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Botulinum Toxin Adverse Events

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Provisional chapter
Botulinum Toxin Adverse Events
Raffaela Pero, Sonia Laneri and Giovanna Fico
Additional information is available at the end of the chapter
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
RaaelaPero, SoniaLaneri and GiovannaFico
Additional information is available at the end of the chapter
Botulinum toxin acts at the neuromuscular junction (motor plaque) blocking the release
and eects of acetylcholine (ACh), a neurotransmier of both the central nervous system
(CNS) and the peripheral nervous system (SNP). By inhibiting the release of acetylcholine,
botulinum toxin interferes with the nervous impulse and causes a characteristic accid
paralysis of the muscles. This eect is used to decrease wrinkles of the facial skin and chin
providing a smooth appearance and for the treatment of a variety of human syndromes
characterized by hyperfunction of selected nerve terminals. Side eects of this treatment
are rare, but are essentially related to the active ingredient of the drug or to medical mal-
practice. These adverse events and their possible therapy are discussed in this chapter.
Keywords: botulinum toxin, adverse events, therapy, esthetic, motor endplate
1. Introduction
Botulinum toxin is a neurotoxic protein produced by the anaerobic bacterium Clostridium
botulinum. There are seven types of distinct botulinum toxin and are indicated with the alpha-
bet leers: A, B, C, D, E, F, and G [1].
Recently, a novel botulinum neurotoxin (BoNT/X) has been identied [2] and the rst botuli-
num-like toxin outside the Clostridia family has been described [3].
The currently used in esthetic medicine is botulinum toxin type A (BoNT-A). It is used for
wrinkles of expression and for those dynamic wrinkles linked to the hypertonia of mimic
muscles [4]. Botulinum toxin acts at the level of the neuromuscular junction (motor end-
plate) blocking the release and eects of acetylcholine, an ester of acetic acid and choline,
responsible for neurotransmission both at the central nervous system (CNS) level and at the
© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
peripheral nervous system (SNP) level. The enzyme acetylcholineesterase, present in the pre-
synaptic nerve endings, continuously hydrolyses the acetylcholine which is then immediately
resynthesized and stored through an active transport mechanism by means of a specic car-
rier protein, within synaptic cholinergic vesicles of storage. Within these cytosolic vesicles,
acetylcholine is transported to the presynaptic region of the neuron (synaptic buon) where it
waits for the ionic signal (calcium ions) to release its role as a neurotransmier [1].
Acetylcholine is normally released into the synaptic space trough a potential action that, by fol-
lowing the axon of the neuron at the last termination level of the nal arborization of the axon,
determines the opening of voltage-dependent ion channels: the channels of calcium. The cal-
cium ions, present in the synaptic space, penetrate inside the synaptic buon and start the real-
izing process of ACh into the synaptic space where it acts on specic receptors (ACh receptors).
ACh receptors are located on the postsynaptic cell membrane of the muscle brocell, which are
of two types: nicotinic and muscarinic. Interacting with ACh receptors, the neurotransmier
achieves its eects by determining, at the postsynaptic level, the opening of sodium-potassium
ion channels through which the sodium ions penetrate into the muscle brocell which, thus, ini-
tiate muscle contraction. Immediately afterward, ACh is hydrolyzed by acetylcholinesterase. By
inhibiting the release of acetylcholine, botulinum toxin interferes with the nervous impulse and
causes a accid paralysis of the muscles. Botulinum toxin is in fact a real muscle relaxant [4].
Botulin toxin is a double-chain polypeptide consisting of a heavy chain and a light chain. The
former has a molecular weight of 100 KDa while the laer has a molecular weight of 50 KDa.
The heavy chain is linked to the light chain via sulde bridges. The two chains perform dier-
ent functions. The heavy chain binds to a receptor on the cell membrane of the synaptic buon,
the SV2 receptor, and begins the endocytosis phenomenon through which the botulinum toxin
enters into the synaptic buon. The heavy chain works like a sort of light chain conveyor [5].
Once penetrated into the synaptic buon, the botulinum toxin releases the light chain that
can perform its protease function capable of hydrolyzing the proteins of the SNARE complex
(SNAP-25, syntaxin, synaptobrevin) of the neuromuscular junction preventing the release of
ACh from synaptic vesicles [6].
