Brodifacoum

Last updated
Brodifacoum [1]
Brodifacoum.svg
Names
IUPAC name
3-[3-[4-(4-Bromophenyl)phenyl]-1,2,3,4-tetrahydronaphthalen-1-yl]-2-hydroxychromen-4-one
Other names
Bromfenacoum
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.054.509 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
RTECS number
  • GN4934750
UNII
  • InChI=1S/C31H23BrO3/c32-24-15-13-20(14-16-24)19-9-11-21(12-10-19)23-17-22-5-1-2-6-25(22)27(18-23)29-30(33)26-7-3-4-8-28(26)35-31(29)34/h1-16,23,27,33H,17-18H2 Yes check.svgY
    Key: VEUZZDOCACZPRY-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C31H23BrO3/c32-24-15-13-20(14-16-24)19-9-11-21(12-10-19)23-17-22-5-1-2-6-25(22)27(18-23)29-30(33)26-7-3-4-8-28(26)35-31(29)34/h1-16,23,27,33H,17-18H2
    Key: VEUZZDOCACZPRY-UHFFFAOYAI
  • Brc1ccc(cc1)c2ccc(cc2)C4Cc3ccccc3C(C4)C\5=C(/O)c6ccccc6OC/5=O
Properties
C31H23BrO3
Molar mass 523.426 g·mol−1
Melting point 228 to 230 °C (442 to 446 °F; 501 to 503 K)
Insoluble
Pharmacology
Oral; dermal; inhalation (dusts) (for poisoning)
Pharmacokinetics:
100%
slow, incomplete, hepatic
Slow; 20—130 days
faeces; very slow
Hazards
Lethal dose or concentration (LD, LC):
270 μg/kg (rat, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger pests such as possums. [2]

Contents

Brodifacoum has an especially long half-life in the body, which ranges up to nine months, requiring prolonged treatment with antidotal vitamin K for both human and pet poisonings. It has one of the highest risks of secondary poisoning to both mammals and birds. [3] Significant experience in brodifacoum poisonings has been gained in many human cases where it has been used in attempted suicides, necessitating long periods of vitamin K treatment. In March 2018, cases of severe coagulopathy and bleeding associated with synthetic cannabinoid use contaminated with brodifacoum were reported in five states of the US.

Chemical synthesis

Brodifacoum is a derivative of the 4-hydroxy-coumarin group. Compounds numbers are found next to their respective compounds in the image below. Compound 1 is the starting ester needed to synthesize brodifacoum. To obtain this starting Compound 1, a simple Wittig condensation of ethyl chloroacetate with 4’-bromobiphenylcarboxaldehyde is accomplished. Compound 1 is transformed into Compound 2 by consecutive hydrolysis, halogenation to form an acid chloride, and then reacted with the required lithium anion. This is done using KOH and EtOH for hydrolysis, and then adding SOCl2 for chlorination to form the acid chloride which reacts with the addition of lithium anion. Compound 2 is then transformed using organocopper chemistry to yield Compound 3 with good stereoselectivity of about 98%. Typically, a Friedel-Crafts type cyclization would then be used to obtain the two-ring system portion of Compound 4, but this results in low yield. Instead, trifluoromethanesulfonic acid in dry benzene catalyzes the cyclization with good yield. The ketone is then reduced with sodium borohydride yielding a benzyl alcohol. Condensation with 4-hydroxycoumarin under HCl yields Compound 5, brodifacoum. [4]

Stereospecific formation of Brodifacoum using an asymmetric organocopper compound. Synthesis of Brodifacoum.png
Stereospecific formation of Brodifacoum using an asymmetric organocopper compound.

Toxicology

Brodifacoum is a 4-hydroxycoumarin anticoagulant, with a similar mode of action to its historical predecessors dicoumarol and warfarin. However, due to very high potency and long duration of action (elimination half-life of 20 – 130 days), it is characterised as a "second-generation" or "superwarfarin" anticoagulant. [5]

Brodifacoum inhibits the enzyme vitamin K epoxide reductase, which is needed for the reconstitution of the vitamin K in its cycle from vitamin K-epoxide, so brodifacoum steadily decreases the level of active vitamin K in the blood. Vitamin K is required for the synthesis of important substances including prothrombin, which is involved in blood clotting. This disruption becomes increasingly severe until the blood effectively loses any ability to clot.

