Periarticular Injection of Ketorolac Augmenting Intravenous Administration of Ketorolac for Postoperative Pain Control: A Randomized Controlled Trial in Simultaneous Bilateral Total Knee Arthroplasty.

Adequate postoperative pain control with minimal side effects is necessary for patients undergoing total knee arthroplasty (TKA). Ketorolac is a frequently used nonsteroidal anti-inflammatory drug due to its excellent disposition in all administration routes; however, it possesses an "analgesic ceiling," which means that higher doses of the drug have no additional analgesic effect. Alternatively, increasing the local concentration of ketorolac via periarticular injection may provide additional pain relief to parenteral administration of ketorolac, but evidence demonstrating the benefits and safety of this approach is limited. Therefore, this study assesses whether local ketorolac injection could yield additional pain reduction to intravenous administration of ketorolac. A total of 54 patients who underwent simultaneous bilateral TKA were enrolled. Randomization was performed to determine whether 50 mg of bupivacaine plus 30 mg of ketorolac (ketorolac group), or only 50 mg bupivacaine (bupivacaine group) would be periarticularly injected into the first knee operated on (more painful), and then the contralateral knee would receive another mixture. Ketorolac (30 mg) was intravenously given every 8 hours for the first 48 hours. Visual analog scales (VASs) were used to assess pain, knee recovery function, and patients' preferred knee. Postoperative VAS pain scores in the ketorolac group were lower than those in the bupivacaine group 6 to 96 hours postoperatively and reached statistical significance 12 (4.25 ± 2.38 vs. 5.06 ± 2.48, respectively; p = 0.04) and 24 hours (4.22 ± 1.94 vs. 5.30 ± 2.12, respectively; p < 0.01) postoperatively. The ketorolac group had higher degrees of knee flexion and straight leg raise. No patient experienced adverse effects of ketorolac. On the day of discharge, 61.11% of the patients favored the knee that received local ketorolac injection (p < 0.01). Adjunct local ketorolac injection to systemic administration is well tolerated and may improve its analgesic effect as determined by the patients' perception.

Predictive Performance of Published Tacrolimus Population Pharmacokinetic Models in Thai Kidney Transplant Patients.

BACKGROUND AND OBJECTIVE: Tacrolimus is a narrow therapeutic index drug with high pharmacokinetic variability, and several tacrolimus population pharmacokinetic (PopPK) models were developed to guide individualized drug dosing. These models, however, may not perform well in other clinical settings. Therefore, we aimed to assess the predictive ability of published tacrolimus PopPK models using a dataset of Thai kidney transplant patients. METHODS: The external dataset was retrospectively collected from medical records of Bhumibol Adulyadej Hospital, Thailand. Published tacrolimus PopPK models were systematically searched from PubMed, Science Direct, CINAHL Complete, and Scopus databases. Models conducted using a nonlinear mixed-effects approach with covariate resemblance to our external dataset were selected. The external dataset consisted of Thai kidney transplant patients receiving oral immediate- or extended-release tacrolimus formulations twice or once daily, respectively. Accuracy and precision of predicted concentrations were evaluated using mean absolute prediction error (MAPE), root mean square error (RMSE), and goodness of fit plots. RESULTS: Only three models produced acceptable population predictions with the MAPE of < 50%. By using the Bayesian posthoc estimate of individual pharmacokinetic parameters, all models well performed with the MAPE and RMSE of < 30% and 40%, respectively, except two models; one could not successfully converge and the other substantially underpredicted tacrolimus concentrations. CONCLUSION: We evaluated ten tacrolimus PopPK models, and eight models resulted in satisfactorily individual predicted tacrolimus concentrations in Thai kidney transplant patients and may be used to aid tacrolimus dose adjustment along with a clinical judgment.

Development of a Physiologically Based Pharmacokinetic Model of Mitragynine, Psychoactive Alkaloid in Kratom (Mitragyna Speciosa Korth.), In Rats and Humans.