The proteins of the SNARE complex play a crucial role in the release of ACh, because they
favor the fusion between the membrane of the synaptic vesicles in which the acetylcholine
and the membrane of the synaptic buon are stored. The protein that is hydrolyzed is SNAP-
25, and in this way, the fusion between the synaptic vesicle membrane in which the acetyl-
choline and the synaptic membrane are crammed is made impossible, and it is for this reason
that the acetylcholine cannot be released into the synaptic space of the motor plate and the
characteristic accid paralysis of the treated muscles is determined [7].
In 1980, botulin toxin was rst described and used by ophthalmologists in humans for the
treatment of strabismus [8], while its esthetic use was rst reported in 1992 by Carruthers and
Carruthers [9].
1.1. Commercial products of botulinum toxin
The most widespread toxin in the world has the trade name of Botox. Botox for esthetic use
are called:
Botulinum Toxin2
Vistabel® 50 U (corresponding to Botox® used in pathology); the storage of the solution
requires a temperature between 2 and 8°C, because the toxin is thermolabile. According to
the technical sheet, it is maintained for up to 4 hours. According to some scientic works,
in 12 hours, the eect is reduced to 50%. According to other works, the eect remains intact
for 6 weeks. When inserting the needle into the bole, the syringe must be sucked: this is
a sort of test to verify that the product is actually under vacuum and has therefore been
stored correctly;
Azzalure® 125 U (corresponding to the Dysport® used in pathology); and
• Bocouture® 50 U (corresponding to Xeomin® used in pathology) is a bare toxin (not a com-
plex protein like the previous ones). Units are not equivalent. The conversion rate is 2.5 (1 U
Vistabel or Bocouture = 2.5 U Azzalure). Bocouture not requires the cold chain; it is stored
at room temperature (0–25°) for 3 years and presents less risk of allergies as albumin is
absent in the commercial preparation [10].
1.2. Therapeutic uses of BTX
In the last 20 years, the therapeutic spectrum of botulinum toxin has greatly increased.
BoNT-A has been used for a wide range of established and emerging applications grouped
into the following categories:
urological disorders,
gastrointestinal/proctological disorders,
pain, and
symptomatic treatment of Parkinson’s disease (PD) [1113].
1.3. Esthetic uses of BoNT-A
In 2002, AIFA authorized the esthetic use of BoNT-A with the following indication: “Temporary
improvement of vertical wrinkles, moderate to severe, between eyebrows to wrinkling, in adults
aged <65 years, when the severity of such wrinkles has an important psychological impact on
the patient.” Although this is the only indication for esthetic use approved by the regulatory
authority, many physicians use the toxin in o-label mode at injection sites other than those
approved, in particular for periocular and frontal wrinkles [14]. Actually, botulinum toxin is
approved by the US Food and Drug Administration (FDA) for esthetic use in the treatment of:
axillary hyperhidrosis,
glabellar lines, and
lateral canthal lines.
Botulinum Toxin Adverse Events 3
The dynamic rhytides of the upper third of the face are the best indication of botulinum toxin
[15, 16].
These dynamic wrinkles depend on both the muscle factor and the photoaging. If the muscle
factor (young subject) predominates and if the skin is ne, you can hope for a good result;
if photoaging is predominant (older subject) and if the skin is thick, the result is less good.
Despite the apparent ease of injections, the correction of these glabellar wrinkles in particular
requires a good understanding of the anatomy and function of the fur muscles of the region.
It is necessary to respect the depression/elevator balance, which is not the same for each face,
and the type of frowning to choose the appropriate doses and to respect the recommended
injection points (Figure 1) [17].
2. Adverse eve nts
Side eects are essentially related to active ingredient of the drug and are referred to both
therapeutic and esthetic use.
2.1. Eects related to the drug
Regarding the side eects related to the drug, those most frequently reported are:
injection of high doses of this drug (more than 200 units in every injection); and
booster within less than 1 month is dangerous [18].
Side eects of this treatment are rare, but can include bruising, headache, allergic reactions
due to allergy to human albumin or sodium chloride present as an excipient in the drug, facial
and palpebral edema, injection site pain, eye pain, erythema, psoriasis, skin infections, vertigo,
nausea, fever, blepharitis, xerostomia, respiratory virosis, itching, asthenia, muscle weakness,
psychiatric disorders, and pneumonia ab ingestis ineectiveness of the drug (the formation of
antibodies against botulinum toxin neutralizes the eect of the toxin itself).
