Large-scale cross-ancestry genome-wide meta-analysis of serum urate.

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

Prevalence and Associations Between Metabolic Syndrome Components and Hyperuricemia by Race: Findings From US Population, 2011-2020.

OBJECTIVE: We explored the trend in prevalence of hyperuricemia and metabolic syndrome in US populations and investigated associations between components of metabolic syndrome and hyperuricemia by race. METHODS: We analyzed data from the four most recent National Health and Nutrition Examination Survey (NHANES) cycles (2011 to March 2020), comprising 10,175 participants. Hyperuricemia is defined as serum urate >7.0 mg/dL (men) or >5.7 mg/dL (women), following the NHANES-III guideline. The definition of metabolic syndrome follows the National Cholesterol Education Program's Adult Treatment Panel III guideline. We estimated the prevalence of metabolic syndrome and hyperuricemia in each cycle and performed subgroup analyses with logistic regression to investigate the patterns of associated components of metabolic syndrome with hyperuricemia. RESULTS: In the most recent cycle (2017 to March 2020), the prevalence of metabolic syndrome was 45.9% and that of hyperuricemia was 20.7%. Over the 2011 to 2020 period, a significant rise in metabolic syndrome prevalence was observed among Hispanic and Asian populations, and the prevalence of hyperuricemia has increased significantly only in the Hispanic population. After adjustment for confounding factors, patients with metabolic syndrome exhibited a higher hyperuricemia in women than in men. Elevated blood pressure was the strongest factor with hyperuricemia. The association was the weakest in the Asian population. Waist circumference was the only significant factor associated with hyperuricemia in the Asian population. CONCLUSION: The prevalence of metabolic syndrome has an increasing pattern, but there was no specific decadal trend in prevalence of hyperuricemia. There is an ethnicity-specific association of metabolic syndrome and hyperuricemia, especially among Asians.

Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval.

The global research and pharmaceutical community rapidly mobilized to develop treatments for coronavirus disease 2019 (COVID-19). Existing treatments have been repurposed and new drugs have emerged. Here we summarize mechanisms and clinical trials of COVID-19 therapeutics approved or in development. Two reviewers, working independently, reviewed published data for approved COVID-19 vaccines and drugs, as well as developmental pipelines, using databases from the following organizations: United States Food and Drug Administration (US-FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Medical Devices Agency (PMDA), and ClinicalTrials.gov. In all, 387 drugs were found for initial review. After removing unrelated trials and drugs, 66 drugs were selected, including 17 approved drugs and 49 drugs under development. These drugs were classified into six categories: 1) drugs targeting the viral life cycle 2) Anti-severe acute respiratory syndrome coronavirus 2 Monoclonal Antibodies, 3) immunomodulators, 4) anti-coagulants, 5) COVID-19-induced neuropathy drugs, and 6) other therapeutics. Among the 49 drugs under development are the following: 6 drugs targeting the viral life cycle, 12 immunosuppression drugs, 2 immunostimulants, 2 HIF-PHD targeting drugs, 3 GM-CSF targeting drugs, 5 anti-coagulants, 2 COVID-19-induced neuropathy drugs, and 17 others. This review provides insight into mechanisms of action, properties, and indications for COVID-19 medications.

The in-silico evaluation of important GLUT9 residue for uric acid transport based on renal hypouricemia type 2.

Uric acid is the end product of purine metabolism. Uric acid transporters in the renal proximal tubule plays a key role in uric acid transport. Functional abnormalities in these transporters could lead to high or low levels of uric acid in the blood plasma, known as hyperuricemia and hypouricemia, respectively. GLUT9 has been reported as a key transporter for uric acid reuptake in renal proximal tubule. GLUT9 mutation is known as causal gene for renal hypouricemia due to defective uric acid uptake, with more severe cases resulting in urolithiasis and exercise induced acute kidney injury (EIAKI). However, the effect of mutation is not fully investigated and hard to predict the change of binding affinity. We comprehensively described the effect of GLUT9 mutation for uric acid transport using molecular dynamics and investigated the specific site for uric acid binding differences. R171C and R380W showed the significant disruption of the structure not affecting transport dynamics whereas L75R, G216R, N333S, and P412R showed the reduced affinity of the extracellular vestibular area towards urate. Interestingly, T125 M showed a significant increase in intracellular binding energy, associated with distorted geometries. We can use this classification to consider the effect mutations by comparing the transport profiles of mutants against those of chemical candidates for transport and providing new perspectives to urate lowering drug discovery using GLUT9.

