Botulinum toxin

Purified botulinum toxin (BTX) was the first bacterial toxin used as a medicine

• Clostridium bacteria and toxin
  • Clostridium species bacteria are sporulating, obligate anaerobic, Gram-positive bacill
    • spores of C. botulinum are ubiquitous, distributed widely in soil and marine sediments worldwide and often found in the intestinal tract of domestic grazing animals
    • under appropriate environmental or laboratory conditions, spores can germinate into vegetative cells that will produce toxin
    • C. botulinum grows and produces neurotoxin in the anaerobic conditions frequently encountered in the canning or preservation of foods
      • seven different strains of Clostridium have been described (designated A, B, C (1 and 2), D, E, F and G), and each produces a distinct neurotoxin identified by the corresponding letter of the bacterial strain producing it, so, there are 7 distinct neurotoxins (BTX-A, -B, -C, -D, -E, -F, -G) (1)
        • humans can be affected by the toxins of 5 strains (A, B, E, F and G) and are not affected by the toxins of strains C and D
        • all 7 toxins may potentially cause botulism in humans given a high enough exposure
        • all 7 neurotoxins are structurally similar but immunologically distinct
          • there is some serum cross-reactivity among the serotypes because they share some sequence homology with one another as well as with tetanus toxin
            
            
• therapeutic indications
  • BTX has evolved from a poison to a versatile clinical tool for a growing list of conditions resulting from muscular hyperfunction
  • in the head and neck, this list includes focal dystonias, vocal tics and stuttering, cricopharyngeal achalasia, various manifestations of tremor, hemifacial spasm, temporomandibular joint dysfunction, migraine, bruxism, masticatory myalgias, sialorrhea and hyperhidrosis
  • use of botulinum toxin-A (BTX-A) is recommended as a treatment option in the management of overactive bladder (OAB) syndrome and idiopathic detrusor overactivity (2)
    
    
• structure and toxicity
  • toxins produced by clostridial bacteria are high-molecular-weight protein complexes that include 3 key proteins: a 150-kDa toxin, a non-toxin hemagglutinin protein, and a non-toxin non-hemagglutinin protein
    • the 150-kDa toxin is composed of a 100-kDa heavy chain and a 50-kDa light chain. Disulfide and noncovalent bonds link the heavy and light chains, and both chains are required for neurotoxicity100. BTX is the most toxic material known
      • is 4 times more lethal in mice than tetanus toxin, 1 × 10^10 more lethal than curare, and 100 × 10^10 more lethal than sodium cyanide
      • estimated human dose (assuming a weight of 70 kg) of type A toxin lethal to 50% of an exposed population (the LD50) is estimated, based on animal studies, to be approximately 0.09-0.15 µg by intravenous administration, 0.7-0.9 µg by inhalation and 70 µg by oral administration
      • based on findings from primate studies
        • human LD50 for intramuscular BTX injection is estimated at 2500-3000 U for a 70-kg adult (35-40 U/kg)
          
          
• mechanism of action
  • BTX is a protease that causes temporary chemical denervation of skeletal muscle by blocking the Ca+2-mediated release of acetylcholine from nerve endings of alpha and gamma motor neurons (myoneural junction), producing a transient dose-dependent weakening of the muscle activity rendering it nonfunctional without systemic effects
  • inhibition of muscular contraction is believed to be followed by the sprouting of new axon terminals, which results in synaptic regeneration and the reestablishment of neuromuscular transmission
  • 7 neurotoxins have different specific toxicities, different durations of persistence in nerve cells and, and different potencies
  • all BTX serotypes, ultimately, inhibit acetylcholine release
  • clinical effect occurs within approximately 3-7 days (typically seen after 1-3 days) after administration, followed by 1-2 weeks of maximum effect, which then levels off to a moderate plateau until full nerve recovery within 3-6 months (typically at approximately 3 months)
    
    
• complications
  • Botox has a large margin of safety
  • most important side effects reported for cosmetic use of BTX include immunogenicity, allergy and local complications. Neutralizing antibodies to BTX-A toxins can lead to loss of treatment effect. Clinical resistance to BTX-A has been estimated as high as 7%
  • in theory, because human albumin is used in the preparation of Botox, a patient could exhibit an allergic reaction, but no case has been reported (1)
  • adverse effects such as pain, oedema, erythema, ecchymosis and short-term hypoesthesia may occur after injection of BTX-A
    • in therapeutic applications, complications were mostly local and relatively mild. There is a vast list and these include (1):
      • pain, erythema, ecchymosis of the region injected; infection at injection site
      • dry eyes, mouth droop, ptosis and lid edema, facial muscle weakness, asymmetry of facial expression during dynamic facial movements, xerostomia, transient dysphagia, restricted mouth opening, nasal regurgitation and nasal speech, headache, blurred vision, dizziness, upset stomach, neck weakness, voice changes, recurrent jaw dislocation, dysarthria, salivary duct calculi and local injuries of the carotid arteries or branches of the facial nerve
      • difficulties in chewing and breathing and risk of aspiration have been reported (1)
    • systemic side effects are rarely reported, generally not dose related, and can include transient weakness, fatigue, nausea and pruritis
      • flu-like syndromes have been reported, but they are generally of brief duration
      • some adverse effects such as xerostomia and dysphagia are more frequently seen after treatment with BTX-B than BTX-A
        
        
• contraindications
  • contraindications to BTX-A are generally few
    • Allergan (preparation of BTX-A) lists Botox contraindications as pregnancy and breastfeeding, disorders of the neuromuscular junction (myasthenia gravis, amyotrophic lateralizing sclerosis, myopathies) and theoretical drug interactions (aminoglycoside antibiotics, quinidine, calcium channel blockers, magnesium sulfate, succinylcholine, and polymyxin)
    • other reported contraindications are Eaton-Lambert syndrome and hypersensitivity to BTX or one of its ingredients

Reference:

• 1) Majid OW. Clinical use of botulinum toxins in oral and maxillofacial surgery. Int J Oral Maxillofac Surg. 2010 Mar;39(3):197-207. Epub 2009 Dec 2.
• 2) Apostolidis P et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol 2009;55: 100-120.