Vanishing Vermin or Festering Fowl?

Image Credit: http://www.gettyimages.com/license/683813427

Image Credit: https://upload.wikimedia.org/wikipedia/commons/f/f8/Carbofuran-from-xtal-3D-balls.png

The environmental toxin carbofuran has been banned in the EU since 2001. It is thought to being illegally used to control mice and rats, so birds of prey are suffering secondary poisoning by consuming tainted rodents.
Carbofuran is an acetylcholinesterase inhibitor in the same class as the V series nerve agents. It is one of the most toxic pesticides, only surpassed by aldicarb and parathion.
Concerns over the impact on non-target organisms and children is what has led to the banning of carbofuran.


http://www.bbc.com/news/uk-northern-ireland-38084466

Poison frogs may lead to new medications

Phyllobates terribillis

 

 

 

Toto Olivera of the University of Utah thinks that research into the function of batrachotoxin, a compound found in the skin of Phyllobates terribillis (Golden Poison Dart Frog), could lead us to a better understanding of electrical impulses in neurons.

 Congenital insensitivity to pain is caused by the same protein that this poison acts on, as well as other disorders like "man on fire" syndrome. The hope is that research on this poison will lead to effective treatments against these disorders and/or development of drugs that prevent pain, similar to how cone snail venom was used to develop ziconotide.

 This article can be found in its entirety at http://www.npr.org/sections/health-shots/2016/11/17/502324984/chemists-recreate-deadly-frog-poison-in-the-lab

Photo credit: Tambako the Jaguar, Getty Images

Exon Skipping Drugs



Eteplirsen CAS# 1173755-55-9

In Eukaryotes, RNA destined to become messenger RNA (mRNA) is composed of exons and introns. Normally, during post-transcriptional processing, introns are removed and the exons are “stitched” together to form a functional mRNA that is used for protein synthesis. In some genetic diseases a mutation in the DNA  is expressed in an exon resulting in disruption of the reading frame of an mRNA molecule. In such cases the resulting protein is nonfunctional. Certain drugs are being/have been developed that allow cellular machinery to skip over the offending exon and express the proper reading frame, producing an mRNA that, in turn, produces a truncated (shorter) but functional or partially functional protein.

In individuals with Duchenne Muscular Dystrophy, mutations in exons result in production of nonfunctional dystrophin a protein that normally prevents damage to muscle proteins when they contract. A new drug, Eteplirsen (Brand name Exondys), that promotes exon skipping has recently been approved to treat individuals with this form of muscular dystrophy. Its approval by the FDA, however, is controversial, in part, because of the small sample size used to assess the efficacy of the drug. Also of concern is the extraordinary expense ($300,000/year) of this drug.

The Chemical and Engineering News (see link below) provides a nice overview concerning this drug and its controversial approval by the FDA.

Jarvis, L.M. (2016) Aftereteplirsen: Duchenne stakeholders contemplate what comes next, Chemical and Engineering News, November 14, 2016, pp. 26-41.

Eteplirsen Image source: (http://lgmpharma.com/product/eteplirsen/)

 

 

Hannalgesin: An alpha-neurotoxin from the King Cobra and it Potential for Analgesia

Envenomation by poisonous snakes is often accompanied by substantial pain at the site of the bite. Thus it is somewhat counterintuitive that some deadly venoms have components that have excellent potential for drug development as analgesics (i.e., pain relievers).

Hannalgesin, a component of king cobra (Ophiophagus hannah) venom, is a potent α-neurotoxin. However, THA903 an undecapeptide  ( 11-amino acid peptide) derived from Hannalgesin appears to have substantial analgesic activity without lethal consequences at therapeutic doses. The peptide is water soluble and can be administered sublingually.

Hannalgesin is a three-finger toxin (3FTx). It was first purified and sequenced  in 1994 by Song et al. Subsequent investigations by Kimi’s group at the National University of Singapore resulted in the development of THA903 and they established that the analgesic effect is due to a relatively short sequence near the C-terminal end of the protein.

The precise mechanism responsible for analgesia is not completely known. However, it seems reasonable that analgesic peptides may be agonists for opiod receptors. The primary sequence for Hannalgesin is presented below. The sequence NPFPT near the C-teminus seems particularly important for analgesia.