Review of Urate-Lowering Therapeutics: From the Past to the Future.

We reviewed all currently available ULT, as well as any medications in development using following databases: United States Food and Drug Administration (FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Medical Devices Agency (PMDA), and ClinicalTrials.gov. We identified a total of 36 drugs, including 10 approved drugs, 17 in clinical testing phases, and 9 in preclinical developmental phases. The 26 drugs currently undergoing testing and development include 5 xanthine oxidase inhibitors, 14 uricosurics, 6 recombinant uricases, and one with multiple urate-lowering mechanisms of action. Herein, we reviewed the benefit and risk of each drug summarizing currently available drugs. New trials of uricosuric agents are underway to develop the new indication. New drugs are going on to improve the potency of recombinant uricase and to develop the new route administration of such as oral formulation. This review will provide valuable information on the properties, indications, and limitations of ULTs.

Efficacy of Xanthine Oxidase Inhibitors in Lowering Serum Uric Acid in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Objective: Current guidelines for gout recommend a treat-to-target approach with serum uric acid (SUA). However, there is little evidence for the dose-dependent effects of urate-lowering therapy (ULT). Herein, we analyzed the reported SUA-lowering effect and SUA target achievement differences for various doses of xanthine oxidase inhibitors. Methods: Approved ULT drugs were selected from the FDA Drug Database. We included prospective randomized controlled trials of ULT drugs from ClinicalTrials.gov, articles published in the journal "Drugs", and Embase, a literature database. A meta-analysis was performed to determine the ability of different ULT drugs and doses to lower and maintain a target SUA < 6 mg/dL. Results: We identified 35 trials including 8172 patients with a baseline SUA of 8.92 mg/dL. The allopurinol, febuxostat, and topiroxostat showed dose-proportional SUA-lowering responses. Compared with allopurinol 300 mg daily, febuxostat 80 mg daily and 120 mg daily more effectively maintained SUA < 6 mg/dL. Conclusion: Allopurinol, febuxostat, and topiroxostat showed dose-proportional ability to lower and achieve a target SUA < 6 mg/dL. Significance and Innovations. We showed dose-dependent SUA lowering effects of allopurinol, febuxostat, and topiroxostat. Febuxostat is effective at ULT compared to allopurinol and could be potentially offered as an alternative agent when patients (1) have CKD, (2) have the human leukocyte antigen HLA-B*5801 allele, and (3) become refractory to allopurinol. Gradual allopurinol dose increase with a lower starting dose is needed in CKD.

Identification of a dysfunctional exon-skipping splice variant in GLUT9/SLC2A9 causal for renal hypouricemia type 2.

Renal hypouricemia (RHUC) is a pathological condition characterized by extremely low serum urate and overexcretion of urate in the kidney; this inheritable disorder is classified into type 1 and type 2 based on causative genes encoding physiologically-important urate transporters, URAT1 and GLUT9, respectively; however, research on RHUC type 2 is still behind type 1. We herein describe a typical familial case of RHUC type 2 found in a Slovak family with severe hypouricemia and hyperuricosuria. Via clinico-genetic analyses including whole exome sequencing and in vitro functional assays, we identified an intronic GLUT9 variant, c.1419+1G>A, as the causal mutation that could lead the expression of p.Gly431GlufsTer28, a functionally-null variant resulting from exon 11 skipping. The causal relationship was also confirmed in another unrelated Macedonian family with mild hypouricemia. Accordingly, non-coding regions should be also kept in mind during genetic diagnosis for hypouricemia. Our findings provide a better pathogenic understanding of RHUC and pathophysiological importance of GLUT9.

Renal Hypouricemia 1: Rare Disorder as Common Disease in Eastern Slovakia Roma Population.

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Kosice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon-intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.

Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia.

Renal hypouricemia is a rare genetic disorder. Hypouricemia can present as renal stones or exercise-induced acute renal failure, but most cases are asymptomatic. Our previous study showed that two recessive variants of SLC22A12 (p.Trp258*, pArg90His) were identified in 90% of the hypouricemia patients from two independent cohorts: the Korean genome and epidemiology study (KoGES) and the Korean Cancer Prevention Study (KCPS-II). In this work, we investigate the genetic causes of hypouricemia in the rest of the 10% of unsolved cases. We found a novel non-synonymous mutation of SLC2A9 (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in SLCA9b (p.Met155Val in SLC2A9a) hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using Xenopus oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the SLC2A9 protein expression level. Our results will shed light on a better understanding of SLC2A9-mediated uric acid transport and the development of a uric acid-lowering agent.

