover, the average mortality rate was 5.38%. Side effects were reported in 14 patients (15.05%). The 2 most common side effects were vomiting and bronchospasm (3 patients; 3.22%). There were 10 patients with uncontrolled seizures at 24 hours (10.75%). The only factor associated with uncontrolled seizures at 24 hours was a history of epilepsy. The uncontrolled seizure group had a higher proportion of epilepsy patients than the seizure-controlled group (70.00% vs 33.73%; P = 0.037). Poor discharge status (not improved/death) was 18.28% (17 patients). There was no significant factor between those with an improved or poor discharge status. CONCLUSIONS: Generic IV LEV was effective and relatively well tolerated in the 3 clinical settings (ie, status epilepticus, acute repetitive convulsive seizures, and postoperative seizures). Further clinical data are still required to confirm the results of this study.(Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Can Generic Intravenous Levetiracetam Be Used for Acute Repetitive Convulsive Seizure or Status Epilepticus? A Randomized Controlled Trial.

INTRODUCTION: Intravenous levetiracetam (IV LEV) is approved for treatment status epilepticus (SE). However, the drug's high cost must be considered when deciding on a treatment strategy. This study aimed to compare the efficacy of brand-name and generic IV LEV for acute repetitive convulsive seizure (ARCS) or SE. METHODS: Forty patients aged 18 years or older who had been diagnosed with SE or ARCS were included in this double-blind study. Patients were randomly assigned at a 1:1 ratio (via computer-generated code) to receive either brand-name or generic IV LEV. The primary outcomes were seizure control and the number of seizure exacerbations during the 24 h after drug administration, while the secondary outcomes were electroencephalographic (EEG) findings, serious adverse events, and clinical outcome at hospital discharge. RESULTS: Forty patients were randomly assigned administration with either brand-name IV LEV (10 SE and 10 ARCS patients) or generic IV LEV; 7 SE and 13 ARCS patients). There was no significant difference in patients' baseline characteristics. The seizure control rate was 75% in the brand-name IV LEV group and 65% in the generic IV LEV group (p value: 0.490). Five (25%) patients in the brand-name IV LEV group, and six (30%) patients in the generic IV LEV group developed seizure exacerbations within 24 h after drug administration (p value 0.723). There were no reports of drug-related adverse events. Two of the patients taking brand-name IV LEV and one taking the generic IV LEV died (p value > 0.999). CONCLUSION: Treatment with the generic IV LEV had comparable outcomes with brand-name IV LEV. The generic IV LEV may be an alternative medication for the treatment of SE and ARCS to reduce treatment costs. TRIAL REGISTRATION: TCTR20190513001. FUNDING: Great Eastern Drug Company.

Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
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OBJECTIVE: Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. METHODS: A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow® P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0-24h), were calculated. RESULTS: Neither the mean values of Emax (90.70 ± 15.15 vs. 89.50 ± 10.71% inhibition) nor of AUEC0-24h (1,892.84 ± 657.22 vs. 1,853.58 ± 673.95% inhibition × h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow® P2Y12 assay were consistent with those of the WBA assay. CONCLUSION: This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.
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The impact of genetic polymorphisms of drug metabolizing enzymes on the pharmacodynamics of clopidogrel under steady state conditions.

Clopidogrel is an antiplatelet drug that requires biotransformation steps to its active metabolite via cytochromes P450 (CYP), particularly CYP2C19 and CYP3A5 as well as paraoxonase-1 (PON1). The impact of CYP3A5 and PON1 genetic polymorphisms on the response of this drug is unclear. This study aimed to elucidate the degree of genetic polymorphisms of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel. Thirty-five healthy subjects were treated with 75 mg/day clopidogrel for 7 days and serial blood samples were collected for measurement of antiplatelet effect using whole blood impedance aggregometry and VerifyNow(®) P2Y12 methods. The areas under the antiplatelet effect-time curves, maximal and minimal antiplatelet effects of clopidogrel obtained from both methods were significantly different among subjects with different CYP2C19 genotypes. In contrast, these pharmacodymamic parameters measured by both methods of subjects with different PON1 or CYP3A5 genotypes were not significantly different. Among the heterozygous CYP2C19*2 subjects, all pharmacodynamic parameters measured by whole blood impedance aggregometry were significantly different between subjects with different CYP3A5*3 genotypes. Our data suggests that CYP2C19 genetic polymorphism play a major role in the clopidogrel response, however, the impact of CYP3A5 genetic polymorphism, may be pronounced in the subjects who carried the loss-functional allele of CYP2C19.