TKCYVTPDVKSETCPAGQDICYTETWCDAWCTSRGKRVNLGCAATCPIVKPGVEIKCCSTDNCNPFPTRKRP

Primary Structure of Hannalgesin

References

Gawade, S. P. (2007). Therapeuticalternatives from venoms and toxins. Indian Journal of Pharmacology, 39(6),260.

Gopalakrishnakone, P., Pu, X. C., Wong, P. T. H., Gwee, M. C. E., & Kini, R. M. (2003). U.S. Patent No. 6,613,745. Washington, DC: U.S. Patent and Trademark Office.

Kini, R. M., & Doley, R. (2010). Structure, function and evolution of three-finger toxins: mini proteins with multiple targets. Toxicon, 56(6), 855-867.

 

Song, J., Chung, M. C. M., Xiong, Y., Wang, W. and Pu, X. (1994) Purification, sequence and pharmacological studies of a new alpha-neurotoxin from Ophiophagus hannah venom. Toxicon 32, 537-538 (Abstract).

Pu, X. C., Wong, P. T. H., & Gopalakrishnakone, P. (1995). A novel analgesic toxin (hannalgesin) from the venom of king cobra (Ophiophagus hannah). Toxicon, 33(11), 1425-1431.

Illustration of king cobra by Sir Joseph Fayer, 1871 (Wikimedia Commons)

Professor R. Manjunatha Kini's website
 

Spider Venom to treat Muscular Dystrophy

Muscular dystrophy opens calcium ion channels, causing the degradation of muscle tissue. Researchers hope to use the venom of the Chilean rose tarantula to close the calcium ion channels and reverse the results of muscular dystrophy.

  http://www.buffalo.edu/home/feature_story/good-venom.html

Glass Company Poisons Air Near Daycare Center

Children in Portland, Oregon at a daycare may be exposed to toxic amounts of selenium in the air, due to a local glass production facility. Concerns were brought up 7 months ago, but levels are still exceedingly high. http://www.kgw.com/news/health/bullseye-glass-blamed-for-toxic-air-near-daycare-again/319528184

Arsenic in Iowa Well Water

36% of wells tested in Iowa contained arsenic, a naturally occurring elemental poison. Iowa does not mandate testing of private wells, so well owners must rely on voluntary testing. Other contaminants such as nitrates and bacteria can also cause serious health risks. Efforts to require testing of wells when homes are sold have met resistance from some legislators and residents and failed to pass recently.


  http://www.desmoinesregister.com/story/news/2016/08/26/testing-shows-danger-iowas-private-wells/88755480/

Three Envenomations by a King Cobra

King cobra (Ophiophagus hannah)

King cobra (Ophiophagus hannah) envenomations are rare in the United States and Great Britain. Recently (May 2, 2016), a North Carolina man (Ali Iyoob) suffered a king cobra bite on his wrist from a snake in his private collection. Instead of calling for assistance he elected to drive himself to a hospital. On the way, he stopped and called 911 to report that he had been bitten by a king cobra. An ambulance was dispatched to his location on the highway. Suffering from classical signs (nausea, blurry vision, perfuse perspiration, anxiety) of king cobra envenomation he was taken to University of North Carolina Hospitals for treatment. King cobra venom can also affect the nervous system causing pain, dizziness, paralysis and respiratory failure. A problem treating envenomation by exotic animals is that most hospitals do not routinely stock the appropriate antivenom. In ali lyoob’s case, a source of of antivenom was located at the Riverbank Zoo in Columbia, South Carolina. After a wait of several hours the antivenom arrived and lyoob was successfully treated. Treatment of snakebite by the appropriate antivenom is often dramatically successful. On the Facebook page of the Reptile Rescue of the Carolinas, lyoob has been described as “a biologist, respected reptile enthusiast and RROTC Liason…”

In an earlier envenomation at the sea aquarium in Myrtle Beach, South Carolina, a professional reptile handler suffered a king cobra bite on his right thumb at 10:15 AM. He drove himself to the regional medical center, arriving at 10:30 AM. Initial complaints included severe pain, nausea and swelling of the thumb. Subsequently, edema and erythema extending to the wrist ensued. The palm was especially involved. During the next 90 minutes neurological symptoms appeared, including bilateral ptosis, confusion, inability to swallow (dysphagia), slurred speech, generalized flaccidity and a decline in oxygen saturation. Because of  respiratory paralysis,  an endotracheal tube was inserted and mechanical ventilation was initiated. This occurred 2 hours after envenomation. Antivenom was administered starting at 2 PM and finishing at 4 PM. Seven hours after envenomation, the patient was alert and removed his endotracheal tube. The next morning most of the neurological symptoms were resolved and the patient left the hospital against medical advice.

