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All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) represent the standard of care for low-intermediate risk acute promyelocytic leukaemia (APL). Leucocytosis during induction with ATRA-ATO represents a common complication with an incidence of up to 60%. To identify predictive factors for this complication, we studied a cohort of 65 low-intermediate risk APL patients treated with ATRA-ATO in three highly specialized Italian centres. Overall, 39/65 (60%) patients developed leucocytosis, with a peak in leucocyte count being most frequent in the second week from diagnosis. All cases were successfully managed with hydroxyurea. Predictive factors for leucocytosis in univariate analysis were lower platelet counts (odds ratio [OR] 0.98, 0.97-1.00, p = 0.018), lower fibrinogen levels (OR 0.36, 0.17-0.66, p = 0.003), higher bone marrow blast infiltration (OR 1.03, 1.01-1.07, p = 0.021) and CD117 expression by flow (OR 1.04, 1.01-1.08, p = 0.012). Multivariate analysis confirmed lower levels of fibrinogen at diagnosis as the strongest predictive factor for the development of leucocytosis (OR 0.36, 0.15-0.72, p = 0.009). Differentiation syndrome (DS) occurred only in patients developing leucocytosis showing a strict correlation with rising leucocytes counts (16/39 vs. 0/26, p < 0.001). In addition, other treatment-related complications including QTc prolongation, cardiac events, liver, and haematological toxicities were significantly more frequent in patients experiencing leucocytosis (22/39 vs. 3/26, p < 0.001). In conclusion, APL patients undergoing ATRA-ATO therapy with lower fibrinogen levels and platelet counts at diagnosis and with a massive bone marrow blast infiltrate should be carefully monitored for the development of leucocytosis during induction. DS and other treatment-related complications seem to occur almost exclusively in patients developing leucocytosis, who should necessarily receive DS prophylaxis and more intensive monitoring and supportive therapy to prevent treatment complications., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: From at least the fifteenth to late nineteenth centuries, peasants in the Austrian province of Styria ate up to several hundred milligrams of arsenic trioxide or sulfide daily or weekly for periods up to a number of years. Taking these doses of arsenic was believed to increase muscular power and enhance the beauty and sexual attractiveness of peasant girls. There do not appear to be contemporaneous records of the known consequences of chronic arsenic exposure. The historical records of arsenic eating there are reviewed and appear to be valid. The benefits are subjective judgements by arsenic eaters. The lack of objective reports of the anticipated external and internal clinical and pathological effects of arsenic poisoning depends on a smaller number of clinical accounts and autopsy reports and the general medical literature of those times, so it is weaker, but it is consistent., Can the Claimed Benefits of Arsenic Eating and the Apparent Absence of Harmful Toxic Effects Be True?: Why the arsenic eaters did not show the well-known consequences of prolonged exposure to high doses of arsenic is not known. Possible explanations include increases in detoxifying metabolism in the consumers due to induced genomic changes and selection in people and in the gut microbiome, as shown in other populations. Whether these effects would suffice to protect people against their high doses of arsenic has not been explored., Conclusion: Although the nature and mechanisms of arsenic toxicity have been extensively described, much still remains to be discovered.

Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg ( p  = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19-3.07, p  = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease.

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide., (© 2023. The Pharmaceutical Society of Korea.)

Objective: To explore the correlation between urinary arsenic and health effects through the determination and analysis of urinary arsenic levels in occupational arsenic exposed workers. Methods: In November 2021, 95 workers exposed to arsenic and its inorganic compounds and 31 administrative personnel from a non-ferrous metal smelter in Yunnan Province were selected as the contact group and control group, respectively. Urine forms of arsenic, blood tumor markers, liver function were detected, and micronucleus test was used to analyze the chromosome damage. The correlation between urine forms of arsenic and health effects were analyzed. Results: Compared with the control group, the concentrations of urinary trivalent inorganic arsenic (iAs(3+)) , pentavalent inorganic arsenic (iAs(5+)) , inorganic arsenic (iAs=ΣiAs(3+)+iAs(5+)) , monomethyl arsenic (MMA) , dimethyl arsenic (DMA) and urinary arsenic (ΣiAs+MMA+DMA) at the end of class in contact group were higher ( P <0.05) . There was no statistically significant difference in blood tumor markers and liver function indicators between the two groups ( P >0.05) . Compared with the control group, the peripheral blood micronucleus rate and cell micronucleus rate in the contact group were significantly increased ( P <0.05) . The urinary arsenic, iAs(5+), inorganic arsenic and DMA were positively correlated with peripheral blood micronucleus rate in contact group ( r (s)=0.48, 0.34, 0.37, 0.23, P <0.05) , and the urinary arsenic, iAs(5+), DMA were positively correlated with peripheral blood micronucleus rate ( r (s)=0.48, 0.34, 0.26, P <0.05) . Conclusion: There is a significant correlation between different valence states of arsenic in the urine and abnormal health effects of occupational arsenic exposed workers. It is necessary to strengthen the detection of arsenic species in the urine of occupational arsenic exposed workers to better protect their health.

