BR102020011146A2 - COMBINED USE OF ANTICHOLINESTERASIC AND CORTICOSTEROID MYOTIC SUBSTANCES FOR THE PREVENTION AND/OR TREATMENT OF OCULAR MYASTHENIA GRAVIS - Google Patents

Abstract

The present invention aims to propose a new drug compound for the treatment of Ocular Myasthenia Graves (MGO). The use of anticholinesterase miotic substances (alone) or in combination with corticosteroids, enables the said treatment, which occurs through the direct action of these substances on the motor plate of the levator palpebrae muscle and extrinsic ocular muscles, responsible for the ocular changes found in this pathology. The methodology for the treatment of MGO is given through the use of anticholinesterase substances (alone) or in combination with corticosteroids, in which anticholinesterase drugs are administered topically in the form of eye drops.

Description

COMBINED USE OF ANTICHOLINESTERASIC AND CORTICOSTEROID MYOTIC SUBSTANCES FOR THE PREVENTION AND/OR TREATMENT OF OCULAR MYASTHENIA GRAVIS FIELD OF THE INVENTION

[001] The present invention is part of the field of Medicine, more precisely in the field of Ophthalmology, and describes a new drug compound for the treatment of Ocular Myasthenia Graves (OGM). The use of anticholinesterase miotic substances (alone) or in combination with corticosteroids makes it possible to treat Myasthenia Gravis, which occurs through the direct action of these substances on the motor plate of the levator palpebrae muscle and extrinsic ocular muscles, responsible for the ocular changes found in this condition. pathology. The present invention also refers to a novel methodology for the treatment of (MGO), through the use of anticholinesterase substances (alone) or in combination with corticosteroids.

FUNDAMENTALS OF THE INVENTION

[002] Acquired myasthenia gravis (MG) is a relatively uncommon disease, with prevalence rates that have increased to about 20 per 100,000 in the US population. This autoimmune disease is characterized by muscle weakness that fluctuates during the day or with muscle exertion (worsening with exertion and improving with rest). In about two-thirds of patients, involvement of extrinsic ocular muscles (EOMs) presents as an initial symptom, usually progressing to other bulbar muscles and limb musculature, resulting in generalized myasthenia gravis (MGG). Sex and age seem to influence the occurrence of MG. Below 40 years there is a female predominance (about 3:1), but in the other age groups the ratio is approximately the same. Childhood MG is uncommon in Europe and North America, comprising 10% to 15% of cases. In Asian countries, however, up to 50% of patients with MG have an onset under 15 years of age, mainly with purely ocular manifestations (MGO).

[003] Myasthenia Gravis is an acquired autoimmune disease caused by the action of autoantibodies directed against the acetylcholine receptor (AChR) of the muscle membrane. The condition is clinically characterized by variable eyelid ptosis, ocular motility abnormalities (ophthalmoplegias), and weakness of voluntary muscles elsewhere in the body.

Clinical Signs

[004] Myasthenia Gravis is a disease of the neuromuscular junction in which patients evolve with weakness and progressive tiredness with physical activity, in cyclic phases of exacerbation and remission, evolving with progressive worsening up to one year from the diagnosis of the disease. AchR antibodies are present in 86% of cases. The role of thymus is important and 70% have thymus enlargement, with 10 to 15% of patients with MGG having thymoma, diagnosed with chest tomography. On the other hand, 30% to 65% of people with thymomas also have myasthenia gravis, which is the most common autoimmune disease associated with thymoma.

[005] In MGG, the immune system produces antibodies that block the chemical signals that make the muscles move, causing severe muscle weakness. People with myasthenia gravis get tired easily. Although patients have decreased muscle strength throughout the body, symptoms caused by weakness in the EOMs, neck, and chest can be the most troublesome. Weakness of EOMs can cause blurred or double vision and drooping eyelids, while weak neck muscles can lead to problems with swallowing. Weakness of the pectoral muscles and diaphragm can cause breathing problems and shortness of breath. In more severe cases, breathing difficulties can lead to airway obstruction, pneumonia and even cardiorespiratory arrest. Myasthenia gravis can be treated with removal of the thymus or with medications.

autoimmunity

[006] At the normal neuromuscular junction (NMJ), acetylcholine is released from the presynaptic membrane, either spontaneously or by a nerve impulse, and leads to the production of electrical potentials at the motor endplate. If the amplitude of this potential is sufficient, we will have an action that propagates along the muscle fiber, triggering the release of calcium in the cytoplasm of the muscle fiber, leading to muscle contraction. The JNM of patients with MG shows significant changes compared to normal JNM, which include a reduction in the number of acetylcholine receptors, an increase in the size of the JNM, destruction of nerve terminals in the motor endplate, and a decrease in the length of the postsynaptic membrane.

[007] The role of autoantibodies in MG is well established in the literature, appearing in 80-90% of patients with MGG. Experimental models also demonstrate that the transfer of autoantibodies between animal species reproduces the disease. About 10 to 20% of patients do not have positive autoantibodies and it is believed that in these cases there are circulating antibodies that are not detectable by current radioimmunoassay techniques. Cellular immunity also plays a role in the pathophysiology of MG and T cells respond to stimuli from antibodies against acetylcholine receptors, which in vitro can influence their production. Hence the importance of the association with thymomas and antibodies against striated muscle-specific tyrosine kinase (anti-MuSK), which are found in 90% of patients with Myasthenia Gravis and Thymoma. It has been suggested that thymus myoid cells serve as antigens for the production of autoantibodies in MG.

Myasthenic Disorders

[008] In the last decades, the better characterization of symptoms and the development of laboratory tests (immunohistochemical) is allowing a greater definition of the different types of ptosis and even diseases of neuromuscular junctions in general. These are the myasthenic disorders, a well-characterized group of NMJ disorders. Its pathogenesis is diverse, including genetic and autoimmune mechanisms. This characterization has become important to establish the best therapeutic strategies, as we will see later.

[009] A better knowledge of congenital myasthenia led to the development of efficient diagnostic algorithms in genetic research, bringing very efficient therapeutic implications. New epidemiological and genetic risk factors have been identified and are considered responsible for the development of myasthenia gravis. The study of the role of innate immunity in myasthenia gravis has identified relevant pathways to explain the causes of the pathology. The description of the pathogenic role of IgG4 anti-MuSK antibodies revealed heterogeneous immune mechanisms that should lead to more specific therapies. Therapeutic algorithms need to be adapted to each subtype of myasthenia. Growing knowledge about genetic and environmental risk factors and the basic immunopathogenesis of myasthenia gravis, including the role of innate immunity, T-cell regulatory impairment, and autoantibody heterogeneity, provides a rationale for treatment with new biological agents.