Figure 1. Fronto-orbital balance of the eyebrows: levator muscles and depressor muscles. The fronto-orbital balance
claries botulinum toxin action: relaxing of the frontalis muscle determines a strength increase of depressor muscles,
with possible ptosis. Instead, relaxing of the depressor muscles causes a strength increase of the frontalis.
Botulinum Toxin4
Botulinum Toxin Adverse Events 5
A scleral show, greater evidence of sclera, can be veried after a functional decit of the eye’s
orbicularis (pars inferior) following interference with the function of this muscle.
Ectropion, anomalous reversal toward the outside of the lower eyelid, is due to functional decit
of the orbicularis muscle of the eye (pars inferior) for chemodenervation of the orbicularis muscle.
A strabismus, deviation of the visual axes, is caused by the malfunction of the extrinsic ocu-
lomotor muscles (lateral rectus) with consequent inability of binocular representation at the
retinal level.
Diplopia is caused by the involvement of the lateral rectus muscle through the diusion of
the toxin inside of the secondary orbitary cavity with inoculation too deep and close to the
margin orbital. Temporary monolateral ocular bandage may be useful (Figure 3) [27–29].
Smile asymmetry is due to the toxin diusion into the nearby zygomaticus major muscle and
asymmetry of mouth mobility is caused by the blockage of the zygomatic muscle with ptosis
of the lip (Figure 4).
Diculty in whistling occurs after a functional decit of the orbicular muscle of the mouth.
Incidence may be reduced using diluted doses of botulinum toxin [30, 31].
Figure 2. Schematic representation of eyelid ptosis complication of BoNT-A administration: uilateral eyelid ptosis.
Botulinum Toxin6
Botulinum toxin is often interesting to mitigate the fold of the marionee, which gives the face
a sad and aged appearance, injecting the depressor of the corner of the mouth, which lowers
the labial commissures. The injection must be low to prevent the lips from spreading to the
orbicularis [32].
At the neck, the araction through the posterior platysmal cords of the area in which the
falling cheeks are delineated can be aenuated by the Nefertiti lift, injecting two or three
small doses along the posterior platysmal chord and the mandibular edge. The anterior and
posterior platysmal chords can be mitigated by small doses of botulinum toxin, injected every
2 cm, pinching and aracting the rope forward [33, 34].
All of these events resolved spontaneously maybe dose-dependent and were aributed to
local diusion of BoNT into adjacent areas [35].
Serious adverse events related to the cosmetic use of botulinum toxin include thyroid eye
disease in a patient with Graves hyperthyroidism, sarcoidal granuloma, pseudoaneurysm of
the frontal branch of the superior temporal artery, and respiratory damage [36–39].
2.3. Side eects of therapeutic use
Recent studies demonstrate that BoNT tracking is not restricted to the neuromuscular junc-
tion, but also involves internalization of the toxin by spinal cord motor neurons and fast
axonal retrograde transportation. Toxin’s eect is sometimes observed beyond the site of local
injection. Major adverse events can include:
Figure 3. Schematic representation of diplopia complication of BoNT-A.
Botulinum Toxin Adverse Events 7
respiratory insuciency, and
muscle weakness.
These systemic events are rare and observed only at high dosages or in patients with underly-
ing medical conditions predisposing to the complications [40–44].
Bahtia et al. reported on three patients in whom treatment of their dystonia with therapeutic
doses of botulinum toxin resulted in clinical muscle weakness distant from the site of injec-
tions. It may be speculated that repeated injections at intervals of 10–12 weeks as in their
patients may have an impact on toxin binding and diusion. In fact, according to authors, the
cause is most likely presynaptic inhibition due to systemic spread of the toxin [45]. Even in the
case of repeated blepharospasm treatments with BoNT-A, an induction of acute myasthenic
crisis has been demonstrated [46].
Figure 4. Schematic representation of asymmetry of mouth mobility of BoNT-A administration.
Botulinum Toxin8
Systemic adverse events have been reported at the time of botulinum toxin A injection
(6% injection episodes) and at follow-up (22% injection episodes) in children with cerebral
palsy (CP), and children in Gross Motor Function Classication System (GMFCS) levels IV
and V have increased rates of systemic adverse events [47].
