Invented by Julie Taylor, Theodore A. Yednock, Biogen MA Inc
Mental health disorders are a growing concern in today’s society. According to the World Health Organization, one in four people in the world will be affected by mental or neurological disorders at some point in their lives. This has led to an increase in the demand for mental health services, including the need for administration agents who can help in the treatment of these disorders.
Administration agents are professionals who work in mental health clinics, hospitals, and private practices. They are responsible for managing the administrative tasks associated with the treatment of mental health disorders. This includes scheduling appointments, managing patient records, and coordinating with other healthcare professionals involved in the patient’s care.
The market for administration agents in the treatment of mental health disorders is growing rapidly. This is due to the increasing demand for mental health services and the need for more efficient and effective administration of these services. The market is expected to continue to grow in the coming years as more people seek treatment for mental health disorders.
One of the main factors driving the growth of the market for administration agents is the increasing awareness of mental health issues. More people are becoming aware of the importance of mental health and are seeking treatment for a variety of disorders, including anxiety, depression, and bipolar disorder. This has led to an increase in the number of mental health clinics and private practices, which in turn has created a need for more administration agents.
Another factor driving the growth of the market is the increasing use of technology in mental health treatment. Many mental health clinics and private practices are now using electronic health records (EHRs) to manage patient records and coordinate care. This has created a need for administration agents who are skilled in the use of EHRs and other technology tools.
The market for administration agents in the treatment of mental health disorders is also being driven by changes in healthcare policy. The Affordable Care Act (ACA) has expanded access to mental health services for millions of Americans, which has increased the demand for mental health professionals, including administration agents.
In conclusion, the market for administration agents in the treatment of mental health disorders is growing rapidly. This is due to the increasing demand for mental health services, the need for more efficient and effective administration of these services, and changes in healthcare policy. As the market continues to grow, it is important for mental health clinics, hospitals, and private practices to invest in the training and development of administration agents to ensure that they are able to provide high-quality care to patients with mental health disorders.
The Biogen MA Inc invention works as follows
A method for chronically reducing the pathological inflammation of a patient is disclosed. The agent used must bind to an alpha-4 dimer or an alpha-4-integrin. The agent must have sufficient binding affinity to suppress pathological swelling, and it is administered in a chronic manner to achieve long-term suppression.
Background for Administration agents for the treatment
Inflammation” is the response of vascularized tissue to injury or infection. It is caused by the adhesion of the leukocytes on the endothelial cell of the blood vessel and their infiltration of the surrounding tissues. In normal inflammation the leukocytes infiltrating the tissue release toxic mediators that kill the invading organisms. They also phagocytize dead cells and debris, and they play a part in the repair of tissues and the immune system. In pathological inflammation, leukocytes infiltrating the tissue are hyper-responsive, and can lead to serious or even fatal damage. See, e.g., Hickey, Psychoneuroimmunology II (Academic Press 1990).
The integrins family is a group of glycoproteins on the cell surface that are involved in adhesion, immune cell movement and activation. The alpha-4 integrin, expressed by all leukocytes (except neutrophils), forms heterodimeric receptors with either beta1 or beta7 subunits. Both alpha-4 Beta-1 (?4??1) and alpha-4 Beta-7 (?4??7) dimers contribute to the activation of cells and their survival in the parenchyma. 151: 2368-79; Koopman et al., 1994 J. Immunol. Leussink, et. al. 2002 Acta Neuropathol. 103:131-136).
Specifically, alpha-4 Beta-1 (also called very late antigen-4, VLA-4), binds to the vascular cell adhesion molecules-1 (VCAM-1(Lobb and al., 19941 J. Clin. Invest. 94:1722-8), is expressed by vascular endothelium in many areas of chronic inflammation. Rev. Immunol. Immunol. Immunol. 144:723-35). The alpha-4-beta-7 dimer interacts mucosal adhesion molecule MAdCAM-1 and mediates the homing of Lymphocytes to gut (Farstad, et al. 1997 Am. J. Pathol. 150: 187-99; and Issekutz et al., 1991 J. Immunol. 147: 4178-84). The expression of MAdCAM-1 is also higher at the sites of inflammation within the intestinal tract in patients with IBD (Briskin and al., 1997). J. Pathol. 151: 97-110).
Adhesion molecule such as alpha-4 Integrins are possible targets for therapeutic agents.” Alpha-4 integrin, a subunit of the VLA-4, which is also a receptor, is one of many targets because it interacts with a ligand on brain endothelial cell. Brain inflammation can have severe effects on diseases and conditions. “Also, the alpha-4-beta-7 integrin dimer plays a key role in lymphocyte homing as well as pathological inflammation of the gastrointestinal system.
