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Technology in Cancer Research &... 2021To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer...
OBJECTIVE
To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts.
METHODS
Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays.
RESULTS
Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups ( 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) ( < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT.
CONCLUSION
These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.
Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Biomarkers; Cell Line, Tumor; Cell Proliferation; Dimercaprol; Disease Models, Animal; Drug Combinations; Drug Compounding; Female; Humans; Mice; Pancreatic Neoplasms; Prognosis; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 34433326
DOI: 10.1177/15330338211036324 -
Italian Journal of Pediatrics Sep 2023There are relatively few studies investigating C-C motif chemokine ligand 2 (CCL2) level in bronchoalveolar lavage fluid (BALF) in children with Mycoplasma pneumoniae...
BACKGROUND
There are relatively few studies investigating C-C motif chemokine ligand 2 (CCL2) level in bronchoalveolar lavage fluid (BALF) in children with Mycoplasma pneumoniae pneumonia (MPP), and the relationship between CCL2 level in BALF and refractory mycoplasma pneumoniae pneumonia (RMPP) is unclear. This study aims to explore the relationship between chemokine CCL2 level in BALF and clinical characteristics and clinical outcome in children with MPP.
METHODS
A total of 51 children with confirmed acute MPP and requiring bronchoalveolar lavage in Department of Pediatrics, Huanghe Sanmenxia Hospital and The First Clinical College of Xinxiang Medical University from October 2021 to February 2023 were selected as the study group. And 11 children with bronchial foreign body were selected as the control group. The study group was divided into the non-refractory mycoplasma pneumoniae pneumonia (NRMPP) group and the RMPP group based on the response to treatment. BALF and clinical data of the patients were collected. And CCL2 levels were tested in the patients. Differences in CCL2 level in BALF and clinical characteristics were tested and compared.
RESULTS
The CCL2 level in BALF of the study group was higher than that of the control group, with significant difference (P < 0.05). With ROC curve, the area under the curve (AUC) of CCL2 in BALF predicting RMPP was 0.94, the cut-off value was 0.645 ng/ml, the sensitivity was 85%, and the specificity was 94%, and the diagnostic value was better than that of serum CRP and LDH. Logistic regression analysis was used to build the RMPP prediction model, and CCL2 showed good predictive value.
CONCLUSION
The level of CCL2 in BALF was high in children with MPP and had a high predictive value for RMPP. CCL2 can be used as one of the biomarkers for predicting RMPP.
Topics: Humans; Child; Bronchoalveolar Lavage Fluid; Pneumonia, Mycoplasma; Chemokines; Dimercaprol; Foreign Bodies
PubMed: 37740208
DOI: 10.1186/s13052-023-01528-2 -
The Journal of Pediatric Pharmacology... Jun 2024The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022.
OBJECTIVE
The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022.
METHODS
Drug shortage data were retrieved from the University of Utah Drug Information Service from January 1, 2001, through December 31, 2022. Shortages of first- and second-line lead chelators were analyzed. Drug class, formulation, administration route, shortage reason, shortage duration, generic status, single-source status, and presence of temporally overlapping shortages were examined. Total shortage months, percentages of study period on shortage, and median shortage durations were calculated.
RESULTS
Thirteen lead chelator shortages were reported during the study period. Median duration was 7.4 months and the longest shortage (24.8 months) involved calcium disodium edetate. Calcium disodium edetate and dimercaprol had the greatest number of shortages, 4 each, and 61.5% of shortages involved parenteral medications. Median shortage duration was 14.2 months for parenteral agents and 2.2 months for non-parenteral agents. All shortages involved generic, single-source products. Supply/demand and manufacturing problems were the most common shortage reasons provided. Overlapping shortages occurred for 3.7% of the study period. Median shortage duration increased from 3 to 11 months in the second half of the study period, and 61.5% of shortages occurred in the second half of the study period.
