1. Botulinum Toxin Type A(DB00083) Approved and Investigational Drug
Chemical Formula: C6760H10447N1743O2010S32
Molecular Weight:
Purified botulinum toxin from Clostridium botulinum, purified from culture via dialysis and acid precipitation.
Indication/Usage
For the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. Also for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents and for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above. Also used cosmetically to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) as well as for the treatment of excessive underarm sweating.)
Pharmacodynamics
A 150 kDa neurotoxic protein produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium containing casein hydrolysate, glucose and yeast extract. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins.

2. Mechanism of Action Toxicity Absorption Category
Botulinum Toxin Type A is not expected to be present in the peripheral blood at measurable levels following IM or intradermal injection at the recommended doses. The recommended quantities of neurotoxin administered at each treatment session are not expected to result in systemic, overt distant clinical effects, i.e. muscle weakness, in patients without other neuromuscular dysfunction. However, sub-clinical systemic effects have been shown by single-fiber electromyography after IM doses of botulinum toxins appropriate to produce clinically observable local muscle weakness.
Mechanism of Action
Botulinum Toxin Type A blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings.
Toxicity
Based on toxicological studies, it has been estimated that the human LD50 by injection is approximately 2800 Units, equivalent to 28 individual vials of BOTOX (Botulinum Toxin Type A) Purified Neurotoxin Complex (100 Units) for a 70 kg adult. When injected intramuscularly, Botulinum Toxin Type A has been shown to be teratogenic or to have embryocidal effects in some animal species.
Absorption
The chemical complexity of Botulinum Toxin Type A combined with its extreme potency limits the opportunity to study its pharmacokinetic profile in humans. Therefore, no human pharmacokinetic studies have been performed. Botulinum Toxin Type A is injected directly into the target organ, a skeletal muscle. Thus, bioavailability of the intravenous or oral route is not of clinical relevance.
Category
Neuromuscular Blocking Agents and Anti-Wrinkle Agents and Antidystonic Agents

3. Experimental Properties
Affected Organisms
Human and other Mammals
Patents
Patent no , Canada, approved: expired:
Patent no , Canada, approved: expired:
Sequence
MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL
Experimental Properties
Hydrophobicity: 0.368
Isoelectric Point: 6.06

4. Targets General References Brands
Synaptosomal-associated protein 25,Rho-related GTP-binding protein RhoB
General References
Montecucco C, Molgo J: Botulinal neurotoxins: revival of an old killer. Curr Opin Pharmacol Jun;5(3): "Pubmed":
Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, O'Brien C, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M: Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology Oct 22;53(7):
"Pubmed":
Shukla HD, Sharma SK: Clostridium botulinum: a bug with beauty and weapon. Crit Rev Microbiol. 2005;31(1):11-8. "Pubmed":
Eisenach JH, Atkinson JL, Fealey RD: Hyperhidrosis: evolving therapies for a well-established phenomenon. Mayo Clin Proc May;80(5):
"Pubmed":
Schurch B, Corcos J: Botulinum toxin injections for paediatric incontinence. Curr Opin Urol Jul;15(4): "Pubmed":
Brands
BOTOX – Allergan
Dysport - Ipsen Pharmaceuticals
Xeomin - MERZ AESTHETICS

5. BOTOX Formulation Used/Prescribed for Dosage Contraindications
BOTOX (onabotulinum toxin A) For Injection is a sterile, vacuum-dried purified botulinum toxin type A. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying. BOTOX (onabotulinum toxin A) For Injection is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A for intramuscular, intradetrusor and intradermal use.
Formulation
Each vial of BOTOX contains either 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride; 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride; or 200 Units of Clostridium botulinum type A neurotoxin complex, 1 mg of Albumin Human, and 1.8 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.
Used/Prescribed for
Complicated skin and skin structure infections (cSSSI), Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.
Dosage
Do not exceed a total dose of 360 Units administered in a 3 month interval
Contraindications
Known Hypersensitivity to Botulinum Toxin, Infection at the Injection Site, Urinary Tract Infection or Urinary Retention