Shared Genetic Background between Parkinson's Disease and Schizophrenia: A Two-Sample Mendelian Randomization Study.

Background and objectives: Parkinson's disease (PD) and schizophrenia often share symptomatology. Psychotic symptoms are prevalent in patients with PD, and similar motor symptoms with extrapyramidal signs are frequently observed in antipsychotic-naïve patients with schizophrenia as well as premorbid families. However, few studies have examined the relationship between PD and schizophrenia. We performed this study to evaluate whether genetic variants which increase PD risk influence the risk of developing schizophrenia, and vice versa. Materials and Methods: Two-sample Mendelian randomization (TSMR) with summary statistics from large-scale genome-wide association studies (GWAS) was applied. Summary statistics were extracted for these instruments from GWAS of PD and schizophrenia; Results: We found an increase in the risk of schizophrenia per one-standard deviation (SD) increase in the genetically-predicted PD risk (inverse-variance weighted method, odds ratio = 1.10; 95% confidence interval, 1.05-1.15; p = 3.49 × 10-5). The association was consistent in sensitivity analyses, including multiple TSMR methods, analysis after removing outlier variants with potential pleiotropic effects, and analysis after applying multiple GWAS subthresholds. No relationships were evident between PD and smoking or other psychiatric disorders, including attention deficit hyperactivity disorder, autism spectrum disorder, bipolar affective disorder, major depressive disorder, Alzheimer's disease, or alcohol dependence. However, we did not find a reverse relationship; genetic variants increasing schizophrenia risk did not alter the risk of PD; Conclusions: Overall, our findings suggest that increased genetic risk of PD can be associated with increased risk of schizophrenia. This association supports the intrinsic nature of the psychotic symptom in PD rather than medication or environmental effects. Future studies for possible comorbidities and shared genetic structure between the two diseases are warranted.

Polygenic analysis of the effect of common and low-frequency genetic variants on serum uric acid levels in Korean individuals.

Increased serum uric acid (SUA) levels cause gout and are associated with multiple diseases, including chronic kidney disease. Previous genome-wide association studies (GWAS) have identified more than 180 loci that contribute to SUA levels. Here, we investigated genetic determinants of SUA level in the Korean population. We conducted a GWAS for SUA in 6,881 Korean individuals, calculated polygenic risk scores (PRSs) for common variants, and validated the association of low-frequency variants and PRS with SUA levels in 3,194 individuals. We identified two low-frequency and six common independent variants associated with SUA. Despite the overall similar effect sizes of variants in Korean and European populations, the proportion of variance for SUA levels explained by the variants was greater in the Korean population. A rare, nonsense variant SLC22A12 p.W258X showed the most significant association with reduced SUA levels, and PRSs of common variants associated with SUA levels were significant in multiple Korean cohorts. Interestingly, an East Asian-specific missense variant (rs671) in ALDH2 displayed a significant association on chromosome 12 with the SUA level. Further genetic epidemiological studies on SUA are needed in ethnically diverse cohorts to investigate rare or low-frequency variants and determine the influence of genetic and environmental factors on SUA.

Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes.

Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

Heritability estimates of individual psychological distress symptoms from genetic variation.

BACKGROUND: Psychological distress symptoms are associated with an increased risk of psychiatric disorders and medical illness. Although psychological distress is influenced by environmental factors, such as socioeconomic status, lifetime events, or interpersonal relationships, substantial interindividual variation also exists. However, heritability and genetic determinants of distress are poorly understood. METHODS: In the Korean Genome and Epidemiology Study sample (n = 12,680), we estimated the heritability of individual psychological distress symptoms using the GCTA-REML method and carried out a genome-wide association study of individual psychological distress symptoms showing significant heritability. RESULTS: We found three psychological distress items showing significant heritability: subjective well-being (9%), fatigue and appetite (11%), and enjoying daily life (8%). Additionally, we found genome-wide significant associations of rs6735649 located between STEAP3 and C1QL2 on chromosome 2 with subjective well-being (P = 1.32 × 10-8, odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.12-1.25) and rs35543418 located between SYT16 and KCNH5 on chromosome 14 with enjoying daily life (P = 1.33 × 10-8, OR = 1.59, 95% CI: 1.35-1.86). LIMITATIONS: The lack of replication in independent cohorts and longitudinal assessment of distress may limit generalizability. CONCLUSIONS: Our results indicate that distress symptoms are partly heritable. Further analysis in larger cohorts investigating gene-environment interactions is required to identify genetic variants that explain the proportion of variation in distress.

