A Poisonous Cure: Botulism, Bioterrorism, and Botox
The great philosopher Paracelsus —who is considered to be the father of Toxicology — in the 15th century said, “ all substances are poisons, there is none which is not a poison…the right dose differentiates a poison from a remedy”. In other words, the dose makes the poison. Such is the case with botulinum neurotoxin (BoNt).
Botulinum neurotoxin is the most potent biological poison known to humans. It causes a potentially fatal food-poisoning disease, known as, botulism. So deadly, BoNT is classified by the Centers for Disease Control (CDC) as a Category A agent with the potential to be used as a weapon of bioterrorism. Yet, Botulinum toxin has also been approved by the U.S. Food and Drug Administration (U.S. FDA) as the anti-wrinkle cosmetic drug, BOTOX. In very minute amounts, BoNT can indeed be used as a therapeutic agent.
Botulism and Clostridium
Botulism is a paralytic disease resulting from exposure to toxins produced by Clostridium Botulinum (C. Botulinum) bacteria. Botulism causes flaccid paralysis of muscles and can lead to respiratory paralysis and death.
There are several types of Botulism, mainly, Food-borne (classic botulism), infantile, and wound botulism. Food-borne botulism is the most common type of botulism to occur in humans and is caused by the preformed toxin present in contaminated foods such as meats, fish, and vegetables. The toxin is heat-labile and can be destroyed by heating to 85 degrees celsius. Botulinum toxins can also be destroyed by acidity (vinegar), salting, or sugaring. Therefore Botulinum contamination usually occurs from the improper preservation or canning of foods. In infantile botulism, the gastrointestinal tract is colonized by C. Botulinum spores that germinate in the intestine, due to lack of competing microbiota. Wound botulism is rare and results from the infection of a wound with the clostridium botulinum bacteria itself or with its spores. Wound botulism is associated with injection drug use. In all cases, the presence or release of the toxin is responsible for causing illness.
There are two other less common forms of Botulism, Inhalation botulism, and Iatrogenic botulism. Inhalation botulism is very rare and occurs when the toxin enters the respiratory tract. Aerosol formation of botulinum neurotoxins are not naturally occurring and would most likely represent an attempt at bioterrorism. Similarly, Iatrogenic botulism is due to human processes and results from the excessive use of BoNTs therapeutically or cosmetically.
C. Botulinum is a gram-positive, rod-shaped, spore-forming bacterium that germinates in anaerobic conditions (devoid of oxygen). C. Botulinum naturally occur in soil and are found in the intestines of some animals. Clostridia indirectly cause Botulism through the action of the toxins that they produce. The toxicity of botulinum neurotoxins rivals that of cobra venom and cyanide.
The toxins that cause Botulism are produced by a diverse group of Clostridium. The groups are considered to be different species, with groups I and II being the main causes of Botulism in humans. Other species that produce botulism in humans are Clostridium baratii and Clostridium buytricum ( group V and VI respectively). The other groups do not affect humans. Group III for instance, produces Botulism in birds.
Botulinum Neurotoxins (BoNTs)
There are 7 distinct botulinum neurotoxins, denoted botulinum neurotoxin A, B, C, D, E, F, and G (BoNT/A-G). BoNT/A, B, E, F, and G are responsible for botulism in humans, while the other forms cause disease in animals and fish. The toxins do not have any odor or taste and are not destroyed by stomach acid or digestives enzymes in the gastrointestinal tract. Once ingested, the toxins cross the intestinal membrane, enter the bloodstream, and distribute to the synapses of motor neurons. BoNTs are extremely toxic, with very small amounts needed to produce lethality.
Six different species, Seven different toxins, BoNT/A is the most toxic, followed by B & E.
- Group I – BoNT A, B, E, F, or G (Proteolytic C. Botulinum)
- Group II – BoNT B, E, F (Non-Proteolytic C. Botulinum)
- Group III – BoNT C, D (C. Botulinum)
- Group IV – BoNT G (C. argentinense)
- Group V – BoNT F (C. baratii)
- Group VI – BoNT E (C. butyricum)
Mechanism of Action
Botulinum neurotoxins are large protein complexes (zinc metalloproteases) that are deposited by the bacteria into food and act as proteases in the body. By cleaving specific proteins necessary for the release of the neurotransmitter acetylcholine into the neuronal-muscular junction, BoNTs cause flaccid muscle paralysis, that affects both striated and smooth muscles. They effectively prevent the innervation of muscles in the body.
Signs & Symptoms of Botulinum Toxicity
Botulism typically presents within 12 to 36 hours after ingestion, and initially causes dry mouth, sore throat, vomiting, diarrhea, and weakness. However, the hallmark sign of botulinum poisoning is acute symmetrical cranial nerve impairment, which results in blurred or double vision, drooping of the upper eyelids, and difficulty speaking and swallowing due to muscle weakness.
Botulism progresses on to descending muscle paralysis which impacts the neck, limbs, and trunk, as well as, causing respiratory arrest. If not treated botulism ultimately results in death. Due to improvements in clinical care, botulism is increasingly less fatal. Measures such as respiratory support and administration of antitoxin have significantly reduced the likelihood of death from botulism. Still, recovery is slow and may require several weeks to months of hospitalization. Prolonged or permanent muscle paralysis is likely an outcome.
Toxin to Therapeutic (The Dose Makes The Poison)
If the dose makes the poison, then it stands to reason, that there may be a therapeutic index, or range of doses between that which is effective, at producing a desirable effect, and that which produces toxic action. In addition to dose, what distinguishes a toxic effect from a therapeutic one is also governed by the duration and route of exposure/administration. As such, when BoNT is extracted as a purified protein, it can be used as a therapeutic drug.
