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Botulinum Toxin

Botox structure

Frivolous or Fundamental?

Botulinum toxin is best known for its use in cosmetic surgery, where it has been used as a ‘face-lift in a bottle’ under the brand name Botox since 1990. The widespread advertising of Botox as a cosmetic treatment, and its popularity among celebrities have led to Botulinum toxin becoming well-known as a frivolous treatment to help the rich appear youthful.

The use of botulinum toxin is currently controversial, because of the method of testng, which is a mouse potency assay, and because it is viewed as a cosmetic treatment.

While cosmetic treatments are the best known application of botulinum toxin, the important clinical uses for which it was researched and developed are often overlooked.


> History

> The action of botulinum toxin

> Testing

> Medical uses -dystonias

> Medical uses - non dystonic disorders

  
History
Botulism is a rare but serious paralytic illness caused by a nerve toxin, botulinum. The term "Botulism" is derived from the Latin meaning "sausage", once a common source of infections, which can come from eating contaminated food.  Botulinum is a potent toxin, produced by the bacterium Clostridium botulinum. It affects the body by blocking nerve function and leading to respiratory and musculoskeletal paralysis.  The C botulinum organism is killed by high temperatures, low pH or the presence of oxygen therefore most cases of food borne poisoning are caused by improperly canned foods.  There are seven distinctly different types, labeled A to G.

The first development of Botulinum toxin as a therapy was to treat disorders of localised muscle hyperactivity.  The first tests of Botulinum toxin type A were carried out in the late 1980’s to treat strabismus.  Other uses of botulinum A were quickly discovered in neurology , otolaryngology and gastroenterology. By the late 1990’s other botulinum types had entered clinical trials.

The action of botulinum toxin
Botulinum neurotoxins are unique in the way they cause specific paralysis of skeletal muscles.  Their action is independent of the route by which the toxin reaches the musles.  Toxin absorbed through the gut usually results in death caused by paralysis of the diaphragm and hence an inability to breathe, rather than from the effects of the toxin on the gut or the heart.  

The Botulinum Toxins cause paralysis by preventing the release of the neurotransmitter acetylcholine as the nerve cells meet muscle, at the neuromuscular junction. This blocks the ability of the nervous system to trigger muscle contractions.

There are three stages to this process;

i)    Binding – the toxin binds rapidly and irreversibly to receptors on the presynaptic nerve (nerve cell) surface.

ii)    Internalisation – the toxin crosses the membrane of the nerve cell and enters
the nerve terminus, where neurotrasmitters are stored ready for release.
 
iii)      Intracellular poisoning - the toxin disables the neurotransmitter release mechanism. This prevents the nerve from being able to release acetylcholine, and without this chemical signal the adjacent muscle will not contract and will be paralysed.  The different types of botulinum toxin target different components of the release mechanism.

The paralysis produced by the prevention of acetylcholine release is eventually overcome as the toxin clears from the neuromuscular junction and the nerve fibres grow around the poisoned region

Intramuscular injection of botulinum toxin causes local paralysis, as the toxin remains around the site of injection. This led to clinical use in disorders where muscles contract inappropriately.  

Testing
Botulinum toxin is an extremely potent neurotoxin with a lethal level in humans of around 1 ng / kg bodyweight (ng = nanogram = 0.000000001 g) and it is therefore vital that material released for clinical use is safe and of the strength stated on the label.

Currently the only method available to reliably measure potency is the mouse potency bioassay.  There are alternative methods are available but some still involve the use of animal experiments and they may not be suitable for initial batch release testing. However, alternative methods are used to confirm potency.

Botulinum toxin has a wide and ever extending range of clinical indications and in order to ensure it is suitable and safe for these uses, animal testing will be required for the foreseeable future.


Medical uses - Dystonias

 

 

 

Dystonia is a syndrome of sustained muscle contractions, often causing twisting and repetitive movements, or abnormal postures.  Primary dystonia in the UK is thought to occur in 650 cases per million population; but because dystonias are often difficult to diagnose or medical advice is not sought the actual number maybe considerably higher.

Blepharospasm
Blepharospasm is a focal dystonia affecting the orbicularis oculi muscles which close the eyelids.  There is intermittent or sustained closure of the eyes, sometimes severe enough to cause functional blindness.  Adjacent body regions such as muscles of the face, neck and throat are often involved (masticatory, laryngeal and cervical muscles).  Previous treatments only showed benefits for fewer than 30% of patients, many of whom complained of associated side effects.  Botulinum toxin A gives functional improvement to more than 70% of patients, who receive injections every three months. Most have immediate relief, although some find that treatment becomes less effective over years of use.

Cervical dystonia
The most common form of dystonia is cervical dystonia or spasmodic torticollis, an abnormal head and neck posture caused by muscle contraction which first occurs in adulthood.  Previous treatments involved a combination of anticholinergic drugs, which often have severe side effects, and muscle relaxants, but now botulinum toxin A is established as the treatment of choice for cervical dystonia, giving improved posture and reducing pain.

Oromandibular dystonia
Oromandibular dystonia is a form of dystonia which affects the lower facial and tongue muscle causing involuntarily tongue movement and opening and closing of the jaw.  Drug treatments are often ineffective but local injection of botulinum toxin improves chewing and speech in patients with jaw closing spasms.

 

 

 

Medical uses - non dystonic disorders

Parkinsons Disease
Drooling is a frequent symptom which occurs in about 75% of in Parkinsons disease patients.  Clinical studies suggest that botulinum toxin injected into the salivary glands can help reduce this symptom and use of botulinum toxin has now progressed to large scale clinical trials.

Hemifacial spasm
These are irregular tic-like contractions and occasional spasms of muscles innervated by one particular facial nerve. They usually occur in people aged of 40 and over.  Drugs occasionally produce modest benefit but the alternative treatment, surgery, carries a significant risk of disfigurement.  Botulinum toxin has proved an effective treatment with spasms improving in almost all patients with few complications. It is considered highly effective and safe for long-term treatments.

Pain Management
Botulinum Toxin has been used successfully in patients as an pain-killer for myofacial pain, migraine and other types of headache.  Although this work is in the early stages it appears that Botulinum Toxin not only reduces associated muscles spasms but also blocks sensitisation of the peripheral nerves which carry pain signals.


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