Coastal Taipans what are they?

The Australian coastal taipan, or Oxyuranus scutellatus, is a venomous species of elapid, native to northern and eastern Australia and New Zealand. The Coastal taipan is relatively common throughout its range and is the longest venomous snake in Australia. (3) The largest of the species have reached up to 9.5 feet and have weighed 6.6 pounds. The snake is similar both morphologically and genetically to the African black mamba. (1)

Citation: austrailianreptilepark.org

Typically the coloaration is light olive to dark brown dorsally with a cream colored ventrum. The snake typically will have reddish eyes. (6)

The Coastal Taipan is considered the third most venomous snake in the world. The venom of this snake is primarily taicatoxin and has a Lethal Dose (LD50) of as low as 0.106mg/kg. That being said, the venom of the coastal taipan is a collection of numerous toxins which make a deadly cocktail. (2)

Typical Taipan behavior as explained by Steve Irwin:

Biotransformative effects:

Taicatoxin is a toxin which acts at multiple areas of the body. The taicatoxin acts on the heart through voltage-dependent L-type calcium channels. It acts systemically, through binding the small conductance Ca²⁺ -activated K+ channels on chromaffin cells which causes the release of catecholamines and endorphins systemically. (4)

citation: https://www.bioscience.org/2002/v7/d/dirksen/fulltext.php?bframe=figures.htm

The Taipoxins and paradoxins act presynaptically to cause the blockage of neuron-musculature communication which eventually leads to paralysis.

Procoagulants also are in coastal taipan venom which works similarly to Factor Xa causing thrombin formation and coagulopathy throughout he body. (5)

Toxicokinetics of Coastal Taipan Venom:

Taicatoxin is the primary toxin, which is made up of three polypeptides. The first polypeptide is an alpha-neurotoxin like peptide.

The second polypeptide is a neurotoxic phospholipase.

The third polypeptide is a serine protease inhibitor. (5)

Taipoxins and paradoxins are other toxins in the coastal taipan venom, which typically affect presynaptic neurons.

citation: https://www.sciencedirect.com/topics/neuroscience/taipoxin

Mechanism of Action of Coastal Taipan Venom:

Taicatoxin works through allowing for a lower the activation threshold for action potentials. This makes it a neurotoxin which can cause a variety of downstream effects. (5)

They actually work on both pre and postsynaptic neurons. The presynaptic neurotoxins bind to the terminal axon at the neuromuscular junction. This then causes paralysis due to neuronal activation blockage. The paralysis will systemically effect all muscle groups. The postsynaptic neurotxoins bind to acetylcholine receptors on muscular end plates.

Additionally, the Factor Xa-like procoagulants work through causing prothrombin to become thrombin which causes fibrinogen to fibrin formation. Clots then form systemically. (6)

The coagulation cascade is shown below:

citation: https://diapharma.com/coagulation/

Carcinogenicity and Teratogenicity of Coastal Taipan venom:

Cardiogenicity and teratogencity has not been evaluated since this is such a potent venom. (6)

Target Organs of Coastal Taipan Venom:

https://en.wikipedia.org/wiki/Circulatory_system#/media/File:Circulatory_System_en.svg

citation: https://qbi.uq.edu.au/brain/brain-anatomy/peripheral-nervous-system

citation: https://www.amazon.com/LAMINATED-ENCAPSULATED-Musculature-measures-91-5x61cm/dp/B0085UQWUO

citation: https://www.dreamstime.com/stock-illustration-urinary-system-also-known-as-renal-anatomy-image97621763

Target organs of coastal taipan venom include the circulatory system, central & peripheral nervous system, musculature and renal system.

Signs and Symptoms of Coastal Taipan Venom:

Bites seldom occur but typically severe pain is immediate, followed by intensification of pain and addition of the following symptoms within 80 minutes, these symptoms can last up to a week and but death usually occurs within 6 hours.

• Intense pain locally at the bite site
• Headache
• Nausea
• Vomiting
• Abdominal pain
• Impaired consciousness
• Fainting
• Convolusions
• Overt bleeding
• Rhabdomyolysis
• Paralysis
• Acute renal failure

The symptoms above are used along with the morphology of the snake for a clinical diagnosis. (6)

The paralysis associated with coastal taipan bites is the most dangerous toxicity related symptom due to the arrest of circulation and breathing. (6)

Treatment for Coastal Taipan Bites?