Tugnoli et al. describes a rst case of generalized muscular weakness associated with signs of
systemic cholinergic autonomic impairment who was treated with 1400 U of BoNT-A for axil-
lary and palmar hyperhidrosis. The authors assert that this case is consistent with a mild but dif-
fuse Botulism-like syndrome, probably related to the high BoNT-A doses uses and to numerous
intradermal injections and the slight build of their patient [48].
All these data demonstrate the possible risk of unwanted adverse eects due to spreading of
the toxin [42].
2.4. Diusion and migration of BoNT
In the diusion phenomena, the concentration gradient and the BoNT molecular size deter-
mine the movement of the toxin beyond the immediate injection site through Brownian
motion even if these muscles are separated by fasciae. In migration instead, a haematic and
neuroaxonal transport of BoNT occurs, which is distant from the muscle and is related to
systemic side eects that may be fatal if left untreated [49, 50].
Experimental studies in rodents have shown that botulinum toxin receptors exist in the cen-
tral nervous system and a small amount of botulinum toxin crosses the blood-brain barrier.
This raises the possibility that botulinum toxin is transported retrogradely, similar to tetanus
toxin, and may cause centrally mediated side eects [51].
Botulinum toxin type-A can induce autonomic eects such as biliary colic, impairment of
gastrointestinal and cardiovascular autonomic pathways, and inhibition of autonomic cholin-
ergic pathways in the bladder. Cholinergic receptors in the pharyngeal and laryngeal sphinc-
ters are likely to be inhibited by systemic spread of BoNT and may be the main reason for
dysphagia/dysphonia [52–54].
One of the suggested mechanisms for transport of the toxin from one part of the body (neck) to
a remote location (toes) is the vascular spread via absorption through the capillary system and
the retrograde axonal spread of the toxin. The injection of proximal upper extremity muscles
with BoNT-A can determine diusion of the toxin into the surrounding muscles resulting in
dysphagia. These data suggest a systemic spread even when toxin is injected in sites anatomi-
cally adjacent to the locus of the side eect. Retrograde axoplasmic spread of the toxin is the
second possible mechanism for the observed distant adverse events.
Recent studies show retrograde transport of enzymatically active toxin molecules via micro-
tubules in the axon to both sensory and motor regions in the spinal cord after intramuscular
and intraneural injections of BoNT-A. In fact, antinociceptive eect of BoNT-A may occur
through retrograde spread of BoNT-A from the sensory nerves in the periphery to the central
nervous system. Moreover, distant eects also may be caused by intrafusal uptake of the toxin
in the muscles spindles as well as neuroplastic changes post-BoNT-A injections. Diusion of
BoNT is aected by a variety of factors; however, dose, concentration, and volume probably
are the greatest contributors that increase the risk of diusion. In general, the BoNT reduction
in amplitude increased with increasing doses and with increasing concentration [55–57].
Botulinum Toxin Adverse Events 9
To limit diusion is target muscle localization using EMG and endoscopic or imaging guidance
2.5. Nonresponsiveness to treatment with BoNT
Nonresponsiveness to BoNT could be as a result of possible factors that include misdiag-
nosis, insucient dose, problems with toxin storage and preparation, and administration.
Another possible reason for lack of clinical eect is immunoresistance to BoNT, which refers
to ineectiveness of the toxin as a result of development of neutralizing antibodies against
the toxin [59].
The formation of neutralizing antibodies to BoNT is increased by a short time period between
injections, the administration of booster injections, and the use of high BoNT doses. To pre-
vent antibody formation against BoNT, the practitioner can use a newer BoNT formulation
with the lowest protein content [60].
3. Contraindications and interactions with some medications
BoNT is contraindicated in patients with known peripheral motor neuropathies or neuro-
muscular disorders, such as Eaton-Lambert syndrome, multiple sclerosis, and myasthenia
gravis, because further chemodenervation may exacerbate muscle weakness. The cause is to
be found in a reduced release of acetylcholine in the neuromuscular endplate, due to the eect
of autoantibodies against the presynaptic channels of calcium [61].