Mitragynine is a major psychoactive alkaloid in leaves of kratom (Mitragyna speciosa Korth.). To understand its disposition in organs, this study aimed to develop a physiologically based pharmacokinetic (PBPK) model that predicts mitragynine concentrations in plasma and organ of interests in rats and humans. The PBPK model consisted of six organ compartments (i.e. lung, brain, liver, fat, slowly perfused tissues, and rapidly perfused tissue). From systematic searching, three pharmacokinetic studies of mitragynine (two studies in rats and 1 study in humans) were retrieved from the literature. Berkeley Madonna Software (version 8.3.18) was used for model development and model simulation. The developed PBPK model consisted of biologically relevant features following involvement of (i) breast cancer-resistant protein (BCRP) in brain, (ii) a hepatic cytochrome P450 3A4 (CYP3A4)-mediated metabolism in the liver, and (iii) a diffusion-limited transport in fat. The simulations adequately describe simulated and observed data in the two species with different dosing regimens. PBPK models of mitragynine in rats and humans were successfully developed. The models may be used to guide optimal mitragynine dosing regimens.

The diagnostic accuracy of isothermal nucleic acid point-of-care tests for human coronaviruses: A systematic review and meta-analysis.

Many recent studies reported coronavirus point-of-care tests (POCTs) based on isothermal amplification. However, the performances of these tests have not been systematically evaluated. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy was used as a guideline for conducting this systematic review. We searched peer-reviewed and preprint articles in PubMed, BioRxiv and MedRxiv up to 28 September 2020 to identify studies that provide data to calculate sensitivity, specificity and diagnostic odds ratio (DOR). Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was applied for assessing quality of included studies and Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) was followed for reporting. We included 81 studies from 65 research articles on POCTs of SARS, MERS and COVID-19. Most studies had high risk of patient selection and index test bias but low risk in other domains. Diagnostic specificities were high (> 0.95) for included studies while sensitivities varied depending on type of assays and sample used. Most studies (n = 51) used reverse transcription loop-mediated isothermal amplification (RT-LAMP) to diagnose coronaviruses. RT-LAMP of RNA purified from COVID-19 patient samples had pooled sensitivity at 0.94 (95% CI: 0.90-0.96). RT-LAMP of crude samples had substantially lower sensitivity at 0.78 (95% CI: 0.65-0.87). Abbott ID Now performance was similar to RT-LAMP of crude samples. Diagnostic performances by CRISPR and RT-LAMP on purified RNA were similar. Other diagnostic platforms including RT- recombinase assisted amplification (RT-RAA) and SAMBA-II also offered high sensitivity (> 0.95). Future studies should focus on the use of un-bias patient cohorts, double-blinded index test and detection assays that do not require RNA extraction.

HLA genotypes and cold medicine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications: a systematic review and meta-analysis.

Serious cutaneous adverse drug reactions [i.e., SJS/TEN with severe ocular complications (SOC)] associated with cold medicine (CM) were reported in several studies. To assess the risks of CM-induced SJS/TEN with SOC, systematic review and meta-analysis were employed. Studies investigating associations between HLA genotypes and CM-induced SJS/TEN with SOC were systematically searched in PubMed, Scopus and the Cochrane Library. Overall odds ratios (ORs) with 95% CIs were calculated using a random-effects model to determine these associations. An initial search of the databases identified 24,011 articles, of which 6 studies met the inclusion criteria. In total from all studies, associations between 81 different HLA genotypes and CM-induced SJS/TEN with SOC (i.e., 22 different HLA-A genotypes, 40 different HLA-B genotypes and 19 different HLA-C genotypes) were investigated. Risk factors to develop SJS/TEN with SOC in patients who used CM were identified from our meta-analysis. HLA-A*0206 (OR = 3.90; 95% CI = 1.96-7.77), HLA-A*3303 (OR = 2.28; 95% CI = 1.31-3.97), HLA-B*4403 (OR = 3.27; 95% CI = 1.52-7.03) and HLA-C*0501 (OR = 2.55; 95% CI = 1.19-5.44) were associated with CM-induced SJS/TEN with SOC. With our results demonstrating a significant association between using of CMs and the severe ADR, a genetic testing can be helpful. However, the CMs are commonly used as an over-the-counter drug in practically almost of people in populations worldwide, the genetic screening prior to use of the CMs might not be cost-effective. Nonetheless, for people with a family history of developing the ADRs with a possible involvement of CMs, a genetic screening may be beneficial.

External evaluation of a published population pharmacokinetic model of valproic acid in Thai manic patients.