Dapagliflozin (DPG) is a sodium-glucose co-transporter 2 inhibitor that is commonly used in the treatment of type 2 diabetes. However, studies have shown that DPG has a protective effect under a variety of experimental conditions through its antioxidative and anti-inflammatory properties. DPG's effect on experimental hepatotoxicity caused by arsenic trioxide (ATO) has yet to be investigated. The purpose of this study was to investigate the protective effect of DPG in preventing hepatic damage caused by ATO and discover the underlying mechanisms. The effect of DPG (1 mg/kg, orally) on ATO (5 mg/kg, i.p.)-induced hepatic injury was evaluated in rats. Serum liver function parameters, as well as oxidative stress biomarkers and inflammatory cytokine levels were assessed. Histopathological changes in the liver were detected using H&E staining. Using Western blotting and PCR techniques, the molecular mechanisms of DPG in ameliorating hepatic injury were investigated. DPG improved liver function by inhibiting histopathological changes, decreasing levels of hepatic function and toxicity parameters measured in both serum and tissues, and exhibiting antioxidant and anti-inflammatory effects, according to the findings. Consistent with the PCR results, DPG also decreased the expression of LC3-II, micro-RNA-122, and micro-RNA-21 while increased the expression of SOCS3. Furthermore, according to western blotting results, DPG was able to reduce the protein expression of AKT, mTOR, PI3K, and STAT3. Although further clinical research is necessary, this study highlights the potential of DPG in preventing liver damage in a rat model of hepatotoxicity induced by ATO., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We used a nontargeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and peroxisome proliferator-activated receptor (PPAR)- α signaling in proximal tubule epithelial cell and endothelial cell clusters. We also revealed highly upregulated genes such as Zbtb16 , Cyp4a14 , and Pdk4 , which are involved in metabolism and metabolic switching and may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase has been previously described in vitro. This, along with our own data, led us to conclude that arsenical-induced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells and that ameliorating these metabolic effects may lead to the development of life-saving therapies. SIGNIFICANCE STATEMENT: In this study, we demonstrate that cutaneous arsenical exposure leads to a transcriptional shift enhancing fatty acid metabolism in kidney cells, indicating that metabolic alterations might mechanistically link topical arsenical exposure to acute kidney injury. Targeting metabolic pathways may generate promising novel therapeutic approaches in combating arsenical-induced acute kidney injury., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Arsenic trioxide (ATO)-induced hepatotoxicity is often observed in acute promyelocytic leukemia (APL) patients and decreases therapeutic effect of ATO. Thus, concerns over hepatotoxicity have been raised. The aim of this study was to explore some noninvasive clinical indicators that can be used to guide the individualized application of ATO in the future. APL patients treated with ATO were identified retrospectively via electronic health records at our hospital from August 2014 through August 2019. APL patients without hepatotoxicity were selected as controls. The association between putative risk factors and ATO-induced hepatotoxicity was estimated with ORs and 95% CIs, which were calculated using the chi-square test. The subsequent multivariate analysis was performed using logistic regression analysis. In total, 58.04% of patients experienced ATO-induced hepatotoxicity during the first week. Elevated hemoglobin (OR 8.653, 95% CI, 1.339-55.921), administration of nonprophylactic hepatoprotective agents (OR 36.455, 95% CI, 7.409-179.364), non-single-agent ATO to combat leukocytosis (OR 20.108, 95% CI, 1.357-297.893) and decreased fibrinogen (OR 3.496, 95% CI, 1.127-10.846) were found to be statistically significant risk factors for ATO-induced hepatotoxicity. The area under the ROC curve values were 0.846 for "overall ATO-induced hepatotoxicity" and 0.819 for "early ATO-induced hepatotoxicity." The results revealed that hemoglobin ≥ 80 g/L, nonprophylactic hepatoprotective agents, and non-single-agent ATO and fibrinogen < 1 g/L are risk factors for ATO-induced hepatotoxicity in newly diagnosed APL patients. These findings can enhance the clinical diagnosis of hepatotoxicity. Prospective studies should be performed in the future to validate these findings., (© 2023. The Author(s).)

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As 4 S 4 ), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL., (© 2023. The Author(s).)

Background: Arsenic exposure can cause adverse health effects. The effects of long-term low-to-moderate exposure and methylations remain unclear., Objective: This study aims to examine the association between low-to-moderate arsenic exposure and urothelial tract cancers while considering the effects of methylation capacity., Methods: In this study, 5,811 participants were recruited from an arseniasis area in Taiwan for inorganic arsenic metabolite analysis. This follow-up study was conducted between August 1995 and December 2017. We identified 85 urothelial tract cancers in these participants, including 49 bladder and 36 upper urothelial tract cancer cases. A Cox proportional hazards model was employed., Results: The analyses revealed a significant association between concentrations of inorganic arsenic in water > 100 ug/L and bladder cancer occurrence, with a hazard ratio (HR) of 4.88 (95% CI 1.35-17.61). A monotonic trend was observed between concentrations of inorganic arsenic in water (from 0 to > 100 ug/L) and the incidence of urothelial tract cancer, including bladder cancer (p < 0.05) and upper urothelial tract cancers (p < 0.05). Participants with a lower primary methylation index or higher secondary methylation index had a prominent effect., Conclusions: Rigorous regulations and active interventions should be considered for populations with susceptible characteristics., (© 2023. The Author(s).)

Background: Arsenic trioxide (ATO) might be effective for myelodysplastic syndrome (MDS) by apoptosis induction and demethylation. But ATO has not been widely recommended for small sample and conflicting conclusion of existing trials. This review aimed to systematically evaluate the efficacy of regimens containing ATO for the MDS and explore optimal combination., Method: Randomized clinical trials (RCTs) about ATO regimens were retrieved from China National Knowledge Infrastructure, Embase and PubMed. With odds ratio (OR) as the effect size, network meta-analysis (NMA) and component network meta-analysis (CNMA) were conducted by R and 'netmeta' package, after study selection, quality assessment and data extraction., Result: Thirty-night RCTs were included with a total of 2125 patients, including 1235 treated by ATO containing regimen. With support therapy alone as reference, no inconsistency and heterogeneity were observed. Although NMA did not demonstrate better efficacy of ATO alone, the result of CNMA indicated that ATO was effective in the improvement of overall remission (ORR) [OR = 2.09(1.61, 2.71)] and complete remission (CR) [OR  = 1.66(1.25, 2.21)]. Five ATO-containing regimens reported could effectively improve ORR, some of them benefit in CR or hematological improvement (HI) as well. ATO + Traditional Chinese Medicine (TCM), ATO + Thalidomide (T)+TCM, ATO + Chemotherapy (Chem)+T + TCM were regarded as the optimal combination, which improved both ORR, CR and HI in theory. ATO did not increase the risk of common adverse events compared to supportive therapy [(OR = 0.90(0.67, 1.21)]., Conclusion: ATO may be an effective and well-tolerant option for patients with myelodysplastic syndrome.

