"The eminent physiologist Claude Bernard wrote in his classic work entitled Experimental Science: "Poisons can be employed as a means for the destruction of life or as agents for the treatment of the sick."
DESCRIPTION
BOTOX is a drug made from a neurotoxin produced by certain strains of the bacterial species: C. botulinum, Clostridium butyricum, Clostridium baratii, and Clostridium argentinense.
It's the same toxin that causes a life-threatening type of food poisoning called BOTULISM.
CLASSIFICATION
DENATURING
Botulinum toxin is denatured at temperatures greater than 60°C (140°F).
CHEMICAL OVERVIEW
There are seven serologically distinct toxin types, designated A through G.
The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulphide bond to a 50-kDa light chain.
This light chain is an enzyme (a protease) that attacks one of the fusion proteins, SNAP-25 (image), at a neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine .
By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism, as opposed to the spastic paralysis seen in tetanus.
It is the most acutely toxic substance known, with a median lethal dose of about 1 ng/kg when introduced intravenously and 3 ng/kg when inhaled. This means that, depending on the method of introduction into the body, a mere 90–270 nanograms of botulinum toxin could be enough to kill an average 90 kg (200 lb) person.
Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) in an anaerobic environment, allowing the spores to germinate and grow.
The growing (vegetative) bacteria produce toxin.
It is the ingestion of preformed toxin that causes botulism, not the ingestion of the spores or the vegetative bacteria.
Infant and wound botulism both result from infection with spores, which subsequently germinate, resulting in production of toxin and the symptoms of botulism.
Proper refrigeration at temperatures below 3°C (38°F) prevents the growth of Clostridium botulinum.
The organism is also susceptible to high salt and low pH levels.
The toxin itself is rapidly destroyed by heat, such as in thorough cooking.
On the other hand, the spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.
Fortunately, ingestion of the spores is safe, except in infants, as the highly oxygenated and highly acidic environment of an adult human digestive system prevents the spores from growing and producing the botulinum toxin.
Botulinum toxin has been recognized and feared as a potential bioterror weapon.
BIOCHEMICAL MECHANISM OF TOXICITY
Image
The primary structure of the neurotoxin is such that the resulting shape (secondary and tertiary structures) causes a highly specific binding and block of acetylcholine release at myoneural junctions.
Botulinum toxin is toxic to all vertebrates through weakening of skeletal muscle, and death may come about through paralysis of the muscles of respiration.
Botulinum toxin blocks cholinergic transmission at all cholinergic synapses in the peripheral nervous system, but conduction along axons is not affected.
The chemical denervation lasts for several months, and recovery of neurotransmission and muscle activity requires sprouting of new nerve endings and functional connections at motor end plates.
The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon terminals. The toxin must get inside the axon terminals in order to cause paralysis.
Following the attachment of the toxin heavy chain to proteins on the surface of axon terminals, the toxin can be taken into neurons by endocytosis.
The light chain is able to cleave endocytotic vesicles and reach the cytoplasm. The light chain of the toxin has protease activity.
The type A toxin proteolytically degrades the SNAP-25 protein, a type of SNARE protein (Details; image)
The SNAP-25 protein is required for vesicle fusion that releases neurotransmitters from the axon endings (in particular Acetylcholine).
Botulinum toxin specifically cleaves these SNAREs, and so prevents neuro-secretory vesicles from docking/fusing with the nerve synapse plasma membrane and releasing their neurotransmitters.
Though it affects the nervous system, common nerve agent treatments (namely the injection of atropine and 2-pam-chloride) will increase mortality by enhancing botulin toxin's mechanism of toxicity.
Attacks involving botulinum toxin are distinguishable from those involving nerve agent in that NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a "positive" when a sample of the agent is tested.
Furthermore, botulism symptoms develop relatively slowly, over several days compared to nerve agent effects, which can be instantaneous.