In addition, brodifacoum (as with other anticoagulants in toxic doses) increases permeability of blood capillaries; the blood plasma and blood itself begin to leak from the smallest blood vessels. A poisoned animal suffers progressively worsening internal bleeding, leading to shock, loss of consciousness, and eventually death.[ citation needed ]

Brodifacoum is highly lethal to mammals and birds, and extremely lethal to fish. It is a highly cumulative poison, due to its high lipophilicity and extremely slow elimination.[ citation needed ]

Following are acute LD50 values for a variety of animals:

* rats (oral)0.27 mg/kg b.w. [6]
* mice (oral)0.40 mg/kg b.w. [6]
* rabbits (oral)0.30 mg/kg b.w. [6]
* guinea-pigs (oral)0.28 mg/kg b.w. [6]
* squirrels (oral)0.13 mg/kg b.w. [7]
* cats (oral) [8] 0.25 mg/kg b.w. [9] [6] — 25 mg/kg b.w. [10] [11] [12] [13] [6] [14]
* dogs (oral)0.25 — 3.6 mg/kg b.w. [6] [9] [10] [11] [12] [13]
* birdsLD50 values for various birds vary from about 1 mg/kg b.w. — 20 mg/kg b.w. [5]
* fish — LC50 for fish:
** trout (96 hours exposure)0.04 ppm [15]

As brodifacoum is not selective and can cause secondary poisoning of predators, [16] its outdoor use is either banned or not recommended; the only exception is use for rodent eradication from islands (where it is feasible), because invasive rodents can be destructive for seabirds. [17] Biological resistance to Brodifacoum has been indicated in some species of rats in sample studies [18]

Brand names

Notice about laying of brodifacoum baits in New Zealand Brodifacoum notice.jpg
Notice about laying of brodifacoum baits in New Zealand
Baitbox containing brodifacoum in Finland Ratpoison Bait Box.JPG
Baitbox containing brodifacoum in Finland

Brodifacoum is marketed under many trade names, including Arakus (Advansia), Biosnap, d-CON, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestoff, Rakan, Ratak+, Rataquill Colombia, Ratshot Red, Rattex, Rodend, Rodenthor, Ratsak, Talon, [19] Volak, Vertox, and Volid.[ citation needed ]

Human poisoning

Treatment

The primary antidote to brodifacoum poisoning is immediate administration of vitamin K1 (dosage for humans: initially slow intravenous injections of 10–25 mg repeated at 3–6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before excessive bleeding ensues. As high doses of brodifacoum can affect the body for many months, the antidote must be administered regularly for a long period (several months, in keeping with the substance's half-life) with frequent monitoring of the prothrombin time. [20]

If unabsorbed poison is still in the digestive system, gastric lavage followed by administration of activated charcoal may be required.

Further treatments to be considered include infusion of blood or plasma to counteract hypovolemic shock, and in severe cases, infusion of blood clotting factor concentrate.

Case reports

Cases of brodifacoum intoxication have been reported in the human medical literature.

In one report, a woman deliberately consumed over 1.5 kg (3 lb) of rat bait, constituting about 75 mg brodifacoum, but made a full recovery after receiving conventional medical treatment. [21]

In another case reported in 2013, a 48-year-old female patient reported 4 days of mild dyspnea, dry cough, bilateral popliteal fossae pain, and diffuse upper abdominal pain. She had no history of liver disease or alcohol or illicit substance abuse. Initial physical examination was remarkable only for mildly pale conjunctivae and mild abdominal tenderness and pain in the left popliteal fossa. A complete blood count and complete metabolic panel were normal. Prothrombin time (PT) was above 100 s, partial thromboplastin time (PTT) was above 200 s and international normalized ratio (INR) was reported as above 12.0. Urinalysis revealed hematuria (blood in the urine). Venous Doppler ultrasound of lower extremities demonstrated left popliteal vein thrombosis. Computed tomography scan of the abdomen demonstrated transmural hematoma, and a fecal occult blood test was positive. A full anticoagulant work-up showed critical reduction of vitamin K-dependent factors II, VII, IX, and X. PT and PTT corrected with mixing studies proving factor deficiency as the cause of the coagulopathy. Lupus anticoagulant studies were negative. Superwarfarin toxicity was suspected and confirmed with an anticoagulant poison panel positive for brodifacoum. The patient was hospitalized and successfully treated with fresh frozen plasma, cryoprecipitate, and vitamin K. In conclusion, paradoxical thrombosis and hemorrhage should raise the suspicion for superwarfarin toxicity in the appropriate clinical setting. Concomitant presentation for thrombosis and hemorrhage with remarkably abnormal PT and PTT should raise the suspicion for brodifacoum poisoning. [22]