Diagnosis

• (i) O teste do Tensilon é realizado com o emprego endovenoso do cloreto de edrofonio que sendo um inibidor da colinesterase de curta ação aumenta a quantidade de acetilcolina na JNM. Este incremento na quantidade de acetilcolina vence o bloqueio dos receptores (AchR). A ptose e oftalmoplegias melhoram em 30 segundos, porém regressam ao basal em 1-2 minutos. Entretanto, o uso endovenoso do cloreto de edrofonio causa efeitos secundários colinérgicos como aumento de secreções oral e brônquica, bradicardia, cólicas abdominais, suor, hipotensão, hiperemia ocular e lacrimejamento. São sintomas frequentemente desconfortáveis para o paciente e, embora, complicações graves como bradicardia e síncope sejam raras, o teste deve ser realizado com monitorização cardíaca e com um agente anticolinérgico disponível: a atropina. Pacientes com arritmias cardíacas e asma brônquica apresentam contraindicações relativas para o teste do Tensilon.
• (ii) A colocação de uma bolsa de gelo sobre as pálpebras por 2-5 minutos é associada com melhora da ptose palpebral e das oftalmoplegias. Este teste tem sensibilidade reportada de 93-97% e especificidade de 97-98%. No entanto, a falta de padronização na sua realização prejudica a interpretação dos resultados observados.
• (iii) Na eletroneuromiografia, testa-se a condução dos nervos e as respostas musculares de contração. Na MG o padrão típico é a fadigabilidade, com redução da resposta muscular aos estímulos repetidos (chamada de decremento da resposta). Há uma porcentagem alta desses exames com resultados falso-negativos, principalmente nos casos leves de MG.
• (iv) A pesquisa de anticorpos contra AchR é o teste mais específico para MG. No entanto, mais de 15% dos pacientes com MG têm títulos de anticorpos contra AchR negativos, especialmente aqueles com alterações oculares isoladas.
• (v) A tomografia de tórax com cortes finos é utilizada na pesquisa de tumores na glândula timo. O timo, no adulto, geralmente é indetectável ou é um remanescente minúsculo.

[010] The diagnosis of MG on clinical grounds can be a challenge for both the neurologist and the ophthalmologist, especially in cases where the weakness is restricted to a few muscles, as in ocular MG. For the clinical diagnosis of MG, several tests described below are used:

• (i) The Tensilon test is performed with the intravenous use of edrophonium chloride which, being a short-acting cholinesterase inhibitor, increases the amount of acetylcholine in NMJ. This increase in the amount of acetylcholine overcomes the blockade of receptors (AchR). Ptosis and ophthalmoplegia improve within 30 seconds, but return to baseline within 1-2 minutes. However, the intravenous use of edrophonium chloride causes cholinergic side effects such as increased oral and bronchial secretions, bradycardia, abdominal cramps, sweating, hypotension, ocular hyperemia and tearing. These are often uncomfortable symptoms for the patient and, although serious complications such as bradycardia and syncope are rare, the test should be performed with cardiac monitoring and an available anticholinergic agent: atropine. Patients with cardiac arrhythmias and bronchial asthma have relative contraindications to the Tensilon test.
• (ii) Placing an ice pack on the eyelids for 2-5 minutes is associated with improvement in eyelid ptosis and ophthalmoplegia. This test has a reported sensitivity of 93-97% and specificity of 97-98%. However, the lack of standardization in its performance impairs the interpretation of the observed results.
• (iii) In electroneuromyography, nerve conduction and muscle contraction responses are tested. In MG, the typical pattern is fatigue, with reduced muscle response to repeated stimuli (called response decrement). There is a high percentage of these tests with false-negative results, especially in mild cases of MG.
• (iv) Screening for antibodies against AchR is the most specific test for MG. However, more than 15% of patients with MG have negative antibody titers against AchR, especially those with isolated ocular changes.
• (v) Thoracic tomography with thin sections is used in the search for tumors in the thymus gland. The thymus, in the adult, is usually undetectable or is a tiny remnant.

Ocular Myasthenia Gravis

[011] Muscle changes in cases of MGO have a similar evolution to changes in other systemic muscles: weakness and fatigability of EOMs, after repeated or sustained effort with improvement upon rest, that is, improvement in the morning (upon waking up) and worsening at twilight. Symptoms vary both in relation to their behavior on different days and on the same day depending on the intensity. Other factors can influence the worsening of symptoms in patients with MGO, such as physical exercise, high temperatures, emotional stress, infections, surgery, among others.

[012] The most commonly affected muscles are the levator palpebrae superioris muscle and the extraocular musculature, with diplopia appearing in 92% of patients. Eyelid ptosis and blurred vision are also common. When asking the patient to look up in a sustained manner or to repeatedly open and close the eyes, diplopia and eyelid ptosis may occur. Occasionally, complete ophthalmoplegia and nystagmus are seen. These symptoms tend to get worse after prolonged reading or at the end of the day. The involvement of the facial mimic muscles (face without expression) is less common.

The Neuromuscular Junction

[013] The nerve endings that innervate the JNMs of the skeletal muscles arise from the terminal arborization of the α-motor neurons of the ventral horns of the spinal cord and brainstem. The JNM itself consists of a synaptic cleft and a 20 nm-thick space that contains acetylcholinesterase (AChE) along with other supporting proteins and proteoglycans. The postsynaptic membrane of the JNM has deep folds with acetylcholine receptors (AChR) tightly packed on top of these folds. When the nerve action potential reaches the synaptic button, depolarization opens voltage-gated calcium channels in the presynaptic membrane, triggering the release of ACh into the synaptic cleft. ACh diffuses into the synaptic cleft to reach postsynaptic membrane receptors, where it triggers the endplate potential (EPP) and is hydrolyzed by AChE within the synaptic cleft.

• (i) O EPP gerado no JNM normal é maior que o limiar necessário para gerar o potencial de ação pós-sináptico por uma medida de múltiplas dobras. Esse fator de segurança da transmissão neuromuscular é reduzido em pacientes com MG.
• (ii) A redução no número ou atividade das moléculas de AChR no JNM diminui o EPP, que pode ser adequado em repouso, mas quando a ACh é reduzida após atividade repetitiva, o EPP pode cair abaixo do limiar necessário para desencadear o potencial de ação, levando à fraqueza muscular. Quando o EPP, em repouso, está consistentemente abaixo do limiar do potencial de ação, leva à fraqueza persistente.

[014] MuSK (muscle-specific tyrosine kinase), a postsynaptic transmembrane protein, is part of the agrin receptor, a protein present in the synaptic basal lamina. The Agrin/MuSK interaction triggers and maintains AChR-dependent clustering and other postsynaptic proteins. Rapsyn, a peripheral membrane protein in the postsynaptic membrane, is required for clustering in AChR. Mice lacking agrin or MuSK do not form JNMs and die at birth due to profound muscle weakness. NMJ findings that influence susceptibility to muscle weakness and MG:

• (i) The EPP generated in normal JNM is greater than the threshold needed to generate the postsynaptic action potential by a multifold measurement. This safety factor of neuromuscular transmission is reduced in patients with MG.
• (ii) Reduction in the number or activity of AChR molecules in JNM decreases EPP, which may be adequate at rest, but when ACh is reduced after repetitive activity, EPP may fall below the threshold required to trigger the action potential , leading to muscle weakness. When the resting PPE is consistently below the action potential threshold, it leads to persistent weakness.