Therapeutic drug monitoring in epilepsy clinic: a multi-disciplinary approach.

Epilepsy is a common public health problem and needs multi-disciplinary treatment. Therapeutic drug monitoring (TDM) is one of step of the multi-disciplinary treatment in epilepsy at Epilepsy clinic, Khon Kaen University (Thailand). The TDM service has been established since 2008. Here, we aimed to study the roles of TDM order and epilepsy control. This is a prospective descriptive study in which data collection was done from January 1 to December 31, 2010, the period when pharmacists took part in assessing the appropriateness in measurement and interpretation of TDM in order to provide suggestions for physicians. The 112 patients under study had an average age of 38.21±15.36 years; 254 samples were collected for therapeutic drug monitoring; phenytoin was submitted mostly for drug monitoring at 46.46%; 44.49% of submissions for drug level monitoring were made owing to a suspected sub-therapeutic level. Associations were found between reasons of sending samples for drug level monitoring and the measured drug levels, i.e., 66.67% of drug levels found was so low that they were undetectable in sample for patients' compliance investigation and 38.94% of the drug levels were found to be sub-therapeutic as for the case where submission of samples was done because of suspected sub-therapeutic level, 40% of the cases were found to be in toxicity range in the cases with suspected over-therapeutic levels and monitoring levels, 58.25% were found to be within the therapeutic range. Pharmacists used the interpreted results in patients' care by recommending physicians to monitor therapeutic drug closely, to adjust the dosage of drugs, and to recommend checking patients' compliance in their use of drugs at 56.5, 38.9, and 4.3%, respectively. Physicians' responses were found to be absolute follow, partial follow and not follow at 77.95, 11.03, and 7.48%, respectively. In conclusion, associations were found between reasons of TDM order and measured drug level. Therapeutic drug monitoring services at the Epilepsy Clinic was useful in supporting clinical information queries. Pharmacists could make use of interpreted drug level information by recommending physicians to monitor drug levels and adjust individual dosage regimen accordingly. It should be noted that physicians accepted pharmacists' recommendation, denoting multi-disciplinary care team that would lead to greater efficiency.

Adjunctive enteral phenobarbital for adult status epilepticus: a brief report.

BACKGROUND: Status epilepticus (SE) is a neurological emergency condition. Intravenous phenobarbital (PB) is recommended for refractory SE treatment. However, intravenous PB is unavailable in Thailand. Enteral PB has been shown to be effective in SE children. METHODS: In adult SE patients, the efficacy of enteral PB as an adjunctive therapy has been reported. This is a case series of adult SE patients who were treated with enteral PB at Khon Kaen University Hospital, Thailand. The clinical features and clinical outcomes are reported. RESULTS: There were six patients; five patients had convulsive SE, and one patient had nonconvulsive SE. All patients received PB enterally, at dosages of 900 mg initially and repeated doses of 900 mg as needed. This was gradually reduced to a maintenance dosage of 180 mg/day. Three out of six patients were completely controlled, whereas the other three patients were partially controlled. Three out of six patients were seizure-free after the initial loading dose of PB. No adverse effects were found in this study. CONCLUSION: In adult patients, enteral PB may be effective as an add-on for refractory SE therapy.

Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals.

Andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (2) are active constituents of Andrographis paniculata (Burm. f.), family Acanthaceae. A. paniculata extracts are reported to have antiviral, antipyretic, immunostimulant and anticancer activities. In this study, 1 and its 14-acetyl- (4) and 3,19-isopropylidenyl- (3) derivatives, as well as 2 and its 3,19-dipalmitoyl-derivative (5), were intraperitoneally tested for their analgesic, antipyretic, anti-inflammatory and acute toxicity effects in animal models. Analgesic effects were tested in mice using hot plate and writhing tests to distinguish the central and peripheral effects, respectively. The results showed that, at 4 mg/kg, all tested substances have significant analgesic effects, and the highest potency was seen with 3, 4 and 5. Increasing the dose of 3 and 5 to 8 mg/kg did not increase the analgesic effect. In the writhing test, 3 and 5, but not 1, showed significant results. In a baker's yeast-induced fever model, 3 and 5 significantly reduced rats' rectal temperature (p < 0.05). In a carrageenan-induced inflammation model, 1, 3 and 5 significantly reduced rats' paw volume. Doses of 3 and 5 up to 100 mg/kg did not show any serious toxic effects. From this study, 3 and 5 are the most interesting derivatives, showing much greater potency than their parent compounds. These could be further developed as analgesic, antipyretic and anti-inflammatory agents, without any serious toxicity.

Predictive risk factors of seizure-related injury in persons with epilepsy.

OBJECTIVE: The clinical risk factors for seizure-related injuries (SRI) in adult persons with epilepsy (PWE) were studied and analyzed to develop a predictive model. METHODS: We enrolled 300 consecutive cases from three epilepsy clinics in Northeast, Thailand. Subjects were eligible if reported to have at least one seizure attack during the past 12 months. Face-to-face questionnaire was used to evaluate SRI, baseline characteristics and other seizure-related variables. RESULTS: There were 247 and 91 PWE who met a criterion and had SRI, respectively. By multivariate logistic regression method, GTC seizure type, having history of seizure attacks at least 12 times/year, and daytime seizure were significant risk factors of having SRI with odds ratio of 2.376, 2.460, and 3.562, respectively. We developed the predictive model for having SRI in PWE and it gave 90.3% sensitivity and 46.7% specificity on the occurrence of SRI. The estimated probability of SRI can be found online at http://sribykku.webs.com/. CONCLUSIONS: The significant predictive factors for SRI in PWE were the occurrence of GTCs, seizures at least 12 times/year or daytime seizures. Clinicians or PWE can easily evaluate the risk of having SRI in individuals by the online predictive model.

Biphasic effects of Morus alba leaves green tea extract on mice in chronic forced swimming model.

In this study, the effects of an aqueous extract of Morus alba leaves green tea (ME) on mouse behaviors (depression, anxiety, climbing activity and thermal response), muscle coordination and muscle strength were studied. Male IRC mice received a single intraperitoneal injection of either the ME, desipramine or diazepam. Thirty minutes after injection, the mice were tested in all experimental models. A significant antidepressant-like effect could be detected in the animals receiving either 100 or 200 mg/kg ME. The effect of 200 mg/kg ME in decreasing the immobility time was comparable to 10 mg/kg desipramine. With higher dose (1000 mg/kg), a significant increase in immobility time could be observed. In the elevated plus maze, no increase in time in the open arm could be observed in mice treated with ME at either 100 or 200 mg/kg. However, high doses of ME (500 or 1000 mg/kg) decreased both time in the open arm and the number of entries in the maze. No change in thermal response could be seen in mice treated with ME at doses up to 500 mg/kg, however, at 1000 mg/kg, the response time to heat was increased significantly. The ME at either 500 or 1000 mg/kg also decreased muscle coordination, strength and climbing activity significantly when compared with the control. This study suggests that ME possesses an antidepressant- without an anxiolytic-like effect, however, at high doses, the extract might show the sedative effect and alter other functions such as muscle strength, animal activity in the maze and pain response.

