The Botox potential

“Allergan has a long-standing commitment to study the potential of Botox to treat a number of different medical conditions,” said Scott Whitcup, M.D., Allergan‘s (the firm producing Botox) Executive Vice President, Research and Development, Chief Scientific Officer. “With today’s approval, Botox is now approved for 26 different indications in more than 85 countries. Most importantly, this FDA approval is a milestone in the treatment of this burdensome condition and will provide a novel option for urologists and their Overactive bladder patients.” Clostridium botulinum produces seven different serotypes of toxin, labeled with letters from A to G. Despite this wide “arsenal” only several serotypes of A and B toxins were bent to clinical use. The A serotype of botulinum toxin (predominant in aesthetic medicine) in its inactive pro-form consists of a single polypeptide chain of about 150 kDa; the proteolytic cleavage, operated by trypsin or other bacterial peptidase, cleaves the protein in two chains , a “heavy” 100 kDa and a “light” 50 kDa, linked by disulfide bridges. From a functional view, these two peptides have quite different tasks: the heavy chain is responsible for binding specifically with glycoproteins present at the top of cholinergic neurons, while the proper toxic function is carried out by the light chain. This latter is an endopeptidase capable of high affinity binding to particular elements called SNARE protein. The toxic activity is expressed by the digestion of proteins associated with sinaptosoma (SNAP-25, syntaxin or synaptobrevin) that prevents the anchoring of vesicles loaded with acetylcholine from motoneurons and directed to the muscle. This results in the complete inhibition of motoneuron/muscle transmission, thus abolishing the contractile function. It was the Belgian microbiologist Emile van Ermengem that, in 1897, first outlined the causal relationship between the Clostridium botulinum and botulism. A few years later, in 1928, P. Tessmer Snipe and Hermann Sommer isolated and purified type A toxin; then we had to wait while until the 50s to understand the effect of this on neuromuscular plates. Ten years later, for the first time, Alan Scott and Edward Schantz utilized preparations of botulinum toxin for therapeutic purposes, and then, coming in 1980, this toxin has been used to treat patients suffering from strabismus or blepharospasm (two eye muscle disorders). To date this type of treatment is indicated for various diseases such as esophageal achalasia, hyperhidrosis (excessive sweating), migraine etc. More that twenty-two years ago Botox got its first FDA approval, making it the first botulinum toxin type A product approved in the world. Today, Botox neurotoxin is approved to treat a total of eight medical conditions in the United States, including the abnormal head position and neck pain that happens with cervical dystonia (CD) in adults; symptoms of severe underarm sweating (severe primary axillary hyperhidrosis) when medicines used on the skin (topical) do not work well enough; for the treatment of increased muscle stiffness in elbow, wrist, and finger muscles in adult patients with upper limb spasticity; for the prophylactic treatment of headaches in adults with Chronic Migraine, a distinct and severe neurological disorder characterized by patients who have a history of migraine and suffer from headaches on 15 or more days per month with headaches lasting four hours a day or longer; for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g. spinal cord injury [SCI], multiple sclerosis [MS]) in adults who have an inadequate response to or are intolerant of an anticholinergic medication; and for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency in adults who have had an inadequate response to or are intolerant of an anticholinergic medication. In addition to its therapeutic uses, the same formulation of Botox with dosing specific to moderate to severe glabellar lines was approved by the FDA in 2002 under the trade name Botox Cosmetic (onabotulinumtoxinA). The success of the founder Botox in the field of facial rejuvenation, has acted as a driving force for the development of many other formulations. Other than Botox Cosmetic (OnabotulinumtoxinA), other firms have on the market various botulinum toxins Ipsen with its Azzalure (AbobotulinumtoxinA), and Merz Pharmaceuticals with its Bocouture (IncobotulinumtoxinA) are just two examples. These products differ for the method of purification of the toxin, for the molecular weight (and therefore to the capacity to spread in the tissue) and for the presence/absence of accessory proteins.