Immunopathogenesis of Myasthenia

• (i) Ligação do complemento e inativação da JNM.
• (ii) Destruição de AChR por endocitose de moléculas - reação cruzada com anticorpos.
• (iii) Bloqueio do AChR funcional - impedindo que a ACh normalmente seja anexada e atue na AChR.

[015] Anti-AChRs affect neuromuscular transmission by at least 3 mechanisms:

• (i) Complement binding and JNM inactivation.
• (ii) Destruction of AChR by endocytosis of molecules - cross-reaction with antibodies.
• (iii) Functional AChR blocking - preventing the ACh from normally attaching to and acting on the AChR.

[016] Pathogenic anti-AChR antibodies are high-affinity IgGs and their synthesis requires activated CD4+ T Lymphocytes to interact with and stimulate B Lymphocytes. Therefore, thymectomy, with the resulting removal of AChR-specific CD4+ T cells, helps to relieve symptoms in patients with MG. Likewise, treatment with anti-CD4+ antibodies has also been shown to have a therapeutic impact. Patients with AIDS and reduced CD4+ T cells notice improvement in myasthenic symptoms.

[017] CD4+ T cells are classified into two main subtypes: Th1 and Th2 cells. Th1 cells secrete pro-inflammatory cytokines, such as IL-2, IFN-γ and TNF-α, which are important in cell-mediated immune responses. Th2 cells secrete anti-inflammatory cytokines, such as IL-4, IL-6 and IL-10, which are important inducers of humoral immune response. IL-4 further stimulates the differentiation of Th3 cells that secrete TGF-β, which is involved in immunosuppressive mechanisms. MG patients have abundant anti-AChR Th1 cells in the blood that recognize many parts of AChR and are able to induce B cells to produce high-affinity anti-AChR antibodies. Th1 cells are indispensable in the development of experimental autoimmune MG (MGAE), as demonstrated in animal models. Therapies against Th1 cytokines (TNF-α and IFN-γ) improved symptoms of MGAE in animal models.

[018] Anti-AChR Th2 cells have a complex role in the pathogenesis of MGAE. They may be protective, but their cytokines IL-5, IL-6 and IL-10 may also facilitate the development of MGAE. CD4+ T cells that express the CD25 marker and the Foxp3 transcription factor are called "Tregs" and are important in maintaining self-tolerance. Tregs in patients with MG may be functionally impaired and are shown to increase after thymectomy with improvement in correlated symptoms. Natural killer T (NKT) cells with Tregs help regulate the anti-AChR response. Mouse models showed inhibition of MGAE development after stimulation of NKT cells. IL-18 stimulates NKT cells to produce IFN-γ, enhancing the action of Th1 in inducing MGAE. IL-18-deficient mice are resistant to MGAE, and pharmacological blockade of IL-18 suppresses MGAE. Patients with MG demonstrated an increase in the serum level of IL-18, which tends to decrease with clinical improvement.

Other Autoantibodies in MG

[019] MG seronegative patients may have anti-MuSK antibodies (up to 40% of this subgroup). The Agrin/MuSK signaling pathway maintains the structural and functional integrity of the postsynaptic JNM apparatus in the adult muscle cell. Anti-MuSK antibodies affect the maintenance of the agrin-dependent AChR cluster in JNM, leading to a reduction in the number of AChRs. Complement-mediated damage may also be responsible for decreasing AChR numbers in JNM. Some studies in human muscle cell cultures have shown cell cycle arrest, downregulation of the AChR subunit with rapsyn and the expression of other muscle proteins, on exposure to sera from antiMuSK MG positive patients.

[020] As exposed in the previous paragraphs, there is a high complexity in the pathophysiology of MG and thus denotes the multiplicity of clinical forms that are found in MGG of different races. According to the present inventor, in the near future, it will be possible to accurately identify the various clinical forms through immunohistological examinations and separate them into more well-defined groups than is currently possible. Including genetic mapping. This will improve the treatment of virtually all forms of MG.

Current Treatment

[021] An extensive analysis of the anti-AChR antibody response (in MG and its experimental model) revealed that the autoimmune attack is T-cell dependent, resulting from the loss of tolerance for self antigens at the thymus level. However, the antigen-antibody reaction and complements are primarily responsible for the loss of postsynaptic AChR and associated destruction of JNM. Therefore, the goal of treating the patient with MG is to stop the autoimmune process by T and B cells as quickly as possible, thus preventing the destruction of JNM.

[022] Since the introduction of corticosteroids in the 1950s, immunomodulatory therapies including thymectomy, intravenous immunoglobulin (IVIg) and some immunosuppressants have been widely used. However, randomized clinical trials have been limited, perhaps because MG is a rare disease and it is difficult to recruit many suitable patients. This can also be attributed to the lack of reliable and validated outcome measures. For this reason, most neurologists chose immunotherapies available in their medical settings in light of their own clinical experiences.

Anticholinesterase Drugs

[023] Acetylcholinesterase inhibitors have been widely used as a basic tool for the treatment and diagnosis of MG since 1934. Their mechanism of action is the competitive blockade of AChE (enzyme), located in the extracellular matrix of the post-synaptic muscle endplate membrane. , folding and breaking ACh into inactive metabolites: choline and acetate. Thus, they prolong the level and duration of ACh neurotransmitter action and are generally effective in relatively early or mild MG, where patients have a sufficient number of remaining AchRs.

[024] Several anticholinesterases are currently available, which are generally classified according to their duration of action. The most commonly used drug is pyridostigmine, which is available in 60 mg tablets and starts working 30 minutes after oral administration, with a duration of action of 3 to 6 hours. It is usually taken every 4 hours while awake. Its dosage should be adjusted to 60-960 mg/day, depending on the clinical response and the patient's needs. The dosage is lower in patients with renal insufficiency because it is excreted via the kidneys. Sustained-release tablets, taken at bedtime, are useful for patients with morning weakness, while the syrup formulation is useful for children or nasogastric tube patients.

[025] Anticholinesterases are well tolerated by most patients and are considered safe. Since they act on synapses (muscarinic and nicotinic), they induce the corresponding adverse cholinergic effects. Muscarinic effects include gastrointestinal tract hypermotility (eg, abdominal pain and diarrhea), excessive salivation and respiratory secretions, increased sweating, and bradycardia or arrhythmia. Nicotinic side effects are muscle fasciculation or muscle spasms. Overdose can lead to severe cholinergic toxicity or seizures (eg, flaccid paralysis or respiratory failure), which results from neuromuscular transmission overstimulated by excess ACh.

corticosteroids

[026] Anticholinesterases do not interfere with antibody production, but only improve the symptoms of MG. However, more recent studies have incorporated cholinergic receptors into the immune system. Thus, updated data indicate that anticholinesterases would have additional anti-inflammatory activity in the treatment of MG.