As with any toxicity case which presents 6 steps are traditionally taken for management:(12)

1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
3. Prevention of further contamination through removing clothing which has been exposed.
4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with benzimidazoles toxicity.
5. There is no antidote to benzimidazoles poisioning.
6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Typical snake bite first aid is shown in the informative video below:

What is important with coastal taipan treatment is to make sure the cardiopulmonary function is sustained as well as treating for shock, blood loss and dehydration. (6)

Use of anti-venom with coastal taipan toxicity:

The anti-venom used to prevent further toxicity and save patients lives are taipain snake antivenom. They selectively bind to the venom which is already bound throughout the body and causing physical symptoms.

The entire vial of 12,000 units of anti-venom should be given to the patient intravenously. The patient should also be evaluated for hypersensitivity reactions to the anti-venom.(6)

Biomarkers for Coastal Taipan Venom do not exist since toxicity is acute and not therapeutic in nature.

Snake Venom use in Medicine: 

Snake venom is currently widely researched to be used a therapeutics and diagnostics.

Below is an incredibly interesting video about collecting venom from russels vipers and the venoms effect on the blood. ****this video includes blood****

What is interesting about this venom is that they are using it as a bioassay. The test it called the Dilute Russell Viper Venom Time, and is useful for identifying whether or not lupus anticoagulants are in the blood.

Propylene glycol what is it?

Propylene Glycol, or propane-2, 2-diol, is a synthetic diol alcohol that absorbs water. Its chemical formula is C₃H₈O₂. It has an atomic weight of 76.095 g-mol^-1 and a density of 1.036 g/cm³.

Typically propylene glycol is a colorless and clear liquid at atmospheric temperatures. It has a melting point of -74 F and a boiling point of 370.8 F. (1)

In industrial settings, propylene glycol is produced through the hydration of propylene oxide and the addition of sulfuric acid or alkali which produces a solution with 20% propylene glycol and 1.5% propylene glycol.(2)

In the laboratory, S-propanediol glycol is produced through the following reaction:

Laboratory production of Propylene Glycol: source Hanessian, Stephen (1983). Total Synthesis of Natural Products: The ‘Chiron’ Approach. Pergamon press. p. 41. ISBN 978-0080307152.

Propylene glycol is typically used in the production of resins and polyester fibers. It also is used as antifreeze, waterbased acrylic paints, coolants, humectant solvent, pharmaceuticals and food additive. (3)

As a solvent, propylene glycol is used in drugs such as:

Lorazepam: source: https://www.realbuyrx.com/Online/ativan-2mg-lorazepam/

Diazepam: source: https://www.mcguffmedical.com/diazepam-c-iv-10mg-100-tabletsbottle

Biotransformative effects:

Biotransformation studies have been performed to understand why ethylene glycol causes toxic effects.

There are two proposed mechanisms of propylene glycol metabolism:

The first is as follows:

Ethylene glycol is transformed in the liver by alcohol dehydrogenase to glyceraldehyde. Aldehyde dehydrogenase causes glyceraldhyde to become glycolic acid. The glycolic acid then be comes glyoxylic acid. At this stage there are several different byproducts which are produced. With thiamine and magnesium interacts, alpha-hydroxy-beta-ketoadipic acid is produced. With pyridoxine, glycine is produced. Additionally, oxalic acid, formic acid and gamma-hydroxy-alpha-ketoglutaric acid is produced. (4)

This pathway is described below in the following photo:

Ethylene Glycol Pathway: source: https://www.atsdr.cdc.gov/csem/csem.asp?csem=12&po=8

The second proposed metabolism is as follows:

Propane-2, 2-diol is transformed in the liver by alcohol dehydrogenase to DL-lactaldehyde. DL-lactaldehyde binds to the enzyme alcohol dehydrogenase, which causes methylglyoxal to be formed. Then the methylglyoxal is reduced by glutathione to D-lactate. DL-lactaldehyde can also be transformed by the enzyme alcohol dehydrogenase, into DL-Lactate which is transformed in the liver and used in gluconeogenesis to make glucose. (5)

The pathway is also described by the following photo:

Propylene Glycol Metabolism: source: https://www.atsdr.cdc.gov/ToxProfiles/tp189.pdf

Toxicokinetics of Propylene Glycol:

Propylene Glycol typically is inhaled, ingested or absorbed through the skin.