The treatment can be performed in the 18–65 age range. Other contraindications are represented
allergy to human albumin and/or sodium chloride,
skin infections,
presence of scleral show,
senile ectropion,
dysphagia, and
psychiatric disorders.
Aminoglycoside antibiotics that can enhance the eect of botulinum toxin are netilmicin,
tobramycin, gentamicin, neomycin, amikacin, kanamycin, and streptomycin. Other drugs that
also interfere with neuromuscular transmission are muscle relaxants such as D-tubocurarine,
baclofen, thiocolchicoside, tizanidine, diazepam, dantrolene, and pridinol [62, 63].
Botulinum Toxin10
4. Rehabilitation of the motor endplate
The rehabilitation of the motor endplate can be very useful in case of side eects following
treatment with botulinum toxin.
Radioiodinated botulinum toxin A (125I-BoNT/A-complex, 67 or 344 U free-125I-BoNT/A)
was injected into the gastrocnemius muscle of rats and measured in various tissues at dier-
ent time points. These “in vivo” studies allowed to establish that after 24 hours, the toxin is no
longer present in the inltrated muscle.
Thus, the side eects reported seem to be related to the damage caused by toxin caused and
not to the presence of it in the muscles. These eects can be visible after 10–12 days [64].
For this reason, it is useless to administer the antitoxin which exerts its action by binding to
the toxin still in circulation, complexing it and making it inactive. Furthermore, the healing
capacity depends on the regeneration of the aected synaptic terminations.
Because the light chain of botulinum toxin causes proteolysis of the SNAP 25 protein, reduc-
ing its endocellular pool, one must reestablish its own physiological endocellular pool.
In practice, it is necessary to stimulate the biosynthesis of the SNAP25 protein to favor the
structural and functional recovery of the motor endplate.
The aim of the therapy is to stimulate the biosynthesis of the SNAP 25 protein, consisting of
about 200 amino acids. So, we can correct side eects such as ectropion, diplopia, palpebral
ptosis, strabismus, scleral show, and asymmetries of smile and mouth mobility.
To improve the biosynthesis of the SNAP 25 protein, it is necessary to take:
a. A proteic diet (meat, sh);
b. Amino acids such as arginine and cysteine as they belong to the molecular composition
of the SNAP-25 protein. Then, we supplement other amino acids: arginine, bioargin, and
c. L-acetylcarnitine which is an agonist of the mitochondrial growth function and reparative
agents (NGF), expounds an antioxidant activity in the neurons of the central and periph-
eral nervous system. L-acetylcarnitine is structurally similar to acetylcholine and plays an
indispensable role for proper cellular energy, metabolism, and neurotransmission;
d. Alpha-lipoic acid (also called thioctic acid), a fat-soluble vitamin that participates in vari-
ous antioxidant mechanisms such as the regeneration of reduced glutathione (GSH) and
ascorbic acid; and
e. L-carnosine, a dipeptide composed of β-alanine and L-histidine; it has the ability to pro-
mote protein regeneration even in dicult situations such as in the late stage of the life
cycle. It has antioxidant properties.
This therapy is able to guarantee fast responses (7–10 days) and in 80% of cases [65–68].
Botulinum Toxin Adverse Events 11
5. Conclusions
The use of BoNts continues to steadily expand and multiply. New indications of clinical use of
BoNTs are continuously emerging in medical therapy and further applications will be devel-
oped in the future. Adverse events occur more frequently after the clinical use of the toxin, but
may also disclose after its esthetic use. The safe utilization of BoNTs requires knowledge of its
indications and pharmacology, anatomy of the treated muscles to avoid serious complications.
Author details
Raaela Pero1*, Sonia Laneri2 and Giovanna Fico3
*Address all correspondence to:
1 Department of Molecular Medicine and Medical Biotechnology, University of Naples
“Federico II”, Naples, Italy
2 Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
3 ASL Napoli 3 Sud, Naples, Italy
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... Botulism is a serious paralytic disease [77]. The toxin acts by blocking the release of a neurotransmitter, acetylcholine, at the neuromuscular junction, interfering with the nervous impulse and causing muscle paralysis [78]. ...