History of Therapeutic Use
The U.S. Food and Drug Administration originally approved botulinum neurotoxins for use as a drug in 1989, for the treatment of several ophthalmic and neuromuscular diseases such as strabismus (“lazy eye”/”crossed-eyes”), blepharospasm (uncontrolled twitching of the eyelids), and hemifacial spasms. It was later approved for cosmetic use in 2002 after it was observed in patients treated for ophthalmologic conditions also experienced a loss of wrinkles around the eyes.
Botulinum Neurotoxins are now used to treat a wide range of disorders characterized by hyperexcitability of peripheral nerves and hypersecretory syndromes. As such it has been employed in the management of chronic migraines as well as the alleviation of axillary hyperhidrosis (excessive sweating) off-label uses are the treatment of facial lines other that forehead wrinkles, tremors, juvenile cerebral palsy, and migraine headaches.
BoNT/A – BOTOX
Botulinum Neurotoxin A (BoNt/A) was the first biological toxin licensed for use as a treatment in humans. When injected intramuscularly, BoNT/A reduces muscle hyperactivity and contractility. The effect is not permanent, but muscles are weakened just enough to relieve spasticity, without causing complete loss of function.
BoNTs are hazardous when exposure is systemic (occurring orally or via inhalation), but controlled localized administration of minuscule amounts of BoNTs are safe. BoNT/A is commonly known as Botox. One vial of Botox contains less than 30 times the amounts of toxin needed to cause death in an average sized adult. The therapeutic dose may be as little as 3 units of BoNT/A. On average 30 units of Botox are used for cosmetic purposes, and as much as 400 units can be safely used in large muscles. Comparably, it takes about 3000 units of toxin or 1 nanogram per kilogram of body weight to cause death.
BoNT/A for Chronic Migraine
Migraines are a debilitating neurological disorder. Chronic migraines are characterized by recurrent episodes of throbbing headaches that last for hours or days. Chronic migraines are accompanied by symptoms such as nausea, sensitivity to light, and sensitivity to sound. Migraines that occur less than 15 times a month are considered “episodic” versus “chronic” migraines which occur 15 or more times a month, for at least 3 months.
BoNT/A was originally recognized as a potential treatment for migraine sufferers when patients reported alleviation of their migraines for up to 4 or 5 months after receiving cosmetic BOTOX treatments. Subsequently, animal and human studies confirmed that BoNT/A effectively reduces the frequency of chronic migraine headaches.
BoNT/A was approved in 2010, for the prevention of headaches in adults with chronic migraine. It is administered every 12 weeks in the form of multiple injections to the superficial muscles around the head. The effects are long-lasting but reversible. However, it is not effective as a treatment for other types of headaches and does not have any effect on the migraine symptoms of nausea, or sensitivity to light and sound.
The exact reason why BoNT/A relieves chronic migraine headaches is not known. For sure, it is not due to BoNTs ability to relax muscles, as aberrant muscle tone does not play a primary role in migraine pain. BoNTs prevent exocytosis and the release of acetylcholine, thereby weakening muscles, but they also have effects on pain and inflammation in the peripheral nervous system. By inhibiting the release of pain peptides, inflammatory mediators known as bradykinins, and the neurotransmitters glutamate, serotonin, dopamine, and norepinephrine from motor-sensory nerves, BoNTs inhibit neurogenic inflammation and desensitize periphery nerves responsible for transmitting pain signals to the central nervous system. Reducing pain signaling from the peripheral nervous system, which essentially blocks the central nervous system from perceiving pain.
Adverse Reactions with Therapeutic Use & Contraindications
There are three Botulinum toxin preparations available for clinical use in the United States. They are commercially known as, BOTOX, MYOBLOC, and DYSPORT. BOTOX and DYSPORT are different preparations of BoNT/A, while MYOBLOC is made with BoNT/B. The preparation differs in potency from each other, and should not be used interchangeably without accounting for this factor.
Repeated treatment may result in a decrease in efficacy, due to a potential for the formation of antibodies against the toxin. However, the use of hybrid toxin may prolong the therapeutic efficacy of BoNTs. Excessive treatment with BoNTs for cosmetic or therapeutic purposes can result in Iatrogenic botulism, which produces symptoms similar to classic botulism. However, this is rare.
Botulinum neurotoxins should not be administered to pregnant women, people with allergies to aminoglycoside antibiotics, those who are on anticoagulant therapy, or to anyone who has a neuromuscular junction disorder. Otherwise, when the appropriate dose and site of administration is chosen, BoNTs are safe and effective as medicinal treatment for a host of ailments, characterized by spasms, twitching, tremors, neurological pain, and secretory disorders.
It is important to keep in mind that there are a number of factors influencing safety and toxicity, such as route of exposure, duration of exposure, concentration, and pharmacodynamics (how the drug affects the body). Aside from the properties of a substance outside the body, or its action within, it is equally important to understand the pharmacokinetics (the effect the body has on the substance). The body may distribute it, neutralize or increase its toxicity through metabolism, clear it through excretion, or accumulate and sequester it in bone, fat, or soft tissue.
Botulinum toxin is only one example of a poisonous substance that can be used in a beneficial way. Even the spores of Clostridium bacteria that produce the toxin, are now being investigated as vehicles for the delivery of anti-cancer drugs. Conversely, substances that are generally considered to be safe, with incorrect use, can be harmful.
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