TREATMENT OF BOTULINUM POISONING
If the symptoms of botulism are diagnosed early, an equine antitoxin, use of enemas, and extracorporeal removal of the gut contents can be used to treat the food-borne illness.
Wound infections can be treated surgically.
The case fatality rate for botulinum poisoning between 1950 and 1996 was 15.5%, down from approximately 60% over the previous 50 years.
Death is generally secondary to respiratory failure due to paralysis of the respiratory muscles, so treatment consists of antitoxin administration and artificial ventilation until the neurotoxins are excreted or metabolised. If initiated on time these treatments are quite effective.
There are two primary Botulinum Antitoxins available for treatment of botulism:
- Trivalent (A,B,E) Botulinum Antitoxin: derived from equine sources utilizing whole antibodies (Fab & Fc portions).
This antitoxin is available from the local health department via the CDC in the USA.
- Heptavalent (A,B,C,D,E,F,G) Botulinum Antitoxin: derived from "despeciated" equine IgG antibodies, which have had the Fc portion cleaved off leaving the F(ab')2 portions.
This is a less immunogenic antitoxin that is effective against all known strains of botulism where not contraindicated.
Disease Listing, Botulism Manual, Additional Information - CDC Bacterial, Mycotic Diseases . Retrieved 2007-08-14.
MEDICAL USES
History of drug
Although botulinum toxin is a lethal naturally occurring substance, it can be used as an effective and powerful medication.
Researchers discovered in the 1950s that injecting overactive muscles with minute quantities of botulinum toxin type-A would result in decreased muscle activity by blocking the release of acetylcholine from the neuron by preventing the vesicle where the acetylcholine is stored from binding to the membrane where the neurotransmitter can be released. This will effectively weaken the muscle for a period of three to four months.
In cosmetics, a Botox injection, consisting of a small dose of botulinum toxin, can be used to prevent formation of wrinkles by paralyzing facial muscles.
Qualifications for Botox injectors vary by county, state and country.
Botox cosmetic providers include dermatologists, plastic surgeons, cosmetic physicians, nurse practitioners, nurses, physician assistants, and medical spas.
The wrinkle preventing effect of Botox lasts for approximately three to four months, up to six months.
The main conditions are:
- CERVICAL DYSTONIA(spasmodic torticollis) : a neuromuscular disorder involving the head and neck. Botulinum Toxin Type B (BTX-B) received FDA approval for treatment of cervical dystonia on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.
More informations: Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia
- BLEPHAROSPASM (excessive blinking) and STRABISMUS (squints): In December 1989, Botox manufactured by Allergan, Inc., was approved by the U.S. Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.
See also botulinum toxin for the treatment of strabismus click
United States Department of Health and Human Services (April 30, 2009). Re: Docket No. FDA-2008-P-0061(PDF, 8.2 MB). Food and Drug Administration. Retrieved 2010-07-26
- Severe primary axillary HYPERHIDROSIS: excessive sweating. While treating patients with hemifacial spasm at Southend Hospital in England in 1993, Khalaf Bushara and David Park were the first to show that botulinum toxin injections inhibit sweating . This was the first demonstration of non-muscular use of BTX-A. Bushara further showed the efficacy of botulinum toxin in treating hyperhidrosis (excessive sweating). BTX-A was later approved for the treatment of excessive underarm sweating.
Botulinum toxin for hyperhidrosis
Bushara KO, Park DM. (November 1994). Botulinum toxin and sweating. Journal of Neurology, Neurosurgery, and Psychiatry 57 (11): 1437–1438. doi:10.1136/jnnp.57.11.1437. ISSN 0022-3050. PMID 7964832.
- ACHALASIA failure of the lower oesophageal sphincter to relax.
Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone.
- MUSCLE SPASMS
The acceptance of BTX-A use for the treatment of muscle pain disorders is growing, with approvals pending in many European countries. The efficacy of BTX-A in treating a variety of other medical conditions (including prostatic dysfunction, asthma, and others) is an area of continued study.
