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Nature Communications Dec 2020Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable...
Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite.
Topics: Animals; Antivenins; Asia; Benzamidines; Central America; Dimercaprol; Disease Models, Animal; Drug Combinations; Drug Evaluation, Preclinical; Guanidines; Kaplan-Meier Estimate; Male; Mice; Neutralization Tests; Serine Proteases; Snake Bites; Toxins, Biological; Viper Venoms
PubMed: 33323937
DOI: 10.1038/s41467-020-19981-6 -
Basic & Clinical Pharmacology &... Jun 2017The efficacy of treatment for intravenous elemental mercury intoxication has not been fully studied with regard to clinical outcome, and treatment recommendations vary....
The efficacy of treatment for intravenous elemental mercury intoxication has not been fully studied with regard to clinical outcome, and treatment recommendations vary. We treated a 41-year-old man with a history of drug abuse and depression who attempted suicide using 1 mL (13.53 g) metallic Hg i.v. He was admitted to the hospital 2 months later for dyspnoea and thoracic pain and was diagnosed with pneumonia. Hg deposits were seen in the lungs and extra-pulmonary organs. His blood level (372 μg/L) exceeded the population level of 5 μg/L by more than 70 times. Dimercaptopropane sulphonate sodium (DMPS; 600 mg/day orally) was administered for 14 days. One year later, the patient presented with dyspnoea on exertion, fatigue, depression and impaired sleep. His chest X-ray showed multiple opacities (size up to 2.8 cm), and psychological testing revealed a selective cognitive deficit in the area of visual attentiveness, flexibility, source memory and impairment of the motor speed of the dominant upper extremity. Mercury blood level was 158 μg/L and mercury urine output was 1380 μg/24 hr. DMPS (800 mg/day orally) was administered for 40 days; the patient eliminated up to 18 mg Hg/day. His Hg blood level and Hg urine output belong to the highest among reported cases. In spite of the therapy, the patient's blood Hg, complaints and psychological tests showed no improvement. This case report confirms that DMPS does not effectively remove intravenous deposits of metallic Hg.
Topics: Adult; Chelation Therapy; Humans; Injections, Intravenous; Male; Mercury Poisoning; Suicide, Attempted; Unithiol
PubMed: 27911474
DOI: 10.1111/bcpt.12725 -
Pediatrics Aug 2017Mercury (Hg) poisoning is considered a rare disease by the National Institutes of Health and the diagnosis can present great challenges to clinicians. Children who are...
Mercury (Hg) poisoning is considered a rare disease by the National Institutes of Health and the diagnosis can present great challenges to clinicians. Children who are exposed to Hg can present with a wide variety of symptoms, including acrodynia, tremor, excessive salivation, and psychiatric symptoms, including insomnia. However, endocrinologic manifestations from Hg exposure are less well known. This is a case report of a 12-year-old boy who presented with body rash, irritability, insomnia, and profuse sweating after returning from a summer camp. The child was initially managed in the outpatient setting, and the investigation was mainly targeted toward infectious etiology, including Rocky Mountain spotted fever and Lyme disease. He was eventually admitted to the hospital with altered mental status and was noted to have hyponatremia with serum sodium of 121 mEq/L. Thyroid studies also revealed elevated free thyroxine levels in the presence of normal triiodothyronine and thyrotropin. The patient developed hypertension and tachycardia, and was found to have elevated 24-hour vanillylmandelic acid and metanephrines. Finally, heavy metal measurements revealed a blood Hg level that was greater than the reference values of 0 to 9 ng/mL. Chelation treatment with 2,3-dimercaptopropane-1-sulfonate was subsequently initiated and over a period of 8 months his symptoms resolved and his thyroid function test returned to normal. This case highlights some of the challenges commonly encountered in identifying Hg exposure. More importantly, it illustrates that exposure to Hg should be considered in children who present with the symptoms and abnormal endocrinologic test results described in this report.
