Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype-guided doses in renal transplantation patients.

AIMS: Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype-guided tacrolimus doses. METHODS: This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype-guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. RESULTS: The genotype-guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over-therapeutic concentration patients was noted in the genotype-guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype-guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37-month follow-up period. CONCLUSIONS: Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.

The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients.

PURPOSE: The aim of this study was to investigate the contributions of non-genetic and genetic factors on the variability of stable warfarin doses in Thai patients. METHODS: A total of 250 Thai patients with stable warfarin doses were enrolled in the study. Demographics and clinical data, e.g., age, body mass index, indications for warfarin and concomitant medications, were documented. Four single nucleotide polymorphisms in the VKORC1 - 1639G > A, CYP2C9*3, CYP4F2 rs2108622, and UGT1A1 rs887829 genes were detected from gDNA using TaqMan allelic discrimination assays. RESULTS: The patients with variant genotypes of VKORC1 - 1639G > A required significantly lower warfarin stable weekly doses (SWDs) than those with wild-type genotype (p < 0.001). Similarly, the patients with CYP2C9*3 variant allele required significantly lower warfarin SWDs than those with homozygous wild-type (p = 0.006). In contrast, there were no significant differences in the SWDs between the patients who carried variant alleles of CYP4F2 rs2108622 and UGT1A1 rs887829 as compared to wild-type allele carriers. Multivariate analysis, however, showed that CYP4F2 rs2108622 TT genotype accounted for a modest part of warfarin dose variability (1.2%). In contrast, VKORC1 - 1639G > A, CYP2C9*3, CYP4F2 rs2108622 genotypes and non-genetic factors accounted for 51.3% of dose variability. CONCLUSIONS: VKORC1 - 1639G > A, CYP2C9*3, and CYP4F2 rs2108622 polymorphisms together with age, body mass index, antiplatelet drug use, amiodarone use, and current smoker status explained 51.3% of individual variability in stable warfarin doses. In contrast, the UGT1A1 rs887829 polymorphism did not contribute to dose variability.

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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Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population.

BACKGROUND: Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. MATERIALS AND METHODS: Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. RESULTS: Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05). CONCLUSION: Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.

Candidate HLA genes for prediction of co-trimoxazole-induced severe cutaneous reactions.

BACKGROUND: Co-trimoxazole is a sulfonamide-containing antibiotic that is effective in the treatment of several infections and for prophylaxis of Pneumocystis jiroveci pneumonia. This drug has been reported as a common culprit drug for the Stevens-Johnson syndrome (SJS) and for toxic epidermal necrolysis (TEN). Human leukocyte antigens (HLAs) play a key role in the immunopathogenesis of severe cutaneous reactions induced by several drugs. This study investigated the association between the HLA class I and HLA-DRB1 polymorphisms and co-trimoxazole-induced SJS/TEN in a Thai population. METHODS: Forty-three patients with co-trimoxazole-induced SJS/TEN and 91 co-trimoxazole-tolerant patients were enrolled in the study. HLA class I and HLA-DRB1 were genotyped using the reverse sequence-specific oligonucleotide probe method. RESULTS: The frequencies of three alleles of HLA, namely HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01, were significantly higher in the co-trimoxazole-induced SJS/TEN group compared with controls. The risks for co-trimoxazole-induced SJS/TEN in patients with the HLA-B*15:02, HLA-C*06:02, or HLA-C*08:01 allele were about 3-11-fold higher when compared with those who did not carry one of these alleles. Individuals who carried the HLA-B*15:02-C*08:01 haplotype had a 14-fold higher risk for co-trimoxazole-induced SJS/TEN. CONCLUSION: Evidence of associations between co-trimoxazole-induced SJS/TEN and HLA alleles including HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01 were found in the study population. These findings may suggest that apart from the HLA molecules, other molecules involved in the molecular pathogenesis of these severe cutaneous adverse drug reactions may play an important role in the susceptibility of individuals to SJS/TEN caused by co-trimoxazole.

Comparative bioavailability of two moxifloxacin tablet products after single dose administration under fasting conditions in a balanced, randomized and cross-over study in healthy volunteers.