In 2006 the first recorded envenomation by a king cobra was reported in Great Britain. A 22 year old man was bitten on his left index finger. Upon arrival at the British equivalent of an emergency room, the patient was lucid but complained of dizziness. Soon, eyelid ptosis developed as did other symptoms, including shortness of breath and the inability to swallow. The patient was then intubated and transferred to the intensive care unit where he displayed hypertension and an erratic pulse. King cobra specific antivenin was administered when it arrived. This was six hours after the bite occurred. Anaphylaxis is a possible complication due to snake antivenom administration. This occurred and was successfully treated and antivenom administration can continued at a slower rate. Seventeen hours after the bite symptoms began to resolve and the endotracheal tube was removed. Twenty-four hours after the bite, the patient was discharged from the intensive care unit and a plastic surgeon continued treatment for the ischemic damage done to his finger.

These envenomations are remarkable in that all were rapidly and successfully treated with king cobra specific antivenom. Without access to venom, death is a very reasonable probability due to respiratory paralysis. It is also worth noting that all of these envenomations occurred in males who were/are skilled in the handling of venomous snakes.



King cobra antivenom is made by the Thia Red Cross and the Central Research Institute in Kasauli, India. In the United States, king cobra antivenom is available from the Miami-Dade Fire Rescue Venom Response Unit (Emergency telephone number: 786-336-6600). Presumably,  zoos that maintain king cobras in their herpetological collections also possess stocks of king cobra antivenom.

References and links

North Carolina Man bitten by Pet King Cobra 

NC man bitten by cobra sentenced after 18 poisonous reptiles found in home, officials say

Gold, B. S., & Pyle, P. (1998). Successful treatment of neurotoxic king cobra envenomation in Myrtle Beach, South Carolina. Annals of emergency medicine, 32(6), 736-738.

Veto, T., Price, R., Silsby, J. F.,& Carter, J. A. (2007). Treatment of the first known case of king cobraenvenomation in the United Kingdom, complicated by severe anaphylaxis. Anaesthesia,62(1), 75-78.

Image by RedGazelle15 on WikiMedia Commons

Pain Relief From the Venom of the Cone Snail (Conus magus)

Conus magus

Ziconodide (Prialt)

All members of the genus Conus are venomous. Conotoxins are peptides containing 10 to 30 amino acids. In general, each conotoxin contains one or more disulfide bonds.

Five types of conotoxins ( (α(alpha)-, δ(delta)-, κ(kappa)-, μ(mu)-, and ω(omega)- conotoxins)) have been described. Of interest is ω-conotoxin. This conotoxin inhibits N-type voltage-dependent calcium channels. Because N-type voltage-dependent calcium channels transmit the pain response, its inhibition ameliorates pain. That is to say ω-conotoxin is a good target compound in the search for new and better analgesics. In fact, the pain-reliever ziconodide (Prialt) is the synthetic version of     ω-conotoxin M VII A.

An overview of the synthesis of ziconolide can be found by clicking on the following link.

Simultaneous Fmoc and Boc Synthesis of a Contryphan Positional Scanning Library and the Conotoxin Prialt on the Overture™ Robotic Peptide Library Synthesizer

 

Unlikely Poisonous animals

This article explores five unlikely animals, that have evolved the ability to be extremely toxic in the wild. 

http://www.medicalnewstoday.com/articles/308864.php


Photo of Blue capped ifrit

 

1. Blue capped ifrit: a bird that assimilates poison it eats onto its skin and feathers.

 

2. Blue-ringed octopus: the most venomous marine animal whose bite will leave a person paralyzed and on the verge of death if not treated quickly.

 

3. Duck-billed platypus: a unique creature already, during mating season the males produce venom that can be secreted by spurs on the hind limbs.

 

4. Cone snails: sea dwellers with temping shells to pick up, have spikes on the outside that can lead to paralysis.

5. Komodo dragon: always considered non-venomous, a new debate has sparked when glands of a dragon were dissected and analyzed to be a host to many toxic chemicals.

