보툴리눔 독소의 약리jkslp.org/upload/pdf/jkslp-23-2-93.pdf · 2016. 11. 8. · botulinum...
TRANSCRIPT
(clostridium
botulinum) (neurotoxin)
(botulinum toxin) (bot- ulism) .1)
Botulus Botulism
(food-borne botulism),
(infant botulism), (wound bot- ulism) .2)
A, B, E
.3)
, (blurred
vision), (dysphagia), (dysarthria)
.4)
(neuromuscular junction)
(presynaptic terminal)
.1) 7 (A, B, C, D,
E, F, G) , A, B, E, F, G
C, D
.5)
, ,
.6,7)
, , ,
.8)
The Pharmacology of Botulinum Toxin
Sang Hyuk Lee, MD, Hyun Sub Lee, MD and Sung Min Jin, MD Department of Otorhinolaryngology-Head and Neck Surgery, Kangbuk Samsung Hospital,
Sungkyunkwan University School of Medicine, Seoul, Korea
Botulinum toxins are the most potent toxins known to mankind. Botulinum toxin acts by blocking the cholinergic neuromus- cular or the cholinergic autonomic innervation of exocrine glands and smooth muscles. Seven distinct antigenic botulinum toxins (A, B, C, D, E, F and G) produced by different strains of Clostridium botulinum have been described and only A and B type of botulinum toxins were clinically used. Toxins were consisted of a heavy chain with a molecular weight of 100 kD and a light chain with a molecular weight of 50 kD. Toxins are bound with an astounding selectivity to glycoprotein structures lo- cated on the cholinergic nerve terminal. Subsequently light chain of toxin is internalized and cleaves different proteins of the acetylcholine transport protein cascade transporting the acetylcholine vesicle from the intracellular space into the synaptic cleft. After a decade of therapeutic application of the toxin, no anaphylaxis or deaths have been reported and systemic adverse effects have not been reported so far. However the toxin’s immunologic properties can lead to the stimulation of antibody production, potentially rendering further treatments ineffective. Botulinum toxin is a safe and effective treatment. Use of bot- ulinum toxin in clinical medicine has grown exponentially in recent years, and many parts of the human body are now being targeted for therapeutic purposes.
KEY WORDSBotulinum toxinPharmacologyMechanism.
E-mail [email protected]
.
,
.9) Louis Smith 1997
(Byzantium) Leo 6(886~911)
.9)
18
.
.10)
Justinus Kerner(1786~1862)
(Fig. 1) 1820 76
“ ” (Fig. 2),11) 1822 155
.
,
,
. ,
.
.12) 1895
Emile Pierre Ma- rie van Ermengem(1851~1922)
Bacillus botulinus .9)
, 1, 2
Edward J. Schantz(1908~2005) A
.13,14)
Alan B. Scott
1980 (blepharospasm) (strabismus)
.15)
A (Botox),
(Dysport), (Xeomin) B
(Myobloc) .
Fig. 1. Justinus Kerner (1786-1862). Fig. 2. Title page of Kerner’s first monograph on sausage poison- ing.
··
450 kDa
(dimer) 900 kDa .
100 kDa (heavy chain) 50
kDa (light chain) (disulfide bond)
,
. 2 (termi- nal) . N-
C-
(internalization)
.
(Fig. 4).
.
, , , , , 6
(Fig. 5).16,17) (choline) (ECF)
CoA
(acetylcholine)
(granule) .
SNARE(soluble neth- ylmaleimide sensitive factor attachment protein receptor)
.
.
(acetylcholinesterase)
.1)
.18) (binding), (inter- nalization), (neuromuscular blockade) 3
Fig. 4. The di-chain structure of a clostridial neurotoxin-botulinum neurotoxin A.
437
TiBS
Therapeutic botulinum toxin preparation
Botulinum toxin (BT) Excipients
Heavy chain (HC) Light chain (LC) HP NHP
Fig. 5. Cholinergic neurotransmission and botulinum toxin’s mech- anism of action.
Acetyl CoA Na+
. C-
, . ,
(endocytosis)
.
. N-
.20)
- (zinc-endopeptidase)
SNARE .
.21)
SNARE
. A
SNAP-25 B VAMP/syn- aptobrevin .22) C
(Table 1).23)
.