The Prevalence of Hyperuricemia Sharply Increases from the Late Menopausal Transition Stage in Middle-Aged Women.

The impact of menopausal transition on change of serum uric acid level remains unknown. The present study evaluated the relationship of menopausal stages with prevalent hyperuricemia in middle-aged women. This cross-sectional study included 58,870 middle-aged Korean women, aged ≥40, who participated in a health examination from 2014 to 2016. Menopausal stages were obtained with a standardized, self-administered questionnaire and were categorized according to the criteria of the Stages of Reproductive Aging Workshop (STRAW+10). Hyperuricemia was defined as a serum uric acid level of ≥6 mg/dL. The prevalence of hyperuricemia increased as menopausal stage increased. The multivariable-adjusted odds ratios (95% confidence intervals) for prevalent hyperuricemia comparing early transition, late transition, and post-menopause to pre-menopause were 1.19 (0.80⁻1.77), 2.13 (1.35⁻3.36), and 1.65 (1.33⁻2.04), respectively. This association was stronger among non-obese compared to obese participants and in those with low high-sensitivity C-reactive protein (hsCRP) levels (<1.0 mg/L) compared to those with elevated hsCRP levels of ≥1.0 mg/L (p for interaction = 0.01). In this large sample of middle-aged women, the prevalence of hyperuricemia significantly increased from the menopausal stage of late transition, independent of potential confounders. Appropriate preventive strategies for reducing hyperuricemia and its related consequences should be initiated prior to menopause.

Novel association between CDKAL1 and cholesterol efflux capacity: Replication after GWAS-based discovery.

BACKGROUND AND AIMS: Although the importance of the functional properties of high-density lipoprotein (HDL) has been increasingly emphasized, studies on the genetic factors associated with HDL function are highly limited. The aim of this study was to identify genetic variants associated with an individual's cholesterol efflux capacity (CEC) using a genome-wide association study approach. METHODS: This study included a discovery group of 607 subjects with coronary artery disease and an independent replication group of 158 subjects. CEC was assessed using a radioisotope and ApoB-depleted serum. Genome-wide associations between the adjusted CEC and genotyped and imputed variants were examined with linear regression, assuming an additive genetic model. Finally, adjustments were made for confounding parameters to assess the independence of associations and to determine R2 of overall model on CEC. RESULTS: In the discovery group, 631 variants showed significant association with CEC, and five of them were found to correlate with CEC in the replication group. One of them was located near LOC541471 in 2q13, whereas the other four (rs117835232, rs117252933, rs118064592, and rs150434350) were located in CDKAL1 in 6p22.3. The association between the presence of any CDKAL1 variant and CEC was significant after adjustment for clinical and laboratory variables. High-density lipoprotein-cholesterol levels also showed a very significant association with CEC. Body mass index, current alcohol use, triglycerides levels, low-density lipoprotein-cholesterol levels and statin use showed borderline associations with CEC. CONCLUSIONS: We identified and replicated genetic variants associated with CEC using a genome-wide association study-based approach. CDKAL1 variants showed correlations with CEC independent of HDL-cholesterol levels and other clinical characteristics.

Association between smoking and gout: a meta-analysis.

Previous studies showed that smoking is linked with the decreased risk of gout, but the results remain controversial. The aim of this meta-analysis was to determine the associations between smoking and the risk of gout. A systematic literature search of PubMed and EMBASE was conducted. Data were extracted by two independent reviewers. The pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of associations, using random effects and fixed effects models. Five studies with a total of 17,915,507 participants with 16,880 gouts were enrolled. Heterogeneity among the effect sizes of five studies was reported as I2 = 87.9%. Our meta-analysis indicated that smoking (ever- vs non-, OR = 0.87, 95% CI = 0.67-1.12) was not associated with the risk of gout in random effects model, whereas there was an association between smoking (ever- vs non-, OR = 0.70, 95% CI = 0.65-0.74) and gout risk in fixed effects model. Our finding indicates that smoking may not be involved in the risk of gout. However, further studies are still needed to confirm our results.

U-Shaped Association Between Serum Uric Acid Level and Risk of Mortality: A Cohort Study.