Propylene Glycol is actually considered very safe and there have been no human deaths from exposure. Propylene glycol is actually cleared by the body within 48 hours of exposure.

Since propylene glycol is not considered hazardous its toxicokinetics is has not been thoroughly investigated.

That being said, when ingested it is absorbed quickly through the gastrointestinal tract. It reaches Tmax within an hour of ingestion. With constant small dosing through food or other sources it can build up to toxic levels in the blood.

If propylene glycol is on skin, say when giving dermal therapeutics, it can be seen in the blood and in the urine at low levels. In one burn victim study, as long as blood concentrations were below 1.3 mg/mL the patients survived. In general, propylene glycol is not readily absorbed through the skin unless it also is mixed with another acid.

Mechanism of Action of Propylene Glycol- toxicity:

The mechanism of action of propylene glycol is due to the effects of glycolic acid and oxalic acid.

Glycolic acid will build up as propylene glycol is broken down and will cause a metabolic acidosis in the patient.

For an explanation of metabolic acidosis check out this youtube video:

Normally, oxalic acid cause the binding of calcium throughout the body, which can cause crystal formation in the body. Normally this can cause kidney issues. Fortunately, propylene glycol does not cause crystal formation but rather just a hypocalcaemia in the patient.(5)

More information about oxalic acid poisoning can be read in this really interesting article!

Dassanayake, Uditha, and Christeine Ariaranee Gnanathasan. “Acute Renal Failure Following Oxalic Acid Poisoning: a Case Report.” Journal of Occupational Medicine and Toxicology (London, England), BioMed Central, 14 Sept. 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3527234/.

Carcinogenicity and Teratogenicity of Propylene Glycol:

Propylene Glycol is actually one of the safer solvents which we have studied in regards to carcinogenicity and teratogenicity. There is no evidence that propylene glycol is a teratogen, genotoxic or carcinogenic. This has been shown in rays, cell lines and mice. (5)

Target Organs of Propylene Plycol:

Propylene glycol is considered safe so it actually doesn’t cause many issues but if a person is immunocompromised, typically the renal and hepatic system is damaged.

If inhaled an acute respiratory acidosis can occur.

Respiratory acidosis: source: https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/acid-base-regulation-and-disorders/respiratory-acidosis

If inhalation is severe enough, cardiac and pulmonary failure could occur. This has not been documented.

Skin irritation can also occur.(5)

Signs and Symptoms of Propylene Glycol:

Signs of propylene glycol tend to be nonspecific but can present as follows.

Rubor: https://www.slideshare.net/anushareddy999/inflammation-84417407

EDEMA

Edema: https://www.slideshare.net/saeidzaxo/leg-edema-family-medicine

TACHYCARDIA

Tachypnea

Initial inebriation leads to the neurologic effects of: stupor, convolusions, and neurotoxicity. (8)

Treatment for Propylene Glycol?

*****Below is adapted from my last Benzimidazole post:(9)****

As with any toxicity case which presents 6 steps are traditionally taken for management:(8)

1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
3. Prevention of further contamination through removing clothing which has been exposed.
4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with selenium toxicity.
5. There is no antidote to selenium poisioning.
6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Management is typically supportive but if severe, hemodialysis can be performed.

Significant propylene glycol toxicity:

In the early 1980’s an 8 month old child was admitted to a hospital for a severe burns after being caught in a house fire. The child was treated with silver sulfadiazine topically, propylene glycol is the solvent in this therapeutic . The child went into cardiorespiratory arrest after administration but it was not determined whether this was due to the fire, smoke or the drug itself. This is incredibly sad story was the only death which could even remotely be linked to propylene glycol. (10)

Citations:

(1) The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. Merck & Co. 1989. ISBN 978-0911910285.

(2) “1,2-propanediol: chemical product info at CHEMINDUSTRY.RU”. Retrieved 3 October2018.

(3): Bradley, Jean-Claude; Abraham, Michael H; Acree, William E; Lang, Andrew (2015). “Predicting Abraham model solvent coefficients”. Chemistry Central Journal. 9 (1): 12. doi:10.1186/s13065-015-0085-4. ISSN 1752-153X. PMC 4369285. PMID 25798192.

(4) “Environmental Health and Medicine Education.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, www.atsdr.cdc.gov/csem/csem.asp?csem=12&po=8.