3~4 .22)
(Table 2).
.24)
.25) D-Penicillamine
.13,26)
Lambert-Eaton syndrome
.27)
Fig. 6. Mechanism of action of botulinum toxin. HN : heavy chain N-terminal subdomain, HC : heavy chain C-terminal subdomain, SNARE : soluble NSF-attachment protein receptors, VAMP : vesi- cle-associated membrane protein, SNAP-25 : synaptosomal-asso- ciated protein of 25 kDa, ACh : acetylcholine, AChR : acetyl- choline receptor.
Motorneuron
Toxin type Substrate Botulinum toxin A SNAP-25 Botulinum toxin B VAMP/synaptobrevin Botulinum toxin C SNAP-25 and Syntaxin Botulinum toxin D VAMP/synaptobrevin Botulinum toxin E SNAP-25 Botulinum toxin F VAMP/synaptobrevin Botulinum toxin G VAMP-synaptobrevin
Table 2. Drug and disease interactions with botulinum toxin
Drug/disease Mechanisms Presynaptic nerve terminal
Aminoglycosides (kanamycin, streptomycin, gentamicin) Calcium channel blockade Aminoquinolines (chloroquine, hydroxychloroquine) Inhibit botulinum toxin binding to synaptotagmin or lysosomal
processing of toxin Cyclosporine Calcium channel blockade Lambert-eaton syndrome Cross-reacting, tumor antigen antibodies against calcium channels
Postsynaptic nerve terminal Myasthenia gravis Autoantibodies to the nicotinic acetylcholine receptor D-Penicillamine Triggers the formation of nicotinic acetylcholine receptor antibodies Tubocurarine, pancuronium, gallamine Postsynaptic acetylcholine antagonist blockers Succinylcholine Postsynaptic acetylcholine agonist blocker
··
.
.
.1)
.
, A
E
.28)
.
4
. 6
12
44% 1~2
70% .29)
1
24 .30)
.
.31)
1%
.31,32)
3
.33)
.34) ,
,
.
.34) , -
.1,35) A B
B
. B
.36)
. 12
, Lambert-Eaton
.
,
.27,37)
.
.
.
: .
REFERENCES 1) Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum
toxin. J Am Acad Dermatol 2000;43(2 Pt 1):249-59. 2) Hatheway CL. Botulism: the present status of the disease. Curr Top
Microbiol Immunol 1995;195:55-75. 3) MacDonald KL, Cohen ML, Blake PA. The changing epidemiology
of adult botulism in the United States. Am J Epidemiol 1986;124(5): 794-9.
4) Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 1998;129 (3):221-8.
5) Coffield JA, Bakry N, Zhang RD, Carlson J, Gomella LG, Simpson LL. In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmaco- logic and molecular biologic approaches. J Pharmacol Exp Ther 1997; 280(3):1489-98.
6) Cherington M. Botulism: update and review. Semin Neurol 2004; 24(2):155-63.
7) Aoki KR, Guyer B. Botulinum toxin type A and other botulinum tox- in serotypes: a comparative review of biochemical and pharmaco- logical actions. Eur J Neurol 2001;8 Suppl 5:21-9.
8) Davletov B, Bajohrs M, Binz T. Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins. Trends Neurosci 2005; 28(8):446-52.
9) Erbguth FJ. Historical notes on botulism, Clostridium botulinum, bot- ulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord 2004;19 Suppl 8:S2-6.
10) Erbguth FJ. From poison to remedy: the chequered history of botu- linum toxin. J Neural Transm 2008;115(4):559-65.
11) Kerner J. Neue Beobachtungen uber die in Wurttemberg so haufig vorfallenden todlichen Vergiftungen durch den Genuss geraucherter. Wurste Osiander, Tubingen;1820.
- 98 -
12) Kerner J. Das Fettgift oder die Fettsäure und ihre Wirkungen auf den thierischen Organismus, ein Beytrag zur Untersuchung des in ver- dorbenen Würsten giftig wirkenden Stoffes. Stuttgart, Tübingen Cot- ta, Stuttgart;1822.