• 1) redução da distribuição e migração de leucócitos;
• 2) inibição específica do recrutamento e migração de linfócitos para um sítio inflamatório;
• 3) bloqueio de várias funções das células T;
• 4) reduzir a produção e secreção de citocinas e outros imunomoduladores de macrófagos ou células T; e
• 5) diminuir a maturação de células dendrídicas.

[027] In contrast, corticosteroids are drugs universally used as first-line immunosuppressants to induce comparatively rapid remission and a link to long-term maintenance therapy using other immunosuppressants. The exact mechanism of action of corticosteroids in MG is poorly understood. The effects on the immune system involve several important pathways, including:

• 1) reduced distribution and migration of leukocytes;
• 2) specific inhibition of lymphocyte recruitment and migration to an inflammatory site;
• 3) blocking various T cell functions;
• 4) reduce the production and secretion of cytokines and other macrophage or T cell immunomodulators; and
• 5) decrease the maturation of dendritic cells.

[028] The high doses, generally used to induce a remission, can also induce apoptosis of various immune cells. Several corticosteroid studies have concluded that remission or marked improvement in MG symptoms occurs in approximately 80% of cases. Oral administration at a dose of 1 mg/kg is commonly used for rapid improvement of myasthenic symptoms. It is worth noting that high doses of steroids can temporarily exacerbate the symptoms of myasthenia in some patients (so-called steroid diving), which usually occurs 4-14 days after onset and lasts for less than 1 week. Hospitalization and careful monitoring of respiratory failure may be necessary for prompt management of steroid-induced worsening. Combination of other therapies (plasma exchange, intravenous infusion of immunoglobulins, etc.) may be necessary in the acute phase.

[029] The many serious side effects of long-term steroid use mean that it should be avoided. Common side effects are Cushing's syndrome, osteoporosis, weight gain, hyperglycemia, diabetes, hypertension, gastritis or ulcer, skin fragility, anxiety, depression, insomnia (steroid psychosis), avascular necrosis of joints, and myopathy.

Immunomodulatory Treatments

[030] The initial goal in treating progressive MG should be to actively modulate immune system breakdown as quickly as possible. Steroid therapy, plasma exchange, and IV immunoglobulins have been used to induce rapid improvement in myasthenia symptoms because they work within days to 1 or 2 weeks after onset. However, their effects are short-term (usually 1 to 2 months) and other immunosuppressants are usually needed to maintain a state of remission. Infusion of a concentrate of IgGs (a blood product composed of immunoglobulin G from blood donors) has been used to treat many immune deficiencies or autoimmune diseases. It acts on the immune system in a number of ways, including accelerating IgG catabolism, suppressing antibody production, inhibiting complement activation and membrane attack complex formation. The rate of improvement associated with this therapy has been reported to be greater than 70%. Most common adverse effects are mild and are related to the infusion process: headache, chills, myalgia, chest discomfort, or shortness of breath may occur early in the infusion, which are usually relieved by decreasing the infusion rate.

[031] Plasma exchange is an extracorporeal blood purification technique. The basic mechanism is the rapid elimination from plasma of a large number of causative autoantibodies and other humoral mediators, including cytokines and immune complexes. The standard method is to remove 2-3 L of plasma three times a week or every other day for five procedures. The clinical efficacy of plasma exchange ranges from 55% to 100%. In most patients, clinical improvement occurs after two to three procedures and usually lasts for 1 to 2 months.

[032] Thymectomy for MG treatment has been performed widely since Blalock and his colleagues first reported its usefulness in 1939. Although there are no randomized controlled trials, clinical experience has led to general acceptance that thymectomy increases the chances of remission and reduces the long-term risk of immunosuppressant treatment. Thymectomy remains a generally accepted treatment for patients with generalized MG with disease onset before age 50 years. There is disagreement regarding the use of thymectomy in children before puberty. In addition, thymectomy is still not recommended for the treatment of anti-MuSK positive patients, because they do not present pathological thymic alterations. However, there is no solid evidence that thymectomy should be considered first to treat patients with generalized MG, those with a thymic abnormality, or those with onset between the ages of puberty and about 50 years. The rate of complete remission reported after thymectomy ranged from 8.3% to 53.1%.

Antineoplastic Agents

[033] Azathioprine (AZA) is a DNA synthesis inhibitor that inhibits the synthesis of purines (adenosine and guanine). It is a prodrug that is metabolized to various active metabolites. These metabolites compete with the purine derivative hypoxanthine and are incorporated into replicating DNA, thereby blocking DNA and RNA synthesis. AZA primarily affects actively proliferating cells (including lymphocytes) and is therefore used as a major drug in organ transplantation and autoimmune disease. Treatment of MG with AZA is associated with a good outcome, and its effectiveness has been reported to be greater than 75%. Cyclophosphamide (CP), a well-known antineoplastic agent, is a prodrug that is converted to an active metabolite (4-hydroxycyclophosphamide) in the liver. It is one of the classic alkylating agents, adding an alkyl group to the guanine base of DNA, leading to cell death. Remission was seen in 75% who were followed up for more than 18 months. Methotrexate (MTX) is an antimetabolite and antineoplastic that also blocks DNA and RNA synthesis, and has a more potent effect on rapidly dividing cells. MTX is recommended by some experts as a second-line immunosuppressant in patients with drug-resistant MG.

The Immunosuppressants

[034] Cyclosporin A (CyA) and tacrolimus (FK506) are calcineurin inhibitors that bind to cytosolic proteins, cyclophilins (immunophilins), of lymphocytes. Activation of T cell receptors by antigens increases intracellular calcium and induces calcineurin activation. Activated calcineurin plays an important role in the transcription of pro-inflammatory cytokines, including interleukins (IL)-2, IFN-γ or tumor necrosis factor alpha (TNF-α), dephosphorylating the transcription factor, T cell nuclear factor activated. CyA-cyclophilin and FK506 protein complexes block calcineurin, inhibiting T cell activation and proliferation.

[035] Until now, uncontrolled trials of CyA have been performed in patients with severe MG who did not respond to thymectomy, steroids, or AZA. About 80% of recruited patients improved after CyA treatment. CyA administration begins with two divided doses of 4-6 mg/kg/day. A regular check-up of blood urea nitrogen and creatinine levels is important. CyA adverse reactions include gingival hyperplasia, convulsion, nephrotoxicity, hepatotoxicity, peptic ulcer, pancreatitis, among others. The use of FK506 is supported by only a few non-randomized, non-controlled studies. Nine (47%) of 19 patients with generalized MG in an open-label clinical trial exhibited improvement in MG.

[036] Rituximab (RTM) is a chimeric monoclonal antibody against the CD20 antigen on pre-B and mature surface B cells. It was initially used to treat B-cell malignancies such as non-Hodgkin's lymphoma and large B-cell lymphoma, but its use has been expanded to include autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. There have been few small, uncontrolled clinical trials for RTM therapy in patients with refractory MG, but with promising results.