(5) “Use of Race and Ethnicity in Public Health Surveillance: Summary of the CDC/ATSDR Workshop.” PsycEXTRA Dataset, 1993, doi:10.1037/e546762006-001.

(6) “Renal Function Markers – Kidney Disease.” ARUPConsult, arupconsult.com/content/renal-function-markers.

(7) “Elevated Liver Enzymes.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 11 Jan. 2018, www.mayoclinic.org/symptoms/elevated-liver-enzymes/basics/definition/sym-20050830.

(8) Plahovinsak, J. “PHRM7588: Toxic Substances.” Carmen.com, 2019.

(9) Palillo, M. 2019. Benzimidazoles- Fungi and Helminths Beware! https://u.osu.edu/palillo.1/

Selenium what is it?

http://www.chemistryexplained.com/elements/P-T/Selenium.html

Selenium is a reactive nonmetal and sometimes an metalloid which is located in period four and group 16 of the periodic table.  Selenium has an atomic weight of 78.971 and an atomic number of 34. Its electron configuration is 3d(10) 4s(2) 4p(4).

Selenium is a solid at atmospheric temperatures as it has a melting point of 430 F and a boiling point of 1265 F.

Typically solid selenium is black, red or grey. It exists as selenid, elemental selenium, selenite, and selenate.

Selenium was first discovered as a byproduct of sulfuric acid production which caused illness in the factory workers. (2)

That being said people who work or live near industries where selenium is produced or processed and near coal burning plants may be exposed to higher levels of selenium in the air.

Selenium is a considered a trace element. Selenium deficiency and over supplementation can cause adverse effects due to the nature of its use in our body. Deficency leads to Keshan disease which is due to nature of selenium as a cofactor to glutathione peroxidase. Oversupplementation can lead to amyotropic lateral sclerosis, malignancy, and increased risk of diabetes.

Due to the fact that selenium can cause adverse effects if under or over supplemented, the recommended daily allowance is 55 mcg/day. (3)

Biotransformative effects:

Biotransformation studies have been have been carried out extensively in plants to help understand the effect of selenium level deficiency in farm animals and humans.

Selenium is intricately related to glutathione pathways in the body so biotransformation is typically studied in relation to this pathway. These compounds include: 2,3-dihydroxypropionyl-selenolanthionine, selenohomolanthionine, methyltio-selenoglutathione, Se-methyl-selenocysteine, 2,3-dihydroxy-propionyl-selenocysteine-cysteine, selenomethionine, methyl-seleno-Se-pentose-hexose, deaminohydroxy-selenohomolanthionine, Se-methyl-selenoglutathione and γ-glutamyl-Se-methyl-selenocysteine. (4)

Glutathione fragmentation showing typical sidechains which nearly all include Selenium. Ruszczyńska, Anna. “Investigation of Biotransformation of Selenium in Plants Using Spectrometric Methods.” Spectrochimica Acta Part B: Atomic Spectroscopy, Elsevier, 4 Feb. 2017, www.sciencedirect.com/science/article/pii/S0584854717300678.

Selenium in the body is used for a variety of cellular processes. Selenoproteins help with oxidation-reduction reactions. These reactions are important for detoxification, glutathione production, and has antioxidant properties.  Additionally, selenium is part of the plasma proteins albumin and globulin, and allow for plasma proteins to bind these proteins for transport through the body. (3)

Toxicokinetics of Selenium:

Selenium typically is ingested or inhaled to cause toxic effects. Inhalation causes the most acute effects, although gastrointestinal absorption can cause toxicity.

Acute effects of selenium toxicity does not occur with elemental selenium but selenium salts, selenid, selenite, and selenate can cause toxicity.

Selenide ions typically are what goes through metabolic processes through the body and has 3 typical outcomes.

1. Glutathione peroxidase, triiodothyronine and other selenoprotein addition as a side chain.
2. Albumin or Globulin binding as a plasma protein sidechain to allow the transport of various substances through the body.
3. Phase I and Phase II biotransfomation typically in the liver where the selenide is methylated so it can be excreted.

Typical metabolism occurs as seen in the following diagram.

Figure 97-1 of goldfranks toxicologic emergencies.

Renal excretion of selenium is typically as trimethyselenide, and low levels of excretetion also occur in the feces.