CONCLUSIONS
All chelators experienced multiple shortages, which became increasingly frequent and prolonged over time. Concurrent shortages occurred, potentially hampering substitution between different agents. Health care stakeholders must build supply chain resilience and develop guidelines regarding how to modify chelation therapy based on shortage conditions.
PubMed: 38863853
DOI: 10.5863/1551-6776-29.3.306 -
Frontiers in Immunology 2023Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid...
Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid arthritis patients annually in Europe. Several recent clinical trials have reported that LDRT can effectively reduce the severity of coronavirus disease (COVID-19) and other cases of viral pneumonia. However, the therapeutic mechanism of LDRT remains unelucidated. Therefore, in the current study, we aimed to investigate the molecular mechanism underlying immunological alterations in influenza pneumonia after LDRT. Mice were irradiated to the whole lung 1 day post-infection. The changes in levels of inflammatory mediators (cytokines and chemokines) and immune cell populations in the bronchoalveolar lavage (BALF), lungs, and serum were examined. LDRT-treated mice displayed markedly increased survival rates and reduced lung edema and airway and vascular inflammation in the lung; however, the viral titers in the lungs were unaffected. Levels of primary inflammatory cytokines were reduced after LDRT, and transforming growth factor-β (TGF-β) levels increased significantly on day 1 following LDRT. Levels of chemokines increased from day 3 following LDRT. Additionally, M2 macrophage polarization or recruitment was increased following LDRT. We found that LDRT-induced TGF-β reduced the levels of cytokines and polarized M2 cells and blocked immune cell infiltration, including neutrophils, in BALF. LDRT-induced early TGF-β production was shown to be a key regulator involved in broad-spectrum anti-inflammatory activity in virus-infected lungs. Therefore, LDRT or TGF-β may be an alternative therapy for viral pneumonia.
Topics: Animals; Mice; COVID-19; Pneumonia, Viral; Inflammation; Cytokines; Arthritis, Rheumatoid; Dimercaprol; Transforming Growth Factors
PubMed: 37304302
DOI: 10.3389/fimmu.2023.1182927 -
Critical Care (London, England) Sep 2023No univocal recommendation exists for microbiological diagnosis of ventilator-associated pneumonia (VAP). Sampling of either proximal or distal respiratory tract likely...
Incidence, microbiological and immunological characteristics of ventilator-associated pneumonia assessed by bronchoalveolar lavage and endotracheal aspirate in a prospective cohort of COVID-19 patients: CoV-AP study.
BACKGROUND
No univocal recommendation exists for microbiological diagnosis of ventilator-associated pneumonia (VAP). Sampling of either proximal or distal respiratory tract likely impacts on the broad range of VAP incidence between cohorts. Immune biomarkers to rule-in/rule-out VAP diagnosis, although promising, have not yet been validated. COVID-19-induced ARDS made VAP recognition even more challenging, often leading to overdiagnosis and overtreatment. We evaluated the impact of different respiratory samples and laboratory techniques on VAP incidence and microbiological findings in COVID-19 patients.
METHODS
Prospective single-centre cohort study conducted among COVID-19 mechanically ventilated patients in Policlinico Hospital (Milan, Italy) from January 2021 to May 2022. Microbiological confirmation of suspected VAP (sVAP) was based on concomitant endotracheal aspirates (ETA) and bronchoalveolar lavage (BAL). Conventional and fast microbiology (FILMARRAY® Pneumonia Panel plus, BAL) as well as immunological markers (immune cells and inflammatory cytokines) was analysed.
