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The Poison That Became a Medicine


The Poison That Became a Medicine

It is no use denying that our society today is one that focuses mainly on image and somehow manages to relate everything to it. The media nowadays has imprinted in our minds a stereotyped model of what is considered to be beautiful,

a model that defies the natural wear and tear that comes with the years and does not even acknowledge the concept of natural aging. This fact led to a frenzied race that tries to keep up with what is “popular and beautiful”, a race in which participants would stop at nothing to reach their goal; even if this means seeking to find the solution in the weirdest of places, bottles of poison given the name “Botox”.


Historical background: 

Botox is the trade name of “botulinum toxin”, an extremely neurotoxic protein produced by the bacteria Clostridium Botulinum. Its journey was somewhat long but here are the main stops:

 

  • In the early 18th century, a physician by the name of Justinuc Kerner first saw the possibility of therapeutic uses of what he called “sausage poison”, since the bacteria producing the toxin tends to grow mainly in meat products that are improperly-handled or ill-prepared. It was Kerner that first coined the name botulism (from the Latin botulus meaning sausage).
  • In 1897, Emile Pierre Van Ermengem managed to identify the bacterium Clostridium Botulinum as the producer of the botolinum toxin; during an outbreak that followed a funeral ceremony in Ellezelles, a Belgian village.
  • It was P.Tessner Snipe along with Hermann Sommer that managed to purify the toxin for the first time.
  • The big discovery came in 1949, when Burgen announced that the mechanism of action related to botulinum toxin was that it was capable of blocking neuromuscular transmission.

Then, the journey of therapeutic research related to botox started:

  • In the 1960s an ophthalmologist by the name of Alan Scott teamed with Edward Schantz to be the first to explore possible therapeutic uses of botulinum toxin.
  • In 1973 Scott began his experiments on monkeys.
  • In 1980 Scott officially used botulinum toxin type A for the first time in humans to treat strabismus and blepharospasm.
  • A new breakthrough took place when Pasricha and colleagues demonstrated successful use of botulinum toxin in cases of achalasia.
  • The good news continued to pour in when Bushara and Park showed it can inhibit sweating.

From that day on, more and more applications for botox treatment came into view. But the main point of attraction was the cosmetic applications that carry the promise of an everlasting youthful face free of wrinkles:

  • Dr. Richard Clark was the first to hypothesize on the possible benefit of botulinum toxin type A in treating wrinkles; he published his findings in the Plastic and Reconstructive Surgery journal in 1989.
  • In 1992, a married couple by the names of Carruthers JD and Carruthers JA published the first study regarding the use of botulinum toxin type A to treat glabellar frown lines.
  • On April 12th 2002, The FDA approved of the use of botulinum toxin type A for temporary improvement of the appearance of moderate to severe frown lines between the eyebrows.

 

The mechanism of action:

Botulinum Toxin stops neurotransmission through blocking acetylcholine release, resulting in a state of chemical denervation. It is a zinc-dependent endopeptide made up of heavy and light chains linked together by disulfide bonds.
Its action follow 4 steps:

botox

  1. Binding: The toxin binds to specific receptors on the surface of the presynaptic cell surface. This step takes around half an hour and is mediated by the heavy chain of the toxin.
  2. Internalization: The plasma membrane of the nerve cell invaginates around the toxin-receptor complex, resulting in the formation of a toxin containing vesicle inside the nerve terminal.
  3. Translocation: The disulfide bond is cleaved releasing the light chain across the endosomal membrane of the endocytic vesicle into the cytoplasm of the nerve terminal.
  4. Blocking: The light chain of the toxin impedes on the release of acetylcholine into the synaptic cleft by cleaving a protein required for the docking of acetylcholine vesicles on the inner side of the nerve terminal plasma membrane.

The final result of the above mentioned mechanism is blocking the normal flow of neurotransmission, rendering the muscle implied unable to contract. These effects last between 2-6 months and then resolve.


Applications:

The main conditions are:

  • Cervical dystonia: One of the few areas of medicine in which the FDA approved the use of botox. A paper was published by Emory University in 2005 reporting the use of serial botox injections for cervical dystonia if physiotherapy fails, and the provided results showed that many patients who received this form of treatment didn't need surgery after.
  • Blepharospasm (excessive blinking): The first trials date bake to the 1980s as stated above.
  • Severe primary axillary hyperhidrosis (excessive sweating): A form of treatment approved by the FDA and by Health Canada, it is 80% effective in decreasing perspiration. Different medical trials and researches point out that this therapy is more effective when applied to the armpits compared to when it is applied to the palms and soles (these sites are much more painful to inject).
  • Strabismus (Squints): As previously mentioned.
  • Achalasia (failure of the lower oesophageal sphincter to relax)
  • Chronic focal painful neuropathies: A common condition in Pain Management Clinics. The studies conducted so far yield promising results but larger test groups are needed.
  • Migraine and other headache disorders:  On the 15th of October, the FDA announced its approval for the use of botox for the treatment of chronic migraine (meaning the patients that suffer from headaches for 14 days a month or more. In this case; botox is given every 12 weeks in multiple sites around the head and neck , with hope to decrease future migraine attacks.
  • Upper limb spasticity: The FDA approved of the use of botox for treatment of upper limb spasticity in adults on March 10th 2010. The news release issued by the American Food and Drug Association stated that botox can be used to treat muscle stiffness in the elbow, wrist and fingers of adults who suffer from upper limb spasticity.   