Lewisite (LEW) is an arsenical vesicant that can be a potentially dangerous chemical warfare agent (CWA). Eyes are particularly susceptible to vesicant induced injuries and ocular LEW exposure can act swiftly, causing burning of eyes, edema, inflammation, cell death and even blindness. In our previous studies, we developed a LEW exposure-induced corneal injury model in rabbit and showed increased inflammation, neovascularization, cell death, and structural damage to rabbit corneas upon LEW exposure. In the present study, we further assessed the metabolomic changes to delineate the possible mechanisms underlying the LEW-induced corneal injuries. This information is vital and could help in the development of effective targeted therapies against ocular LEW injuries. Thus, the metabolomic changes associated with LEW exposures in rabbit corneas were assessed as a function of time, to delineate pathways from molecular perturbations at the genomic and proteomic levels. New Zealand white rabbit corneas (n = 3-6) were exposed to LEW vapor (0.2 mg/L; flow rate: 300 ml/min) for 2.5 min (short exposure; low dose) or 7.5 min (long-exposure; high dose) and then collected at 1, 3, 7, or 14 days post LEW exposure. Samples were prepared using the automated MicroLab STAR® system, and proteins precipitated to recover the chemically diverse metabolites. Metabolomic analysis was carried out by reverse phase UPLC-MS/MS and gas chromatography (GC)-MS. The data obtained were analyzed using Metabolon's software. The results showed that LEW exposures at high doses were more toxic, particularly at the day 7 post exposure time point. LEW exposure was shown to dysregulate metabolites associated with all the integral functions of the cornea and cause increased inflammation and immune response, as well as generate oxidative stress. Additionally, all important metabolic functions of the cells were also affected: lipid and nucleotide metabolism, and energetics. The high dose LEW exposures were more toxic, particularly at day 7 post LEW exposure (>10-fold increased levels of histamine, quinolinate, N-acetyl-β-alanine, GMP, and UPM). LEW exposure dysregulated integral functions of the cornea, caused inflammation and heightened immune response, and generated oxidative stress. Lipid and nucleotide metabolism, and energetics were also affected. The novel information about altered metabolic profile of rabbit cornea following LEW exposure could assist in delineating complex molecular events; thus, aid in identifying therapeutic targets to effectively ameliorate ocular trauma., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Darinaparsin is a novel organic arsenical compound of dimethylated arsenic conjugated to glutathione, with antitumor activity and a mechanism of action markedly different from other available agents. This phase 2, nonrandomized, single-arm, open-label study evaluated the efficacy and safety of intravenous darinaparsin (300 mg/m2 over 1 hour, once daily for 5 consecutive days, per 21-day cycle) and its pharmacokinetics at multiple doses in 65 Asian patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The primary end point was the overall response rate (ORR). The ORR based on central assessment was 19.3% (90% confidence interval, 11.2-29.9), which was significantly higher than the predefined threshold of 10% (P = .024). The ORR was 16.2% in patients with PTCL-not otherwise specified and 29.4% in patients with angioimmunoblastic T-cell lymphoma. Tumor size decreased in 62.3% of patients. Treatment-emergent adverse events (TEAEs) were observed in 98.5% of patients. Grade ≥3 TEAEs with an incidence rate of ≥5% included anemia (15.4%), thrombocytopenia (13.8%), neutropenia (12.3%), leukopenia (9.2%), lymphopenia (9.2%), and hypertension (6.2%). Darinaparsin is effective and well tolerated, with TEAEs that were clinically acceptable and manageable with symptomatic treatment and dose reductions. This trial was registered at www.clinicaltrials.gov as #NCT02653976., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Our study aimed to explore whether type 2 diabetes (T2DM) can affect arsenic metabolism in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide. We found that compared with non-diabetic APL patients, the concentrations of arsenic metabolites in APL patients with T2DM increased significantly and positively correlated with blood glucose (P < 0.05). Meanwhile, APL patients with T2DM were more prone to liver injury and QTc interval prolongation due to altered arsenic methylation capacity. Then we cultured HEK293T cells at different glucose concentrations, and the results showed that the cells with high glucose had higher concentrations of arsenic metabolites compared to other cells. Meanwhile, the high glucose significantly increased the mRNA and protein expression levels of the arsenic uptake transporter AQP7 in HEK293T cells. Overall, our study demonstrated that T2DM can lead to elevated concentrations of arsenic metabolites in APL patients by increasing AQP7 expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Chemotherapy, all-trans retinoic acid (ATRA), and arsenic are effective options for acute promyelocytic leukemia (APL). We conducted a 20-year retrospective analysis of newly diagnosed (ND) APL patients treated with arsenic, ATRA and mitoxantrone. After achieving complete remission (CR), patients received 3-5 cycles of chemotherapy followed by AS4S4 maintenance for 3 years. Eighty-eight ND APL patients were treated with either oral AS4S4 (n = 42) or arsenic trioxide (ATO) (n = 46). The 8-year overall survival (OS) rate was 100% in the AS4S4 group and 90% in the ATO group. The disease-free survival (DFS) rates were 100% and 87.1% (p = 0.027), respectively. Patients in the ATO group had more side effects. A subsequent cohort of 33 ND APL patients received triple therapy with oral AS4S4, ATRA, and chemotherapy. The 13-year OS and DFS rates were 100% and 90.9%. Our long-term analyses show that APL patients with oral AS4S4 had better outcomes compared to ATO, with no need for hospitalization., (© 2022. Japanese Society of Hematology.)

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) form the backbone of the treatment of acute promyelocytic leukaemia (APL), with the addition of chemotherapy for high-risk patients. We describe our experience of treating patients with APL of all risk classes with ATO and ATRA without chemotherapeutic agents. Patients received induction with ATO and ATRA followed by three cycles of consolidation with ATO and ATRA (each 1 month apart) after achieving morphological remission. Patients with intermediate- and high-risk disease received a further 2 years of maintenance with ATRA, 6-mercaptopurine and methotrexate. A total of 206 patients were included in the study. The majority of the patients were intermediate risk (51.9%), followed by high risk (43.2%). Differentiation syndrome was seen in 41 patients (19.9%). Overall, 25 patients (12.1%) died within 7 days of initiating therapy. Seven patients relapsed during follow-up. The mean (SD) estimated 5-year event-free survival (EFS) and overall survival (OS) in the entire cohort was 79% [5.8%] and 80% [5.8%] respectively. After excluding patients who died within 7 days of therapy initiation, the mean (SD) estimated 5-year EFS and OS was 90% [5.8%] and 93% [3.9%] respectively. Our study shows that treatment of all risk classes of APL with ATO and ATRA without chemotherapy is associated with excellent long-term outcomes in the real-world setting., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Worldwide, more than 200 million people are estimated to be exposed to unsafe levels of arsenic. Chronic exposure to unsafe levels of groundwater arsenic is responsible for multiple human disorders, including dermal, cardiovascular, neurological, pulmonary, renal, and metabolic conditions. Consumption of rice and seafood (where high levels of arsenic are accumulated) is also responsible for human exposure to arsenic. The toxicity of arsenic compounds varies greatly and may depend on their chemical form, solubility, and concentration. Surprisingly, synthetic organoarsenicals are extremely toxic molecules which created interest in their development as chemical warfare agents (CWAs) during World War I (WWI). Among these CWAs, adamsite, Clark I, Clark II, and lewisite are of critical importance, as stockpiles of these agents still exist worldwide. In addition, unused WWII weaponized arsenicals discarded in water bodies or buried in many parts of the world continue to pose a serious threat to the environment and human health. Metabolic inhibition, oxidative stress, genotoxicity, and epigenetic alterations including micro-RNA-dependent regulation are some of the underlying mechanisms of arsenic toxicity. Mechanistic understanding of the toxicity of organoarsenicals is also critical for the development of effective therapeutic interventions. This review provides comprehensive details and a critical assessment of recently published data on various chemical forms of arsenic, their exposure, and implications on human and environmental health., (© 2022. The Author(s).)