New Therapeutic Assays

[037] Other experimental immunotherapies are being investigated, including adoptive cell gene therapy, genetically modified antigen-presenting cells, syngeneic AChR fragments and drugs linked to complement activation, haematopoietic stem cell halogen transplantation, among others. However, current therapies control almost all of the most severe and life-threatening systemic symptoms in patients with GMG. The treatment of MG must be tailored according to the clinical manifestations or subtypes, functional impairment, clinical status and activities of daily living of individual patients. As mentioned above, in progressive MG it is desirable to block the abnormal immune process as quickly as possible, minimizing adverse reactions to therapy.

• (i) A timectomia pode ser considerada preferencialmente em pacientes com MG generalizada pós-púbere com uma condição médica estável, se o timoma for descoberto na tomografia computadorizada de tórax.
• (ii) O tratamento sintomático com anticolinesterásico pode ser suficiente em pacientes com MGO. Em casos não controlados com quantidades suficientemente grandes de anticolinesterásicos, os esteroides podem ser considerados.
• (iii) Se a resposta aos esteroides estiver incompleta, um imunossupressor de primeira linha pode ser adicionado.

[038] In summary, the experience of the present inventor and also of the literature has standardized some guidelines in the treatment for MG, considering that it can be maintained for years in many cases:

• (i) Thymectomy may be considered preferentially in patients with postpubertal generalized MG with a stable medical condition, if the thymoma is discovered on chest CT.
• (ii) Symptomatic anticholinesterase treatment may be sufficient in patients with MGO. In cases not controlled with sufficiently large amounts of anticholinesterases, steroids may be considered.
• (iii) If the steroid response is incomplete, a first-line immunosuppressant may be added.

The Miotic Eye Drops

[039] Miotics belong to a class of drugs well known in ophthalmology. Pharmacologically, they belong to the category of cholinergics, which have been studied and used for centuries in the eyes of humans. The oldest representative of cholinergics used in medicine is atropine (exceptionally a mydriatic drug, whose function is opposite to miotics). Also called belladonna for its mydriatic and sensual effect in women (middle age), atropine blocks ACh receptors in the motor plate of the sphincter pupillae muscle, thus inhibiting the cholinergic action of the receptor and therefore being a potent eye dilator. Atropine and its mydriatic derivatives also block the ciliary muscles, being used in refractive exams for their cycloplegic action.

• (ii.a) Os inibidores reversíveis (por exemplo, fisiostigmina, neostigmina, edrofonio, rivastigmina, donepezila e piridostigmina) tem tempo de ação entre um e dois dias ativando com maior potência os receptores colinérgicos.
• (ii.b) Os inibidores irreversíveis da acetilcolinesterase são os mióticos mais potentes e com efeitos colaterais mais frequentes. A ação destes colinérgicos podem durar vários dias ou semanas, dependendo da concentração. Como colírio, o mais conhecido representante deste grupo é o iodeto de fosfoline usado como hipotensor ocular ou em estrabismo acomodativo, por décadas.

[040] Separately, miotic cholinergic drugs are categorized into two drug groups:
(i) Cholinergic agonist substances: in this group are found drugs that have an action similar to ACh (but more potent) and that bind to cholinergic receptors, remaining in the active sites of smooth muscles for a longer time, therefore, they have a longer action. potent and prolonged than ACh. Classic examples are pilocarpine and carbachol, with an action period of approximately six hours. ACh, pure, has a very short-lived effect and disappears from the motor endplate of activated muscle in a few minutes.
(ii) Acetylcholinesterase enzyme inhibitors: This group is subdivided into reversible and irreversible inhibitors of the acetylcholinesterase enzyme, which degrades ACh in the motor end plate where the cholinergic receptors of the parasympathetic system are located. They have a longer action time than the previous group.

• (ii.a) Reversible inhibitors (eg physistigmine, neostigmine, edrophonium, rivastigmine, donepezil and pyridostigmine) have an action time of between one and two days, activating cholinergic receptors with greater potency.
• (ii.b) Irreversible acetylcholinesterase inhibitors are the most potent miotics and have the most frequent side effects. The action of these cholinergics can last for several days or weeks, depending on the concentration. As eye drops, the best known representative of this group is phospholine iodide, used as an ocular hypotensor or in accommodative strabismus for decades.

[041] All cholinergic substances, for centuries, have been used in medicine (oral, muscular or intravenous). Specifically, they have been used for over a century in ophthalmology (ocular route) as an ocular hypotensor. In general, they comprise a group of substances that act primarily on the parasympathetic system (partially on the sympathetic nervous system), activating muscarinic cholinergic receptors and mimicking (or potentiating) the action of ACh, causing ocular miosis (a clinical sign that typifies the group as of miotics). Some authors include mydriatic drugs in this group as they bind to the same parasympathetic ACh receptors (motor plate), however blocking them.

• (a) Derivados Ésteres da Acetilcolina: Betanecol, Carbacol e Metacolina;
• (b) Alcaloides: Muscarina e Pilocarpina;

(ii) Drogas de Ação Indireta - Não tem ação direta sobre os receptores colinérgicos, inibindo a enzima que tem o poder de destruir a acetilcolina, portanto, os inibidores da acetilcolinesterase ou anticolinesterásicos. Proporcionam maior tempo de ação da acetilcolina e maior potência que o neurotransmissor natural.[042] Miotic cholinergics can be subdivided into 3 groups:
(i) Direct-acting cholinergic agonists - are drugs that act directly on the acetylcholine receptor, activating it and mimicking (or potentiating) the action of this neurotransmitter:

• (a) Acetylcholine Ester Derivatives: Bethanechol, Carbachol and Methacholine;
• (b) Alkaloids: Muscarine and Pilocarpine;

(ii) Indirect Action Drugs - They have no direct action on cholinergic receptors, inhibiting the enzyme that has the power to destroy acetylcholine, therefore, acetylcholinesterase inhibitors or anticholinesterases. They provide longer action time of acetylcholine and greater potency than the natural neurotransmitter.

[043] Reversible: Edrophonium, Neostigmine, Physiostigmine, Pyridostigmine, Rivastigmine, Donepezil, Galantamine and Memantine.

• (a) Grupo dos similares da Atropina: Homatropina, Tropicamida e Ciclopentolato;
• (b) Grupo da Atropina: Atropina (Beladona), Hioscina (escopolamina) e Pirenzepina.

[044] Irreversible: Malathion, Parathion and Phospholine Iodide.
(iii) Mydriatic cholinergics - These agents block the actions of the parasympathetic system, having ocular activity similar to sympathomimetic drugs, especially in mydriasis and cycloplegia.

• (a) Atropine-like group: Homatropine, Tropicamide and Cyclopentolate;
• (b) Atropine Group: Atropine (Belladonna), Hyoscine (scopolamine) and Pirenzepine.