Other uses of botulinum toxin type A that are widely known but not specifically approved by FDA (off-label uses) include treatment of:

  • Pediatric incontinence, incontinence due to overactive bladder, and incontinence due to neurogenic bladder.
  • Lichen Simplex Chronicus: Unrelenting pruritis is the hallmark of this condition. A study conducted by Heckmann et al showed that the pruritis associated with lichen simplex chronicus can be successfully treated with botox type A.
  • Anal fissure: This was mentioned in a study published by Lisa S. Poritz on March 18th 2010. The published paper stated that injection of botox in the internal sphincter achieves what could be considered a "chemical sphincterotomy", with effects that last up to 3 months during which the acute fissure (and sometimes the more persistent chronic form) is allowed to heal. Surgical sphincterotomy will be indicated if the patient experiences recurrence of symptoms after 3 months of relief.   
  • Vaginismus : A persistent and involuntary contraction of the perineal muscles that surround the vagina when any penetration of the vagina is tried, whether it was with the penis or any instrument (a tampon, a speculum or a finger). In 1997 a study by Brin and Vapnek  was published reporting a case of secondary vaginismus treated first with 10 units of botox followed by 40 units injected. The patient was able to have intercourse for the first time in 8 years and the results lasted for 24 months.
  • Spastic disorders associated with injury or disease of the central nervous system including trauma, stroke, multiple sclerosis, Parkinson's disease, or cerebral palsy.
  • Allergic rhinitis: Mainly to lessen the degree of rhinorrhea  associated with allergic rhinitis. The primary studies stated that topical botox treatment is a safe and effective method of controlling nasal secretions.
  • Focal dystonias affecting the limbs, face, jaw, or vocal cords: The most common of which is the focal dystonia of the hand (also known as writer's cramp). Cohen et al demonstrated successful control of this spectrum of symptoms by repeated injection of botox every 2 weeks until symptoms subside.
  • TMJ pain disorders
  • Raynaud's phenomenon: For reasons that are not clear, botox injections help with the severe pain associated with Raynaud's phenomenon and it also improves the circulation (often abnormal in those patients) when other conservative measure fail.
  • Diabetic neuropathy.
  • Piriformis Syndrome: A painful condition that occurs when the sciatic nerve is trapped or impeded by the piriformis muscle or tendon. Studies show that combining botox injections with physiotherapy and stretching exercises (performing stretch exercises while the botox is still effective) led to superior results when compared with botox injections alone.

All this vast list and we didn't even start with the cosmetic applications!!! The novelty of what botox promises to do lies in the fact that all the current available cosmetic and plastic surgeries and procedures (autologus fat transplantation, collagen injections, laser resurfacing) do not tackle the main culprit behind wrinkle formation, the muscle.
The list of cosmetic application includes:

  • Glabellar furrows: The first FDA approved cosmetic application of botox injections. The results can last for up to 6 months followed by full recovery of the paralyzed muscles. One of the most troubling side effects is eyelid ptosis that may persist for up to 2-4 weeks.
  • Brow lift: Huang et al reported the largest brow lift of 2 to 3 cm after 5 U of botox type A  was injected into the glabellar region of each brow, and an additional 10 U was injected at four sites along the orbital rim, starting at the midpupillary line and extending to the lateral brow.
  • Lateral canthal lines: So as to get rid of what is known as "crow's feet appearance" when smiling or laughing. The risk of eyelid ptosis is also a source of concern in this case.
  • Transverse forehead lines: These lines are formed when the patient raises his or her eyes and attempts a surprised look. Botox injection in this area should be able to make these line softer and to increase the eye’s aperture.
  • Neck rejuvenation: This is possible by regularly injecting the vertical bands of the platysma with small doses of botox type A ( a total dose of 15-20 U).
  • Other applications: Botox treatment is being studied in order to test its effectiveness in diminishing nasolabial and mental folds and mouth wrinkles, but more studies are needed before safe application can be done.