In 2015, 19 inmates in New York City's Rikers Island jail claimed that they had been poisoned with the chemical. The inmates had noticed "what appeared to be blue and green pellets in the meatloaf" they were eating on March 3, and felt ill afterwards. A sample was analyzed and tested positive for brodifacoum; the NYC Department of Correction stated it was investigating the incident. [23] [24]

A 20-year-old female college student presented with abdominal pain and blood in urine. She was tested for warfarin, a common anticoagulant also used in some rodenticides, which returned a negative result. Vitamin K and fresh plasma were administered to treat symptoms. Three weeks later, she returned with bleeding into her calf, and was subsequently tested for superwarfarin chemicals. The test showed that brodifacoum was in her bloodstream. She later admitted to consuming seven packets of rodenticide. [25]

A 48-year-old businessman was admitted with a severe nosebleed and abnormal coagulation parameters. Standard treatment of vitamin K and fresh plasma was administered to stem the nosebleed. Two weeks later, he presented again with bleeding into the calf. Continual doses of vitamin K were necessary to counteract the brodifacoum. He denied taking any of the brodifacoum found in his home contained within packages of Contrac. [25]

Recreational drug use

Brodifacoum has been mixed with synthetic cannabinoids such as K2 and Spice, reportedly "to extend the duration of the drug euphoria". [26]

As of November 26, 2018, at least eight fatalities and 320 cases of severe coagulopathy and bleeding associated with synthetic cannabinoid use had been reported in Illinois, Wisconsin, Maryland, Missouri, Florida, North Carolina, Indiana, Pennsylvania, Kentucky, Virginia, and West Virginia. [27] [28] [29] The first case occurred in Illinois on March 7, 2018. [30] Brodifacoum was suspected to be present in these products in Illinois. Products named Matrix and Blue Giant from a convenience store in Chicago have tested positive for brodifacoum and AMB-FUBINACA (FUB-AMB). [31] [32] [33]

In another report, a 17-year-old boy presented to the hospital with a severe bleeding disorder. He was found to have habitually smoked a mixture of brodifacoum and marijuana. Despite treatment with vitamin K, the bleeding disorder persisted for several months. He eventually recovered. [34]

Related Research Articles

<span class="mw-page-title-main">Vitamin K</span> Fat-soluble vitamers

Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation or for controlling binding of calcium in bones and other tissues. The complete synthesis involves final modification of these so-called "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor.

<span class="mw-page-title-main">Warfarin</span> Anticoagulant medication

Warfarin is an anticoagulant used as a medication under several brand names including Coumadin. While the drug is described as a "blood thinner", it does not reduce viscosity but rather inhibits coagulation. Accordingly, it is commonly used to prevent blood clots in the circulatory system such as deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Less commonly, it is used following ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously.

<span class="mw-page-title-main">Prothrombin time</span> Blood test that evaluates clotting

The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in such things as the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X.

<span class="mw-page-title-main">Bleeding diathesis</span> High tendency to bleed due to a blood clotting disorder

In medicine (hematology), bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability, in turn caused by a coagulopathy. Therefore, this may result in the reduction of platelets being produced and leads to excessive bleeding. Several types of coagulopathy are distinguished, ranging from mild to lethal. Coagulopathy can be caused by thinning of the skin, such that the skin is weakened and is bruised easily and frequently without any trauma or injury to the body. Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation.

<span class="mw-page-title-main">Rodenticide</span> Chemical used to kill rodents

Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despite the crucial roles that rodents play in nature, there are times when they need to be controlled.

<span class="mw-page-title-main">Hypoprothrombinemia</span> Medical condition

Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.

<span class="mw-page-title-main">Coumatetralyl</span> Chemical compound

Coumatetralyl is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type used as a rodenticide.

<span class="mw-page-title-main">Phenprocoumon</span> Drug

Phenprocoumon is a long-acting blood thinner drug to be taken by mouth, and a coumarin derivative. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders such as heart attacks and pulmonary (lung) embolism. The most common adverse effect is bleeding. The drug interacts with a large number of other medications, including aspirin and St John's Wort. It is the standard coumarin used in Germany, Austria, and other European countries.

<span class="mw-page-title-main">Dicoumarol</span> Chemical compound

Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K. It is also used in biochemical experiments as an inhibitor of reductases.

<span class="mw-page-title-main">4-Hydroxycoumarins</span> Group of anticoagulant drugs

4-Hydroxycoumarins are a class of vitamin K antagonist (VKA) anticoagulant drug molecules. Chemically, they are derived from coumarin by adding a hydroxy group at the 4 position to obtain 4-hydroxycoumarin, then adding a large aromatic substituent at the 3-position. The large 3-position substituent is required for anticoagulant activity.