Alpha-4 Beta-1 Integrin is expressed on extracellular surfaces of activated monocytes and lymphocytes. These cells have been implicated as a pathogen in the development of acute inflammatory lesions of the brain and the blood-brain barrier breakdown (BBB) associated with Multiple Sclerosis (MS).” (Coles et.al., 1999 Ann. Neurol. 46(3): 296-304). In vitro and in vivo, agents against alpha-4-integrin were tested in animal models for their antiinflammatory potential. See Yednock et al., 1992 Nature 356: 63-66; U.S. Pat. No. No. On Nov. 24, 1998 and U.S. Pat. No. Thorsett et al. received No. 6,001,809 on Dec. 14, 1999. On Dec. 14, 1998. In vitro experiments show that alpha-4-integrin antibodies prevent lymphocytes from attaching to brain endothelial cell. Animals with an artificially-induced condition that mimics multiple sclerosis (experimental autoimmune encephalomyelitis, EAE) were tested to see if alpha-4 antibodies would prevent inflammation and paralysis. These experiments collectively identify anti-alpha-4 antibodies as potential therapeutic agents to treat multiple sclerosis, and other inflammatory disorders and diseases.
The Crohn’s Disease (CD) is another example of pathological inflammation that involves alpha-4-integrins. It is a chronic and incurable transmural intestinal inflammation. The disease is marked by abnormal immune cell migration in the mucosa of the intestine, involving macrophages, neutrophils, and T cells (Schreiber, et. al., Gastroenterology, 101, 1020-30, 1991). The first-line treatment for Crohn’s is 5-aminosalicylates (5-5-ASAs), but these have a low level of efficacy. Corticosteroids also have a variety of short- and longer-term side-effects (Munkholm et. al., 1994, Gut 35: 360-2). Immunosuppressive drugs such as 6-mercaptopurine and methotrexate are used to treat patients who have failed first-line therapy. However, these drugs can cause serious side effects and have a long-term effect. Clin. North Am. 81: 71-101, viii). Recent advances in biologics with faster onsets of action for the treatment of Crohn’s have also been made. However, these agents face similar issues, such as side effects and long-term efficacy.
The present invention provides a method of chronically reducing inflammation in a person via the chronic administration an agent that selectively bonds to alpha-4. The chronic dosage regimen of an alpha-4 drug is designed so that (1) it binds specifically to alpha-4 or an integrin dimer containing alpha-4, and (2) it is repeated to maintain alpha-4 receptor saturation to a level sufficient to suppress pathological inflammatory. The invention’s agent can suppress inflammation by binding to and inhibiting all integrin dimers that contain the alpha-4 subunit or it can bind to one dimer in particular, such as alpha-4 beta-1.
In one embodiment, the efficacy a chronic dose regime can be measured by measuring the saturation of a particular integrin dimer. In one example, alpha-4-beta-1 integrin dimer may be involved in multiples sclerosis. The saturation level required for a chronic administration regimen that is effective can therefore be determined by measuring the saturation of alpha-4-beta-1 dimer receptor.
In another embodiment, when multiple integrin dimers may be involved in the pathological inflammation, a combination dimer receptors could be measured to assess the efficacy a chronic administration regimen. In one example, it is believed that both alpha-4-beta-1 and alpha-4-beta-7 dimers play a role in the pathological inflammation of inflammatory bowel diseases. The measurement of alpha-4 Beta-1 and alpha-4 Beta-7 saturation levels can be useful in determining the effectiveness of a chronic administration regime.
In one embodiment, a physiological marker for the pathological inflammation can be used to determine the success of a long-term dosage regimen. In a chronic dose regime for MS, the effectiveness of the dosage regimen can be determined by detecting the level of brain lesions with an imaging technique. Magnetic resonance imaging (MRI) is one example. The success of a dosage regimen for chronic CD can also be determined by detecting the serum C-reactive proteins in the patient. Another example is that the dosage regime’s success can be measured by a group of wellness criteria, such as a reduction in CDAI for a CD patient.
Another embodiment of the invention contemplates treating an inflammatory disorder of the gastrointestinal system (e.g. Crohn’s Disease, ulcerative colitis, and inflammatory bowel diseases) in a subject by administering a therapeutically-effective amount of a formulation comprising natalizumab, sufficient to treat or alleviate said inflammatory condition of the gastrointestinal system in said subject.
In a specific embodiment of the invention, a dosage regimen is provided wherein repeated administrations of an agent are provided to achieve a level alpha-4 receptor saturation of 65-100% within a patient. This provides chronic suppression of the pathological inflammation within the patient. In another embodiment, the agent will be repeatedly administered in order to achieve levels of about 75-100%. In a further specific embodiment, the drug is repeatedly administered in order to achieve levels of about 80-100%.
A feature is that the unwanted effects of pathological inflammation in a patient can be suppressed over a long period, such as six months, a year, or two years.
The invention consists of a method that maintains sufficient levels of anti-alpha-4 Integrin agents over long periods of time to suppress pathological inflammation during those periods.
The dosage form is designed to provide lower levels of inflammation pathological over a longer period of time as compared with a single dose.
The invention has the advantage that the agents used are low-toxic and well tolerated.
The following description of the formulations and methods will help those who are familiar with the subject to understand the other advantages and features of this invention.
BRIEF DESCRIPTIONS ABOUT THE DRAWINGS
FIG. The percentage of active scans is shown in Figure 2. Active scans include those that contain one or more Gd-enhancing lesions.
FIGS. In an MS study, Figures 3A-C and 4-A-C depict the serum concentrations after the time points of the dosage regimen. FIGS. FIGS. The levels of the 6-mg/kg studies are shown in Figures 4A-C.
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