 

Contraindications:

 

  1. Previous allergic reactions.
  2. Injection in infected or inflamed areas.
  3. Pregnancy (class C).
  4. Breast feeding.

 

Relative contraindications:

 

  1. Diseases of neuromuscular junction (such as myasthenia gravis) for fear of exacerbating generalized weakness.
  2. Simultaneous application with botox and administration of drugs that decrease neuromuscular transmission (Calcium channel blockers and aminoglycosides to name a few).

 

Side effects:

 

  1. Paralysis of the wrong muscle group: Often as a result of poor planning of the sites of injection or the dose applied.
  2. Allergic reactions: Due to the chemical structure of the molecule (protein).
  3. Bruising at the site of injection: Not a side effect of the toxin, more likely to be the result of faulty administration.
  4. General symptoms: Such as headaches, flu-like symptoms, blurred vision, dry mouth and fatigue.

 

Facts and Stats:

 

  • In September 2005, a paper published in the Journal of American Academy of Dermatology reported from the FDA saying that use of Botox has resulted in 28 deaths between 1989 and 2003, though none were attributed to cosmetic use.
  • The FDA announced on February 2008 that "botox has been linked in some cases to adverse reactions, sometimes including respiratory failure and death, following treatment for a variety of conditions using a wide range of doses".
  • 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.
  • In April 2009, the FDA updated its mandatory boxed warning cautioning that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism.
  • A recent study came up with troublesome results when it announced that the cosmetic use of botox type A for glabellar wrinkles can affect human cognition. This came when David Havas and colleagues announced in 2010 that  when participants were asked to read emotional (angry, happy, sad) sentences before and 2 weeks after botox injections in the glabellar area, reading time for the sad and angry sentences were longer than before the treatment while the time remained unchanged when reading the happy sentences. Thesefindings lead to the belief that facial muscle paralysis has a selective effect on processing the emotional content.
  • Another alarming banner was waved when researchers at the Faculty of Kinesiology at the University of Calgary in Canada announced that botox injections cause muscles to waste away in areas not injected, after observing 18 rabbits injected with botox type A for 6 months. The study, published in The Journal of Biomechanics in December 2010, found that botox injections lead to 50% muscle atrophy in the limb that was injected, but more alarmingly loss of muscle occurred also in limbs that were not injected. This suggests thatthe toxin can spread away from injection sites even when administered properly.

 

Conclusion:

It may seem that any sane person will come to the conclusion that the risks associated with botox injections outweigh its benefits, especially with the average population only knowing botox to be associated with fanatics who have lots of money and choose to play with their looks.
But one cannot ignore the growing list of people with chronic conditions who are benefitting from emerging indications for botox treatment.
Can science sacrifice this lengthy list of truly ill people for the sake of side effects that developed due to misuse of this product? A tough decision to make!


اضغط هنا للقراءة باللغة العربية

Prepared by: Dr. Zaina Habrawi


Source :

1-Montecucco C, Molgó J (2005). "Botulinal neurotoxins: revival of an old killer". Current opinion in pharmacology 5 (3): 274–279. doi:10.1016/j.coph.2004.12.006. PMID 15907915
2-Frank J. Erbguth (2004). "Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin". Movement Disorders (John Wiley & Sons on behalf of the Movement Disorder Society) 19 (S8): S2–S6. doi:10.1002/mds.20003. PMID 15027048.
3-Scott AB, Pasricha, PJ. Ravich WJ, Kalloo AN (January 1993). "Botulinum toxin for achalasia.". Lancet 341: 244–5.. PMID 8093528. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8093528
4-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
5-Plastic & Reconstructive Surgery:  December 2009 - Volume 124 - Issue 6 - pp 455e-456e ,Botox for vaginismus treatment, Pacik Peter, MD.
6-http://www.dermanetwork.org/article/advantages-and-disadvantages-of-hyperhidrosis-botox-treatment.html
7-Botox injection treatment for piriformis syndrome.
8-Botulinum toxin in primary care medicine, Eric S. Felber, JAOA  Vol 106, October 2006.
9-FDA News release, October 15th 2010.
10-FDA News release, March 10th 2010.
11-Botox injections, Robert A, Hauser, MD and Mervat Wahba, MD. November 23rd 2009.
12-Cautions concerning botox therapy, Martin T. Taylor, DO, PhD, JAOA Vol.107 May 2007.
13-"Study says botox causes muscles to waste away, Is this just another scare story?", Lorna Jackson,13/12/2010.
14-"Botox therapy for ischemic digits" Neumeister, Chambers, Herron and colleagues. Journal of the American Society of Plastic surgeons, July 2009.
15-"Botox causes muscles to waste away on to fat, scientist warn", Sophie Borland, December 4th 2010.






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