RESULTS
Seventy-nine patients were included. Exposure to antibiotics and steroid therapy before ICU admission occurred in 51/79 (64.6%) and 60/79 (65.9%) patients, respectively. Median duration of MV at VAP suspicion was 6 (5-9) days. Incidence rate of microbiologically confirmed VAP was 33.1 (95% CI 22.1-44.0) and 20.1 (95% CI 12.5-27.7) according to ETA and BAL, respectively. Concordance between ETA and BAL was observed in 35/49 (71.4%) cases, concordance between BAL and BAL in 39/49 (79.6%) cases. With BAL as reference standard, ETA showed 88.9% (95% CI 70.8-97.7) sensitivity and 50.0% (95% CI 28.2-71.8) specificity (Cohen's Kappa 0.40, 95% CI 0.16-0.65). BAL showed 95.0% (95% CI 75.1-99.9) sensitivity and 69% (95% CI 49.2-84.7) specificity (Cohen's Kappa 0.60, 95% CI 0.39-0.81). BAL IL-1β differed significantly between VAP (135 (IQR 11-450) pg/ml) and no-VAP (10 (IQR 2.9-105) pg/ml) patients (P = 0.03).
CONCLUSIONS
In COVID-19 ICU patients, differences in microbial sampling at VAP suspicion could lead to high variability in VAP incidence and microbiological findings. Concordance between ETA and BAL was mainly limited by over 20% of ETA positive and BAL negative samples, while BAL showed high sensitivity but limited specificity when evaluating in-panel targets only. These factors should be considered when comparing results of cohorts with different sampling. BAL IL-1β showed potential in discriminating microbiologically confirmed VAP.
CLINICAL TRIAL REGISTRATION
NCT04766983, registered on February 23, 2021.
Topics: Humans; COVID-19; Pneumonia, Ventilator-Associated; Cohort Studies; Incidence; Prospective Studies; Bronchoalveolar Lavage; Dimercaprol
PubMed: 37749631
DOI: 10.1186/s13054-023-04658-5 -
Toxicon: X Jun 2022Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by (boomslang) results in venom-induced consumption coagulopathy...
Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by (boomslang) results in venom-induced consumption coagulopathy (VICC), whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at US$6000/vial, typically unaffordable for most snakebite patients. We therefore investigated the and preclinical efficacy of four SVMP inhibitors to neutralise the effects of venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS The venom of exhibited an SVMP-driven procoagulant phenotype . Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom , whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenoming using mixed sex CD1 mice, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The preclinical results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for snakebite envenoming. These two drugs have been previously shown to be effective against VICC in preclinical models, and thus we conclude that marimastat and DMPS should be further explored as potentially valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.
PubMed: 35321116
DOI: 10.1016/j.toxcx.2022.100118 -
BMJ Case Reports Sep 2021A 38-year-old man presented at the emergency department with abdominal pain, vomiting, generalised weakness and altered consciousness. He had been ingesting opioids for...
A 38-year-old man presented at the emergency department with abdominal pain, vomiting, generalised weakness and altered consciousness. He had been ingesting opioids for over 5 years and had several past hospital admissions for abdominal pain. His investigations showed deranged liver function tests, anaemia and basophilic stippling on the peripheral blood smear. Further investigations revealed a significant increase in the serum lead level. We started chelation with peroral penicillamine 250 mg every 6 hours for 2 days and switched to intramuscular dimercaprol 4 mg/kg every 12 hours and intravenous calcium ethylenediamine tetraacetic acid 50 mg/kg in two divided doses daily for the next 5 days. We then discharged him home; he had become clinically stable by that time. We repeated his lead level and followed him up in the clinic. In this report, we emphasise the consideration of lead toxicity in opioid abusers and bring to attention a rare way of lead chelation in resource-limited settings.