Selenium will cause toxicokinetic effects through affecting metabolic pathways but this has not been investigated in-depth as of yet! (3)

Mechanism of Action of Selenium- deficency and toxicty:

The mechanism of action of selenium depend on whether or not deficiency is prominent. Typically this will cause decreases in glutathione peroxidase activity as selenium is its cofactor. This then leads to decreased detoxification of glutathione S-transferase dependent substances. Some very prominent examples of this are  alfatoxin B and acetaminophen. (3)

Additionally, selenium has been proposed as an antioxidant which during deficiency causes decreased erythrocyte glutathione peroxidase. This then leads to increased capillary permeability which can cause osmotic changes throughout the body. (4)

For more information on selenium as an antioxidant please see this paper for alot of useful information!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698273/

Selenium toxicity is typically due to extreme levels of oral, inhaled or oral exposure. The exposure is usually to selenious acid, selenium oxide and dioxide. The latter of the two are converted into selenious acid once in the body which causes irritation, circulatory, skeletal muscle and gastrointestinal effects. (3)

Carcinogenicity and Teratogenicity of Selenium:

Selenium is somewhat special since it actually is currently being investigated for its anti-cancer effects. Selenium is not considered a carcinogen, but rather shows interesting use as a treatment for cancer metastasis. The reasoning for this is it has it helps the body to deal with oxidative stress. The selenoprotein, GPX, as been associated with certain tumor development, but this is a down stream pathway which is not due to selenium ingestion itself. (5)

Teratogenesis is not common in people but has been shown to lead to birth defects in animals. Stunted growth, fetal death, and skeletal abnormalities have been shown. (6)

Selenium deficiency birth defects
https://www.thegoatspot.net/threads/what-causes-weak-legs.195330/

White muscle disease from selenium deficiency: 

I just wanted to mention also that the Environmental Protection Agency (EPA) has determined that one specific form of selenium, selenium sulfide, is a probable human carcinogen. This evidence of classification of selenium sulfide is based on inadequate data from human studies and sufficient evidence in animals.

Target Organs of Selenium:

Target organs of acute selenium exposure include dermal, ophthalmic, respiratory and oral mucosa. This is usually due to the direct exposure to selenious acid.

Chronic selenium exposure typically affects the skin, central nervous system, musculoskeletal system and nail beds. (3)

Chronic selenium exposure causing nail bed koilonychia:
https://www.sciencedirect.com/topics/medicine-and-dentistry/nail-abnormality

Signs and Symptoms of Selenium:

Signs of selenium exposure range dramatically depending on chronicity or acute nature of toxicity. Typically acute exposure presents as:

Caustic burns

Caustic burns:
https://en.wikipedia.org/wiki/Chemical_burn

Rose eye conjunctivitis

Rose eye conjunctivitis:
https://parenting.firstcry.com/articles/conjunctivitis-during-pregnancy-causes-symptoms-and-remedies/

Bronchospasm

Bronchospasm:
https://www.normalbreathing.com/d/bronchospasm.php

Circulatory failure

Circulatory Failure:
https://www.google.com/search?q=circulatory+failure&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiHubOV9sHiAhVUtZ4KHRV7D_oQ_AUIDygB&biw=754&bih=385#imgrc=uadjVbcwh27rrM:

Chronic symptoms include fatigue, fever, nail deformities, diarrhea and skin lesions. These chronic symptoms tend to be few and far in between. When chronic exposure does occur, reduction in dietary selenium levels will lead to resolution of symptoms. (8)

Treatment for Selenium?

*****Below is adapted from my last Benzimidazole post:(9)****

As with any toxicity case which presents 6 steps are traditionally taken for management:(8)

1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
3. Prevention of further contamination through removing clothing which has been exposed.
4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with selenium toxicity.
5. There is no antidote to selenium poisioning.
6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Management of selenium toxicity is mainly related to pain management when caustic burns to the dermis or ophthalmic structures are seen. (7)

Essentiality and Biomarkers for Selenium?

Selenium is considered an essential trace element due to its properties as a glutathione peroxidase cofactor. Currently GPX3 and SEPP1 are considered useful biomarkers of selenium deficiency. Levels of less than 20 ug/kg in animals and <55 ug/day in humans is considered deficient levels.

Although GPX3 and SEPP1 are considered useful in the detection of selenium deficiency, they are not diagnostic in evaluation they are suggestive markers. (10)

Citations:

(1) Meija, Juris; et al. (2016). “Atomic weights of the elements 2013 (IUPAC Technical Report)”. Pure and Applied Chemistry. 88 (3): 265–91. doi:10.1515/pac-2015-0305.

