Botulinum toxin prevention

Focal spasticity Botulinum toxin Prevents release of acetylcholine in the neuromuscular junction Individualized... 

A FIGURE 17-36 Release of neurotransmitters and the recycling of synaptic vesicles. Step D Synaptic vesicles loaded with neurotransmitter (red circles) move to the active zone and then dock at defined sites on the plasma membrane of a presynaptlc cell. Synpatotagmin prevents membrane fusion and release of neurotransmitter. Botulinum toxin prevents exocytosls by proteolytically cleaving VAMR the v-SNARE on vesicles. Step... 

Treatment—Since C. botulinum toxin blocks the actions of nerves that activate muscles necessary for breathing, an antitoxin can be injected up to about 24 hours (based on monkey studies) after exposure to a lethal toxin dose and still prevent death. The two types of available antitoxins prepared from horse sera are trivalent (includes types A, B, E) and heptavalent (types A, B, C, D, E, F, and G) preparations. It should be noted that patients face a theoretical risk of developing serum sickness from such antitoxins. 

Botulinus toxin comes from Clostridium botulinum, an organism that causes food poisoning. Botulinus toxin prevents the release of ACh from nerve endings by mechanisms that are not clear. Death occurs from respiratory failure caused by the inability of diaphragm muscles to contract. 

Botulinum toxin Cholinergic vesicles Prevents release... 

This type of response may be caused by several mechanisms. For instance, the muscle relaxation induced by succinylcholine, discussed in more detail in chapter 7, is due to blockade of neuromuscular transmission. Alternatively, acetylcholine antagonists such as tubocurarine may compete for the receptor site at the skeletal muscle end plate, leading to paralysis of the skeletal muscle. Botulinum toxin binds to nerve terminals and prevents the release of acetylcholine the muscle behaves as if denervated, and there is paralysis. This will be discussed in more detail in chapter 7. 

By destroying the protein, the toxin prevents the release of the neurotransmitter acetylcholine from small packets at the ends of nerves by exocytosis. These nerves, attached to voluntary muscles, need acetylcholine to allow the flow of signals (impulses) between the nerve and the muscle. By preventing the release of acetylcholine, botulinum toxin blocks muscle contraction, causing paralysis and relaxation. The therapeutic action relies on relaxation of muscles, generally in the face. It is therefore used to treat blepharospasm (uncontrolled contractions) and stroke-induced permanent facial muscle contractions. 

The complex of SNAREs and SNAP25 is the target of the powerful Clostridium, botulinum, toxin, a protease that cleaves specific bonds in these proteins, preventing neurotransmission and causing the death of the organism. Because of its very high specificity for these proteins, purified botulinum toxin has served as a powerful tool for dissecting the mechanism of neurotransmitter release in vivo and in vitro. 

Botulinum toxin injection has been documented as a means to control severe spasticity in various clinical situations. This intervention, for example, can help remove spastic dominance in certain patients so that volitional motor function can be facilitated. For example, judicious administration of botulinum toxin can result in improved gait and other functional activities in selected patients with cerebral palsy, stroke, or traumatic brain injury.7,36,49,78 Even if voluntary motor function is not improved dramatically, reducing spasticity in severely affected muscles may produce other musculoskeletal benefits. For example, injection of botulinum toxin can reduce spasticity so that muscles can be stretched or casted more effectively, thus helping to prevent joint contractures and decreasing the need for surgical procedures such as heel-cord lengthening and adductor release.12,98... 

These injections can likewise enable patients to wear and use orthotic devices more effectively. Injection into the triceps surae musculature can improve the fit and function of an ankle-foot orthosis by preventing excessive plantar flexor spasticity from pistoning the foot out of the orthosis.49 Injections into severely spastic muscles can also increase patient comfort and ability to perform ADL and hygiene activities. Consider, for example, the patient with severe upper extremity flexor spasticity following a CVA. Local injection of botulinum toxin into the affected muscles may enable the patient to extend his or her elbow, wrist, and fingers, thereby allowing better hand cleansing, ability to dress, decreased pain, and so forth.7... 

This chapter deals with botulinum toxin type A (BOTOX) in the treatment of strabismus, blepharospasm, and related disorders. Botulinum toxin type A (BOTOX) has been used to treat strabismus, blepharospasm, Meige s syndrome, and spasmodic torticollis. By preventing acetylcholine release at me neuromuscular junction, botulinum toxin A usually causes a temporary paralysis of the locally injected muscles. The variability in duration of paralysis may be related to me rate of developing antibodies to me toxin, upregulation of nicotinic cholinergic postsynaptic receptors, and aberrant regeneration of motor nerve fibers at me neuromuscular junction. Complications related to this toxin include double vision (diplopia) and lid droop (ptosis). 

Botulinum toxin acts in the CNS by which of the following a preventing the reuptake of acetylcholine... 