OBJECTIVE: In addition to the controversy regarding the association of hyperuricemia with cardiovascular disease (CVD) mortality, few studies have examined the impact of a low uric acid level on mortality. We undertook the present study to evaluate the relationship between both low and high uric acid levels and the risk of all-cause and cause-specific mortality in a large sample of Korean adults over a full range of uric acid levels. METHODS: A cohort study was performed in 375,163 South Korean men and women who underwent health check-ups from 2002 to 2012. Vital status and cause of death were ascertained from the national death records. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for mortality outcomes were estimated using Cox proportional hazards regression analysis. RESULTS: During a total of 2,060,721.9 person-years of follow-up, 2,020 participants died, with 287 CVD deaths and 963 cancer deaths. Low and high uric acid levels were associated with increased all-cause, CVD, and cancer mortality. The multivariable-adjusted HRs for all-cause mortality in the lowest uric acid categories (<3.5 mg/dl for men and <2.5 mg/dl for women) compared with the sex-specific reference category were 1.58 (95% CI 1.18-2.10) and 1.80 (95% CI 1.10-2.93), respectively. Corresponding HRs in the highest uric acid categories (≥9.5 mg/dl for men and ≥8.5 mg/dl for women) were 2.39 (95% CI 1.57-3.66) and 3.77 (95% CI 1.17-12.17), respectively. CONCLUSION: In this large cohort study of men and women, both low and high uric acid levels were predictive of increased mortality, supporting a U-shaped association between serum uric acid levels and adverse health outcomes.

Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2.

BACKGROUND: VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. Tanibirumab (TTAC-0001) is a fully human IgG1 monoclonal antibody derived from a fully human naïve single-chain variable fragment (ScFv) phage library that was developed to inhibit the effects of VEGF in the treatment of solid tumors, especially those of the brain. METHODS: In the present study, we conducted intravenous pharmacokinetic studies of TTAC-0001 in mice, rats, and cynomolgus monkeys. At the doses studied (3 mg/kg, 10 mg/kg, 30 mg/kg), TTAC-0001 exhibited dose proportionality in mice and monkeys. At a dose of ~10 mg/kg, the clearance of TTAC-0001 from serum was 0.017 mL/h in mice, 0.35 mL/h in rats, and 2.19 mL/h in cynomolgus monkeys, and the terminal half-life ranged from 20-30 h among the three species. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of TTAC-0001 in humans using allometric scaling. The predicted serum clearance of TTAC-0001 in humans was 102.45 mL/h and the terminal half-life was 27.52 h. RESULTS: The maximum life span-corrected clearance value was 72.92 mL/h. The observed clearance in humans was more similar to the predicted scaled clearance. CONCLUSION: We investigated the pharmacokinetics of TTAC-0001 in mice, rats, and cynomolgus monkeys after intravenous administration. At the doses studied, TTAC-0001 exhibited dose proportionality in mice and monkeys. The scaled pharmacokinetics of TTAC-0001 reported here was useful for designing first-in-human studies. Allometric scaling in the therapeutic antibody is feasible.

Caffeic acid, morin hydrate and quercetin partially attenuate sulfur mustard-induced cell death by inhibiting the lipoxygenase pathway.

Sulfur mustard (SM) is an alkylating agent, which has been used as in chemical warfare in a number of conflicts. As the generation of reactive oxygen species (ROS), and adducts in DNA and proteins have been suggested as the mechanism underlying SM­induced cytotoxicity, the present study screened several antioxidant candidates, including tannic acid, deferoxamine mesylate, trolox, vitamin C, ellagic acid and caffeic acid (CA) to assess their potential as therapeutic agents for SM­induced cell death. Among several antioxidants, CA partially alleviated SM­induced cell death in a dose­dependent manner. Although CA treatment decreased the phosphorylation of p38 mitogen­activated protein (MAP) kinase and p53, p38 MAP kinase inhibition by SB203580 did not affect SM­induced cell death. As CA has also been reported as a 15­lipoxygenase (15­LOX) inhibitor, the role of 15­LOX in SM­induced cytotoxicity was also examined. Similar to the results observed with CA, treatment with PD146176, a specific 15­LOX inhibitor, decreased SM­induced cytotoxicity, accompanied by decreases in the production of tumor necrosis factor­α and 15­hydroxyeicosatetraenoic acid. Furthermore, the present study investigated the protective effects of two natural 15­LOX inhibitors, morin hydrate and quercetin, in SM­induced cytotoxicity. As expected, these inhibitors had similar protective effects against SM­induced cytotoxicity. These antioxidants also reduced the generation of ROS and nitrate/nitrite. Therefore, the results of the present study indicated that the natural products, CA, quercetin and morin hydrate, offer potential as adjuvant therapeutic agents for SM­induced toxicity, not only by reducing inflammation mediated by the p38 and LOX signaling pathways, but also by decreasing the generation of ROS and nitrate/nitrite.