(2) Weeks, Mary Elvira (1932). “The discovery of the elements. VI. Tellurium and selenium”. Journal of Chemical Education. 9

(3): Hoffman, Robert S, Mary A. Howland, Neal A. Lewin, Lewis Nelson, Lewis R. Goldfrank, and Neal Flomenbaum. Goldfrank’s Toxicologic Emergencies. , 2015. Print.

(4) Ruszczyńska, Anna. “Investigation of Biotransformation of Selenium in Plants Using Spectrometric Methods.” Spectrochimica Acta Part B: Atomic Spectroscopy, Elsevier, 4 Feb. 2017, www.sciencedirect.com/science/article/pii/S0584854717300678.

(4) Combs, G F, et al. “Mechanisms of Action of Selenium and Vitamin E in Protection of Biological Membranes.” Federation Proceedings, U.S. National Library of Medicine, Oct. 1975, www.ncbi.nlm.nih.gov/pubmed/1100438/.

(5) Chen, Yu-Chi et al. “Is selenium a potential treatment for cancer metastasis?.” Nutrients vol. 5,4 1149-68. 8 Apr. 2013, doi:10.3390/nu5041149

(6) EPA. “Selenium Compounds.” EPA.GOV, www.epa.gov/sites/production/files/2016-09/documents/selenium-compounds.pdf.

(7) Curtis D. Klaassen. Casarett And Doull’s Toxicology : the Basic Science of Poisons. New York :McGraw-Hill Education, 2013.

(8) Plahovinsak, J. “PHRM7588: Toxic Substances.” Carmen.com, 2019.

(9) Palillo, M. 2019. Benzimidazoles- Fungi and Helminths Beware! https://u.osu.edu/palillo.1/

Benzimidazoles what are they?

Benomyl, the most common of the Benzimidazoles. source: https://en.wikipedia.org/wiki/Benomyl

Benzimidazoles are a class of fungicides which was invented by DuPont industries as a methyl ester of [1-(butylcarbamoyl)-1H-benzimidazol-2-yl]carbamic acid. (1)

Production of Benzimidazoles are through a condesation reaction between phenylenediamine and formic acid as seen below in the equation below:(2)

C₆H₄(NH₂)₂ + HC(OCH₃)₃ → C₆H₄N(NH)CH + 3 CH₃OH

Benzimidazoles additionally have anti-helminthic effects on Nematodes, lungworms, some cestodies, some trematodes and adult flukes.(3)

The typical chemical conformation of benzimidazole- a imidazole and benzene bicyclic compound. source: https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+2797

https://www.google.com/search?biw=738&bih=657&tbm=isch&sa=1&ei=BHxAXdLmIZjPtQaW07XoBA&q=benzimidazole+product&oq=benzimidazole+product&gs_l=img.3…1060.4004..4119…0.0..0.235.947.5j2j1……0….1..gws-wiz-img…….0j0i8i30j0i24.QlI-Q1UndrI&ved=0ahUKEwjS-PGik93jAhWYZ80KHZZpDU0Q4dUDCAY&uact=5#imgrc=MOu66yWBhVAr0M:

Biotransformative effects:

Biotransformation studies have been have been carried out in various animal models ranging from rodents to ruminants to humans.

When in regards to the Benzimidazole, Albendazole, typically this process occurs as a 2 step process yielding albendazole sulphoxide and albendazole sulphone. albendazole sulphoxide is mediated by CYP3A and Flavine monooxygenases while albendazole sulphone is mediated through CYP1A.

When Fenbendazole is the Benzimidazole being used, typically biotransformation occurs into sulphoxide. The exact enzymes causing this are not definitively known but likely are due to CYP1A1/2. (4)

https://www.google.com/search?q=benzimidazole+biotransformation&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiEifPtk93jAhVSHqwKHcgND0IQ_AUIESgB&biw=746&bih=657&dpr=1.8#imgrc=-QZcK7LI1fjDHM:

Toxicokinetics of Benzimidazoles:

Benzimidazole will cause toxicokinetic effects through affecting metabolic pathways. Research into the specific pathways involved is sparse, but some definitive toxicokinetics have been shown.

