Cost-minimization analysis in the treatment of spasticity in children with cerebral palsy with botulinum toxin type A: an observational, longitudinal, retrospective study. Objective: Cost-minimization analysis of onabotulinumtoxinA and abobotulinumtoxinA , taking into account the real dose administered to children with spasticity associated with dynamic equinus foot deformity due to cerebral palsy. Method: A single centre, observational, longitudinal, and retrospective study which included spastic paediatric patients aged 2-toyears and treated with onabotulinumtoxinA or abobotulinumtoxinA from December to October , in the Paediatric Neurology Unit of a first-level Spanish hospital. A longitudinal analysis of spasticity severity was made to confirm the similar effectiveness of both treatments. Cost minimization was analyzed using the dose administered and the direct costs pharmacological and medical visits costs from the perspective of the National Health System in euros. Results: We analyzed patients with paediatric spasticity: were treated only with onabotulinumtoxinA , only with abobotulinumtoxinA , and 60 with both treatments.

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Summary Backgroound and objectives Botulinum toxin BTX is one of the most potent bacterial toxins known and its effectiveness in the treatment of some pain syndromes is well known.

However, the efficacy of some of its indications is still in the process of being confirmed. The objective of this study was to review the history, pharmacological properties, and clinical applications of BTX in the treatment of pain of different origins. Contents Botulinum toxin is produced by fermentation of Clostridium botulinum, a Gram-positive, anaerobic bacterium.

Botulinum toxin, a neurotoxin with high affinity for cholinergic synapses, blocks the release of acetylcholine by nerve endings without interfering with neuronal conduction of electrical signals or synthesis and storage of acetylcholine.

It has been proven that BTX can selectively weaken painful muscles, interrupting the spasm-pain cycle. Several studies have demonstrated the efficacy and safety of BTX-A in the treatment of tension headaches, migraines, chronic lumbar pain, and myofascial pain. Conclusions Botulinum toxin type A is well tolerated in the treatment of chronic pain disorders in which pharmacotherapy regimens can cause side effects.

The reduction in the consumption of analgesics and length of action of 3 to 4 months per dose represent other advantages of its use. However, further studies are necessary to establish the efficacy of BTX-A in chronic pain disorders and its exact mechanism of action, as well as its potential in multifactorial treatments. Entretanto, algumas de suas indicagoes ainda estao em fase de comprovagao com relagao a sua eficacia.

Comprovadamente, a TxB pode enfraquecer seletiva-mente a musculatura dolorosa, interrompendo o ciclo espasmo-dor. O autor, Justinus Kerner, asso-ciou mortes resultantes de intoxicagao com um veneno encontrado em salsichas defumadas do latim botulus que significa salsicha. Em , Alan Scott conduziu os primeiros testes com a TxB-A injetada em seres humanos para o tratamento de estrabismo 2. Posteriormente sua indicagao se estendeu para as distonias segmentares, tremores e outros movimentos anormais.

Este complexo proteico consiste em uma neurotoxina com A percenta-gem da clivagem varia de acordo com o sorotipo. O uso da TxB para distonia focal tornou-se difundido. No grupo placebo, a melhora da dor local foi de apenas 0. Os pacientes com dor mais intensa VAS maior que 6. The history of botulinum toxin BTX begins in when the first description of botulism i.

The author, Justinus Kerner, associated deaths caused by intoxication with a poison found in smoked sausages from the Latin, botulus means sausage. He concluded that poison interfered with the excitability of the motor and autonomous nervous system. This led to the publication of two studies describing the clinical characteristics of botulism 1. Kerner proposed several potential medical uses of BTX at the time, especially in disorders of the central nervous system, which have been supported lately by new studies Only in the bacterial agent as well as the mechanism of action responsible for the toxicity of botulism were discovered; the discovery was attributed to Professor Emile Van Ermengen, who published a paper in 2.

Botulinum toxin, one of the most potent bacterial toxins known, is a result of the fermentation of Clostridium botulinum, a Gram-negative, spore-forming, anaerobic organism commonly found in the soil and oceans throughout the world 3. Eight immunologically distinct serotypes have been identified.

Although all serotypes inhibit the release of acetylcholine from nerve endings, their intracellular proteins, mechanisms of action, and potencies vary considerably. Type A is the most extensively studied serotype; however, the number of studies on the effects of the remaining serotypes has been increasing. Posteriorly, its indication was extended to segmental dystonias, tremors, and other abnormal movements.