13) Bucknall RC, Balint G, Dawkins RL. Myasthenia associated with D-penicillamine therapy in rheumatoid arthritis. Scand J Rheuma- tol Suppl 1979(28):91-3.
14) Schantz EJ, Johnson EA. Botulinum toxin: the story of its develop- ment for the treatment of human disease. Perspect Biol Med 1997; 40(3):317-27.
15) Scott A. Botulinum toxin injection to correct strabism. Trans Am Ophthalmol Soc 1979;79:924-7.
16) Booij LH. Neuromuscular transmission and its pharmacological blockade. Part 4: Use of relaxants in paediatric and elderly patients, in obstetrics, and in the intensive care unit. Pharm World Sci 1997; 19(1):45-52.
17) Martin AR. Principles of neuromuscular transmission. Hosp Pract (Off Ed) 1992;27(8):147-58.
18) Mochida S, Poulain B, Eisel U, Binz T, Kurazono H, Niemann H, et al. Molecular biology of Clostridial toxins: expression of mRNAs en- coding tetanus and botulinum neurotoxins in Aplysia neurons. J Physiol (Paris) 1990;84(4):278-84.
19) Simpson LL. Molecular pharmacology of botulinum toxin and teta- nus toxin. Annu Rev Pharmacol Toxicol 1986;26:427-53.
20) Montecucco C, Schiavo G, Tugnoli V, de Grandis D. Botulinum neu- rotoxins: mechanism of action and therapeutic applications. Mol Med Today 1996;2(10):418-24.
21) Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus and bot- ulinum neurotoxins: mechanism of action and therapeutic uses. Phi- los Trans R Soc Lond B Biol Sci 1999;354(1381):259-68.
22) Dressler D, Benecke R. Pharmacology of therapeutic botulinum tox- in preparations. Disabil Rehabil 2007;29(23):1761-8.
23) Tsui JK. Botulinum toxin as a therapeutic agent. Pharmacol Ther 1996;72(1):13-24.
24) Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute toxicity of aminoglycoside antibiotics as an aid in detecting botulism. Appl En-
viron Microbiol 1984;48(5):951-5. 25) Simpson LL. The interaction between aminoquinolines and presyn-
aptically acting neurotoxins. J Pharmacol Exp Ther 1982;222(1):43-8. 26) Albers JW, Hodach RJ, Kimmel DW, Treacy WL. Penicillamine-as-
sociated myasthenia gravis. Neurology 1980;30(11):1246-9. 27) Vincent A, Lang B, Newsom-Davis J. Autoimmunity to the voltage-
gated calcium channel underlies the Lambert-Eaton myasthenic syn- drome, a paraneoplastic disorder. Trends Neurosci 1989;12(12):496- 502.
28) Eleopra R, Tugnoli V, Rossetto O, De Grandis D, Montecucco C. Dif- ferent time courses of recovery after poisoning with botulinum neu- rotoxin serotypes A and E in humans. Neurosci Lett 1998;256(3):135-8.
29) Gartlan MG, Hoffman HT. Crystalline preparation of botulinum tox- in type A (Botox): degradation in potency with storage. Otolaryngol Head Neck Surg 1993;108(2):135-40.
30) Carruthers A, Carruthers J. History of the cosmetic use of Botulinum A exotoxin. Dermatol Surg 1998;24(11):1168-70.
31) Critchfield J. Considering the immune response to botulinum toxin. Clin J Pain 2002;18(6 Suppl):S133-41.
32) Dressler D, Hallett M. Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol 2006;13 Suppl 1:11-5.
33) Greene P, Fahn S, Diamond B. Development of resistance to botuli- num toxin type A in patients with torticollis. Mov Disord 1994;9(2): 213-7.
34) Brin MF. Botulinum toxin: chemistry, pharmacology, toxicity and im- munology. Muscle Nerve Suppl 1997;6:S146-68.
35) Lange DJ, Rubin M, Greene PE, Kang UJ, Moskowitz CB, Brin MF, et al. Distant effects of locally injected botulinum toxin: a double- blind study of single fiber EMG changes. Muscle Nerve 1991;14(7): 672-5.