Corticosteroids in Ophthalmology

[045] Corticosteroids are a class of drugs with anti-inflammatory and immunosuppressive action, being derived from cortisol, which is a substance naturally produced in the adrenal glands. The corticoid, therefore, is a synthetic derivative of this hormone, with the same nucleus, but its structure is modified to enhance its action and function in the body. Also known as corticosteroids, glucocorticoids (GC) and steroidal anti-inflammatory drugs, they are very potent and have the most diverse indications for use. However, they don't just work where the problem is, and they can change the functioning of all human tissues. Its use requires care and medical indication is essential, as well as following the dosage guidelines to the letter and the protocol for withdrawing the drug from the body as well.

[046] Corticosteroids are divided into two classes according to the types of steroid hormones that the adrenal gland produces: glucocorticoids and mineralocorticoids. Glucocorticoid (often synonymous with corticosteroid) is the most important cortisol in the human body and is also naturally produced, being responsible for regulating and sustaining various actions of the body, such as metabolic, cardiovascular, immunological and homeostatic functions. It is in this class of corticosteroids that the drugs used as immunosuppressants and anti-inflammatory drugs are concentrated, being, therefore, of great importance for the treatment of autoimmune diseases, such as Lupus and MG. The class of mineralocorticoids are part of the second class of steroid hormones, they will not be used in the present invention.

• (i) Ação curta: cortisona, hidrocortisona (suprimem o ACTH por 8 a 12 horas).
• (ii) Ação média: prednisona, prednisolona, metilprednisolona e triancinolona (suprimem o ACTH por 12 a 36 horas).
• (iii) Ação longa: dexametasona e betametasona (suprimem ACTH por 36 a 72 horas).

[047] Corticosteroids are available in the most different dosage forms and recommendations for use. It can be found in oral medications (tablets and syrups), in an injectable form, as eye drops, for topical use (ointments and creams) and even inhalation. Over the decades, this medication, which is quite old, has been improved, new molecules have been created and their side effects more documented, causing companies to include other drugs in their formulations that help to combat them or prevent them from becoming infected. aggravate. As for the duration of action, they are classified as short, medium or long acting, according to the time of ACTH suppression after a single dose equivalent to 50 mg of prednisone. The relative potency of GCs depends on their affinity for the plasma receptor:

• (i) Short acting: cortisone, hydrocortisone (suppress ACTH for 8 to 12 hours).
• (ii) Medium action: prednisone, prednisolone, methylprednisolone and triamcinolone (suppress ACTH for 12 to 36 hours).
• (iii) Long acting: dexamethasone and betamethasone (suppress ACTH for 36 to 72 hours).

[048] In ophthalmic formulations (eye drops and ointments) they are used to treat conjunctivitis, irritation, eye redness, uveitis, among others. In the most severe cases of intra and extraocular inflammation, corticosteroids are used systemically (orally or intravenously). The commercially available forms are dexamethasone, betamethasone and prednisolone; weaker corticosteroids such as fluomethalone have limited value but fewer side effects. The main undesirable effect of the different types of topical ocular corticosteroids is ocular hypertension. Other side effects found are related to changes in the tear film, with dry eye and lower resistance to microbial infections. It is important to note that cataracts only occur when using corticosteroids systemically. Cataracts are not described by the topical use of these drugs.

Immunosuppressants in Ophthalmology

[049] Ocular inflammation is a significant cause of ocular morbidity and visual impairment. MGO, despite reaching only extraocular structures (in most cases) should be treated as if it were part of this group of pathologies. Topical, periocular, intraocular, and systemic corticosteroids are highly effective in treating appropriate forms of ocular inflammation. However, its use may be limited by local and systemic side effects, especially if long-term therapy is required. As a result, immunosuppressive agents have increasingly been used to control ocular inflammation alongside or in place of corticosteroids.

• (i) Antimetabólitos (primariamente metotrexato, micofenolato mofetil (MMF) e azatioprina).
• (ii) Inibidores de células T (geralmente ciclosporina, menos frequentemente tacrolimus ou sirolimus).
• (iii) Agentes alquilantes (ciclofosfamida e clorambucil).
• (iv) Agentes biológicos (inibidores do fator de necrose tumoral (TNF), inibidores de linfócitos e inibidores de interleucinas). Os principais objetivos da terapia imunossupressora são (1) controlar a inflamação quando os corticosteroides não o fazem; (2) para prevenir a toxicidade induzida por corticosteroides quando a dosagem necessária de corticosteroides excede o nível desejado ou seguro; e (3) para tratar síndromes específicas de uveite de alto risco conhecidas por responderem mal aos corticosteroides isoladamente.

[050] The four categories of agents used in ophthalmology today are:

• (i) Antimetabolites (primarily methotrexate, mycophenolate mofetil (MMF) and azathioprine).
• (ii) T cell inhibitors (usually cyclosporine, less often tacrolimus or sirolimus).
• (iii) Alkylating agents (cyclophosphamide and chlorambucil).
• (iv) Biological agents (tumor necrosis factor (TNF) inhibitors, lymphocyte inhibitors and interleukin inhibitors). The main goals of immunosuppressive therapy are (1) to control inflammation when corticosteroids do not; (2) to prevent corticosteroid-induced toxicity when the required dosage of corticosteroids exceeds the desired or safe level; and (3) to treat specific high-risk uveitis syndromes known to respond poorly to corticosteroids alone.

[051] Growing evidence shows the effectiveness of immunosuppressive drugs in achieving these goals, as well as improving visual function, preventing ocular complications, and in some cases even disease remission. However, among all medications for systemic use for eye diseases, immunosuppressants are the ones with the greatest risks, such as a predisposition to systemic infections and tumors in general. These factors greatly limit the use of these drugs only to severe inflammation, which requires treatment for short periods.

[052] The exception, that we currently find these considerations, is related to the dry eye condition. Specifically in this ocular syndrome, immunosuppressants are used in the form of topical eye drops in daily divided doses for treatment. Therefore, for decades, immunosuppressants in drops have been used in ophthalmology (cyclosporine, tacrolimus, among others), which has brought great knowledge to professionals in the area of this group of drugs.

Systemic Drugs in Ophthalmic Drops

[053] As explained in the previous paragraphs, there is a wide variety of chemical compounds that are used both in systemic administration routes and their respective representatives in the form of eye drops and ointments for topical use in ophthalmology. Taking this idea as the basis of the present invention, in addition to all the technical and scientific considerations presented so far, the present inventor started to consider the possibility of using systemic anticholinesterases (already used in MGO for almost a century) to treat ocular symptoms. in the various forms of myasthenia, as a new and exceptional use of these drugs.

[054] In addition, other drugs (which are also commonly used in MGO) used systemically (but which already have the same combinations in the topical ocular form), could be co-administered with anticholinesterases for the treatment of MGO.