Moxifloxacin, a 4th generation of fluoroquinolones, is a broad spectrum antibacterial agent against respiratory tract pathogens, including Gram-positive and Gram-negative bacteria, anaerobic bacteria and atypical respiratory tract pathogens. In order to evaluate the efficacy and safety of generic moxifloxacin products, the bioequivalence of these generic products with an approved reference formulation should be demonstrated. Thus, the aim of this study was to compare the rate and extent of absorption of a new generic film coated moxifloxacin tablet product (Rapiflox®, Atlantic Laboratories Corporation Ltd., Bangkok, Thailand) with that of a reference product (Avelox®, Bayer Health Care AG, Leverkusen, Germany) when given as a single dose. A crossover study was performed in 20 healthy Thai volunteers. The subjects received either a 400 mg tablet of the reference or test product after overnight fasting. Blood samples were collected at pre-dose (0 hour) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 34 hours post-dose. Moxifloxacin plasma level was measured by a validated HPLC method with fluorescence detector. Pharmacokinetic parameters were calculated using a non-compartmental model. The geometric mean of maximum concentration (Cmax) of the test product was 4,069.64 ng/ml, with median time to achieve maximum concentration (tmax) at 2 hours (range 0.25 - 6.00 hours), while the geometric mean Cmax and median tmax of the reference product was 4,211.98 ng/ml and 2.00 hours (range 0.25 - 8.00 hours). Furthermore, the geometric means of AUC0-tlast and AUC0-∞ for the test product were 49,731.66 and 51,865.89 ng×h/ml while those of the reference product were 51,927.97 and 54,455.93 ng×h/ml. The geometric mean of the ratios of Test/Reference for the logtransformed Cmax, AUC0-tlast and AUC0-∞ of moxifloxacin and their 90% CIs were 96.62% (83.21 - 112.19%), 95.77% (87.07 - 105.34%) and 95.24 (86.52 - 104.85%), respectively. Therefore, it can be concluded that these two moxifloxacin tablet products were bioequivalent in healthy Thai volunteers under fasting condition.

HLA-B*1502 strongly predicts carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Thai patients with neuropathic pain.

BACKGROUND: Carbamazepine (CBZ) is one of the standard pharmacological treatments for neuropathic pain. However, its serious adverse drug reactions include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, HLA-B*1502 allele was implicated as a genetic marker of CBZ-induced SJS/TEN in some Asian epilepsy populations. METHODS: This is a case control study to describe the clinical characteristics of SJS/TEN in Thai patients with neuropathic pain who were treated with CBZ, and to determine the association of HLA-B*1502 in these patients, comparing with those who exposed to CBZ for at least 6 months without any cutaneous reactions. RESULTS: Thirty-four SJS/TEN patients and 40 control patients were included in this study. Mean age of SJS/TEN patients was 47 years. SJS/TEN was developed in 10.8 ± 1.4 days after initiation of CBZ. HLA-B*1502 allele was found in 32 of 34 SJS/TEN patients (94.1%) but it was found only in 7 of 40 control patients (17.5%). The association was very strong with an odds ratio of 75.4. Sensitivity and specificity of this HLA-B*1502 genotype test were 94.1% and 82.5%, respectively, while the positive predictive value and negative predictive value were 1.43% and 99.98%, respectively. Positive and negative likelihood ratios were 5.37 and 0.07, respectively. CONCLUSIONS: HLA-B*1502 is a strong genetic marker for CBZ-induced SJS/TEN in Thai patients with neuropathic pain. The screening for this marker should be performed prior to initiation of CBZ treatment to assess the risk of this serious side effect.

NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine.

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15∗3 and NUDT15∗2 genotypes were at a 10-15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15∗3 and NUDT15∗2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients.

Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 ( NUDT15 ) genes have been proposed as key determinants of 6-mercaptopurine (6-MP)-induced myelosuppression in pediatric acute lymphoblastic leukemia (ALL). In the present study, genotypes of TPMT and NUDT15 were investigated in 178 Thai pediatric patients with ALL by the TaqMan SNP genotyping assay and DNA sequencing. The frequency of TPMT*3C was 0.034. Among NUDT15 variants, NUDT15*3 is the most common variant with the allele frequency of 0.073, whereas those of NUDT15*2 , NUDT15*5 , and NUDT15*6 variants were 0.022, 0.011, and 0.039. These data suggest that a high proportion of Thai pediatric ALL patients may be at risk of thiopurine-induced myelosuppression.

Acute valproic acid overdose: enhance elimination with multiple-doses activated charcoal.

Multiple dose activated charcoal (MDAC) is used to enhance elimination of toxic substance in acute poisoning. However, its role in acute valproic acid (VA) overdose is controversial. The authors report a case of VA overdose that successfully recovered with MDAC treatment. The half-life of VA in the presented patient was decreased from 12 to 8 hours during MDAC administration. MDAC treatment in acute poisoning enhanced VA elimination four times than without treatment. MDAC should be considered for the treatment of acute VA intoxication.

Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation.

Background Dosage quantities of tacrolimus (TAC) vary according to cytochrome P450 3A5 (CYP3A5) genotype. Genotyping is expected to optimize the response to TAC response and to minimize adverse effects. In Thailand, kidney transplantation is reimbursable with the same diagnosis-related group payment regardless of patient's CYP3A5 genotype. Objective This study aimed to determine the costs of TAC administration, therapeutic drug monitoring (TDM), and hospitalization for kidney transplantation across CYP3A5*1/*1, *1/*3, and *3/*3 genotypes. Setting A single transplant center in a university hospital. Method This is an observational study that collected data from patients pooled from both arms of a randomized controlled trial that tested initial doses of TAC. Main outcome measure TAC and TDM cost and hospitalization cost for transplantation were compared between genotypes. Results The CYP3A5*1/*1 patients had the highest median combined TAC-TDM cost and hospitalization cost ($1062 and $9097), followed by CYP3A5*1/*3 ($859 and $6467) and CYP3A5*3/*3 patients ($761 and $5604). The CYP3A5*1/*1 patients had a higher hospitalization cost by $2787 over the CYP3A5*1/*3 patients, despite marginal significance. The CYP3A5*1/*1 patients had a significantly higher cost of TAC plus TDM (by $309) and hospitalization cost (by $3275) than the CYP3A5*3/*3 patients. Both study costs were significantly higher in patients with delayed graft functioning than in patients with instant or slow graft functioning. Conclusion The benefits of genotype detection in patients with CYP3A5*1/*1 should be considered for a higher reimbursement rate because of the substantial differences in total hospitalization cost for kidney transplantation among patients with different CYP3A5 genotypes.

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.

Outcomes of a Randomized Controlled Trial Comparing Modified High Dose Omeprazole and Amoxicillin Triple Therapy with Standard Triple Therapy for Helicobacter Pylori Eradication

Background: Helicobacter pylori (H. pylori) infection is related to peptic ulcer diseases and gastric cancer and eradication of H. pylori should be expected to decrease the risk of their development. Factors affecting H. pylori eradication are antibiotic resistance, CYP2C19 genotypes, drug regimen and patient compliance. Increment of omeprazole and amoxicillin dosage in clarithromycin-containing triple therapy regimen may overcome these problems and may be a better choice than the conventional clarithromycin-containing triple therapy regimen. Objective: To compare the eradication rates with modified triple therapy (MTT) and standard triple therapy (STT) as first-line treatment. Materials and Methods: The study was an open label, multicenter, randomized controlled trial. A total of 170 patients infected with H. pylori diagnosed by rapid urease test were randomly assigned into 2 groups. The first was treated with a 14-day MTT (20 mg omeprazole t.i.d., 500 mg amoxicillin t.i.d., and 500 mg clarithromycin b.i.d.) and the second with a 14-day STT (20 mg omeprazole b.i.d., 1000 mg amoxicillin b.i.d., and 500 mg clarithromycin b.i.d.). H. pylori eradication was evaluated by 14C-urea breath test. CYP2C19 genotypes, clarithromycin resistance, side effects and patient compliance were also recorded. Results: There were 85 patients in each group. The H. pylori eradication rate in the MTT group was 84.7% by ITT analysis and 91.1% by PP analysis, compared to the STT group values of 76.5% and 87.8% (p = 0.18 and 0.51), respectively. CYP2C19 genotypes and patient compliance were similar in both groups. Prevalence of clarithromycin resistance was 7.0%. Side effects were all mild with no significant differences between the twogroups. Conclusions: MTT is not superior to STT. From this study, MTT may not be recommended as the first-line treatment for H. pylori infection in Thailand because eradication rates proved to be less than 90% by ITT analysis.