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The rising threats to worldwide security (affecting the military, first responders, and civilians) urge us to develop efficient and versatile technological solutions to protect human beings.Soldiers, medical personnel, firefighters, and law enforcement officers should be adequately protected, so that their exposure to biological warfare agents (BWAs) is minimized, and infectious microorganisms cannot be spread so easily. Current bioprotective military garments include multilayered fabrics integrating activated carbon as a sorptive agent and a separate filtrating layer for passive protection. However, secondary contaminants emerge following their accumulation within the carbon filler. The clothing becomes too heavy and warm to wear, not breathable even, preventing the wearer from working for extended hours. Hence, a strong need exists to select and/or create selectively permeable layered fibrous structures with bioactive agents that offer an efficient filtering capability and biocidal skills, ensuring lightweightness, comfort, and multifunctionality. This review aims to showcase the main possibilities and trends of bioprotective textiles, focusing on metal–organic frameworks (MOFs), inorganic nanoparticles (e.g., ZnO-based), and organic players such as chitosan (CS)-based small-scale particles and plant-derived compounds as bioactive agents. The textile itself should be further evaluated as the foundation for the barrier effect and in terms of comfort. The outputs of a thorough, standardized characterization should dictate the best elements for each approach.
Facial botulinum toxin injection is a skill developed with experience. Inaccurate injections of the toxin can cause local complications as well as patient distress. Trainees typically learn to perform facial injections following detailed study of medical anatomy diagrams. However, anatomy diagram depictions of a ‘standard’ face may not be generalisable to the varied facial anatomy of real patients. Augmented reality (AR) technology may provide a more individualised approach. In this study, an AR smartphone app, designed for the development of recreational social media filters, was repurposed to create a face filter that overlaid facial muscles and corresponding botulinum toxin injection sites onto the face of any subject detected by the supporting device’s camera. The primary outcome was to determine if accuracy in injection site identification was superior using the AR app versus a standard facial anatomy diagram. Ten participants who were naïve to administering facial injections used both the AR app and anatomy diagram to mark 10 injection sites on the face of a test subject using a makeup pen. The distance between these sites and the ‘gold standard’ injection sites as determined by an expert botulinum toxin practitioner was calculated. Participants were more accurate with the AR app than with the diagram, with average distance from expert-identified location 4.60 mm versus 6.75 mm, respectively (p<0.01). Further research is needed in optimising this technology prior to trialling its use in patients; however, AR has tremendous potential to become a useful adjunct for procedures requiring anatomical knowledge of facial muscles.
Na área da estética, a toxina botulínica é bastante utilizada para diversos tipos de tratamento, sendo considerada bastante eficaz. O objetivo dessa pesquisa é descrever através de uma revisão integrativa as vantagens e intercorrências da toxina botulínica devido a importância do seu uso na medicina e odontologia com finalidades terapêuticas e estéticas. A busca foi realizada nos bancos de dados LILACS, utilizando-se os Descritores em Ciências da Saúde (DeCs) “toxina botulínica” e “estética facial”. Foram selecionados 10 publicados em português disponíveis online, publicados entre 2009 e 2020, de onde emergiram os resultados. Observou-se que as vantagens são superiores as intercorrências desde que possua conhecimento da anatomia facial, função muscular e farmacologia da neurotoxina. Sendo assim, uma opção segura, pouco invasiva, acessível e eficaz quando aplicada em músculos corretos trazendo benefícios estéticos e terapêuticos.
Introduction: Scalp injection with mesotherapy ( LC cell hair essence ) helps in anchoring hair follicles and might have good therapeutic efficacy and lower side effects than Botox in the treatment of Androgenetic alopecia (AGA). Objective: To assess the trichoscopy and the clinical therapeutic response of LC hair essence serum injection versus Botulinum toxin (A) injection in the treatment of Androgenetic Alopecia. Patients and methods: 62 AGA patients were included in the present study. Group (I) consisted of 31 patients who injected 1 ml of LC hair essence serum diluted with 0.5 ml of 0.9% normal saline once weekly for 8 weeks and Group (II) involved 31 patients who were injected with 50 units of Botulinum toxin-A. Trichoscopic examination and photo documentation were done for every case before starting treatment (baseline) & after treatment with monthly follow-up to the patients. Results: There was a significant difference between baseline trichoscopy findings and at the end of 6th month in Botox Group and the difference was highly significant in LC Group, there was a statistically significant increase in the frequency of side effects (irritation and headache) among Group II compared to Group I. Conclusion: Botox can induce significant results in the treatment of AGA with mild and tolerable side effects but with high cost. while LC hair serum exhibit excellent results with fewer side effects.