Prothrombin complex concentrate (PCC), also known as factor IX complex, sold under the brand name Kcentra among others, is a combination medication made up of blood clotting factors II, IX, and X(3-factor PCC) or, when also containing factor VII as does Kcentra, 4-factor PCC. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy. It is given by slow injection into a vein. Another product, activated prothrombin complex concentrate or FEIBA, may be used for acquired hemophilia.

<span class="mw-page-title-main">Diphenadione</span> Chemical compound

Diphenadione is a vitamin K antagonist that has anticoagulant effects and is used as a rodenticide against rats, mice, voles, ground squirrels and other rodents. The chemical compound is an anti-coagulant with active half-life longer than warfarin and other synthetic 1,3-indandione anticoagulants.

<span class="mw-page-title-main">Bromadiolone</span> Chemical compound

Bromadiolone is a potent anticoagulant rodenticide. It is a second-generation 4-hydroxycoumarin derivative and vitamin K antagonist, often called a "super-warfarin" for its added potency and tendency to accumulate in the liver of the poisoned organism. When first introduced to the UK market in 1980, it was effective against rodent populations that had become resistant to first generation anticoagulants.

<span class="mw-page-title-main">Difenacoum</span> Chemical compound

Difenacoum is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type. It has anticoagulant effects and is used commercially as a rodenticide. It was first introduced in 1976 and first registered in the USA in 2007.

<span class="mw-page-title-main">Vitamin K antagonist</span> Group of substances

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonize the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for more than 50 years.

<span class="mw-page-title-main">Flocoumafen</span> Chemical compound

Flocoumafen is a fluorinated, second-generation anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type. It is a second generation chemical in this class, used commercially as a rodenticide. It has a very high toxicity and is restricted to indoor use and sewers. This restriction is mainly due to the increased risk to non-target species, especially due to its tendency to bio-accumulate in exposed organisms. Studies have shown that rodents resistant to first-generation anticoagulants can be adequately controlled with flocoumafen. It was synthesized in 1984 by Shell International Chemical.

<span class="mw-page-title-main">Chlorophacinone</span> Chemical compound

Chlorophacinone is a first-generation anticoagulant rodenticide. The mechanism of action results in internal bleeding due to non-functional clotting factors. It was used as a toxin to control rodent populations. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant medication

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">4-Hydroxycoumarin</span> Chemical compound

4-Hydroxycoumarin is a coumarin derivative with a hydroxy group at the 4-position.

d-CON American brand of rodent control products

d-CON is a brand of rodent control products, which is distributed and owned in the United States by the UK-based consumer goods company Reckitt.