Toxic Parsnip

A wild poisonous weed has started to spread quickly throughout Iowa and the Midwest. Parsnip is becoming increasingly prevalent in road side ditches and along trails. 

Coming into contact with the oils in this plant can cause severe burning and itching. This is due to the sap in the plant that once exposed to sunlight, starts to break down skin and tissue. This leads to severe sunburn and hypersensitivity. 

http://www.cbsnews.com/news/wild-parsnip-giant-hogweed-toxic-plants-to-watch-out-for/

Toxic Algal Bloom In Utah

Microcystin, a cyanotoxin

There was a toxic algal bloom contaminating the waters in Utah lake in Salt Lake City. This algal bloom was caused by the increased levels of phosphorus being dumped into the water by seven companies. 330 individuals have presented with symptoms from exposure to toxic levels of cyanobacteria, and 100 ducks have been found dead. Symptoms in humans include: headaches, abdominal pain, diarrhea, vomiting, respiratory problems, and skin irritations. Barbara Crouch, director of the Utah Poison Control Center has stated, "There is not a lot of human health information known about this." Currently the state is taking precautions and stopping the use of the contaminated water for irrigation of farmers' plants. Understandably this is causing some upheaval amongst the farmers but cross contamination into the drinking water and to food sources could potentially endanger hundreds of other individuals. 

http://www.deseretnews.com/article/865658274/Toxic-algal-bloom-impacting-people-animals-and-farms-in-2-counties.html?pg=all

Killer Bees

 

 "Closeup of Africanized honey bees (AHBs) surrounding a

European queen honey bee (EHB), marked with a pink dot for identification."

 Wikimedia Commons

(Scott Bauer, USDA Agricultural Research Service, United States)

A study comprised data from 2001 to 2013 on animals that caused the most human deaths per year. It was noted that shark attacks should be on the bottom of our priority lists, and it is actually bees, wasps, and hornets that cause the highest number of animal related human deaths. These bees even beat out mammals such as deer, that are common factors in vehicular deaths. Bees, wasps, and hornets on average cause 58 human deaths per year, leading them to be the deadliest creatures.

http://www.newser.com/story/208510/the-surprising-animal-most-likely-to-kill-you.html

Click on the link to see a more complete breakdown of the deadliest animals. 

10 Crazy Drugs You Didn't Know Existed

An interesting article on some of the most outrageous drugs that have been developed or discovered. Often times these drugs have not taken off on the streets because they are either too potent for humans to consume, or they cause the opposite of psychedelic affects and actually induce some depression and psychotic breaks. 

One example is a common house hold spice, nutmeg. It takes a very high dose to have any hallucinations, but it is a legal alternative. Unfortunately nutmeg usually leaves a person feeling anxious and with a sense of doom. There are also numerous negative physical side effects. This all helps to explain why nutmeg has not taken off as a potential schedule 1 drug. 

http://listverse.com/2013/01/10/10-crazy-drugs-you-dont-know-and-dont-want-to/

There are nine other crazy drugs to check out and see the effects to the human body, like cooking the user from the inside. 

Intravenous caffeine can be used to treat migraine headaches.

Caffeine

Ketorolac

 

 



Caffeine is a widely used legal stimulant. Most caffeine is consumed in beverages, e.g., coffee and tea. In some cases, however, the effects of caffeine may be used to treat serious disease and is administered intravenously. In one recent investigation Baraloo et al. (2016) compared the use of intravenously administered caffeine with that of ketorolac, also administered intravenously. The authors concluded that "Caffeine is as effective as ketorolac and can be a reasonable first line abortive medication in emergency department management of acute migraine."

Sometimes withdrawal headaches are caused when individuals, who typically consume substantial amounts of caffeine containing beverages, abruptly stop this practice. Thus it is interesting that, in some cases, caffeine can be used to treat headaches. The mechanisms by which this occurs is not completely clear.

Ketorolac is a non-steroidal anti-inflammatory. Like aspirin, ketorolac is a cyclooxygenase inhibitor and thus inhibits the synthesis of prostgalandins and the attendant pain response due to their synthesis.

Baratloo, A., Bafarani, S. A., Forouzanfar, M. M., Hashemi, B., Friedman, B. W., & Abdalvand, A. (2016). Intravenous caffeine versus intravenous ketorolac for the management of moderate to severe migraine headache. Bangladesh Journal of Pharmacology, 11(2), 428-432.