Botulinum toxin was first used in the treatment of spasticity in ; the results of its use in muscles with severe spasm for six months in adults with hemiplegia secondary to stroke were published. Neurologists realized the potential of using BTX in neurologic disorders involving excessive muscle contraction or tonus 5.

The active principle of BTX is a protein complex derived from Clostridium botulinum. This protein complex consists of a ,Dalton neurotoxin linked non-covalently to non-toxic accessory proteins that stabilize and protect the pharmacologically active component, resulting in a final molecular weight that varies from , to , Daltons The composition and total molecular weight of the macromole-cular complex depend on the serotype and species of Clos-tridium botulinum that produced it, as well as on purification and analysis methods.

Commercially, BTX types A and B are biological agents obtained in laboratory, being stable, crystalline, lyophilized substances associated with human albumin, and used after dilution in normal saline NS 7. In physiological conditions, it is expected that the complex will dissociate and release pure neurotoxin since those complexes are stable only in acid pH 4. Botulinum toxin is composed of a light and a heavy protein chain linked by a disulfide bridge.

The heavy chain is responsible for the internalization of BTX into pre-synaptic cholinergic terminals. On the other hand, the light chain is a zinc endopeptidase responsible for its toxic effects. Ingenious and patient biochemical studies have shown that those toxins are highly specific proteases that cleave presynaptic SNARE proteins Soluble NSF Attachment protein Receptors involved with the exocytosis process of synaptic vesicles in nerve endings.

Destruction of those pre-synaptic proteins is the basis of the action of those toxins on the release of neurotransmitters 8. Botulinum toxin is a neurotoxin with high affinity for cholinergic synapses, blocking the release of acetylcholine from. The intramuscular injection of BTX in appropriated doses and locations causes partial chemical denervation and reduction of muscular contraction without causing complete paralysis. In glandular tissue, it blocks the secretion.

After local intramuscular administration of a selected dilution of BTX, it deposits rapidly in the interstitial tissue and specifically in the motor neuron terminal of skeletal muscles neuromuscular junction. Inhibition of the release of acetylcholine by BTX involves several steps. First, BTX binds irreversibly to receptors in the pre-synaptic membrane of the motor nerve ending. This binding specificity guarantees the high selectivity of BTX for cholinergic synapses. Those pre-synaptic receptors are responsible for the endocytosis of the neurotoxin into the motor nerve ending 7.

After internalization the molecule is separated in two polypeptide chains by proteases present in the motor nerve ending. Cleavage of BTX is considered the decisive step for its activation since as a single ,Dalton chain it has little pharmacological activity.

Cleaving results in two poly-peptide fragments: a heavy chain with , Daltons and a light chain with 50, Daltons. The percentage of cleaving varies according to the serotype. The light chain is translocated through the membrane of the endocytic vesicle into the cytosol showing a high-specificity for SNARE protein complex.

The protein target also varies according to the serotype. Playing the role of enzymes, the light chains of each serotype cleave a distinct peptidic bond in one or more sites of the SNARE proteins in such a way that none of the serotypes attacks the same location, and, therefore, their actions and potencies vary considerably, although all subtypes present the same final effect: inhibition of the release of acetylcholine from nerve endings 4.

Proteolytic cleavage of the SNARE complex by the light chain of BTX prevents the synaptic vesicle from anchoring on the internal surface of the cellular membrane, blocking, therefore, vesicular fusion and preventing the release of acetyl-choline, leading to the development of flaccid paralysis on affected muscle fibers chemical denervation.

This translates clinically in dose-dependent weakness or paralysis of the skeletal muscle. The initial effect on the muscle affects the function of the alpha motor neuron,. Their inhibition results on a reduction in muscle tonus due to the consequent reduction of the afferent feedback on alpha motor neuron from the muscle spindle 1,10,11 Figure 1. The onset of action of BTX on the skeletal muscle takes a few days 2 to 5 days , but occasionally it can take up to two weeks.

Once instituted, the effects last for six weeks to six. Figure 1 - Analgesic Actions of Botulinum Toxin. On the left, the muscular and sensorial pathophysiology that triggers pain. On the right, the analgesic effects of botulinum toxin on those pathophysiological mechanisms.