Objective: To evaluate external predictability of a population pharmacokinetic model of valproic acid in Thai patients with mania to ensure its appropriateness for use in other clinical settings. Methods: The published population pharmacokinetic model was evaluated for its predictive ability (at both individual and population levels) and its precision by means of mean absolute prediction error (MAPE), root mean square error (RMSE) and normalised prediction distribution error (NPDE). Results: Forty-six steady-state serum valproic acid concentration levels from 30 manic patients were retrospectively collected from routine therapeutic drug monitoring at Srithanya Hospital, Thailand. For the prediction-based diagnostics, the MAPE and RMSE were 10.44% (95% CI 8.12% to 12.76%) and 12.99% (95% CI 9.51% to 15.72%), respectively, suggesting that the proposed model was relatively predictive and had a good precision. In simulation-based diagnostics, the NPDE results also showed that the model appropriately predicted valproic acid concentration levels, as indicated by a normal distribution of NPDEs with a mean and a variance of 0 and 1, respectively. Conclusion: The predictability of the population pharmacokinetic model of valproic acid in Thai patients with mania was confirmed. This model could be applied in other clinical settings.

A Δ9-Tetrahydrocannabinol Physiologically-Based Pharmacokinetic Model Development in Humans.

BACKGROUND AND OBJECTIVE: ∆9-Tetrahydrocannabinol (THC) exhibits several therapeutic effects, such as analgesics, anti-emetic, antispastic, and muscle relaxation properties. Knowledge concerning THC disposition in target organs is crucial for THC therapy. The objective of this study was to develop a physiologically-based pharmacokinetic (PBPK) model of THC in humans to characterize tissue-specific pharmacokinetics of THC in organs of interest. METHODS: The model was extrapolated from the previously developed PBPK model conducted in mice, rats, and pigs. The model consisted of seven compartments: brain, lungs, liver, kidneys, fat, and rapidly perfused and slowly perfused tissues. P-glycoprotein was included in the brain compartment to characterize an efflux of THC from the brain. Physiologic, biochemical, and physicochemical parameters were determined and acquired from the literature. Model validation was performed by comparisons of the predicted and observed THC concentrations acquired from published studies. RESULTS: The developed PBPK model resulted in good agreement between the predicted and observed THC concentrations across several studies conducted following IV bolus, IV infusion, oral, and smoking and inhalation, with the coefficient of determination (R2) ranging from 0.54 to 0.95. CONCLUSIONS: A PBPK model of THC in humans was developed. The model could describe THC concentration-time profiles in several dosing scenarios (i.e., IV bolus, IV infusion, oral administration and inhalation).

Development of a Physiologically-Based Pharmacokinetic Model of Δ9-Tetrahydrocannabinol in Mice, Rats, and Pigs.

BACKGROUND AND OBJECTIVE: There has been an increase in the use of cannabis. Delta-9-tetrahydrocannabinol, (THC) is the major psychoactive compound, which has both therapeutic and narcotic effects. THC pharmacokinetics are important for designing optimal dosing regimens, and physiologically-based pharmacokinetic (PBPK) models are used to predict a compound's actions in target organs. Extrapolation of the model from animals to humans can be applied for predicting THC exposure in humans. Here, we aimed to develop a PBPK model of THC in mice, rats, and pigs. METHODS: A PBPK model of THC in mice, rats, and pigs was developed based on seven compartments, i.e., lungs, brain, fat, kidneys, liver, and rapidly perfused and slowly perfused tissues. A flow-limited model was employed to explain THC distribution across tissues. Physiological parameters (i.e., organ blood flows and organ volumes, and biochemical as well as physicochemical parameters, were acquired from the literature. Qualification of the model was assessed based on agreement between simulated and observed THC concentrations. RESULTS: The developed PBPK model consisted of the seven compartments with P-glycoprotein involvement in the brain satisfactorily explained the observed data acquired from three studies. Although some under- and over-predictions exist, the model adequately captured the behavior of the observed data from all three species, with the coefficient of determination (R2) ranging from 0.47 to 0.99. CONCLUSIONS: A PBPK model of THC in mice, rats, and pigs was successfully developed and validated. This model can be further applied for inter-species extrapolation to humans.

HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity: a systematic review and meta-analysis.

Associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity have been reported. To consolidate the results from all available reports in scientific databases, systematic review and meta-analysis techniques were used to quantify these associations. Studies investigating associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity were systematically searched in PubMed, Human Genome Epidemiology Network, and the Cochrane Library. Primary outcomes were the associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity. Overall odds ratios (ORs) with the corresponding 95%CIs were calculated using a random-effect model to determine the associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity. A clear association between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity was identified in our analyses. The summary OR was 6.23 (95%CI = 4.11-9.45). Similar associations were also found in the subgroup analyses by lapatinib treatment regimens. ORs were 10.04 (95%CI = 6.15-16.39), 8.65 (95%CI = 4.52-16.58), and 3.88 (95%CI = 2.20-6.82) in the lapatinib group, lapatinib + trastuzumab group, and lapatinib + chemotherapy or lapatinib + trastuzumab + chemotherapy group, respectively. Since HLA-DRB1*07:01 is associated with lapatinib-induced hepatotoxicity, genetic screening of HLA-DRB1*07:01 in breast cancer patients prior to lapatinib therapy is warranted for patient safety. In addition, further studies should define the risk of HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity in specific ethnicities.

Human continuous hydrogen cyanide inhalation predictor with a physiologically based pharmacokinetic (PBPK) model.

Hydrogen cyanide (HCN) is volatile and highly toxic with acute and chronic effects on humans. Gaseous HCN enters the atmosphere from natural processes or industrial activities, which lead to human exposure. Effective intervention in cases of HCN inhalation requires an efficient diagnostic tool. The existing physiologically based pharmacokinetic (PBPK) model for HCN cannot clearly simulate continuous HCN inhalation or predict HCN levels in inhaled air. The current study presents a PBPK model for continuous inhalation of HCN, called Human Continuous Cyanide Inhalation Predictor (HCCIP). Since existing data on pharmacokinetics of HCN inhalation are limited, HCCIP utilizes extensive data from the current authors' PBPK model on cyanide ingestion. The structure of HCCIP comprises the lungs, kidneys, liver, and slowly perfused tissue. In both the human body and in exhaled air, HCCIP features the ability to predict concentration-time courses of cyanide. Moreover, HCCIP can predict HCN concentration in inhaled air from known blood cyanide levels. After completion, the results of HCCIP were validated against preexisting published datasets. The simulation results agreed with these datasets, validating the model. The HCCIP model is an effective tool for assessing risk from continuous HCN inhalation, and HCCIP extends the capabilities of air dispersion modeling, such as AERMOD or CALPUFF, to assess HCN risk from specific release sources.

Assessing potential hydrogen cyanide exposure from cyanide-contaminated mine tailing management practices in Thailand's gold mining.

This study assessed the effectiveness of the current cyanide management practice of a large gold mine as a case study of Thailand's cyanide-contaminated mine waste management policy. Most gold mines worldwide use cyanide to extract gold from ore, and various cyanide compounds, including hydrogen cyanide (HCN), are then discharged into a tailing storage facility (TSF). From there, HCN volatizes into the air, and people inhaling HCN can experience chronic, acute, or even fatal effects. Although recently only two gold mines operated in Thailand, many new gold mines are under consideration for future. Unfortunately, no specific government regulations for cyanide-contaminated mine waste management exist besides guidelines from environmental impact assessments prepared by the gold mines themselves. This raises concerns that cyanide volatilization may threaten public health. The current study addresses the need for vital scientific analysis by applying AERMOD modeling to simulate HCN dispersion from the gold mine studied, under 20 scenarios of various pH levels and cyanide concentrations. The results show that the HCN emissions cause acute effects to the public under most scenarios. Chronic effects also occur in scenarios of low pH or high cyanide concentration; however, no simulation showed fatalities. This study determined an acceptable cyanide concentration in TSF that is low enough to theoretically avoid dangerous public exposure. Results show that the mine's recent cyanide discharge limit of 20 mg/l, set by the mine itself, is not safe. To limit dangers from the mine's HCN emissions, cyanide levels in tailings must be carefully calculated and regulated using the HCN dispersion model, being sure to account for pH.

Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (Mitragyna speciosa): A systematic review.