The eye is ten times more vulnerable to chemical warfare agents than other organs. Consistently, exposure to vesicant arsenical lewisite (LEW) manifests significant corneal damage leading to chronic inflammation, corneal opacity, vascularization, and edema, culminating in corneal cell death. However, despite the progress has made in the research field investigating arsenical-induced pathogenesis of the anterior chamber of the eye, the retinal damage resulted from exposure to arsenicals has not been identified yet. Therefore, we investigated the effects of direct ocular exposure (DOE) to LEW and phenylarsine oxide (PAO) on the retina. DOE to arsenicals was conducted using the vapor cap method at the MRIGlobal facility or an eye patch soaked in solutions with different PAO concentrations at UAB. Animals were assessed at 1, 3, 14, and 28 days postexposure. Results of the study demonstrated that both arsenicals cause severe retinal damage, activating proinflammatory programs and launching apoptotic cell death. Moreover, the DOE to PAO resulted in diminishing ERG amplitudes in a dose-dependent manner, indicating severe retinal damage. The current study established a prototype mouse model of arsenical-induced ocular damage that can be widely used to identify the key cellular signaling pathways involved in retinal damage pathobiology and to validate medical countermeasures against the progression of ocular damage., (Copyright © 2022. Published by Elsevier Ltd.)

Darinaparsin, an active ingredient of DARVIAS ® Injection 135 ‍mg, is a novel organic arsenical compound of dimethylated arsenic conjugated to glutathione. Darinaparsin is thought to induce apoptosis and cell-cycle arrest and suppress tumor growth by disrupting mitochondrial functions and increasing production of intracellular reactive oxygen species. Darinaparsin is processed at the cell surface by γ-glutamyltranspeptidase (γ-GT), leading to formation of dimethylarsino-cysteine, which is imported via a cystine transporter expressed on cell surface membranes. Numerous tumor cells express high levels of γ-GT and cystine transporter, to maintain high levels of glutathione as an intracellular antioxidant. Darinaparsin is a novel antineoplastic agent designed to exploit the characteristics of tumor cells and to be efficiently taken up by tumor cells to inhibit their growth. In a global phase 2 pivotal study of darinaparsin in Asian patients with relapsed or refractory peripheral T-cell lymphoma (r/r PTCL), the overall response rate was 19.3% (90% confidence interval: 11.2-29.9%) and grade ≥3 drug-related adverse events with an incidence rate ≥5% included neutropenia (9.2%, n = 6), anemia (6.2%, n = 4) and thrombocytopenia (6.2%, n = 4) in 65 patients receiving darinaparsin. Based on the results of this phase 2 trial, which demonstrated the anti-tumor activity and acceptable safety profile of darinaparsin in patients with r/r PTCL, Solasia pharma K.K. received approval for darinaparsin for the treatment of r/r PTCL in June 2022, and Nippon Kayaku Co., Ltd. launched this drug in August 2022. Darinaparsin is expected to contribute to the clinical practice of PTCL as a new treatment option for this disease.

Background: Acute promyelocytic leukaemia (APL) characterized by t (15;17) leading to formation of fusion protein PML-RARA is an acute leukaemia with highest mortality. A remarkable improvement in the outcomes has been witnessed due to evolution of highly effective targeted therapies replacing the traditional chemotherapy is most patients. However limited data is available regarding treatment outcomes of APL using various novel regimens from developing countries like Pakistan., Methods: This was a retrospective descriptive study which included APL patients treated at AFBMTC Rawalpindi from 2005 to 2020. It included a total of 51 eligible patients with a diagnosis of de novo APL confirmed by the presence of PML-RARA transcript or presence of t (15;17) by cytogenetics or FISH analysis. The protocols used for treatment included the UKAML MRC 12, the LPA-99/LPA-2005 PETHEMA, the APML4 and non-chemotherapy based ATO-ATRA protocol., Results: The study included 51 patients in which 31 (60.78%) were male and 20 (39.2%) were female. The median age at diagnosis was 30 years (range 5-70). The commonest symptom was fever seen in 43 (84.3%) patients and bruising was the commonest physical finding present in 44 (86.3%) patients. High-risk patients were 23 (46.1%), 18 (35.3%) were intermediate risk and 10 (19.6%) were low risk. The LPA99/LPA2005 was most frequently employed protocol being used in 36 (72%) patients. There were 2 deaths during induction and 44 (86.3%) achieved CR post induction. The median follow up time was 32 months (range 1 to 190 months) with an overall survival (OS) of 76.5% and a relapse free survival (RFS) of 66.7., Conclusions: Our study shows APL is a highly curable malignancy and outcomes have improved with newer non chemotherapy based therapies. It can also be concluded that outcomes of APL gradually improved over the past 2 decades due to improvement in supportive care, provision of blood products and use of newer protocols. The prognosis remains less favourable in high risk patients.