Topics: Chelation Therapy; Child; Diagnosis, Differential; Humans; Hyperthyroxinemia; Hyponatremia; Male; Mercury Poisoning; Metanephrine; Patient Admission; Rare Diseases; Unithiol; Vanilmandelic Acid
PubMed: 28701428
DOI: 10.1542/peds.2016-1402 -
Journal of Bronchology & Interventional... Apr 2023E-cigarette or vaping-use related acute lung injury (EVALI) is a spectrum of radiographic and histologic patterns consistent with acute to subacute lung injury. However,...
Bronchoalveolar Lavage (BAL) and Pathologic Assessment of Electronic Cigarette or Vaping Product Use-associated Lung Injury (EVALI): The EVALI-BAL Study, A Multicenter Cohort.
BACKGROUND
E-cigarette or vaping-use related acute lung injury (EVALI) is a spectrum of radiographic and histologic patterns consistent with acute to subacute lung injury. However, limited data exist characterizing bronchoalveolar lavage (BAL) findings. The goal of this study is to further define the pathologic findings from BAL and biopsy samples of subjects with EVALI across 7 institutions.
METHODS
A multicentered registry of patients admitted with EVALI who underwent flexible bronchoscopy with BAL+/-transbronchial biopsy from July 2019 to April 2021 was compiled for retrospective evaluation from 7 academic institutions throughout the United States. Radiographic and cytopathologic findings and frequencies were correlated with the substance vaped.
RESULTS
Data from 21 subjects (42.9% women) who were predominantly White (76.2%) with a median age of 25 years (range, 16 to 68) with EVALI were included in this study. Sixteen patients (76.2%) reported use of tetrahydrocannabinol; the remainder used nicotine. BAL was performed in 19 of the 21 subjects, and transbronchial lung biopsy was performed in 7 subjects. BAL findings revealed neutrophilic predominance (median, 59.5%, range, 3.1 to 98) in most cases. Ten BAL samples demonstrated pulmonary eosinophilia ranging from 0.2% to 49.1% with one subject suggesting a diagnosis of acute eosinophilic pneumonia associated with the use of e-cigarettes. Lipid-laden macrophages were noted in 10 of 15 reports (66.7%). Transbronchial biopsy most frequently demonstrated patterns of organizing pneumonia (57.1%).
CONCLUSION
EVALI-associated BAL findings typically demonstrate a spectrum of nonspecific inflammatory changes, including neutrophilia, lipid-laden macrophages, and in some cases eosinophilia.
Topics: Humans; United States; Female; Adolescent; Young Adult; Adult; Middle Aged; Aged; Male; Lung Injury; Electronic Nicotine Delivery Systems; Retrospective Studies; Bronchoalveolar Lavage; Dimercaprol; Lipids
PubMed: 35993570
DOI: 10.1097/LBR.0000000000000890 -
The Turkish Journal of Pediatrics 2019Çelebi-Tayfur A, Yaradılmış RM, Ulus F, Çaltık-Yılmaz A, Özayar E, Koşar B, Büyükkaragöz B, Horasanlı E. Bismuth intoxication resulting in acute kidney...
Çelebi-Tayfur A, Yaradılmış RM, Ulus F, Çaltık-Yılmaz A, Özayar E, Koşar B, Büyükkaragöz B, Horasanlı E. Bismuth intoxication resulting in acute kidney injury in a pregnant adolescent girl. Turk J Pediatr 2019; 61: 292-296. Bismuth intoxication is a rare cause of acute kidney injury (AKI) and is usually reversible by appropriate therapeutic measures. We present here a case of an adolescent pregnant girl who developed AKI due to an overdose of colloidal bismuth subcitrate (CBS, total amount of 6 g). She received parenteral chelating agent dimercaprol for 14 days. Continuous venovenous hemodiafiltration (CVVHD) with high-flux membrane was carried out in the first 3 days of chelating therapy and intermittent hemodialysis for 11 days, thereafter. The patient recovered clinically and was discharged after 21 days. She gave birth to a healthy term boy. At the last visit, the baby was 6 months old with normal growth and development as well as normal kidney functions. Neither deterioration in renal functions nor emergence of proteinuria was recorded in the patient during follow-up care after hospital discharge. In cases of AKI due to an overdose of CBS, treatment with dimercaprol combined with high flux hemodiafiltration and subsequently hemodialysis appears to be both useful and safe for bismuth elimination.