Basic knowledge of epilepsy among medical students.

BACKGROUND: The medical students' knowledge about basic medical neuroscience in the preclinical level may be fragmented and incomplete. OBJECTIVE: Evaluate the knowledge of students prior to a lecture on epilepsy in clinical level. MATERIAL AND METHOD: One hundred ten fourth-year medical students' knowledge was accessed by a self-administered questionnaire. RESULTS: The presented results revealed that 91.8% of respondents knew that epilepsy arose from a transient dysfunction in the brain. Generalized tonic-clonic seizures (GTCs) were the most common type (91.5%) they knew and absence seizures were the least common type (33.6%) they knew. All of them knew that eating pork and punishment of gods did not cause epilepsy. However 50% thought that genetics was a cause and 80.3% did not know that stroke and sleep deprivation (92.7%) cause epilepsy. About treatment and prognosis, only 28.2% of respondents thought epilepsy can be cured and patients should take antiepileptic drugs (AEDs) for seizure free 2-5 years (48.2%), life long (33.6%). They knew that the patients should be prohibited from driving (80%), working on machinery (74.5%), and (27.3%) avoid drinking. However, they knew that the patients could marry (100%), get pregnant (98.2%), and lactate (91.9%). Regarding the first aid management, 50.9% of them recommended that placing a piece of wood between the teeth during a seizure and perform chest compressions (20.0%). Means knowledge scores is about 60%, the highest score is the definition of epilepsy (90.2%) and the lowest is type of seizure (43%). CONCLUSION: The findings indicated that lecturers should review aspects ofpathophysiology and emphasize on type of seizure, cause, consequences, and prognosis including first-aid management.

Very high dose phenobarbital for refractory status epilepticus.

BACKGROUND: Refractory status epilepticus (RSE), defined as status epilepticus that fails to respond to first, second and third-line therapy. The RSE is associated with high morbidity and mortality. Treatment guidelines of RSE give a spectrum of options, such as, continuous intravenous (i.v.) midazolam (MDL), or continuous i.v. propofol (PRO) as alternatives to phenobarbital (PB) or continuous i.v. pentobarbital (PTB). OBJECTIVE: To study the efficacy of very-high-dose phenobarbital (VHDPB) for treatment RSE. STUDY DESIGN: Retrospective study MATERIAL AND METHOD: The authors collected and analyzed data from adult patients who were diagnosed with RSE. RESULTS: The authors present 10 patients with RSE who were treated with VHDPB. All of them were generalized convulsive status epilepticus (GCSE). Ages ranged from 16-86 years old (mean.: 43 years). PB dosage ranged 40-140 mg/kg/day (mean: 70 mg/kg/day). The duration of status epilepticus (SE) varied widely, ranged 1-44 days (mean: 7 days). PB level ranged 35.29-218.34 ug/mL (mean 88.1 ug/mL). RSE was controlled by VHDPB 70%, 30% were not controlled. CONCLUSION: VHDPB were considered as alternative treatment for RSE.

Steady-state bioequivalence study of clozapine tablet in schizophrenic patients.

