Surgery – Miscellaneous – Methods
Reexamination Certificate
2002-03-14
2004-02-10
McDermott, Corrine (Department: 3738)
Surgery
Miscellaneous
Methods
C600S300000
Reexamination Certificate
active
06688311
ABSTRACT:
BACKGROUND
The present invention relates to methods for determining an effect of a Clostridial toxin upon a muscle. In particular, the present invention relates to use of a dermal topography method for determining an effect of a Clostridial toxin upon a facial muscle.
Movement of the face can be due to contractions of muscles underlying the skin and different muscles can move different parts of the face. For example, elevation of the brow results from contraction of the frontalis muscle. Electromyographic methods have been used to study the activity of various facial muscles. See e.g. Fridlund A. et al.,
Guidelines for Human Electromyographic Research, Psychophysiology
1986; 23(5): 567-590; Vitti M, et al.,
Electromyographic Investigation of Procerus and Frontalis Muscles
, Electromyogr. clin. Neurophysiol. 1976,16: 227-236, and; Tassinary L. et al.,
A Psychometric Study of Surface Electrode Placements for Facial Electromyographic Recording: I. The Brow and Cheek Muscle Regions
, Psychophysiology 1989; 26(1): 1-16.
In particular, electromyography, including surface electromyography (sEMG) has been used to investigate activity of the frontalis muscle and resultant brow displacement. See e.g. van Boxtel A, et al.,
Amplitude and bandwidth of the frontalis surface EMG: Effects of electrode parameters
, Psychophysiology 1984; 21(6): 699-707, and; Pennock J. D., et al.,
Relationship between muscle activity of the frontalis and the associated brow displacement
, Plast Reconstr Surg November 1999; 104(6): 1789-1797.
Additionally, it is known to study skin topography by making a silicone rubber negative replica (a mold) of a skin surface area. The mold captures three dimensional details of the skin surface and computerized image analysis of skin line density, depths and length analysis shown can be carried out thereon. Grove, G. L., et al,
Objective method for assessing skin surface topography noninvasively
, chapter one, pages 1-32 of
Cutaneous Investigation in Health and Disease
, edited by Leveque J-L., Marcel Dekker, Inc. (1989). This method has been used to study how micro-furrows on the forearm can increase in depth from about 33 &mgr;m in children to up to about 100 &mgr;m in the elderly. Corcuff P. et al.,
Skin relief and aging
, J Soc Cosmet Chem 1983; 34:177-190. The same silicone rubber impression method has been used to examine the effect of a topical cream to treat photodamaged skin, as by reduction of periorbital (crows feet) wrinkles. Leyden J. J., et al.,
Treatment of photodamaged facial skin with topical tretinoin
, J Am Acad Dermatol 1989; 21(3) (part 2): 638-644, and; Grove G. L., et al.,
Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream
, J Am Acad Dermatol 1991; 25(2) (part 1): 231-237.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals known as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botutinum toxin type A is the most lethal natural biological agent known to man. bout 50 picograms of botulinum toxin (purified neurotoxin complex) type A
1
is a LD
50
in mice. One unit (U) of botulinum toxin is defined as the LD
50
upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C
1
, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. The botulinum toxins apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. Botulinum toxin type A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, hemifacial spasm and cervical dystonia.
1
Avaible from Allegran, Inc. of Irvine, Calif. under the tradeneme BOTOX®.
Botulinum toxin type B has also been approved by the FDA for the treatment of cervical dystonia. Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months.
Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. Botulinum toxin types B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally, botulinum toxin type C
1
has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes.
The molecular weight of the botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum toxin types B and C
1
is apparently produced as only a 500 kD complex. Botulinum toxin type D is produced as both 300 kD and 500 kD complexes. Finally, botulinum toxin types E and F are produced as only approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine, CGRP and glutamate.
Botulinum toxin type A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in
Allergan Inc.
Donovan Stephen
McDermott Corrine
Sweet Thomas
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