36) Eleopra R, Tugnoli V, Quatrale R, Rossetto O, Montecucco C, Dressler D. Clinical use of non-A botulinum toxins: botulinum toxin type C and botulinum toxin type F. Neurotox Res 2006;9(2-3):127-31.
botulinum) (neurotoxin)
(botulinum toxin) (bot- ulism) .1)
Botulus Botulism
(food-borne botulism),
(infant botulism), (wound bot- ulism) .2)
A, B, E
.3)
, (blurred
vision), (dysphagia), (dysarthria)
.4)
(neuromuscular junction)
(presynaptic terminal)
.1) 7 (A, B, C, D,
E, F, G) , A, B, E, F, G
C, D
.5)
, ,
.6,7)
, , ,
.8)
The Pharmacology of Botulinum Toxin
Sang Hyuk Lee, MD, Hyun Sub Lee, MD and Sung Min Jin, MD Department of Otorhinolaryngology-Head and Neck Surgery, Kangbuk Samsung Hospital,
Sungkyunkwan University School of Medicine, Seoul, Korea
Botulinum toxins are the most potent toxins known to mankind. Botulinum toxin acts by blocking the cholinergic neuromus- cular or the cholinergic autonomic innervation of exocrine glands and smooth muscles. Seven distinct antigenic botulinum toxins (A, B, C, D, E, F and G) produced by different strains of Clostridium botulinum have been described and only A and B type of botulinum toxins were clinically used. Toxins were consisted of a heavy chain with a molecular weight of 100 kD and a light chain with a molecular weight of 50 kD. Toxins are bound with an astounding selectivity to glycoprotein structures lo- cated on the cholinergic nerve terminal. Subsequently light chain of toxin is internalized and cleaves different proteins of the acetylcholine transport protein cascade transporting the acetylcholine vesicle from the intracellular space into the synaptic cleft. After a decade of therapeutic application of the toxin, no anaphylaxis or deaths have been reported and systemic adverse effects have not been reported so far. However the toxin’s immunologic properties can lead to the stimulation of antibody production, potentially rendering further treatments ineffective. Botulinum toxin is a safe and effective treatment. Use of bot- ulinum toxin in clinical medicine has grown exponentially in recent years, and many parts of the human body are now being targeted for therapeutic purposes.
KEY WORDSBotulinum toxinPharmacologyMechanism.
E-mail [email protected]
.
,
.9) Louis Smith 1997
(Byzantium) Leo 6(886~911)
.9)
18
.
.10)
Justinus Kerner(1786~1862)
(Fig. 1) 1820 76
“ ” (Fig. 2),11) 1822 155
.
,
,
. ,
.
.12) 1895
Emile Pierre Ma- rie van Ermengem(1851~1922)
Bacillus botulinus .9)
, 1, 2
Edward J. Schantz(1908~2005) A
.13,14)
Alan B. Scott
1980 (blepharospasm) (strabismus)
.15)
A (Botox),
(Dysport), (Xeomin) B
(Myobloc) .
Fig. 1. Justinus Kerner (1786-1862). Fig. 2. Title page of Kerner’s first monograph on sausage poison- ing.
··
450 kDa
(dimer) 900 kDa .
100 kDa (heavy chain) 50
kDa (light chain) (disulfide bond)
,
. 2 (termi- nal) . N-
C-
(internalization)
.
(Fig. 4).
.
, , , , , 6
(Fig. 5).16,17) (choline) (ECF)
CoA
(acetylcholine)
(granule) .
SNARE(soluble neth- ylmaleimide sensitive factor attachment protein receptor)
.
.
(acetylcholinesterase)
.1)
.18) (binding), (inter- nalization), (neuromuscular blockade) 3
Fig. 4. The di-chain structure of a clostridial neurotoxin-botulinum neurotoxin A.
437
TiBS
Therapeutic botulinum toxin preparation
Botulinum toxin (BT) Excipients
Heavy chain (HC) Light chain (LC) HP NHP
Fig. 5. Cholinergic neurotransmission and botulinum toxin’s mech- anism of action.
Acetyl CoA Na+
. C-
, . ,
(endocytosis)
.
. N-
.20)
- (zinc-endopeptidase)
SNARE .
.21)
SNARE
. A
SNAP-25 B VAMP/syn- aptobrevin .22) C
(Table 1).23)
.
3~4 .22)
(Table 2).