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome.

BACKGROUND: Brugada syndrome (BrS) is an inherited primary arrhythmia disorder leading to sudden cardiac arrest. SCN5A, encoding the α-subunit of the cardiac sodium channel (Nav1.5), is the most common pathogenic gene of BrS. An implantable cardioverter defibrillator (ICD) is the standard treatment for secondary prevention. This study aimed to evaluate association of the SCN5A variant with this cardiac conduction disturbance and appropriate ICD shock therapy in Thai symptomatic BrS patients with ICD implants. METHODS AND RESULTS: Symptomatic BrS patients diagnosed at university hospital were enrolled from 2008 to 2011. The primary outcome of the study was an appropriate ICD shock defined as having non-pacing-associated ICD shock after the occurrence of ventricular tachycardia or ventricular fibrillation. Associations between SCN5A polymorphisms, cardiac conduction disturbance, and potential confounding factors associated with appropriate ICD shock therapy were analyzed. All 40 symptomatic BrS patients (median age, 43 years) with ICD implantations were followed for 24 months. There were 16 patients (40%) who had the appropriate ICD shock therapy after ICD treatment. An independent factor associated with appropriate ICD shock therapy was SCN5A-R1193Q with an adjusted hazard ratio of 10.550 (95% CI, 1.631-68.232). CONCLUSIONS: SCN5A-R1193Q is associated with cardiac conduction disturbances. It may be a genetic marker associated with ventricular arrhythmia leading to appropriate ICD shock therapy in symptomatic BrS patients with ICD treatment. Because of the small sample size of study population and the appropriate ICD shock outcome, further large studies are needed to confirm the results of this study.

Ceftazidime overdose-related nonconvulsive status epilepticus after intraperitoneal instillation.

We report a case of ceftazidime-related nonconvulsive status epilepticus (NCSE) in a 70-year-old female patient with continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. She was given ceftazidime intravenously which was then changed to intraperitoneal installation after clinical improvement. She received 11 g of ceftazidime via intraperitoneal installation for two days after being discharged from the hospital. Her consciousness was altered with mutism, asterisxis, and horizontal nystagmus. Her EEG showed continuous generalized three spikes-and-wave per second that were abolished after intravenous diazepam. Ceftazidime-related NCSE was suggested and ceftazidime therapy was stopped. Hemodialysis was done while phenytoin was also given to control the convulsions. Her consciousness improved after hemodialysis. Serum ceftazidime measured before and after hemodialysis on the second and third day were 105.2/39.4, 36.2/5.2 microg/mL (normal peak level 55 microg/mL), respectively. Repeated evaluation on day 6 showed normal EEG without epileptiform activity. She was later discharged with full recovery.

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.

Non-BMPR2 mutation heritable pulmonary arterial hypertension in Southeast Asia.

A 29-year-old Thai man presented with progressive dyspnea and evidence of pulmonary hypertension. Computed tomography was negative for pulmonary embolism. Cardiac catheterization confirmed the diagnosis of pulmonary arterial hypertension (mean pulmonary artery pressure 54 mm Hg, left ventricular end-diastolic pressure 4 mm Hg, and pulmonary vascular resistance 25 Wood units) without an intracardiac shunt. Two family members had been previously diagnosed with pulmonary hypertension. There was no evidence of left heart disease or respiratory disorders. Based on the definite diagnosis of pulmonary hypertension in 3 family members, heritable pulmonary arterial hypertension was confirmed. Genetic testing indicated no BMPR2 mutation.

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.