- UPPER MOTOR NEURON SYNDROME
BTX-A is now a common treatment for muscles affected by the upper motor neuron syndrome, for muscles with an impaired ability to effectively lengthen.
Muscles affected by the Upper Motor Neuron Syndrome frequently are limited by weakness, loss of reciprocal innervation, decreased movement control and spasticity.
Joint motion may be restricted by severe muscle imbalance related to the Upper Motor Neuron Syndrome, when some muscles are markedly overactive.
Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, and so improved ability to exercise.
In June 2009 its use for treating muscles with spasticity led a UK doctor to successfully help an Australian man who had required a wheelchair for mobility following a stroke 20 years prior to walk.
- MIGRAINE and other headache disorders.
OnabotulinumtoxinA (trade name Botox) received FDA approval for treatment of chronic migraines on October 15, 2010, although it is ineffective for the treatment of episodic migraines. The toxin is injected into the head and neck to treat these chronic headaches.
Approval followed evidence presented to the agency from two studies funded by Botox maker Allergan, Inc. showing a very slight improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment.
For more informations about the clinical program and trials:
a. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program
b. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial
c. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial
Walsh, Sandy (October 15, 2010). FDA approves Botox to treat chronic migraine. FDA Press Releases. Retrieved 2010-10-15.
SIDE EFFECTS
Side effects, which are generally minor and temporary, can be predicted from the mode of action (muscle paralysis) and chemical structure (protein) of the molecule, resulting broadly speaking in two major areas of side effects: paralysis of the wrong muscle group and allergic reaction.
Bruising at the site of injection is a side effect not of the toxin, but rather the mode of administration.
Bruising is prevented by the clinician applying pressure to the injection site, but may still occur, and will last around 7–10 days. In cosmetic use, this can result in inappropriate facial expression such as drooping eyelid, double vision, uneven smile, or loss of the ability to close eyes.
This will wear off in around six weeks.
When injecting the masseter muscle of the jaw, loss of muscle function will result in a loss or reduction of power to chew solid foods.
All cosmetic treatments are of limited duration, and can be as short a period as six weeks, but usually one sees an effective period of between three and eight months.
At the extremely low doses used medicinally, botulinum toxin has a very low degree of toxicity.
Other adverse events from cosmetic use include headaches, dysphagia, flu-like syndromes, blurred vision, dry mouth, fatigue, allergic reactions and swelling or redness at the injection site.
Individuals who are pregnant, have egg allergies or a neuromuscular disorder are advised to avoid Botox.
Markus, Ramsey (September 30, 2009). Botox for Wrinkles. Baylor College of Medicine. Retrieved 2010-07-14.
LINKS TO DEATHS
The use of Botox has resulted in 28 deaths between 1989 and 2003, though none were attributed to cosmetic use.
On February 8, 2008, the FDA announced that Botox has "been linked in some cases to adverse reactions, including respiratory failure and death, following treatment of a variety of conditions using a wide range of doses," due to its ability to spread to areas distant to the site of the injection.
In January 2009, the Canadian government warned that botox can have the adverse effect of spreading to other parts of the body, which could cause muscle weakness, swallowing difficulties, pneumonia, speech disorders and breathing problems.
Several cases of death have been linked to the use of fake Botox.
_ Coté TR, Mohan AK, Polder JA, Walton MK, Braun MM (September 2005). "Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases". J. Am. Acad. Dermatol. 53 (3): 407–15. doi 10.1016/j.jaad.2005.06.011(05)01985-7/abstract . PMID 16112345
MANUFACTURERS
Popularly known by one of its trade names, Botox or Dysport, it is used for various cosmetic and medical procedures.
In the United States, BOTO is manufactured by Allergan, Inc. for both therapeutic and cosmetic use.
Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea, in 2009
Petrou, Ilya (Spring 2009). Medy-Tox Introduces Neuronox to the Botulinum Toxin Arena (PDF). The European Aesthetic Guide.
Work of Federica Casasco e Maria Luisa Favale.