6. Side- effects Drug Interactions References
Spread of Toxin Effects, Hypersensitivity, Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia, Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity, Urinary Retention in Patients Treated for Bladder Dysfunction
Drug Interactions
Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission, Anticholinergic Drugs, Other Botulinum Neurotoxin Products, Muscle Relaxants
References

7. Dysport Formulation Used/Prescribed for Dosage Contraindications
Dysport (abobotulinumtoxinA), is a purified neurotoxin type A complex produced by fermentation of the bacterium Clostridium botulinum type A, Hall Strain. It is purified from the culture supernatant by a series of precipitation, dialysis, and chromatography steps. The neurotoxin complex is composed of the neurotoxin, hemagglutinin proteins and non-toxin non-hemagglutinin protein. Dysport is supplied in a single-use, sterile vial for reconstitution to be administered as intramuscular injection
Formulation
Each vial contains 500 or 300 Units of lyophilized abobotulinumtoxinA, 125 micrograms human serum albumin and 2.5 mg lactose. Dysport may contain trace amounts of cow's milk proteins.
Used/Prescribed for
Dysport is indicated for the treatment of Cervical Dystonia and Glabellar Lines
Dosage
In Cervical Dystonia: Initial dose of DYSPORT ® is 500 Units given intramuscularly. Re-treatment every 12 to 16 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 250 and 1000 Units to optimize clinical benefit. In Glabellar Lines: A total dose of 50 Units of DYSPORT ®, divided in five equal aliquots of 10 Units each, should be administered to affected muscles to achieve clinical effect
Contraindications
DYSPORT® is contraindicated in patients with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation
Side- effects
In Cervical Dystonia: Most commonly observed adverse reactions (> 5% of patients) are: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, neck pain, musculoskeletal pain, dysphonia, injection site pain, and eye disorders. In Glabellar Lines: The most frequently reported adverse events (≥2%) are nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis and nausea

8. Drug Interactions References
Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission, Anticholinergic Drugs, Other Botulinum Neurotoxin Products, Muscle Relaxants
References

9. Xeomin Formulation Used/Prescribed for Dosage Contraindications
The active ingredient of XEOMIN is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is separated from the proteins. XEOMIN is a sterile white to off-white lyophilized powder after reconstitution with preservative-free 0.9% Saline for Injection to be administered intramuscularly.
Formulation
One vial of XEOMIN contains 50 or 100 Units of incobotulinumtoxinA, 1 mg of human albumin, and 4.7 mg sucrose.
Used/Prescribed for
Xeomin is indicated in Cervical Dystonia, Blepharospasm, Glabellar Lines
Dosage
In Cervical Dystonia: Initial dose of Xeomin is 120 Units given intramuscularly. In Blepharospasm: The total initial dose of XEOMIN in both eyes should not exceed 70 Units (35 Units/eye).In Glabellar Lines: The total recommended XEOMIN dose is 20 Units per treatment session divided into five equal intramuscular injections of 4 Units each.
Contraindications
Known hypersensitivity to the active substance botulinum neurotoxin type A or to any of the excipients and Infection at the proposed injection sites
Side- effects
In Cervical Dystonia: The most commonly observed adverse reactions (≥5% of patients and > placebo) are dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain. In Blepharospasm: The most commonly observed adverse reactions (≥5% of patients and > placebo) are eyelid ptosis, dry eye, dry mouth, diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection. In Glabellar Lines:The most commonly observed adverse reaction (>1% of patients and > placebo) is headache

10. Drug Interactions References
oncomitant treatment of XEOMIN and aminoglycoside antibiotics, spectinomycin, or other agents that interfere with neuromuscular transmission (e.g., tubocurarine-like agents), or muscle relaxants, should be observed closely because the effect of XEOMIN may be potentiated 
References