Quaternary ammonium compounds

[055] Quaternary ammonium compounds are a family of antimicrobial compounds of strong cationic active agents, and possess powerful disinfecting activity for both gram-positive and gram-negative bacteria (although the latter, to a lesser extent). They are substances that can be used as disinfectant actives in various applications such as common disinfectants, fungicides, viruscides, germicides, bactericides, bacteriostatics and fungi and mold control agents. In addition, quaternary ammonium compounds can be used as microbicides for use in paper and cardboard manufacturing, algaecides for use in swimming pools or recirculating water cooling towers, and incorporated as preservatives in several segments. One of its most used representatives in the pharmaceutical industry, mainly as a preservative for eye drops, is benzalkonium chloride (BAK).

[056] It is known that some anticholinesterase drugs belong to this same group of quaternary ammonium compounds, such as neostigmine and edrophonium chloride. The present inventor has disclosed that anticholinesterase drugs can be used properly as preservatives at various concentrations, without altering the pharmacological activities described and claimed in the present invention. That is, it is possible to use them alone in industrial bottles without any other preservative, or even use them in active chemical compounds in the treatment of myasthenia, supporting another drug with the same objective, with minimal side effects.

The Prostaglandins

[057] Prostaglandins (PGs) comprise a group of physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Pgs are found in almost all human tissues. They are enzymatically derived from arachidonic acid (fatty acid), being a subclass of eicosanoids and the prostanoid class of fatty acid derivatives. Structural differences between PGs are responsible for their different biological activities. A given PG can have different and even opposite effects on different tissues in some cases. The ability of the same prostaglandin to stimulate a reaction in one tissue and inhibit the same reaction in another tissue is determined by the type of receptor to which PG binds. They act as autocrine or paracrine factors with their target cells present in the immediate vicinity of the site of their secretion. Prostaglandins differ from endocrine hormones in that they are not produced in one specific location, but in many locations in the human body.

[058] The synthesis of PGs involves the metabolism of arachidonic acid by cyclooxygenase enzymes to a PG intermediate. Specific PG synthases convert this PG intermediate into the primary PG molecules (PGE 2, PGF2α, PGI 2, and PGD 2). Once produced, PGs are secreted and mediate signaling through G protein-coupled receptors, which are distinct for each PG. Activation of PG receptors leads to a range of effects on a variety of cell and tissue types, including skeletal muscle. Specifically, the main action of PGF2α in the skeletal muscle cell cytosol is the increase in intracellular calcium, probably through the modulation of K channels. This is the most important mechanism in muscle contraction triggered by PGs.

[059] PGs have also been implicated in skeletal muscle growth. Different PGs can control myoblast proliferation, differentiation and fusion. Once myotubules are formed, muscle cell size continues to increase through increased protein synthesis. PGs regulate this growth stage by altering protein degradation and protein synthesis in myotubules. Consistent with a general role for PGs in skeletal muscle growth, inhibition of PG production blocks myofibril growth in vivo. These data suggest that PGs regulate muscle cell growth by influencing multiple steps of myogenesis.

Prostaglandins in Ophthalmology

[060] Launched on the market in the late 1990s, the PG group is considered the most effective among ocular hypotensives and its side effects are already well established in the medical literature. More than 30 years after the initial studies on PGs, PGF2α is the most used drug in the treatment of glaucoma in recent years. However, their mechanism of action is still somewhat unknown, although it is assumed that PGs improve aqueous drainage via the suprachoroid, by facilitating the transport of fluid through the ciliary muscle fibers. Thus, the smooth muscle relaxation action of PGF2α, which are the intraocular muscles, is well known. However, there are no reports on the activity of PGs in EOMs.

[061] According to the present inventor, PGF2α would not cause such an accentuated contraction in the EOMs as that which occurs among other extrinsic body muscles, but it may alter the influx of calcium in the EOMs, potentiating the action of ACh in the motor plates of these muscles. In addition, the continuous use of these drugs in MG could recover part of the musculature that has become atrophic by the disease. In previous tests, the present inventor found an improvement in eyelid ptosis and diplopia in myasthenic patients, after the introduction of PGF2α as an adjuvant drug in the treatment of MG.

[062] Currently, prostraglandin eye drops are used with a dosage of one drop daily, as they have a half-life of 24 hours, similar to anticholinesterases, thus facilitating their joint formulation. As an eye prescription, in this category of PGs (PGF2α), the best known eye drops are latanoprost, bimataprost, travaprost and unoprostone.

STATUS OF THE TECHNIQUE

[063] Some prior art documents describe options for the treatment of Ocular Myasthenia Gravis using some drugs alone or in combination, for example:

[064] The document entitled "THE USE OF ANTI-CHOLINESTERASICS USED IN MYASTHENIA GRAVIS" focuses on the study of current therapeutic measures related to the cholinergic system that are employed in Myasthenia Gravis. Neostigmine and pyridostigmine are used by patients and, in parallel with these drugs, the use of glucocorticoids is common, resulting in better results. Although the route of administration is different, the document also informs that several treatments were performed in which both drugs were administered. This scientific text that indicates the forms of systemic treatment of Myasthenia Gravis. Although these treatments use the same drugs described in the present invention, they are administered by systemic routes, that is, it meets the objectives of this invention, mainly by reducing the toxic effects of drugs in high concentration, which should be replaced by local instillations of these drugs. substances (in much lower concentrations).

[065] The document "METHODS FOR TREATMENT OF REFRACTORY GENERALIZED MYASTHENIA GRAVIS" aims to evaluate immunosuppressive therapies (STIs) the current standard of care, which usually combines cholinesterase inhibitors, corticosteroids and immunosuppressive drugs (most commonly azathioprine [AZA], cyclosporine and mycophenolate mofetil [MMF]), most individuals with MG have their disease reasonably well controlled.

[066] The document "OCULAR NEOSTIGMINE DROPS FOR DIAGNOSING MYASTHENIA GRAVIS" presents an eye drop used in cases of Myasthenia Gravis, which contains acetylcholinesterase inhibitors as the active ingredient. However, this document only uses an anticholinesterase alone (neostigmine) for the diagnosis of Myasthenia Gravis. At no time is it mentioned as a treatment for the pathology, nor in association with other medications.

[067] Therefore, given the state of the art, the present invention unexpectedly proposes the use of miotic anticholinesterase substances (alone) or in combination with corticosteroids, for the preparation of a drug compound for the treatment of Myasthenia Gravis.

SUMMARY OF THE INVENTION

[068] The present invention aims to propose a new and unprecedented use of anticholinesterase drugs alone, or in association with corticosteroids, for the preparation of a formulation in eye drops for topical use, which will be applied in the treatment of Ocular Myasthenia Gravis. The novel therapeutic application of this composition is revealed through a mechanism of action in which the traditional ocular parasympathetic system is activated, local infiltration of drugs, or indirect activation of cholinergic receptors of extrinsic ocular muscles (including the levator palpebrae muscle) via the ciliary ganglion. (oculomotor nerve).

DETAILED DESCRIPTION OF THE INVENTION

[069] The present invention relates to the use of anticholinesterase miotic substances (alone) or in combination with corticosteroids. Said use makes it possible to treat Myasthenia Gravis.