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The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.
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The genome of Weissella oryzae SG25T was recently sequenced and a botulinum neurotoxin (BoNT) like gene was identified by bioinformatics methods. The typical three-domains organization of BoNTs with a N-terminal metalloprotease domain, a translocation and a cell binding domains could be identified. The BoNT family of neurotoxins is rapidly growing, but this was the first indication of the possible expression of a BoNT toxin outside the Clostridium genus. We performed molecular modeling and dynamics simulations showing that the 50 kDa N-terminal domain folds very similarly to the metalloprotease domain of BoNT/B, whilst the binding part is different. However, neither the recombinant metalloprotease nor the binding domains showed cross-reactivity with the standard antisera that define the seven serotypes of BoNTs. We found that the purified Weissella metalloprotease cleaves VAMP at a single site untouched by the other VAMP-specific BoNTs. This site is a unique Trp-Trp peptide bond located within the juxtamembrane segment of VAMP which is essential for neurotransmitter release. Therefore, the present study identifies the first non-Clostridial BoNT-like metalloprotease that cleaves VAMP at a novel and relevant site and we propose to label it BoNT/Wo.
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Cysteine string protein (CSP) is a member of the DnaJ/Hsp40 family of co-chaperones that localises to neuronal synaptic vesicles. Its name derives from the possession of a string of 12-15 cysteine residues, palmitoylation of which is required for targeting to post-Golgi membranes. The DnaJ domain of CSP enables it to bind client proteins and recruit Hsc70 chaperones, thereby contributing to the maintenance of protein folding in the presynaptic compartment. Mutation of CSP in flies, worms and mice reduces lifespan and causes synaptic dysfunction and neurodegeneration. Furthermore, recent studies have revealed that the neurodegenerative disease, adult-onset neuronal ceroid lipofuscinosis, is caused by mutations in the human CSPα-encoding DNAJC5 gene. Accumulating evidence suggests that the major mechanism by which CSP prevents neurodegeneration is by maintaining the conformation of SNAP-25, thereby facilitating its entry into the membrane-fusing SNARE complex. In this review, we focus on the role of CSP in preventing neurodegeneration and discuss how recent studies of this universal neuroprotective chaperone are being translated into potential novel therapeutics for neurodegenerative diseases. Copyright © 2015. Published by Elsevier Ltd.
Fifty-six injections of botulinum A toxin have been given to humans for correction of strabismus. The paralysis has been localized to the injected muscle in all cases. No systemic complications of any kind have ensued. The maximum time of paralysis occurs four to five days following the injection, and then gradually diminishes, depending on dose. The maximum correction of strabismus has been 40 prism diopters. The maximum follow-up after injection is six months. Injection of botulinum A toxin into extraocular muscle to weaken the muscle appears to be a practical adjunct or alternative to surgical correction.
Aim: To determine the incidence of common adverse events after botulinum toxin A (BoNT-A) injections in children with cerebral palsy (CP) and to identify whether the severity of CP influences the incidence of adverse events. Method: This was an observational study of patients attending a BoNT-A clinic at a tertiary paediatric hospital (2010-2014). Data examined included procedural adverse events at the time of injection and at follow-up. Systemic adverse events were defined as lower respiratory tract illnesses, generalized weakness, dysphagia, and death. Severity of CP was categorized by the Gross Motor Function Classification System (GMFCS). The relationships between GMFCS and adverse events were analysed using negative binomial regression models. Results: In total, 591 children underwent 2219 injection episodes. Adverse events were reported during the procedure (130 [6%] injection episodes) and at follow-up (492 [22%] injection episodes). There were significantly increased rates of systemic adverse events in injection episodes involving children in GMFCS level IV (incidence rate ratio [IRR] 3.92 [95% confidence interval] 1.45-10.57]) and GMFCS level V (IRR 7.37 [95% confidence interval 2.90-18.73]; p<0.001). Interpretation: Adverse events after BoNT-A injections are common but mostly mild and self-limiting. Children in GMFCS levels IV and V are at increased risk of systemic adverse events. The relationship between CP severity and BoNT-A adverse events is complex and further research is required to better understand this relationship. What this paper adds: Adverse events reported at the time of botulinum toxin A injection occurred in 6% of injection episodes. Adverse events were reported at follow-up in 22% of injection episodes. Children in Gross Motor Function Classification System (GMFCS) levels IV and V have increased rates of systemic adverse events. Children in GMFCS levels IV and V report less local weakness and pain.