Topics: Acute Kidney Injury; Adolescent; Bismuth; Drug Overdose; Female; Hemodiafiltration; Humans; Pregnancy; Pregnancy Complications; Renal Dialysis
PubMed: 31951346
DOI: 10.24953/turkjped.2019.02.024 -
Journal of Advanced Pharmaceutical... 2015Acne vulgaris is a chronic inflammatory disease, and its treatment is challenging due to the multifactorial etiology and emergence of antibiotic-resistant...
Acne vulgaris is a chronic inflammatory disease, and its treatment is challenging due to the multifactorial etiology and emergence of antibiotic-resistant Propionibacterium acnes strains. This study was focused to reduce antibiotics usage and find an alternate therapeutic source for treating acne. Lipid extracts of six Chlorella species were tested for inhibition of lipase, reactive oxygen species (ROS) production, cytokine production using P. acnes (Microbial Type Culture Collection 1951). Lipase inhibitory assay was determined by dimercaprol Tributyrate - 5, 5'- dithiobis 2-nitrobenzoic acid method and ROS production assay was performed using nitro-blue tetrazolium test. The anti-inflammatory activity of algal lipid extracts was determined by in vitro screening method based on inhibition of pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) produced by human peripheral blood mononuclear cells. Minimum inhibitory concentration (MIC) values of lipid extracts were determined by microdilution method, and the fatty acid methyl esters (FAME) were analyzed by gas chromatography-mass spectroscopy. Chlorella ellipsoidea has the highest lipase inhibitory activity with 61.73% inhibition, followed by Chlorella vulgaris (60.31%) and Chlorella protothecoides (58.9%). Lipid extracts from C. protothecoides and C. ellipsoidea has significantly reduced the ROS production by 61.27% and 58.34% respectively. Inhibition of pro-inflammatory cytokines TNF-α showed the inhibition ranging from 58.39% to 78.67%. C. vulgaris has exhibited the MICvalue of 10 μg/ml followed by C. ellipsoidea, C. protothecoides and Chlorella pyrenoidosa (20 μg/ml). FAME analysis detected 19 fatty acids of which 5 were saturated fatty acids, and 14 were unsaturated fatty acids ranging from C14 to C24. The results suggest that lipid extracts of Chlorella species has significant inhibitory activity on P. acnes by inhibiting lipase activity. Further, anti-inflammatory reaction caused by the pathogen could be reduced by the inhibiting the production of ROS and inflammatory mediators TNF-α and exposes new frontiers on the antiacne activities of Chlorella lipid extracts.
PubMed: 25709963
DOI: 10.4103/2231-4040.150364 -
Environmental Technology Jun 2019An ultrafiltration membrane prepared by polyethersulfone (PES) was modified with Bismuth-BAL chelate (BisBAL) and was used in submerged membrane bioreactor system....
An ultrafiltration membrane prepared by polyethersulfone (PES) was modified with Bismuth-BAL chelate (BisBAL) and was used in submerged membrane bioreactor system. Moreover, a control membrane reactor was also tasked to evaluate the effect of BisBAL on the membrane performance. The flux profile, transmembrane pressure, the effect of chemical treatment, cake layer formation, anti-fouling properties against extracellular polymeric substances (EPS) and soluble microbial products (SMP) were studied. The UF modified membrane demonstrated a sustained permeability, low cleaning frequency, and longer filtration time. In terms of anti-EPS and SMP accumulation, the modified membrane showed a lower membrane resistance. It can be illustrated from scanning electron microscopy and confocal laser scanning microscope images that the modified membrane had presented better properties than bare PES membrane, as it was looser and thinner. Thus, the UF membrane proved to be more efficient in terms of permeability and lifetime.