[070] The anticholinesterase drugs of the present invention can be selected from the group consisting of: neostigmine, pyridostigmine, physistigmine and edrophonium chloride, however, not limited exclusively to these.

[071] These drugs have a concentration ranging from 0.0001% to 4.0%. They can be used alone or in combination with topical or systemic anti-inflammatory drugs, such as corticosteroids and/or immunosuppressants. It is important to reaffirm that the anticholinesterases mentioned in the present invention (alone) also have anti-inflationary action.

[072] Corticosteroid drugs are selected from the group consisting of, but not limited to, dexamethasone, fluomethalone, and hydrocortisone.

[073] Immunosuppressive agents are selected from the group consisting of tacrolimus, cyclosporine, everolimus, sirolimus, but not limited to these.

[074] Additionally, it is noteworthy that anticholinesterase drugs (some used in the present invention are quaternary ammoniums - neostigmine and edrophonium chloride) and, therefore, have microbicidal action, and can be administered without the need for the use of preservatives, reducing the presence of adverse reactions such as pruritus, ocular dryness and hyperemia.

[075] According to updated data, anticholinesterase drugs are active on the ocular immune system and therefore could additionally act as immunomodulators in the treatment of myasthenia gravis.

Location and Action Mechanism

[076] The new therapeutic application is revealed through the mechanism of action in which the parasympathetic system (traditional and nitrergic) is activated. The mechanism occurs through the direct action of these substances on the motor plate of the levator palpebrae muscle and extrinsic ocular muscles, responsible for the ocular changes found in this pathology. Thus, anticholinesterase drugs act on the synaptic cleft of the extrinsic ocular muscles (including the levator palpebrae muscle).

[077] The present invention also provides a method of treating Ocular Myasthenia Gravis, in which anticholinesterase drugs are administered topically in the form of eye drops, with application of 1 to 10 drops, from 12 to 12 hours to 48 to 48 hours in each eye.

[078] In one embodiment, the present invention further provides a method of treatment in which anticholinesterase drugs are administered topically in the form of eye drops or in combination with topical or systemic anti-inflammatory drugs, such as corticosteroids and/or immunosuppressants.

Advantages of the Invention

• - Baixa liposolubilidade de alguns anticolinesterásicos utilizados na presente invenção, que não atravessam o tecido corneano para o interior do globo ocular, diminuindo os efeitos colaterais intraoculares, como catarata e descolamento de retina. Também é uma contrapartida importante, em relação aos mesmos fármacos de uso sistêmico, pela pouca penetração destes em tecidos oculares avasculares.
• - O tempo de ação prolongada dos anticolinesterásicos tópicos (meia vida por volta de 24 horas) apresenta uma vantagem adicional sobre essas drogas via sistêmica, que têm pouca penetração nos tecidos orbitários e são rapidamente metabolizados pelos tecidos oculares, exigindo a administração sistêmica em várias doses diárias.
• - Ação rápida após administração e distribuição dos fármacos por todos os tecidos oculares, auxiliada pela ação das pálpebras, no reflexo de piscar. Permite o uso de baixas concentrações dos fármacos aplicados localmente, sendo observados menores efeitos colaterais sistêmicos e locais.
• - Ação adicional anti-inflamatória potencializada pela combinação (anticolinesterásicos e corticoides), já que os anticolinesterásicos são considerados atualmente como imunomoduladores.
• - Ação microbicida dos anticolinesterásicos isoladamente (amônios quaternários), dispensando o uso de conservantes.

[079] Among the advantages of using anticholinesterase drugs directly on the corneal surface, we can mention:

• - Low lipid solubility of some anticholinesterases used in the present invention, which do not cross the corneal tissue into the eyeball, reducing intraocular side effects, such as cataracts and retinal detachment. It is also an important counterpart, in relation to the same drugs for systemic use, due to their low penetration in avascular ocular tissues.
• - The prolonged duration of action of topical anticholinesterases (half-life around 24 hours) has an additional advantage over these drugs via the systemic route, which have little penetration into orbital tissues and are rapidly metabolized by ocular tissues, requiring systemic administration in several doses. daily.
• - Rapid action after administration and distribution of drugs to all ocular tissues, aided by the action of the eyelids on the blink reflex. It allows the use of low concentrations of drugs applied locally, with fewer systemic and local side effects being observed.
• - Additional anti-inflammatory action potentiated by the combination (anticholinesterases and corticosteroids), since anticholinesterases are currently considered as immunomodulators.
• - Microbicidal action of anticholinesterases alone (quaternary ammonium), dispensing with the use of preservatives.

[080] Although the invention has been widely described, it is obvious to those skilled in the art that various changes and modifications can be made to improve the design, without said changes not being covered by the scope of the invention.

BIBLIOGRAPHIC REFERENCES

[081] Liu GT, Volpe NJ, Galetta SL. NeuroOphthalmology. Diagnosis and management. Sanders-Elsevier 2010: 471-79.

[082] Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: Past, present, and future. J Clin Invest. 2006; 116:2843-54.

[083] Al-Haidar M. Benatar M, Kaminski HJ. Ocular Myasthenia. Neurol Clin 2018; 36: 241-51.

[084] Luchanok U, Kaminski HJ. Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 2008; 21:8-15.

[085] Kawashima K, Fujii T, Moriwaki Y, Misawa H, Horiguchi K: Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs. Int Immunopharmacol. 2015;29(1):127-34.

Claims (9)

Use of anticholinesterase substances, characterized by the fact that it is for the preparation of a medication, mainly eye drops for topical use, for the treatment of Myasthenia Gravis. Use according to claim 1, characterized in that it is optionally combined with corticosteroids. Use according to claim 1, characterized in that the anticholinesterase substances are selected from the group consisting preferably of neostigmine, pyridostigmine, physistigmine and edrophonium chloride. Use according to claim 2, characterized in that the corticosteroids are selected from the group consisting mainly of dexamethasone, fluomethalone and hydrocortisone. Use according to any one of claims 1 to 4, characterized in that the substances have a concentration ranging from 0.0001% to 4.0% alone or in combination with topical or systemic anti-inflammatory drugs, such as corticosteroids and/or immunosuppressive agents. Use according to claim 5, characterized in that the immunosuppressive agents are selected from the group consisting mainly of tacrolimus, cyclosporine, everolimus and sirolimus. Use according to claim 1, characterized in that they act through the activation of the traditional local parasympathetic and nitrergic system, acting directly on the synaptic cleft of the extrinsic ocular muscles (including the levator palpebrae muscle), or indirectly via the ciliary ganglion and oculomotor nerve. Use according to claim 1, characterized in that the anticholinesterase substances are administered topically in the form of eye drops, with application of 1 to 10 drops, from 12 to 12 hours to 48 to 48 hours in each eye. Use according to claim 8, characterized in that the anticholinesterase substances are optionally administered in combination with topical or systemic anti-inflammatory drugs, such as corticosteroids and/or immunosuppressants.