Drugs in Popular Culture: Lucy in the Sky with Diamonds

LSD

A lot of songs reference drugs. It has been claimed that Lucy in the Sky with Diamonds, a song on The Beatles 1967  album, Sgt. Pepper's Lonely Hearts Club Band, is a mnemonic for LSD. John Lennon denied this. Tim Kasser's blog and his book Lucy in the Mind of Lennon provides in-depth detail concerning this song.

Seven things you didn’t know about “Lucy in the Sky with Diamonds".

Lucy in the Mind of Lennon

Heroin was once recommended as a treatment for morphine addiction.



Heroin

Morphine

Heroin was once recommended as a treatment for morphine addiction. Note that heroin is a semi-synthetic compound, meaning that it is synthesized by acetylation of morphine which is a natural product.

"A silver lining to what is absolutely a tragedy"

"A silver lining to what is absolutely a tragedy"

The sheer volume of deaths due to heroin overdoses has led to an increase in donor organs for transplant.

So many people are dying of drug overdoses that they’re easing the donated organ shortage

First Venomous Frog Discovered

 Corythomantis greening

When one thinks about venomous creatures, frogs are not the first animals to come to mind. It is true that some frogs produce very toxic skin secretions. However, frogs that inject a venom have been described only recently. Greening's frog (Corythomantis greening) and Bruno's casque-headed frog (Aparasphenodon brunoi) both have bony spines on their skulls that pierce the skin and deliver their toxic skin secretions. Note that a toxic substance is a venom if it is injected into the target species.

Jared, C., Mailho-Fontana, P. L., Antoniazzi, M. M., Mendes, V. A., Barbaro, K. C., Rodrigues, M. T., & Brodie, E. D. (2015). Venomous frogs use heads as weapons. Current Biology, 25(16), 2166-2170.

http://www.bbc.com/earth/story/20150806-first-venomous-frogs-discovered


Image attribution: G.A. Boulenger

By Boulenger, G.A. - Boulenger, G. A. 1896. Descriptions of new batrachians in the British Museum. Annals and Magazine of Natural History, Series 6, 17: 401–406, Public Domain, https://commons.wikimedia.org/w/index.php?curid=34513543

Snake Bite Fatalities in the United States

Photo by Mark Bratton



Crotalus scutulatus

"According to the Centers for Disease Control and Prevention, of the 7,000 to 8,000 people bitten by venomous snakes in the U.S. every year, only 5 die."
Snake Bite Death Statistics Worldwide

Krokodil

Krokodil (desmorphine)

 

Krokodil (desmorphine)

This is one nasty drug. Note its similarity to morphine. The flesh-eating effect of this drug is probably due to to contaminants introduced during its manufacture. These contaminants are often not removed in clandestine laboratories that make this drug for recreational use (abuse),

Ketamine

Ketamine

Ketamine has substantial notoriety as a street or party drug. It has been described as a "dissociative anesthetic: a drug that distorts perception of sight and sound and produces feelings of detachment (dissociation) from the environment and self."
http://www.drugfreeworld.org/drugfacts/prescription/ketamine.html
Most recently, ketamine has been put on "fast track" approval by the U.S. Food and Drug Administration as a medication to treat depression. It has been described as " the first new treatment for major depressive disorder in about half a century."
http://www.cnn.com/2016/08/17/health/ketamine-depression-treatment/index.html


Compared to other drugs of abuse, fatalities due to ketamine use or overdose are relatively rare, but they do occur. Ketamine has also been used as a date rape drug.
A critical review of ketamine can be found at the following web site.
http://www.who.int/medicines/areas/quality_safety/4.3KetamineCritReview.pdf

Greetings:

This blog originated in the course Drugs, Poisons and Venoms, a course that I teach at the University of Northern Iowa. One of the goals of this course is to provide students with up-to-date content, relevant to the course, that is not yet available in textbooks. I will provide some of this content. Students also provide content. The only requirements for submissions are that they be relevant to the course, well written and interesting. Although recent findings and information are a priority, submissions focusing on older topics are welcome. I expect that most  submissions will be in the range of 25 to 250 words.

When possible, submissions should link to an article or publication that provides more detail. And, if the submission concerns a specific chemical, the structure of the chemical should be provided.

Lastly, if a journal article is referenced, it should be cited in proper form.