BACKGROUND AND OBJECTIVE: Kratom (Mitragyna speciosa) is a tropical tree found in southern Thailand and northern states of the Malay Peninsula. Kratom is commercially available and used as an alternative to treat opioid withdrawal. Mitragynine is the major indole alkaloid found in kratom leaves. This review aimed to summarize available pharmacokinetic information about mitragynine. METHODS: PubMed, Scopus, and Web of Science were systematically searched from their inceptions to June 2018. All types of pharmacokinetic studies of mitragynine were included for further systematic review. RESULTS: Seventeen articles were reviewed. Mitragynine is a lipophilic weak base passively transported across the intestinal wall and blood brain barrier. 85-95% is bound to plasma protein and extensively metabolized by phase I and particularly phase II enzymes. Actions on CYP enzymes are unlikely to impact drug metabolism at concentrations likely to exist in kratom-consuming humans. In rats and humans, mitragynine is rapidly absorbed after orally administration (Tmax˜1.5 h, Cmax˜0.3-1.8 µM). Vd was 37-90 L/kg; t1/2 was 3-9 hr; mostly excreted as metabolites in urine. Bioavailability was estimated as 21%. It also rapidly penetrated and redistributed in brain. A quality assessment tool tailored for pharmacokinetic studies was also created which rated some studies of lower value. CONCLUSION: Rudimentary pharmacokinetics of mitragynine was described in this systematic review. However, the discovered studies provided scant information on the role of metabolism and redistribution into tissues nor the rate of excretion.

Paraquat exposure and Parkinson's disease: A systematic review and meta-analysis.

To reconcile and unify available results regarding paraquat exposure and Parkinson's disease (PD), we conducted a systematic review and meta-analysis to provide a quantitative estimate of the risk of PD associated with paraquat exposure. Six scientific databases including PubMed, Cochrane libraries, EMBASE, Scopus, ISI Web of Knowledge, and TOXLINE were systematically searched. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. Of 7,309 articles identified, 13 case control studies with 3,231 patients and 4,901 controls were included into our analysis. Whereas, one prospective cohort studies was included into our systematic review. A subsequent meta-analysis showed an association between PD and paraquat exposure (odds ratio = 1.64 (95% CI: 1.27-2.13; I2 = 24.8%). There is a statistically significant association between paraquat exposure and PD. Thus, future studies regarding paraquat and Parkinson's disease are warranted.

Association between HLA-B*5901 and methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.

Methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening adverse drug reactions. Based on previous studies, HLA genotypes may play an important role in methazolamide-induced SJS/TEN. Therefore, to identify the associations between HLA genotypes and methazolamide-induced cutaneous adverse drug reactions (cADRs) (i.e., SJS/TEN and hypersensitivity syndrome), a systematic review and meta-analysis were performed. Two studies (one study in Korean and another in Han Chinese) met the inclusion criteria. The studies included 13 patients with methazolamide-induced SJS/TEN, 30 methazolamide-tolerant, and 768 population controls. Associations between HLA-B*5901, HLA-B*5901-Cw*0102 haplotype, and methazolamide-induced SJS/TEN were identified in methazolamide-tolerant and population controls. Overall ORs were 305.0 (95% CI = 11.3-8, 259.4) in methazolamide-tolerant and 715.3 (95% CI = 83.1-6,158.5) in population control. In addition, statistically significant associations between the HLA-Cw*0102 and methazolamide-induced SJS/TEN were found in methazolamide-tolerant (OR = 12.1; 95% CI = 1.3-111.7) and population control (OR = 17.5; 95% CI = 3.2-96.6). Since HLA-B*5901 and HLA-B*5901-Cw*0102 haplotype are associated with methazolamide-induced SJS/TEN, genetic screening prior to methazolamide therapy in Asian populations is warranted.

Association Between HLA-B*1301 and Dapsone-Induced Cutaneous Adverse Drug Reactions: A Systematic Review and Meta-analysis.