Background Botulinum toxin A (BTX-A) is a medical product that is used widely in cosmetics, and concern over the safety profile has increased among injectors and patients. Objective The purpose was to enhance the statistical effect size using a meta-analysis to detect the incidence rate of adverse events (AEs) in the treatment of facial wrinkles. MethodsA systematic search was performed for randomized, double-blind, placebo-controlled trials published through July 2015. ResultsWe searched 16 trials, including 42,405 individual participants, and found that in all enrolled facial rejuvenation studies, patients in the BTX-A group had significantly more AEs than those patients in the placebo group (RR = 1.24; 95 % CI 1.07–1.43; p = 0.003). For crow’s feet lines injection analysis, the BTX-A group did not exhibit any significant increase in AEs compared with the control group (RR = 1.19; 95 % CI 0.96–1.48; p = 0.12), except in injection site hematoma (RR = 2.14; 95 % CI 1.13–4.07; p = 0.02) in the treatment group. For frown wrinkle injection analysis, AEs were significantly observed in the BTX-A group (RR = 1.47; 95 % CI 1.23–1.77; p < 0.0001), particularly headaches (RR = 1.53; 95 % CI 1.15–2.03; p = 0.003), eyelid ptosis (RR = 5.56; 95 % CI 1.68–18.38; p = 0.005), and heavy eyelids (RR = 6.94; 95 % CI 1.27–37.93; p = 0.03). Conclusion This meta-analysis confirmed the safety profile of BTX-A for glabellar and crow’s feet lines, and BTX-A usage for the removal of upper facial wrinkles, which have some significant mild-to-moderate adverse profiles, including headache, eye disorder, eyelid ptosis, and heavy eyelids. Facial injectors should abide by the technical standards of neurotoxic drugs and be familiar with the local pharmacological effects to lessen the severe side effects. Level of Evidence IThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A5 online Instructions to Authors
The American Academy of Neurology (AAN) has updated its guidelines on the use of botulinum neurotoxins in neurological disorders. The new guidelines provide individual recommendations for the four products that are commercially available in the USA; however, the clinical differences between the products are still not clear.
Botulinum toxin A was Food and Drug Administration approved in 2002 for the temporary correction of glabellar frown lines. Since that time, a variety of neuromodulators have established a convincing profile for both safety and efficacy in the treatment hyperdynamic rhytides of the upper face. With increasing clinical experience and expertise, these applications have been expanded to include targeted treatment of muscles in both the mid and lower face. This article details common techniques using botulinum toxin to treat orbicularis oris, depressor anguli oris, mentalis, and masseter muscles for the temporary correction of unwanted lower face hyperdynamic rhytides and facial contouring. Although we detail our suggested quantity of units per injection site based on onabotulinumtoxinA, all neuromodulators can be used in all of these suggested treatment areas with adjustment of the quantity of units based on the efficacy of the specific neuromodulator. A more compete discussion on the relative efficacy of all neuromodulators is beyond the scope of this article.
While the steps in the action of botulinum neurotoxin (BoNT) are well known, the factors underlying the timing of these steps are not fully understood. After toxin is injected into a muscle, it resides in the extracellular space and must be taken up into the nerve terminals. More toxin will be taken up if near the endplate. Toxin is distributed mainly by convection and there is likely little diffusion. Toxin that is not taken up will go into the general circulation where it may have a slight systemic effect. The uptake is activity and temperature dependent. Encouraging the unwanted muscle contractions after injection should be helpful. Cooling will decrease the uptake. The times for washout from the extracellular space and uptake of the toxin are not well established, but are likely measured in minutes. Toxin in the general circulation has a long half time. The time from injection to weakness is determined by how long it takes to get sufficient damage of the SNARE proteins to interfere with synaptic release. Toxins are zinc dependent proteases, and supplemental zinc may produce a greater effect. There will be weakness as long as there is residual toxin in the nerve ending. Copyright © 2015. Published by Elsevier Ltd.