The emerging science--and art--of neurotoxin treatment
There are up to 133 possible applications for Clostridium botulinum type-A toxin
Poststroke spasticity, cerebral palsy, migraine, tension headache, tics, twitches, jerks, spasms, uncontrolled blinking, movement disorders, spasmodic dysphonia, drooling, sweaty palms and underarms, deep forehead lines, crow's feet around the eyes. These are just a few of up to 133 possible applications for the neurotoxin Dysport, a formulation of Clostridium botulinum type-A toxin (Bt-A).
You won't find any other drug in the world with as many indications backed by reputable medical evidence, according to Dr. Raymond Rosales, who chaired a recent intensive hands-on Dysport workshop hosted by the department of neurosciences of the University of the East Ramon Magsaysay Memorial Medical Center. Rosales, a consulting neurologist at the University of Santo Tomas Hospital and Metropolitan Hospital, is among the top authorities on neurotoxin research.
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Bt-A is the most powerful neurotoxin that in its early stages of development was considered a biological weapon. In very minute doses, however, it is able to relax overactive muscles and provide a major therapeutic benefit for patients suffering from complications of neuromuscular conditions. It acts on the neuromuscular junction to inhibit the release of the neurotransmitter acetylcholine (ACTH) to effectively paralyze the hyperactive muscle, allowing the patient to develop or recover normal functions and lead a better life. Its effects are temporary, ranging from three months to one year depending on the indication.
There are seven types of botulinum toxin named alphabetically: A, B, C, D, E, F, and G. They are so identified based on the presynaptic neuronal receptor they act on. For instance, A, the most potent in this group, acts on SNAP-25 (synaptosomal-associated protein of 25k daltons) while B acts on VAMP (vesicle-associated member protein or synaptobrevin). What is the significance of this difference? Bt-B, which is available in the United States, is used to manage patients who have developed tolerance to the effects of Bt-A. In Japan, scientists are trying to develop clinical uses for Type-F.
Two brands of Bt-A are available in the Philippines. Allergan's Botox is used by cosmetologists, aesthetic surgeons, and dermatologists for cosmetic management of facial frown lines and wrinkles. Then there is Dysport, which its manufacturer, Ipsen, says has become the choice for therapeutic applications, particularly by neurologists and rehabilitation-medicine specialists.
Both have the same active ingredient, but Rosales emphasized that the clinician should recognize their differences and make a choice depending on the benefits that the patient may gain from either. One difference is the unit of measure, a critical factor in dosing strategy. Botox is available in vials containing 100 Botox units while Dysport comes in a vial with 500 Speywood units. Several studies gave equivalence ratios ranging from equal to four Dysport (Speywood) units to one Botox unit. Most of the published studies seem to agree that the best equivalence ratio is three Dysport units to one Botox unit. The difference in the definition of units arises as a result of the different assay methodologies used by the two companies.
Equivalence ratio
Rosales performed a retrospective study of the hundreds of patients he had injected with either Botox or Dysport, keeping a series for each and doing a crossover. Results showed that the equivalence ratio at which the two products would demonstrate relatively similar clinical parameters is 2.5 Dysport units to one Botox unit. At a ratio of 3:1, overall parameters appear to favor Dysport. Rosales's initial findings were validated in a subsequent neuromuscular study done in cooperation with the University of the Philippines Institute of Biochemical Sciences in which the equivalence ratio was 2.54 Dysport units to one Botox unit.
The findings are important in relation to cost. In the management of poststroke upper-limb spasticity, for instance, it has been determined that one Dysport vial of 500 units was enough for the average Asian to relieve spasticity for each limb. With Botox, the same patient would need at least two vials of 100 units for each limb. Since equivalent doses of Dysport cost between 23- and 48-percent lower than Botox, patients may be able to get optimal benefits.
The difference in protein load is also significant as it may be linked to the development of tolerance. The higher the protein load, the higher is the possibility for tolerance to develop. In a recent study, Pickett et al. found that the toxin protein load of Dysport is 40-percent lower than that of Botox for equivalent dose (3: 1). Published data show that as high as 17 percent of patients develop antibodies to Botox (Allergan, 2002) compared with 2.5 percent for Dysport (Kessler, 1999).
Diffusion is also a factor, which Rosales pointed out, may be an advantage or a disadvantage. There would be instances when Bt-A spread would be favorable (such as when injecting large muscles like the biceps or the gastrocnemius), while there would be instances where less spread would be ideal, particularly for eye injections. In either case, however, operator skill and experience come into play, as dosing strategy, dilution, and injection technique become critical factors for success.
Rosales challenged the assumption that Dysport diffuses more than Botox. He injected Dysport to the limb of a patient with spasticity and measured muscle activity on the opposite limb with single-fiber EMG. The readings demonstrated jitters, indicating toxin spread. He repeated the procedure using Botox and the EMG readings were similar. But he stressed that in both cases, the changes were largely subclinical. Whether the diffusion is through hematologic or neurologic transport, however, remains to be seen, he said.
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Unlike surgery, Bt-A is reversible. Its reversibility is attributed to the reinnervation at the neuromuscular junction of the motor endplates. According to Rosales, it was previously believed that collateral sprouts observed by electron microscope to emanate from the main nerve terminal serve to provide reinnervation. However, newer evidence shows that transmission of impulses through these sprouts were not the real root of the reinnervation, but rather the return to normal activity of the main nerve terminal. When this happens, the collateral sprouts were observed to retract.
Bt-A action on cholinergic terminals provide effective inhibition to the barrage of ACTH, providing relief to hyperactive muscles or glands. These cholinergic terminals are the alpha motor neurons found in the extrafusal muscles (nicotinic), the gamma motor neurons in the intrafusal muscles (nicotinic), the preganglionic parasympathetic, parasympathetic (nicotinic), and postganglionic terminals--including the parasympathetic (muscarinic) in the salivary glands and the sympathetic (muscarinic) receptors in the sweat glands.
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