Importance: Dapsone-induced hypersensitivity syndrome (DHS) is a life-threatening adverse drug reaction. Based on available epidemiologic studies, HLA genotypes may play an important role in DHS. Objective: To assess the association between HLA-B*1301 and dapsone-induced cutaneous adverse drug reactions (cADRs). Data Sources: Human studies investigating associations between HLA-B*1301 and dapsone-induced cADRs were systematically searched without language restriction from the inception of each database until September 12, 2017, in PubMed, the Human Genome Epidemiology Network), and the Cochrane Library. Combinations of HLA genotypes, dapsone, and synonymous terms were used; reference lists were searched in selected articles. Study Selection: Two reviewers identified studies investigating the associations between HLA-B*1301 and dapsone-induced cADRs that reported sufficient data for calculating the frequency of HLA-B*1301 carriers among case and control patients, in which all patients received dapsone before HLA-B*1301 screening. An initial search of the databases identified 391 articles, of which 3 studies (2 in Chinese populations and 1 in a Thai population) met the inclusion criteria. Data Extraction and Synthesis: Overall odds ratios (ORs) with 95% CIs were calculated using a random-effects model to determine the association between HLA-B*1301 and dapsone-induced cADRs. Subgroup analyses by type of cADR were also performed. PRISMA guidelines were used to abstract and assess data. Main Outcomes and Measures: Primary outcomes were associations between HLA-B*1301 and dapsone-induced cADRs in dapsone-tolerant controls. The outcomes are reported as overall OR. Statistical heterogeneity was assessed using the Q statistic and I2 tests. Results: From the 3 included studies, there were 111 unique patients with dapsone-induced cADRs (subsequently used in the meta-analysis), 1165 dapsone-tolerant patients, and 3026 healthy controls. The cases included 64 men and 49 women (2 patients were missing from the meta-analysis; 1 each from 2 of the 3 studies); mean age was 39.7 years. An association between HLA-B*1301 and dapsone-induced cADRs was identified (summary OR, 43.0; 95% CI, 24.0-77.2). Subgroup analyses among types of cADRs produced similar findings in DHS (OR, 51.7; 95% CI, 16.9-158.5), dapsone-induced severe cADRs (Stevens-Johnson syndrome and toxic epidermal necrolysis [SJS/TEN] plus drug rash [adverse skin reaction to a drug] along with eosinophilia and systemic symptoms [DRESS]) (OR, 54.0; 95% Cl, 8.0-366.2), dapsone-induced SJS/TEN (OR, 40.5; 95% CI, 2.8-591.0), and dapsone-induced DRESS (OR, 60.8; 95% CI, 7.4-496.2). There was no heterogeneity (I2 = 0%, P = .38). Conclusions and Relevance: Associations between HLA-B*1301 and dapsone-induced cADRs were found in dapsone-tolerant and healthy control groups. For patient safety, genetic screening for HLA-B*1301 in Asian populations before dapsone therapy is warranted.

Association Between HLA genotypes and Oxcarbazepine-induced Cutaneous Adverse Drug Reactions: A Systematic Review and Meta-Analysis.

PURPOSE: To systematically review and quantitatively synthesize associations between HLA genotypes and oxcarbazepine-induced cutaneous adverse drug reactions (OXC-cADRs), including Stevens-Johnson syndrome (SJS) and maculopapular rash. METHODS: Studies investigating associations between HLA genotypes and OXC-cADRs were systematically searched irrespective of language, in PubMed, HuGENet (Human Genome Epidemiology Network), and the Cochrane Library from their inception until January, 2017. Inclusion criteria were studies investigating associations between HLA genotypes and OXC-cADRs that reported sufficient data for calculating the frequency of HLA genotype carriers among cases and controls. Overall odds ratios (ORs) with corresponding 95%CIs were calculated using a random-effects model to determine the association between HLA genotypes and OXC-cADRs.  RESULTS: The initial searches identified 91 articles, of which 6 studies met the selection criteria. The studies included 229 patients with OXC-cADRs, 251 OXC-tolerant patients, and 2,358 participants from general populations of Han Chinese, Korean, and Thai ethnicities.  Associations between HLA-B*1502 and OXC-induced SJS were found in both the general population [OR=30.2 (95%CI=3.45-264)] and in OXC-tolerant individuals [OR=26.4 (95%CI=7.98-87.6)]. An association between the HLA-B*1502 and OXC-induced maculopapular rash was found in the general population [OR=5.67 (95%CI=2.03-15.9)] while HLA-A*3101 also associated with OXC-induced maculopapular rash [overall OR=29.2 (95%CI=6.70-128)].  CONCLUSIONS: Strong associations between the HLA-B*1502 and OXC-cADRs (SJS and maculopapular rash) were found in both controls from general population and OXC-tolerant groups. There was also an association between HLA-B*3101 and OXC-induced maculopapular rash. For patient safety, genetic screening especially for HLA-B*1502 prior to OXC therapy at least in these closely related ethnicities is warranted. Further studies need to better define other ethnicities at risk and a wider range of MHC gene subtypes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

A pharmacokinetic model of drug-drug interaction between clopidogrel and omeprazole at CYP2C19 in humans.