Oral injestion tends to be the most rapid route of absorption in the body and the Benzimidazoles tend to be more fat soluble than water soluble. Excretion is through in the urine as 5-hydroxythiabendazole.(11)

Mechanism of Action of Benzimidazoles:

Although the exact mechanism of action for Benzimidazoles are not known there are a few clear effects.

On fungi, growth is stunted through inhibiting microtubule formation (5).

In parasite nematodes, several different effects have been found to be associated with Benzimidazoles including: fumarate reductase inhibition, energy production inhibition, glucose transport and uptake inhibition, as well as, microtubule degeneration and dissolution.(6)(7)

Carcinogenicity and Teratogenicity of Benzimidazoles:

Typically benzimidazoles have been shown to cause liver tumors in rats. Benzimidazoles have not been shown to cause carcinogenesis normally in other species. (8)

Teratogenesis is common in benzimidazoles but is dependent on the dose and species. In cattle, pigs and horses this will present as skeletal defects in the animals.(9)

In humans teratogenesis has been reported to present as anopthalmia when the benzimidazole, benomyl is given. (5) Anopthalmia is the abscence of the globe and ocular tissue as seen below:

source: https://www.cdc.gov/ncbddd/birthdefects/anophthalmia-microphthalmia.html

When the law gets involved with Benzimidazoles Exposures:

The most historically relevant exposure to benzimidazoles was in Miami in 1996. A child was born with anopthalmia due to the mother’s occupation as a gardener. A law suit ensued with a final verdict of 4 million dollars!

Target Organs of Benzimidazoles:

Studies have shown that benzimidazole will affect the testes, Gastrointestinal tract, bone marrow and liver if exposure is chronic. (10) Additionally, benomyl can cause a contact dermititis. (5)

https://www.google.com/search?q=contact+dermatitis&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiPhNCElN3jAhXDmq0KHb3YCVkQ_AUIESgB&biw=555&bih=657&dpr=1.8

Signs and Symptoms of Benzimidazoles:

Inhalation and dermal contact are the most common routes of exposure of benzimidazoles which can lead to toxicity. Signs can present nonspecifically as weakness, nausea, dizziness, headaches, and irritation to mucosa, skin and the lungs. When inhaled a hypersensitivity can occur leading to bronchospasm and wheezing. Dermal exposure can lead to hypersensitivity dermatitis. (11)

Treatment for Benzimidazoles?

As with any toxicity case which presents 6 steps are traditionally taken for management:(12)

1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
3. Prevention of further contamination through removing clothing which has been exposed.
4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with benzimidazoles toxicity.
5. There is no antidote to benzimidazoles poisioning.
6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Biomarkers for Benzimidazoles?

There are currently no biomarkers for benzimidazole. Scientists seem to have no interest in making a biomarker for benzimidazoles in the future.

BUT! Benzimidazoles has been recently found to be a useful stain for endoplasmic reticulum and golgi apparatus! Follow the link below for a video of the fluorescence in a live cell! (13)

https://figshare.com/articles/Video_1_New_Properties_of_a_Bioinspired_Pyridine_Benzimidazole_Compound_as_a_Novel_Differential_Staining_Agent_for_Endoplasmic_Reticulum_and_Golgi_Apparatus_in_Fluorescence_Live_Cell_Imaging_AVI/7021787/1

Additionally, specific benzimidazoles have been shown to be preliminarily useful as anti-inflammatories! see video below for the full details: (14)

Citations:

(1) ChEBI. 2015. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3015

(2) E. C. Wagner and W. H. Millett (1943). “Benzimidazole”. Organic Syntheses; Collective Volume, 2, p. 65.

(3) Bowman, Dwight D. Georgis’ Parasitology for Veterinarians. Philadelphia :W.B. Saunders Co., 1999.

(4) Velik, J, et al. “Benzimidazole Drugs and Modulation of Biotransformation Enzymes.” Research in Veterinary Science, W.B. Saunders, 24 Sept. 2003, www.sciencedirect.com/science/article/pii/S0034528803001498.

(5) Curtis D. Klaassen. Casarett And Doull’s Toxicology : the Basic Science of Poisons. New York :McGraw-Hill Education, 2013.

(6) L.C. Davidse, Ann. Rev. Phytopathol., 24 (1986), p. 43

(7) J.C. Havercroft, R.A. Quinlan, K. Gull. J. Cell. Sci., 49 (1981), p. 195

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