Topics: Bioreactors; Bismuth; Dimercaprol; Membranes, Artificial; Organometallic Compounds; Sewage
PubMed: 29409397
DOI: 10.1080/09593330.2018.1435735 -
Biochimie Nov 2014Dimercaptopropanesulfonic acid (DMPS) has been approved for the treatment of arsenic poisoning through promoting arsenic excretion and modulating arsenic species. To...
Dimercaptopropanesulfonic acid (DMPS) has been approved for the treatment of arsenic poisoning through promoting arsenic excretion and modulating arsenic species. To clarify how DMPS regulates the excretion of arsenic species, we investigated the effects of DMPS on the biomethylation of arsenite (As(3+)) in HepG2 cells. In the experiments, we found that DMPS at low concentrations dramatically decreased the content of arsenic in HepG2 cells and inhibited the cellular methylation of As(3+). Three aspects, the expression of human arsenic (III) methyltransferase (hAS3MT), the accumulation of cellular reactive oxygen species (ROS) and the in vitro enzymatic methylation of arsenic, were considered to explain the reasons for the inhibition of DMPS in arsenic metabolism. The results suggested that DMPS competitively coordinated with As(3+) and monomethylarsonous acid (MMA(3+)) to inhibit the up-regulation of arsenic on the expression of hAS3MT and block arsenic involving in the enzymatic methylation. Moreover, DMPS eliminated arsenic-induced accumulation of ROS, which might contribute to the antidotal effects of DMPS on arsenic posing.
Topics: Antidotes; Apoptosis; Arsenic; Arsenic Poisoning; Blotting, Western; Cell Survival; Dose-Response Relationship, Drug; Gene Expression; Hep G2 Cells; Humans; Methylation; Methyltransferases; Organometallic Compounds; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Unithiol
PubMed: 25194983
DOI: 10.1016/j.biochi.2014.08.017 -
Scientific Reports May 2016Local changes in pH are known to significantly alter the state and activity of proteins and enzymes. pH variations induced by pulses propagating along soft interfaces...
Local changes in pH are known to significantly alter the state and activity of proteins and enzymes. pH variations induced by pulses propagating along soft interfaces (e.g. membranes) would therefore constitute an important pillar towards a physical mechanism of biological signaling. Here we investigate the pH-induced physical perturbation of a lipid interface and the physicochemical nature of the subsequent acoustic propagation. Pulses are stimulated by local acidification and propagate - in analogy to sound - at velocities controlled by the interface's compressibility. With transient local pH changes of 0.6 directly observed at the interface and velocities up to 1.4 m/s this represents hitherto the fastest protonic communication observed. Furthermore simultaneously propagating mechanical and electrical changes in the lipid interface are detected, exposing the thermodynamic nature of these pulses. Finally, these pulses are excitable only beyond a threshold for protonation, determined by the pKa of the lipid head groups. This protonation-transition plus the existence of an enzymatic pH-optimum offer a physical basis for intra- and intercellular signaling via sound waves at interfaces, where not molecular structure and mechano-enyzmatic couplings, but interface thermodynamics and thermodynamic transitions are the origin of the observations.
Topics: Acoustics; Hydrogen-Ion Concentration; Lipids; Protons; Signal Transduction; Static Electricity; Thermodynamics; Unilamellar Liposomes; Unithiol
PubMed: 27216038
DOI: 10.1038/srep22874 -
Frontiers in Pharmacology 2023Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have...
Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)-a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar ECs comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.
PubMed: 38273820
DOI: 10.3389/fphar.2023.1328950