During the period when the effect is more intense, histological exam reveals muscular atrophy and changes of the fibers After two to three months, its action starts to decrease gradually. Two mechanisms are responsible for the reversal of local paralysis: 1 "Neuronal budding", with the formation of axonal budding, reinnervation, and formation of new and smaller end-plates with temporary muscle reinnervation extra-junctional acetylcholine receptors , and 2 Regeneration of acetylcholine coupling proteins in the vesicles SNARE complex 14, whose function is reestablished in one to four months The metabolic pathway of BTX is not properly documented, but it can be explained by the presence of proteases that cause degradation of the polypeptidic chains.

Since these are protein complexes alien to the human body, the main characteristic of the BTX complex is the activation of the patients' immune system. Despite being used clinically for local administration, the presence of BTX in the blood stream has been demonstrated.

High doses, frequent applications short intervals , and high protein load associated with BTX in commercially available presentations increase the risk of developing neutralizing antibodies.

It has been observed that the development of neutralizing antibodies against BTX in the treatment of dystonias has similar prevalence in children and adults, usually occurring between the first and fourth year after beginning the treatment, and this probability reduces after this period with low immunogenecity after 18 years of treatment When antibodies against BTX are formed, the duration of action and maximal duration of the therapeutic effects are usually decreased after a few administrations partial therapeutic failure.

It should be emphasized that further, well-based, clinical studies are necessary to observe the use of BTX-B since it is less potent than BTX-A because its cleavage and consequent activation occur at a lower proportion , requiring higher doses in IU , i. Studies indicate that a dose between 7, and 10, IU of BTX-B is necessary in patients with cervical dystonia to produce a reasonable therapeutic effect. These are undesirable side effects, but it is also an interesting phenomenon that demonstrates greater affinity of these serotypes for autonomic fibers It has been proved that BTX can cause selective weakness of painful muscles and disrupt the spasm-pain cycle, providing sustained pain relief, allowing patients to perform physical exercises that are fundamental for long-term recovery As mentioned before, BTX was initially used in the treatment of motor disorders, such as dystonias, and further studies demonstrated significant benefits regarding pain which frequently exceeded the improvement of the muscle spasm and did not correspond strictly to the area of neuromuscular effects.

This suggested that this drug could have a direct effect on pain mechanisms independently of its neuromuscular actions. In humans, the analgesics effects of BTX-A were first demonstrated after observing significant pain relief in cervical dystonia. Although the antidystonic and anti-spasmodic effects of BTX-A are frequently attributed to the blockade of acetylcholine release from synaptic vesicles, recent animal studies suggest other analgesic mechanisms for this neurotoxin.

At the moment, evidence suggest that the analgesic properties observed are part of a more complex mechanism of analgesia that goes beyond simple muscle relaxation.

Studies raise the possibility of a complex interaction of BTX with peripheral tissues and occasional indirect influences on central pain mechanisms 10, As mentioned before, the apparent specificity of BTX for cholinergic nerves in vivo is due to the presence of specific.

Alternatively, it has been observed in experimental models that internalization of BTX by the nerve ending inhibits immediately the exocytosis of other neurotransmitters, such as norepinephrine, and the mechanism of action is identical to that observed in cholinergic synapses, i. In this context, it is possible to state that the high affinity of BTX for cholinergic synapses is part of what makes it so useful in neuromuscular disorders.

On the other hand, several exceptions to this specificity have been observed in the laboratory. Botulinum toxin type A was associated with the release of substance P in culture of neurons from the dorsal root ganglion of mice embryos, as well as the reduction of the stimulated release but not the basal release of calcitonin gene-related peptide CGRP in cultures of neurons from the trigeminal ganglion.

Additionally, prior administration subcutaneous of BTX-A in mice paws attenuated significantly the inflammatory response induced by the subcutaneous administration of formalin, a pain-evoking agent, besides reducing glutamate release by the peripheral axon of the nociceptor. Reduced activity of dorsal horn neurons in the spinal cord has also been demonstrated. Thus, besides being a potent inhibitor of the release of acetylcholine, BTX would have an inhibitory effect in other neurotransmitters and neuropeptides, explaining its anti-inflammatory and analgesic actions Further studies are necessary to elucidate the mechanisms involved in this inhibitory action of BTX on the nociceptor, but it is believed that there are four possible ways by which BTX can interrupt painful signals:.

Studies with BTX-A were the basis for this reference. Immediately after, BTX-B was introduced in clinical studies of cervical dystonia, and its effectivity and safety was demonstrated. The use of BTX for focal dystonia became widespread.

This was followed by reports on its efficacy in spasticity and other neurological conditions.


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