.24)
.25) D-Penicillamine
.13,26)
Lambert-Eaton syndrome
.27)
Fig. 6. Mechanism of action of botulinum toxin. HN : heavy chain N-terminal subdomain, HC : heavy chain C-terminal subdomain, SNARE : soluble NSF-attachment protein receptors, VAMP : vesi- cle-associated membrane protein, SNAP-25 : synaptosomal-asso- ciated protein of 25 kDa, ACh : acetylcholine, AChR : acetyl- choline receptor.
Motorneuron
Toxin type Substrate Botulinum toxin A SNAP-25 Botulinum toxin B VAMP/synaptobrevin Botulinum toxin C SNAP-25 and Syntaxin Botulinum toxin D VAMP/synaptobrevin Botulinum toxin E SNAP-25 Botulinum toxin F VAMP/synaptobrevin Botulinum toxin G VAMP-synaptobrevin
Table 2. Drug and disease interactions with botulinum toxin
Drug/disease Mechanisms Presynaptic nerve terminal
Aminoglycosides (kanamycin, streptomycin, gentamicin) Calcium channel blockade Aminoquinolines (chloroquine, hydroxychloroquine) Inhibit botulinum toxin binding to synaptotagmin or lysosomal
processing of toxin Cyclosporine Calcium channel blockade Lambert-eaton syndrome Cross-reacting, tumor antigen antibodies against calcium channels
Postsynaptic nerve terminal Myasthenia gravis Autoantibodies to the nicotinic acetylcholine receptor D-Penicillamine Triggers the formation of nicotinic acetylcholine receptor antibodies Tubocurarine, pancuronium, gallamine Postsynaptic acetylcholine antagonist blockers Succinylcholine Postsynaptic acetylcholine agonist blocker
··
.
.
.1)
.
, A
E
.28)
.
4
. 6
12
44% 1~2
70% .29)
1
24 .30)
.
.31)
1%
.31,32)
3
.33)
.34) ,
,
.
.34) , -
.1,35) A B
B
. B
.36)
. 12
, Lambert-Eaton
.
,
.27,37)
.
.
.
: .
REFERENCES 1) Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum
toxin. J Am Acad Dermatol 2000;43(2 Pt 1):249-59. 2) Hatheway CL. Botulism: the present status of the disease. Curr Top
Microbiol Immunol 1995;195:55-75. 3) MacDonald KL, Cohen ML, Blake PA. The changing epidemiology
of adult botulism in the United States. Am J Epidemiol 1986;124(5): 794-9.
4) Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 1998;129 (3):221-8.
5) Coffield JA, Bakry N, Zhang RD, Carlson J, Gomella LG, Simpson LL. In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmaco- logic and molecular biologic approaches. J Pharmacol Exp Ther 1997; 280(3):1489-98.
6) Cherington M. Botulism: update and review. Semin Neurol 2004; 24(2):155-63.
7) Aoki KR, Guyer B. Botulinum toxin type A and other botulinum tox- in serotypes: a comparative review of biochemical and pharmaco- logical actions. Eur J Neurol 2001;8 Suppl 5:21-9.
8) Davletov B, Bajohrs M, Binz T. Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins. Trends Neurosci 2005; 28(8):446-52.
9) Erbguth FJ. Historical notes on botulism, Clostridium botulinum, bot- ulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord 2004;19 Suppl 8:S2-6.
10) Erbguth FJ. From poison to remedy: the chequered history of botu- linum toxin. J Neural Transm 2008;115(4):559-65.
11) Kerner J. Neue Beobachtungen uber die in Wurttemberg so haufig vorfallenden todlichen Vergiftungen durch den Genuss geraucherter. Wurste Osiander, Tubingen;1820.
- 98 -
12) Kerner J. Das Fettgift oder die Fettsäure und ihre Wirkungen auf den thierischen Organismus, ein Beytrag zur Untersuchung des in ver- dorbenen Würsten giftig wirkenden Stoffes. Stuttgart, Tübingen Cot- ta, Stuttgart;1822.
13) Bucknall RC, Balint G, Dawkins RL. Myasthenia associated with D-penicillamine therapy in rheumatoid arthritis. Scand J Rheuma- tol Suppl 1979(28):91-3.
14) Schantz EJ, Johnson EA. Botulinum toxin: the story of its develop- ment for the treatment of human disease. Perspect Biol Med 1997; 40(3):317-27.
15) Scott A. Botulinum toxin injection to correct strabism. Trans Am Ophthalmol Soc 1979;79:924-7.
16) Booij LH. Neuromuscular transmission and its pharmacological blockade. Part 4: Use of relaxants in paediatric and elderly patients, in obstetrics, and in the intensive care unit. Pharm World Sci 1997; 19(1):45-52.
17) Martin AR. Principles of neuromuscular transmission. Hosp Pract (Off Ed) 1992;27(8):147-58.
18) Mochida S, Poulain B, Eisel U, Binz T, Kurazono H, Niemann H, et al. Molecular biology of Clostridial toxins: expression of mRNAs en- coding tetanus and botulinum neurotoxins in Aplysia neurons. J Physiol (Paris) 1990;84(4):278-84.
19) Simpson LL. Molecular pharmacology of botulinum toxin and teta- nus toxin. Annu Rev Pharmacol Toxicol 1986;26:427-53.
20) Montecucco C, Schiavo G, Tugnoli V, de Grandis D. Botulinum neu- rotoxins: mechanism of action and therapeutic applications. Mol Med Today 1996;2(10):418-24.
21) Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus and bot- ulinum neurotoxins: mechanism of action and therapeutic uses. Phi- los Trans R Soc Lond B Biol Sci 1999;354(1381):259-68.
22) Dressler D, Benecke R. Pharmacology of therapeutic botulinum tox- in preparations. Disabil Rehabil 2007;29(23):1761-8.
23) Tsui JK. Botulinum toxin as a therapeutic agent. Pharmacol Ther 1996;72(1):13-24.
24) Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute toxicity of aminoglycoside antibiotics as an aid in detecting botulism. Appl En-
viron Microbiol 1984;48(5):951-5. 25) Simpson LL. The interaction between aminoquinolines and presyn-
aptically acting neurotoxins. J Pharmacol Exp Ther 1982;222(1):43-8. 26) Albers JW, Hodach RJ, Kimmel DW, Treacy WL. Penicillamine-as-
sociated myasthenia gravis. Neurology 1980;30(11):1246-9. 27) Vincent A, Lang B, Newsom-Davis J. Autoimmunity to the voltage-
gated calcium channel underlies the Lambert-Eaton myasthenic syn- drome, a paraneoplastic disorder. Trends Neurosci 1989;12(12):496- 502.
28) Eleopra R, Tugnoli V, Rossetto O, De Grandis D, Montecucco C. Dif- ferent time courses of recovery after poisoning with botulinum neu- rotoxin serotypes A and E in humans. Neurosci Lett 1998;256(3):135-8.
29) Gartlan MG, Hoffman HT. Crystalline preparation of botulinum tox- in type A (Botox): degradation in potency with storage. Otolaryngol Head Neck Surg 1993;108(2):135-40.
30) Carruthers A, Carruthers J. History of the cosmetic use of Botulinum A exotoxin. Dermatol Surg 1998;24(11):1168-70.
31) Critchfield J. Considering the immune response to botulinum toxin. Clin J Pain 2002;18(6 Suppl):S133-41.
32) Dressler D, Hallett M. Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol 2006;13 Suppl 1:11-5.
33) Greene P, Fahn S, Diamond B. Development of resistance to botuli- num toxin type A in patients with torticollis. Mov Disord 1994;9(2): 213-7.
34) Brin MF. Botulinum toxin: chemistry, pharmacology, toxicity and im- munology. Muscle Nerve Suppl 1997;6:S146-68.
35) Lange DJ, Rubin M, Greene PE, Kang UJ, Moskowitz CB, Brin MF, et al. Distant effects of locally injected botulinum toxin: a double- blind study of single fiber EMG changes. Muscle Nerve 1991;14(7): 672-5.
36) Eleopra R, Tugnoli V, Quatrale R, Rossetto O, Montecucco C, Dressler D. Clinical use of non-A botulinum toxins: botulinum toxin type C and botulinum toxin type F. Neurotox Res 2006;9(2-3):127-31.