References

  1. ↑ Merck Index , 11th Edition, 1368
  2. ↑ Eason, C.T. and Wickstrom, M. Vertebrate pesticide toxicology manual, New Zealand Department of Conservation
  3. ↑ Rodenticides: Topic Fact Sheet, National Pesticide Information Center
  4. ↑ van Heerden P. S.; Bezuidenhoudt B. C. (1997), "Efficient Asymmetric Synthesis of the Four Diastereomers of Diphenacoum and Brodifacoum", Tetrahedron, 43 (17): 6045–6056, doi:10.1016/S0040-4020(97)00254-8
  5. 1 2 "Brodifacoum (HSG 93, 1995)". Inchem.org. Retrieved 2013-12-08.
  6. 1 2 3 4 5 6 7 "Brodifacoum (PDS)". Inchem.org. Archived from the original on 2013-12-13. Retrieved 2017-12-05.
  7. ↑ Matschke, George H.; Baril, Steve F.; Blaskiewicz, Raymond W. (December 1983). "Population Reduction of Richardson's Ground Squirrels Using a Brodifacoum Bait". Great Plains Wildlife Damage Control Workshop Proceedings --- University of Nebraska-Lincoln.
  8. ↑ Published LD50 values of brodifacoum for cats vary widely, from 25 mg kg-1(Rammell et al., 1984;Godfrey, 1985) to 0.25 mg kg-1(Haydock and Eason, 1997)
  9. 1 2 Brodifacoum at InChem.com
  10. 1 2 KAUKEINEN, D.E. 1979. Experimental rodenticide (Talon) passes lab tests; moving to field trials in pest control industry. Pest Control 46(1):19-21.
  11. 1 2 Brodifacoum (Talon, Havoc) - Chemical Profile 1/85
  12. 1 2 "MSDS Data Sheet for TALON RAT AND MOUSE KILLER" (PDF). Archived from the original (PDF) on 2009-09-14. Retrieved 2010-07-06.
  13. 1 2 "The Veterinarian's Guide to accidental rodenticideingestion by dogs & cats" (PDF). Archived from the original (PDF) on 2016-07-09. Retrieved 2016-08-20.
  14. ↑ Brodifacoum residues in target and non-target species following an aerial poisoning operation on Motuihe Island, Hauraki Gulf, NEW ZEALAND Pdf
  15. ↑ "Pest Control Product Labels And MSDS" (PDF). Wil-kil.com. Retrieved 2013-12-08.
  16. ↑ "Rodenticides".
  17. ↑ Broome, Keith; Murphy, Elaine; Cunningham, Celia; Eason, Charles , T. (2010). "New Zealand's Use of Brodifacoum in Eradication Efforts and Current Investigation of New Baits and Toxins". Proceedings of the Vertebrate Pest Conference. 24. doi:10.5070/V424110625.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Sran, Suman P. K.; Gartrell, Brett G.; Fisher, Penny; Armstrong, Doug P. (2022). "Apparent resistance to brodifacoum in". Wildlife Research. 50: 28–38. doi: 10.1071/WR21064 .
  19. ↑ "Talon Rat and Mouse Killer Pellets". www.yates.com.au. Retrieved 2023-01-19.
  20. ↑ Olmos V, López CM (2007). "Brodifacoum poisoning with toxicokinetic data". Clin Toxicol. 45 (5): 487–9. doi:10.1080/15563650701354093. PMID   17503253. S2CID   33470724.
  21. ↑ Lipton R.A.; Klass E.M. (1984). "Human ingestion of a 'superwarfarin' rodenticide resulting in a prolonged anticoagulant effect". JAMA . 252 (21): 3004–3005. doi:10.1001/jama.252.21.3004. PMID   6502864.
  22. ↑ Franco, David; Everett, George; Manoucheri, Manoucher (2013). "I smell a rat". Blood Coagulation & Fibrinolysis. 24 (2): 202–4. doi:10.1097/mbc.0b013e328358e959. PMID   23358203.
  23. ↑ Marzulli, John. "EXCLUSIVE: Rikers Island meatloaf that left 19 inmates sick did have rat poison, lab tests confirm". New York Daily News . Retrieved 28 April 2015.
  24. ↑ Sydney Lupkin, "22 Rikers Island Prisoners Sickened By Rat Poison in Meatloaf, Lawyer Says, Daily News April 29, 2015
  25. 1 2 Weitzel, J. N. (1990), "Surreptitious Ingestion of a Long-Acting Vitamin K Antagonist/Rodenticide, Brodifacoum: Clinical and Metabolic Studies of Three Cases", Blood , 76 (12): 2555–2559, doi: 10.1182/blood.V76.12.2555.2555 , PMID   2265249
  26. ↑ Gottlieb, Scott (July 19, 2018). "Statement from FDA warning about significant health risks of contaminated illegal synthetic cannabinoid products that are being encountered by FDA". U.S. Food and Drug Administration. Retrieved 3 August 2024.
  27. ↑ "COCA Clinical Action: Outbreak Alert Update: Potential Life-Threatening Vitamin K-Dependent Antagonist Coagulopathy Associated With Synthetic Cannabinoids Use". Centers for Disease Control and Prevention (CDC). 2018-11-26. Archived from the original on 2021-12-06. Retrieved 2018-11-26.
  28. ↑ McCoppin, Robert. "Illinois gets donation of nearly 800,000 vitamin K tablets to treat poisoning from synthetic marijuana". chicagotribune.com.
  29. ↑ "Synthetic Marijuana Expands to Florida - Florida Department of Health in Hillsborough". hillsborough.floridahealth.gov.
  30. ↑ Center for Acute Disease Epidemiology, Iowa Department of Public Health Coagulopathies Associated with Contaminated Synthetic Cannabinoids Archived 2018-05-04 at the Wayback Machine April 6, 2018
  31. ↑ Howard, Jacqueline; Baldacci, Marlena. "Fake weed leaves two dead, 54 with severe bleeding". CNN.
  32. ↑ "3 arrested in Chicago in connection to synthetic pot; 2 deaths, 54 others cases of severe bleeding". WGN-TV. 2 April 2018.
  33. ↑ "Masoud et al complaint - Department of Justice". www.justice.gov.
  34. ↑ La Rosa F; Clarke S; Lefkowitz J B (1997). "Brodifacoum intoxication with marijuana smoking". Archives of Pathology & Laboratory Medicine. 121: 67–69.

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