The current Centers for Disease Control and Prevention (CDC) therapy for the public is an FDA-approved, bivalent, botulinum equine antitoxin against serotypes A and B. The trivalent antitoxin against types A, B, and E is no longer available. In cases of exposure to any of the other botulinum toxin serotypes, the US Army can provide an investigational heptavalent (ABCDEFG) equine antitoxin, but the time required for typing a toxin subtype would limit its effectiveness in such cases as an outbreak. A parenteral vaccine against the toxin is currently available, but the need exists for newer nonparenteral vaccines that could be administered orally or via inhalation. 

Nemroinuscular blocking agents used in clinical practice interfere with this process. Natural substances that prevent the release of acetylcholine at nerve endings exist, e.g. Clostridium botulinum toxin (see p. 429) and some venoms. 

Botulinum toxin is one of several toxins produced by the bacterium Clostridium botulinum. The toxin binds with high affinity to peripheral cholinergic nerve endings, such as those at the neuromuscular junction and in the autonomic nervous system, preventing the release of the neurotransmitter acetylcholine (1). This action at the neuromuscular junction can cause weakness and even paralysis of the muscles supplied by the affected nerves. Sprouting of the terminal nerves eventually results in re-innervation of the muscles and return of function. Doses are measured in mouse units (MU), IMU being the LD50 in Swiss-Webster mice. 

A pentavalent botulinum toxoid (botulinum toxin in different antigenic types) has been used for more than 30 years in some countries to prevent the disease in laboratory workers and to protect troops against attack. Pre-exposure immunization for the general population is neither feasible nor desirable the vaccine is ineffective for postexposure prophylaxis. Treatment of botulism consists of passive immunization and supportive care. Most licensed antitoxins contain antibodies against the most common toxin types A, B, and E. About 9% of recipients of equine antitoxin developed urticaria, serum sickness, or other hypersensitivity reactions. In 2% of recipients anaphylaxis occurred within 10 minutes of antitoxin... 

Chemical Abstracts Service Registry Number CAS 93384-43-1. Botulinum toxins comprise a series of seven related protein neurotoxins that prevent fusion of synaptic vesicles with the presynaptic membrane and thus prevent release of acetylcholine. Exposure in a battlefield or terrorist setting would most likely be to inhaled aerosolized toxin. The clinical presentation is that of classical botulism, with descending skeletal muscle weakness (with an intact sensorium) progressing to respiratory paralysis. A toxoid vaccine is available for prophylaxis, and a pentavalent toxoid can be used following exposure its effectiveness wanes rapidly, however, after the end of the clinically asymptomatic latent period. Because treatment is supportive and intensive (involving long-term ventilatory support), the use of botulinum toxin has the potential to overwhelm medical resources especially at forward echelons of care. 

Although more than 3,000 laboratory workers have received the pentavalent vaccine over the past 30 years, it is not administered broadly for several reasons. The toxoid is relatively scarce, expensive, requires several injections, has the side effects described previonsly, and the natnral disease is very rare. The drawbacks of immunizing the entire popnlation clearly outweigh the expense of preventing a very small number of cases. In addition, active immunity to botulinum toxin would preclude the use of the toxin for other medicinal purposes (36). The heptavalent vaccine wonld not be helpfnl postexposure in an ontbreak scenario, because the toxoid requires several injections over several months to induce immunity. A recombinant vaccine, which may overcome these limitations, is in development (36). 

Theoretically, decontamination of a site after an aerosolized or food-borne release of botulinum toxin might prevent additional exposures. Botulinum toxin is easily inactivated in the environment with bleach or heat. Unfortunately, recognition of a covert release would probably occur long after decontamination would be helpful. If epidemiologic investigation identified a possible food source, and if the food were still available in the distribution chain, public health authorities would remove the food from potential consumers and submit it for laboratory testing. 

Food-borne botulism results from the ingestion of food contaminated with preformed toxins or toxin-producing spores from C. bo-tulinum. C. botulinum poisoning is relatively rare only 110 cases are reported per year in the United States. Botulism is almost always associated with improper preparation or storage of food. Seven distinct toxins (A to G) have been described. The toxins, which are produced by the bacteria and released on lysis, are the most potent biologic or chemical toxins known to humans. The toxin prevents the release of acetylcholine at the peripheral cholinergic nerve terminal. Toxin activity has prompted the use of minute locally injected doses to treat select spastic disorders, such as blepharospasm, hemifacial spasm, and certain dystonias. ... 

Presynaptic membrane depolarization opens voltage-dependent Ca2+ channels, and the influx of this ion causes fusion of the synaptic vesicle membranes with the presynaptic membrane, leading to exocytosis of ACh- Botulinum toxin ( in Figure II-2-1) interacts with synaptobrevin and other proteins to prevent ACh release. 

---