Topics: Abdominal Pain; Adult; Analgesics, Opioid; Brain Diseases; Humans; Lead; Lead Poisoning; Male
PubMed: 34544696
DOI: 10.1136/bcr-2020-240977 -
Heliyon Apr 2024Mercury's neurotoxic effects have prompted the development of advanced control and remediation methods to meet stringent measures for industries with high-mercury... (Review)
Review
Mercury's neurotoxic effects have prompted the development of advanced control and remediation methods to meet stringent measures for industries with high-mercury feedstocks. Industries with significant Hg emissions, including artisanal and small-scale gold mining (ASGM)-789.2 Mg year, coal combustion-564.1 Mg year, waste combustion-316.1 Mg year, cement production-224.5 Mg year, and non-ferrous metals smelting-204.1 Mg year, use oxidants and adsorbents capture Hg from waste streams. Oxidizing agents such as O, Cl, HCl, CaBr, CaCl, and NHCl oxidize Hg to Hg for easier adsorption. To functionalize adsorbents, carbonaceous ones use S, SO, and NaS, metal-based adsorbents use dimercaprol, and polymer-based adsorbents are grafted with acrylonitrile and hydroxylamine hydrochloride. Adsorption capacities span 0.2-85.6 mg g for carbonaceous, 0.5-14.8 mg g for metal-based, and 168.1-1216 mg g for polymer-based adsorbents. Assessing Hg contamination in soils and sediments uses bioindicators and stable isotopes. Remediation approaches include heat treatment, chemical stabilization and immobilization, and phytoremediation techniques when contamination exceeds thresholds. Achieving a substantially Hg-free ecosystem remains a formidable challenge, chiefly due to the ASGM industry, policy gaps, and Hg persistence. Nevertheless, improvements in adsorbent technologies hold potential.
PubMed: 38571637
DOI: 10.1016/j.heliyon.2024.e28253 -
Translational Neurodegeneration Apr 2021The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is...
BACKGROUND
The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits.
METHODS
DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein.
RESULTS
DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein's ability to upregulate TRPA1 was also verified in vitro using cell lines.
CONCLUSIONS
These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.
Topics: Acrolein; Animals; Behavior, Animal; Cerebral Cortex; Dimercaprol; Dopaminergic Neurons; Hydroxydopamines; Male; Motor Activity; Neostriatum; Neuroprotective Agents; Pain; Pain Measurement; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Substantia Nigra; TRPA1 Cation Channel
PubMed: 33910636
DOI: 10.1186/s40035-021-00239-0 -
Neurotoxicity Research Oct 2022Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson's disease. We assessed whether three neuronal...
Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson's disease. We assessed whether three neuronal cell lines are sensitive to killing by ferroptosis. Ferroptosis inducer erastin killed LUHMES neurons at sub-micromolar concentrations, whereas neuronal cells derived from SH-SY5Y cells or neural stem cells were at least 50-fold less sensitive. LUHMES differentiated neurons were likewise sensitive to killing by RSL3 or ML210, inhibitors of the glutathione peroxidase 4 enzyme (GPX4) that consumes GSH to detoxify lipid peroxides. Additional assays showed that erastin, RSL3, and ML210 increased lipid peroxide levels, and that LUHMES neurons were protected from both peroxide accumulation and cell death by ferrostatin-1. A possible role of iron was assessed by evaluating the effects of five metal chelators on cytotoxicity of erastin and RSL3. LUHMES neurons were protected from RSL3 by three of the chelators, 2,3-dimercapto-1-propanesulfonic acid (DMPS), deferoxiprone (DFX), and deferiprone (DFP). Collectively, these results demonstrate the vulnerability of LUHMES neurons to ferroptosis by chemical treatments that disrupt glutathione synthesis, lipid peroxide detoxification, or iron metabolism. The same vulnerabilities may occur in CNS neurons, which reportedly generate low levels of GSH and metallothioneins, limiting their ability to neutralize oxidative stresses and toxic metals. These results suggest a rationale and methods to search for environmental toxicants that may exploit these vulnerabilities and promote neurodegenerative diseases.
Topics: Humans; Carbolines; Chelating Agents; Deferiprone; Dopaminergic Neurons; Ferroptosis; Glutathione; Iron; Lipid Peroxides; Neuroblastoma; Phospholipid Hydroperoxide Glutathione Peroxidase; Unithiol
PubMed: 35922689
DOI: 10.1007/s12640-022-00538-y