PURPOSE: To compare the bioavailability of two clozapine formulations (100 mg Clozaril tablet from Novartis Pharmaceuticals UK Ltd., UK, as a Reference formulation and 100 mg Cloril tablet from Atlantic Laboratories Corp., Ltd., Thailand, as a Test formulation). The present study was conducted under real-life conditions in schizophrenic patients using a steady-state, multiple-dose, randomized crossover design to avoid the risk of adverse effects in healthy volunteers and pharmacokinetic difference between single and multiple-dose of the drug. METHODS: The subjects received 100 mg bid of either the Reference formulation or the Test formulation for 7 days. At day-7 of each study phase, blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h after drug administration. Plasma was separated and stored at -80 degrees C until assay. The plasma concentration of clozapine was determined by high performance liquid chromatography. Pharmacokinetic parameters were calculated from the observed plasma-concentration time profiles. The bioequivalence between the two formulations was assessed by calculating individual peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC(0-12 h)) ratios. RESULTS: All subjects well tolerated both clozapine formulations. No serious side effects were reported. The Tmax, terminal half-life and the total plasma clearance of clozapine (uncorrected for bioavailability) observed in the present study were comparable to those observed in other previous reports. All of the pharmacokinetic parameters investigated in the present study calculated from the subjects after administration of Test and Reference formulations were close. The 90% confident interval for the ratio of means for the lnCmax (0.9784-1.0622) and lnAUC(0-12h) (0.9559-1.0441) are within the guideline range of bioequivalence (0.80 to 1.25). CONCLUSION: The result demonstrated that the Test formulation was bioequivalent to the Reference formulation (Clozaril) when orally administered in schizophrenic patients, in terms of both the rate and extent of absorption.

Knowledge of epilepsy among teachers in Khon Kaen Province, Thailand.

INTRODUCTION: Epileptic patients face social stigmatization due to negative attitudes and incorrect knowledge on epilepsy. OBJECTIVES: To evaluate knowledge of epilepsy among teachers in Khon Kaen province. MATERIAL AND METHOD: A self-administered questionnaire distributed to 102 teachers who attended the training lectures on epilepsy. The number of correct responses for each item were collected. The statistical analysis included the percentage of correct response and the means of the total scores. RESULTS: Most (78.4%) respondents understood that a seizure is an abnormal electrical discharge in the brain, while 54.9% thought it included a form of abnormal movement and 1% demonic possession. The generalized tonic-clonic seizure (GTCs) was the type of seizure with which most respondents were familiar (90.2%), while 23.5% had knowledge of absence seizures. The respondents identified the following as causes for epilepsy: 1) head injury (84%); 2) genetic disease (74.5%); 3) high fever (68%); and, 4) brain tumor (57%). A small minority associated epilepsy with eating pork (11%) and even fewer (2%) with a non-organic/non-physical cause. Only 16% of respondents thought epilepsy was incurable, and a quarter (27%) of the teachers thought epileptics required anti-epileptic drugs (AEDs) life long, while 20 and 9 percent believed patients would take AEDs for 3-6 months and only for episodes, respectively. About 57% of the teachers thought epileptics needed AEDs for 2-5 years. Most (77-79%) respondents thought epileptics were prohibited from using machinery or driving, and 63% thought alcohol would be prohibited. Almost two-thirds of the teachers (64%) thought they should try to place an object between the teeth of a person having an episode in order to prevent a biting injury to the tongue and 27% would restrain the person and perform chest compressions (CPR). The average total score for correct answers on the questionnaire was about 60% (29.26/50). Respondents generally understood that epilepsy is controllable (82%) and were able to identify a seizure (78.4%). The lowest scores were found in the section on identifying the types of seizures (37.8%). CONCLUSION: Teachers' knowledge of epilepsy was incomplete; thus, an epilepsy education campaign is needed and should emphasize the types of seizures, the causes of epilepsy, and management.

Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands.

A novel synthetic approach towards N1-alkylated 3-propyl-1,4-benzodiazepines was developed in five synthetic steps from 2-amino-4-chlorobenzophenone, in which the N-oxide 4 served as a key intermediate. The structure-activity relationship optimization of this 3-propyl-1,4-benzodiazepine template was carried out on the N1-position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK2) receptor. The N-allyl-3-propyl-benzodiazepine 6d displayed an affinity towards the CCK2 (CCK-B) receptor of 170 nM in a radiolabelled receptor-binding assay. The anxiolytic activity of this allyl-3-propyl-1,4-benzodiazepine 6d was subsequently determined in in-vivo psychotropic assays. This novel ligand had ED50 values of 4.7 and 5.2 mg kg(-1) in the black and white box test and the x-maze, respectively, and no significant sedation/muscle relaxation was observed.