Arsenic (As) and its compounds are widely used in many applications. Long-term exposure to As can cause acute and chronic poisoning. In severe cases, it can lead to adverse effects, such as gene mutation, cell cancer and fetal malformation. The objective of this study was to accurately estimate As exposure frequency and time. Quantitative analysis of As in single hairs obtained from APL (acute promyelocytic leukemia) patients treated with As 2 O 3 was performed by LA-ICP-MS. An informative As concentration distribution profile of single hair was applied to estimate the As exposure frequency and time. As exposure frequency was estimated according to the number of As concentration peaks. As exposure time was estimated according to the hair growth length in combination with the hair growth rate. The validation results demonstrate that this method was more efficient than the traditional method; compared with the traditional method, which provides estimates in months, our model shortened the As exposure time estimate to the range of a few days, which considerably improved the inference accuracy. Therefore, these results can be used for forensic toxicology studies, environmental exposure monitoring, etc.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Qinghuang Powder (QHP), an oral arsenic, has become an effective drug in the treatment of myelodysplastic syndromes (MDS) in Xiyuan Hospital, China Academy of Chinese Medical Sciences for many years, and the action mechanism of the compound or active ingredient As 2 S 2 of QHP has been elucidated. Considering the relatively safety, chemotherapy-free and convenient oral profile, QHP is widely used in the clinical treatment for MDS patients, especially for elderly patients. In this review, the authors document the efficacy and safety of oral arsenic-containing compound QHP in the treatment of MDS, with a special focus on the association of efficacy of QHP with the cytogenetics, prognostic risk, DNA methylation, gene mutation, blood arsenic concentration, mechanism of action of As 2 S 2 and the countermeasures against adverse reactions of gastrointestinal tract., (© 2020. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Realgar-Indigo naturalis formula (RIF) is a traditional Chinese medicine containing As 4 S 4 and effective in treating acute promyelocytic leukemia (APL). The dose of RIF remains to be determined in pediatric patients. Comparison of plasma arsenic concentrations and toxicity between RIF and arsenic trioxide (ATO) treatment in APL may help to establish an appropriate therapeutic dose of RIF for children. From October 2018 to March 2020, 19 pediatric patients with APL treated with SCCLG-APL protocol were included, 9 in RIF group at 135 mg/kg/day orally three times daily, and 10 in ATO group at 0.16 mg/kg/day intravenously over 12 h daily. Peak and trough plasma arsenic concentrations were assayed at D1, 2, 7 and 14 of induction treatment. Urine arsenic excretions were assessed with spot urine samples and the measurements were adjusted using creatinine. Toxicities were compared between two groups. The plasma arsenic concentration reached steady state at D7 either in the RIF or ATO group, and the mean peak and trough concentrations were similar between two groups (P > 0.05), which were 0.54 μmol/L and 0.48 μmol/L in RIF group, and 0.63 μmol/L and 0.51 μmol/L in ATO group, respectively. Urine arsenic excretion rate was positively correlated with the concentration of plasma arsenic. The rates of treatment-related adverse events were similar in two groups. In conclusion, the dose of RIF at 135 mg/kg/day may be an appropriate therapeutic dose in children with APL. Urine arsenic level can be used as an indicator to estimate plasma arsenic concentration. Trial registration www.clinicaltrials.gov NCT02200978., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diphenylarsinic acid (DPAA) is a non-natural pentavalent organic arsenic and was detected in well water in Kamisu, Ibaraki, Japan in 2003. Individuals that had consumed this arsenic-contaminated water developed cerebellar symptoms such as myoclonus. We previously revealed that DPAA exposure in rats in vitro and in vivo specifically affected astrocytes rather than neurons among cerebellar cells. Here, we evaluated adverse effects of DPAA in cultured normal human cerebellar astrocytes (NHA), which were compared with those in normal rat cerebellar astrocytes (NRA) exposed to DPAA at 10 μM for 96 h, focusing on aberrant activation of astrocytes; increase in cell viability, activation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and transcription factors (CREB, c-Jun, and c-Fos), upregulation of oxidative stress-responsive factors (Nrf2, HO-1, and Hsp70), and also hypersecretion of brain cytokines (MCP-1, adrenomedullin, FGF-2, CXCL1, and IL-6) as reported in NRA. While DPAA exposure at 10 μM for 96 h had little effect on NHA, a higher concentration (50 μM for 96 h) and longer exposure (10 μM for 288 h) induced similar aberrant activation. Moreover, exposure to DPAA at 50 μM for 96 h or 10 μM for 288 h in NHA induced hypersecretion of cytokines induced in DPAA-exposed NRA (MCP-1, adrenomedullin, FGF-2, CXCL1, and IL-6), and IL-8 besides into culture medium. These results suggested that aberrantly activated human astrocytes by DPAA exposure might play a pivotal role in the pathogenesis of cerebellar symptoms, affecting adjacent neurons, microglia, brain blood vessels, or astrocyte itself through these brain cytokines in human., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Since their use during the First World War, Blister agents have posed a major threat to the individuals and have caused around two million casualties. Major incidents occurred not only due to their use as chemical warfare agents but also because of occupational hazards. Therefore, a clear understanding of these agents and their mode of action is essential to develop effective decontamination and therapeutic strategies. The blister agents have been categorised on the basis of their chemistry and the biological interactions that entail post contamination. These compounds have been known to majorly cause blisters/bullae along with alkylation of the contaminated DNA. However, due to the high toxicity and restricted use, very little research has been conducted and a lot remains to be clearly understood about these compounds. Various decontamination solutions and detection technologies have been developed, which have proven to be effective for their timely mitigation. But a major hurdle seems to be the lack of proper understanding of the toxicological mechanism of action of these compounds. Current review is about the detailed and updated information on physical, chemical and biological aspects of various blister agents. It also illustrates the mechanism of their action, toxicological effects, detection technologies and possible decontamination strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Millions of people worldwide are exposed to arsenic, a metalloid listed as one of the top chemical pollutants of concern to human health. Epidemiological and experimental studies link arsenic exposure to the development of cancer and other diseases. Several mechanisms have been proposed to explain the effects induced by arsenic. Notably, arsenic and its metabolites interact with proteins by direct binding to individual cysteine residues, cysteine clusters, zinc finger motifs, and RING finger domains. Consequently, arsenic interactions with proteins disrupt the functions of proteins and may lead to the development and progression of diseases. In this review, we focus on current evidence in the literature that implicates the interaction of arsenic with proteins as a mechanism of arsenic toxicity. Data show that arsenic-protein interactions affect multiple cellular processes and alter epigenetic regulation, cause endocrine disruption, inhibit DNA damage repair mechanisms, and deregulate gene expression, among other adverse effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Arsenic (As), as well as its various compounds have been widely used for nearly 4000 years either as drugs or poisons. These compounds are valuable in the treatment of various diseases ranging from dermatosis to cancer, thereby emphasizing their important roles as therapeutic agents. The ability of As compounds, especially arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL), has fundamentally altered people's understanding of the poison, and has become a major factor in the re-emergence of Western medicine candidates to treat leukemia and other solid tumors. However, long-term exposure to As has been correlated with numerous disadvantageous influences on health, particularly carcinogenesis. Importantly, accumulating evidence suggests that biotransformation of As, as a step to eliminate As from the human body, can induce alterations at the genetic and epigenetic levels, resulting in therapeutic effects or carcinogenesis. In this article, we aimed to provide a systematic overview of the primary contributions associated with As and its compounds, as well as the detailed mechanisms applied in APL cells and carcinogenic toxicology. This review may help to understand the underlying mechanisms and safe wide clinical applications of medicinal As along with its compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a second-generation peptide arsenical that inactivates mitochondria in proliferating tumour cells by covalently reacting with mitochondrial inner-membrane adenine nucleotide transferase. The toxicokinetics of PENAO has been investigated in Sprague-Dawley rats to inform route of administration and dosing for human clinical trials. PENAO was well tolerated at 3.3 mg/kg daily intravenous injections but associated with significant toxicity at 10 mg/kg, primarily in the males. The major target organ for toxic effects was the kidney, with changes observed in tubular dilation, presence of casts, basophilic tubules, lymphoid aggregates and interstitial fibrosis. Kidney function was impaired in males with dose-dependent increase in serum creatinine concentration. The severity of the microscopic lesions was reduced in the females, but not the males, at the completion of the four-week recovery period. The elimination phase half-life of PENAO varied between 0.4 and 1.7 h and volume of distribution ranged from 0.25 to 0.88 L/kg for the different dose groups and treatment days, suggesting that PENAO distributes in the extracellular fluids at the doses tested. The area under the curve and clearance values indicate that male rats had reduced elimination of PENAO compared to females, which may account for the increased toxicity in males. PENAO is significantly better tolerated in rodents than its predecessor, GSAO. As GSAO was generally well tolerated with few side effects in a phase I trial in patients with solid tumours, these findings bode well for the tolerability of intravenous dosing of PENAO in patients.

Arsenic trioxide (ATO) is the backbone of acute promyelocytic leukemia (APL) treatment and is dosed based on weight with no upper limit, therefore obese patients receive large doses and may be vulnerable to adverse effects and dose holdings. Twenty-seven patients receiving ATO during induction were categorized as obese ( N  = 16) or non-obese ( N  = 11) based on body mass index (BMI) ≥30 kg/m 2 in this retrospective study. Doses were held or modified due to composite adverse effects in 9 (56%) obese patients and 7 (64%) non-obese patients ( p  = 1.00). There were higher rates of dose holdings (13% versus 0%; p  = .5) and dose modifications (13% versus 0%; p  = .5) due to hepatotoxicity in obese versus non-obese patients. There were no differences in efficacy parameters. These data suggest that obese patients have similar overall incidence of adverse effects to ATO as non-obese patients; any difference in risk of hepatotoxicity will require clarification in a larger study.

Historically, arsenic exposure has been associated with herpes zoster (HZ) infection, however the risk is not well characterized in arsenic trioxide (ATO) treated patients with acute promyelocytic leukemia (APL). We aimed to characterize the risk of HZ in 112 ATO treated patients with APL with and without antiviral prophylaxis (AVP). HZ occurred in 13/112 (11.6%) within 6 months of completing ATO, including one case of HZ encephalitis. AVP reduced the incidence of HZ (17.5% vs. 4.1%, RR 0.24 [95% CI 0.05-1.0, p  = .025]) with a number needed to treat of 7.7. HZ despite AVP occurred later than HZ in patients without AVP (7.8 vs. 2.3 months from starting ATO, p  = .11). Older age and prior HZ increased the risk of HZ in patients not receiving AVP. Routine AVP should be considered in patients with APL receiving ATO, particularly in older patients and those with a history of HZ.

Diphenylarsinic acid (DPAA), an artificial phenyl arsenic compound, is considered a groundwater pollutant in Japan. Previous human and animal studies suggested that DPAA affects the central nervous system; however, these effects are poorly understood. The present study investigated the toxicokinetic characteristics and effects of DPAA on dopamine (DA) in the striatum of free-moving mice after a single oral administration. In a simultaneous blood and brain microdialysis study, only DPAA was detectable in both blood and striatum dialysate samples immediately after DPAA administration. DPAA concentrations in the striatum and blood dialysate rapidly reached a maximum, then decreased over time in an essentially parallel manner. A more detailed brain microdialysis examination of intracerebral kinetics revealed that the concentration of DPAA in the striatum dialysate began to increase within 15 min, reaching a maximum approximately 1 h after administration, and then decreased with a biological half-life of approximately 2 h. Moreover, a single oral administration of DPAA at 0.5-32 mg/kg affected the extracellular DA level in the striatum. The effect on DA level changed slowly after DPAA administration, with a bell-shaped dose-response relationship. The present study suggests that DPAA is rapidly absorbed into the blood circulating in the gastrointestinal tract and passes through the blood-brain barrier to subsequently affect DA levels in the striatum in mice after a single oral administration., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220)., Methods: Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles., Results: Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile., Conclusions: These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: A high incidence of upper urinary tract urothelial carcinoma has been reported in the southwestern area of Taiwan, where arsenic water contamination was considered the main cause. However, there is no definite proof to show a correlation between arsenic water contamination and upper urinary tract urothelial carcinoma. To investigate the clinical and epidemiological features of patients with upper urinary tract urothelial carcinoma between arsenic water endemic and non-endemic areas, we analyzed patients in terms of characteristics, stratified overall survival, disease-free survival, and cancer-specific survival., Methods: The records of a total of 1194 patients diagnosed with upper urinary tract urothelial carcinoma were retrospectively reviewed. Clinical data and current medical status were collected from the medical records. Statistical analyses were performed to determine the clinical variables and stratified survival curves between endemic and non-endemic groups., Results: Female predominance was revealed in both endemic and non-endemic groups (male:female ratio = 1:1.2-1.4). No statistical differences were found in histological types, staging, and tumor size between the two groups. Nonetheless, patients with characteristics of aging and having end-stage renal disease were outnumbered in the non-endemic group, while a higher prevalence of previous bladder tumors and more ureteral tumors were found in the endemic group. Adjusted stratified cumulative survival curves suggested a poorer prognosis in endemic patients, especially in disease-free survival of early stage disease., Conclusions: A higher mortality rate with more previous bladder cancer history and ureteral tumors was seen in patients with upper urinary tract urothelial carcinoma residing in the arsenic water contamination area. This may be attributed to the long-term carcinogenic effect of arsenic underground water.

Chronic exposure to inorganic arsenic (iAs) is associated with chronic kidney disease (CKD) and urinary cancer, but the risks are poorly understood. Human biomonitoring can serve as a tool to better quantify human exposure and to conduct risk assessment. We aimed to assess the population risks of CKD and urinary cancer due to iAs intake based on the blood arsenic concentrations of 601 participants in Taiwan. A physiologically based pharmacokinetic modeling-based reverse dosimetry was conducted to estimate the daily intakes of iAs (DI iAs ). We performed the benchmark dose (BMD) modeling for CKD using participants' estimated glomerular filtration rate (eGFR) and the estimated DIiAs to derive a point of departure (POD). Margin of exposure (MOE) was used to characterize the risks. The population with eGFR values of <60 mL/min/1.73 m 2 had significantly higher DI iAs (median: 3.20 μg/kg/day, 2.5th-97.5th percentiles: 2.35-4.67 μg/kg/day) than those with normal renal function (1.99, 1.22-3.42 μg/kg/day). The POD for CKD was 1.557 μg/kg/day, which could serve as a possible reference value for CKD risk assessment. The MOEs indicated that the CKD risk due to iAs intake may potentially be a cause for high concern for the population with reduced renal function. The iAs-induced urinary cancer risk may be a cause for moderate-to-high concern., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exposure to inorganic arsenic (iAs) is a significant public health concern with individuals around the globe exposed to harmful levels through contaminated drinking water. Exposure to iAs during pregnancy is of particular concern and has been associated with pregnancy complications and adverse child health later in life. Effects of in utero exposure may be mediated through alterations in key signaling pathways in the placenta that regulate fetal growth and development. A pathway of interest is the glucocorticoid receptor (GR)- signaling pathway, which is known to regulate fetal and placental development. While prior research has shown that iAs alters GR-associated gene expression in trophoblasts, the mechanisms that underlie these perturbations remain unknown. In the present study, we set out to elucidate the molecular mechanisms that underpin observed alterations in GR-associated gene expression. We also aimed to determine whether the methylated metabolites of iAs, namely monomethyl‑arsenic (MMA) and dimethyl‑arsenic (DMA), also influence GR-associated signaling in the placenta. The data indicate that iAs alters GR activation in a dose-dependent manner, reduces nuclear translocation, and reduces DNA binding. Additionally, the results demonstrate that MMA and DMA alter the expression of eight GR-associated genes, modulate GR activation, and alter DNA binding. These data are significant as they highlight the role of iAs as an endocrine disruptor and for the first time explore the effects of MMA and DMA on endocrine signaling in the placenta., (Copyright © 2020. Published by Elsevier Inc.)

A 55-year-old woman developed acute promyelocytic leukaemia during treatment with all-trans-retinoic acid and arsenic trioxide. Initially, she presented with symptoms of epigastric pain, vomiting, and nausea, and she developed acute pancreatitis. She was treated with parenteral nutritional supplementation for 20 days. However, the patient continued to develop refractory hyponatraemia, hypotension, and apathy. Finally, the patient was diagnosed with Wernicke encephalopathy (WE) using head magnetic resonance imaging. The patient underwent high-dose intravenous thiamine administration, and her symptoms were alleviated. WE is a rare adverse event during acute pancreatitis therapy. Acute pancreatitis that is caused by all-trans-retinoic acid and arsenic trioxide is a rare complication of acute promyelocytic leukaemia during chemotherapy. Further study is essential to improve our comprehension of the risk factors for complications in patients with acute promyelocytic leukaemia, considering that the associated complications were potentially caused by multiple etiological factors. A better understanding of these risk factors may help to improve the prognosis of patients with acute promyelocytic leukaemia at an early stage.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.

Background: Arsenic trioxide is the first-line treatment for acute promyelocytic leukemia (APL); however, abnormalities of ventricular repolarization and QT interval prolongation are the most common adverse effects. We explore ventricular repolarization dynamic changes and the influence of clinical factors in APL patients during arsenic trioxide induction therapy., Methods: APL patients receiving arsenic trioxide induction therapy were included. Arsenic trioxide effects on ventricular repolarization-related indicators such as QTc, QT interval dispersion (QTd), heart rate-corrected J to T-peak (JTpC), and T-peak to T-end covariate (TpTec) interphase were statistically analyzed. Furthermore, logistic regression analysis was conducted to explore the correlation between various clinical factors and changes in repolarization indexes., Results: Ninety-three patients were recruited finally. Seven patients with QTc > 500 ms after arsenic trioxide treatment were discontinued from the study. QTc, QTd and JTpC interphase prolonged on day 8; TpTec prolongation was observed at the late induction stage. The risk factors were disease risk, hemoglobin and lactate dehydrogenase for QTc; hemoglobin for QTd; disease risk and hemoglobin for JTpC and TpTec., Conclusion: QTc, QTd and JTpC were prolonged in the early use of arsenic trioxide and in contrast with TpTec. Hypothrombinemia was a common risk factor of ventricular repolarization prolongation and should be considered in preventing cardiac adverse effects of arsenic trioxide in APL patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2018. Published by Elsevier B.V.)

: High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As 2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As 2+ -compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered., Competing Interests: The authors declare no conflicts of interest.

Glycyrrhetinic acid (GA) is the bioactive ingredient in Glycyrrhizae Radix et Rhizoma. Our previous study has reported that GA has protective effect on realgar-induced hepatotoxicity. However, the details of the hepatoprotective mechanisms of GA on realgar-induced liver injury remain to be elucidated. In the study, mice were divided into control, GA-control, realgar, and co-treated groups. Their liver tissues were used for metabonomics study by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method. The results illustrate that GA significantly ameliorate the liver injury and metabolic perturbations caused by realgar. Some metabolites, such as phenylalanine, pyroglutamic acid (PGA), proline, carnitine, nicotinamide, choline, lysophosphatidylcholine (LPC) 16 : 0 and LPC 18 : 2 were found responsible for the hepatoprotective effect of GA. These metabolites are associated with the methylation metabolism of arsenic, cell membrane structure, energy metabolism and oxidative stress. From the results of this study, we infer that the potential hepatoprotective mechanism of GA on realgar-induced liver injury may be associated with reducing arsenic accumulation and its methylation metabolism in the liver, promoting the conjugation of arsenic and GSH to play detoxification effect, and ameliorating the liver metabolic perturbations caused by realgar., (Copyright © 2020 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Background: Arsenic exposure through drinking water is an established lung carcinogen. Evidence on non-malignant lung outcomes is less conclusive and suggests arsenic is associated with lower lung function. Studies examining low-moderate arsenic (< 50 μg/L), the level relevant for most populations, are limited. We evaluated the association of arsenic exposure with respiratory health in American Indians from the Northern Plains, the Southern Plains and the Southwest United States, communities with environmental exposure to inorganic arsenic through drinking water., Methods: The Strong Heart Study is a prospective study of American Indian adults. This analysis used urinary arsenic measurements at baseline (1989-1991) and spirometry at Visit 2 (1993-1995) from 2132 participants to evaluate associations of arsenic exposure with airflow obstruction, restrictive pattern, self-reported respiratory disease, and symptoms., Results: Airflow obstruction was present in 21.5% and restrictive pattern was present in 14.4%. The odds ratio (95% confidence interval) for obstruction and restrictive patterns, based on the fixed ratio definition, comparing the 75th to 25th percentile of arsenic, was 1.17 (0.99, 1.38) and 1.27 (1.01, 1.60), respectively, after adjustments, and 1.28 (1.02, 1.60) and 1.33 (0.90, 1.50), respectively, based on the lower limit of normal definition. Arsenic was associated with lower percent predicted FEV1 and FVC, self-reported emphysema and stopping for breath., Conclusion: Low-moderate arsenic exposure was positively associated with restrictive pattern, airflow obstruction, lower lung function, self-reported emphysema and stopping for breath, independent of smoking and other lung disease risk factors. Findings suggest that low-moderate arsenic exposure may contribute to restrictive lung disease.

Objective: To investigate the relation of blood arsenic concentration (BAC) with clinical effect and safety of arsenic-containing Qinghuang Powder (, QHP) in patients with myelodysplastic syndrome (MDS)., Methods: Totally 163 patients with MDS were orally treated with QHP for 2 courses of treatment, 3 months as 1 course. The BACs of patients were detected by atomic fluorescence spectrophotometry at 1, 3, and 6 months during the treatment, and the effective rate, hematological improvement and safety in patients after treatment with QHP were analyzed., Results: After 2 courses of treatment, the total effective rate was 89.6% (146/163), with 31.3% (51/163) of hematological improvement and 58.3% (95/163) of stable disease. The hemoglobin increased from 73.48 ± 19.30 g/L to 80.39 ± 26.56 g/L (P<0.05), the absolute neutrophil count increased from 0.81 ± 0.48 × 10 9 /L to 1.08 ± 0.62 × 10 9 /L (P<0.05), and no significant changes were observed in platelet counts (P>0.05). Among 46 patients previously depended on blood transfusion, 28.3% (13/46) completely got rid of blood transfusion and 21.7% (10/46) reduced the volume of blood transfusion by more than 50% after treatment. The BACs were significantly increased in patients treated for 1 month with 32.17 ± 18.04 μ g/L (P<0.05), 3 months with 33.56 ± 15.28 μ g/L (P<0.05), and 6 months with 36.78 ± 11.92 μ g/L (P<0.05), respectively, as compared with those before treatment (4.08 ± 2.11 μ g/L). There were no significant differences of BACs among the patients treated for 1, 3 and 6 months (P>0.05). The adverse reactions of digestive tract during the treatment were mild abdominal pain and diarrhea in 14 cases (8.6%), and no patients discontinued the treatment. The BACs of patients with gastrointestinal adverse reactions were significantly lower than those without gastrointestinal adverse reactions (22.39 ± 10.38 vs. 37.89 ± 11.84, μ g/L, P<0.05). The BACs of patients with clinical effect were significantly higher than those failed to treatment (40.41 ± 11.69 vs. 23.84 ± 12.03, μ g/L, P<0.05)., Conclusion: QHP was effective and safe in the treatment of patients with MDS and the effect was associated with BACs of patients.

QTc prolongation has been observed during arsenic trioxide and realgar's clinical use, and become a huge obstacle for the application. Our lab has obtained the soluble arsenic from realgar named realgar transforming solution or RTS. In this study, we first evaluated the cytotoxicity on NB4 cell and found that RTS could remarkably inhibit proliferation of NB4 than arsenic trioxide. Then we figured out the QTc prolongation of RTS treatment contrasted with arsenic trioxide; results revealed that arsenic trioxide prolonged corrected QTc of mice by 20.1% and showed 1.9-fold higher cytotoxicity on H9c2 cell than RTS. On the contrary, there could not find any QTc prolongation of mice in RTS treatment. Also, arsenic trioxide elevated the intercellular calcium accumulation of H9c2 cell by 2.02-fold v.s control and RTS. HE staining and Masson's trichrome staining had shown that there was no injured section after RTS treatments. I K1 currents of rat ventricular cardiomyocytes were diminished by 45.0% after treating with arsenic trioxide while RTS showed no significance than the control group. The results above indicated that RTS could serve as an alternative arsenic agent on leukemia and had a lower risk of cardiotoxicity., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Arsenic exposure has been related to numerous adverse cardiovascular outcomes. The aim of this study was to investigate the cross-sectional and prospective association between arsenic exposure with echocardiographic measures of left ventricular (LV) geometry and functioning., Methods: A total of 1337 young adult participants free of diabetes mellitus and cardiovascular disease were recruited from the SHFS (Strong Heart Family Study). The sum of inorganic and methylated arsenic concentrations in urine (ΣAs) at baseline was used as a biomarker of arsenic exposure. LV geometry and functioning were assessed using transthoracic echocardiography at baseline and follow-up., Results: Mean follow-up was 5.6 years, and median (interquartile range) of ΣAs was 4.2 (2.8-6.9) µg/g creatinine. Increased arsenic exposure was associated with prevalent LV hypertrophy, with an odds ratio (95% CI) per a 2-fold increase in ΣAs of 1.47 (1.05-2.08) in all participants and of 1.58 (1.04-2.41) among prehypertensive or hypertensive individuals. Measures of LV geometry, including LV mass index, left atrial systolic diameter, interventricular septum, and LV posterior wall thickness, were positively and significantly related to arsenic exposure. Among measures of LV functioning, stroke volume, and ejection fraction were associated with arsenic exposure., Conclusions: Arsenic exposure was related to an increase in LV wall thickness and LV hypertrophy in young American Indians with a low burden of cardiovascular risk factors. The relationship was stronger in participants with prehypertension or hypertension, suggesting that potential cardiotoxic effects of arsenic might be more pronounced in individuals already undergoing cardiovascular adaptive mechanisms following elevated systemic blood pressure.