BACKGROUND: Clopidogrel is a thienopryridine antiplatelet agent commonly used in the management of cardiovascular diseases. Clopidogrel is metabolized by hepatic CYP2C19 and CYP2B6, therefore, co-administration of clopidogrel and CYP2C19 inhibitors can alter pharmacokinetics of clopidogrel. Omeprazole is a proton pump inhibitor used for decreasing gastric acid production. Omeprazole is known to be a potent inhibitor of CYP2C19. Thus when the drugs are simultaneously administered, clopidogrel plasma concentration levels can be increased. However, plasma levels of the active metabolite of clopidogrel can be significantly decreased, thereby, its antiplatelet activity is reduced. OBJECTIVES: We aimed to develop a mathematical model describing a drug-drug interaction between clopidogrel and omeprazole in humans. METHODS: Searching for pharmacokinetic interaction studies between clopidogrel and omeprazole in humans was performed in PubMed. Six studies were selected into our modeling purposes to develop 3 mathematical models (i.e. 4 studies for clopidogrel alone, 1 study for omeprazole alone and 1 study for clopidogrel-omeprazole interaction). Subsequently, concentration-time course data from the selected studies were extracted. Computer codes and simulations were performed using the Advanced Continuous Simulating Language Extreme (ACSLX) program. RESULTS: We successfully developed 3 mathematical models which are able to describe all of the datasets. CONCLUSIONS: Our clopidogrel-omeprazole pharmacokinetic interaction model with a description of competitive inhibition at CYP2C19 could successfully describe concentration-time courses from the selected datasets. Our interaction model may be useful in predicting plasma levels of clopidogrel and its active metabolite.

A physiologically-based pharmacokinetic model of methotrexate incorporating hepatic excretion via multidrug-resistance-associated protein 2 (Mrp2) in mice, rats, dogs, and humans.

An updated physiologically-based pharmacokinetic (PBPK) model of methotrexate (MTX) was built based on an earlier model developed by Bischoff et al. (1971). MTX has been known to be a substrate of multidrug-resistance-associated protein 2 (Mrp2). A three-dimensional quantitative structure-activity relationship model (3D-QSAR) of Mrp2 was developed by Hirono et al. (2005). In our updated PBPK model of MTX, using the computational chemistry-derived binding affinity (Km), a Mrp2-mediated biliary excretion process was incorporated as the MTX excretory pathway. Our model simulation results are consistent with numerous datasets obtained from mice, rats, dogs, and humans, at a variety of dose levels. Comparisons were made between our updated PBPK model and the earlier one from Bischoff et al. using a PBPK Index approach. Our new PBPK model was further verified against additional pharmacokinetic datasets from rats under special experimental conditions (cannulated bile duct) and Eisai hyperbirilubinemic rats.

Development of a physiologically based pharmacokinetic model of paraquat.

Paraquat (N, N'-dimethyl-4,4'-bipyridium dichloride) is a potent and widely used herbicide in agricultural countries, including Thailand. The presence of this chemical in the body can lead to toxic effects in the liver, kidney, and lung. Pulmonary toxicity has been identified as the main cause of acute toxicity in animals and humans. Chronic exposure to paraquat is associated with Parkinson's disease in humans. Paraquat is transported into the lungs by neutral amino acid transporter. Therefore, a physiologically based pharmacokinetic (PBPK) model of paraquat was developed with a description of the protein transporter mechanism. To develop a PBPK model of paraquat, a pharmacokinetic study of paraquat in rats was selected from the ThaiLIS and Pubmed database. The selected study contained tissue-specific concentration-time course information such as paraquat concentration levels in liver, kidney and lung. Physiologic parameters were acquired from the literature or determined using a Markov-Chain Monte Carlo (MCMC) technique. The developed PBPK model consisted of 5 organ compartments (i.e. kidney, liver, slowly perfused organs, richly perfuse organs and lung), featuring an incorporation of neutral amino acid transporter in the lung. Our model simulations could explain the data from the literature and adequately describe pharmacokinetics of paraquat in the rats. This developed PBPK model may be able help in understanding of paraquat-induced Parkinson's disease as well as in risk assessment of paraquat.

Additive Synergism between Asbestos and Smoking in Lung Cancer Risk: A Systematic Review and Meta-Analysis.

Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31-2.21), (ii) 5.65; (A-S+, 3.38-9.42), (iii) 8.70 (A+S+, 5.8-13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26-1.77) and the multiplicative index = 0.91 (95% CI = 0.63-1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00-1.28) and 0.51 (95% CI = 0.31-0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits.