13th June 2004
WHAT ARE THE INVESTIGATIVE DRUGS FOR MULTIPLE SCLEROSIS?
Immunosuppressants
Many drugs being investigated for chronic progressive multiple sclerosis are immunosuppressants, which block certain factors in the immune system that contribute to the inflammatory process. Each of these drugs can produce serious side effects, including susceptibility to infection and many others. Evidence on their benefits is uncertain, mainly because of study limitations. Still, they may help some patients with severe MS. Among immunosuppressant agents or procedures that have been investigated with little or no obvious benefits or unacceptably high side effects are total lymphoid irradiation, sulfasalazine, cyclosporine, acyclovir, and oral bovine myelin.
Mitoxantrone. Mitoxantrone (Novantron) has been approved for secondary progressive MS. Two studies suggested that it may be of some help in reducing progression and relapse rates. Cumulative doses can have toxic effects on the heart, however, and so the drug is only used for a limited period.
Methotrexate. In some patients, low doses of the immunosuppressant methotrexate may slow the course of chronic-progressive MS, particularly in those with secondary progressive MS. To date, studies have found beneficial effects only on the upper body, however. Although this drug, like all immunosuppressants, can have toxic side effects, it may be taken in low doses for MS and so side effects are generally minimal.
Azathioprine. Azathioprine (Imuran) is designed to suppress the immune system and reduce the number of cells attacking the CNS myelin. It is used with or without steroids and is sometimes used as an alternative to patients with relapsing-remitting MS who do not respond to either interferon beta or glatiramer acetate. One study reported that 40% of patients had not experienced a relapse after taking the drug for three years, although others report only modest benefits. The drug has no effect on progression of disability.
Cyclophosphamide. Cyclophosphamide (Cytoxan) blocks cell growth and also suppresses the immune system. Some studies, but not all, have reported benefits for patients with chronic progressive MS. Two small 2001 studies suggested that monthly intravenous administration or a combination with interferon-beta may help some patients with rapidly deteriorating MS. Cyclophosphamide has many side effects, including hair loss, nausea, vomiting, infertility, lung scarring, and blood abnormalities, and should be used for patients who do not respond to methotrexate.
Cladribine. Cladribine (Leustatin) may be effective in delaying progression in patients with chronic progressive MS. It has no significant effect on relapsing-remitting MS.
Experimental Agents
Monoclonal Antibodies. Monoclonal antibodies are specially designed antibodies directed against a specific substance. They are being developed to target immune factors thought to be responsible for MS. Early studies on one of the monoclonal antibodies, natalizumab (Antegren), have reported fewer relapses and fewer new lesions on MRI scans in patients. At six months there were no changes in disability. Common side effects include headache and stomach pain.
Aminopyridines. Aminopyridines are potassium-blocking compounds that appear to improve nerve conduction through demyelinated areas. In small, preliminary trials, 4-aminopyridine, or AP, has been associated with mild to marked improvement in vision, strength, and coordination and was well tolerated. Beneficial effects, however, lasted only a few hours. A related compound, 3,4-diaminopyridine, or DAP, has also produced temporary improvements in nerve conduction without harmful side effects, even when taken for several weeks. One study comparing the two drugs, however, found that AP was superior in improving walking, fatigue, and overall function. Side effects of AP are more apt to include dizziness and confusion. DAP may cause abdominal pain, numbness, or tingling. Overdose can occur at relatively low doses in both drugs and may cause epileptic seizures.
Cannabis. Cannabis, the source of marijuana, has been found to improve tremor and spasticity in animal studies. In one study of MS patients, a third reported improvements in pain, spasms, tremor, mood, appetite, fatigue, vision, sexual and urinary function, and memory. Cannabis may, however, worsen balance and posture in patients with spasticity due to MS. Four studies of cannabis used in capsules or in an oral spray are currently underway in England.
Plasmapheresis. Plasmapheresis with plasma exchange is a procedure in which blood is removed from the body. Blood cells are separated from plasma (the liquid portion of blood) and mixed with replacement plasma, which is then returned to the body. The replacement plasma is thought to dilute antibodies and other immunologically active substances that may trigger MS. Small investigative studies are suggesting this procedure may have significant benefits for certain patients with severe MS, particularly if they are younger and have any early response to this treatment. Side effects include risk of infection and blood clotting problems.
Oligodendrocyte Implants. A newly developed, minimally invasive method to transplant modified oligodendrocyte cells directly into the brain is under investigation. Such cells stimulate nerve and axon growth. In one 2000 study, 75% of patients treated with the new therapy improved significantly compared with 34% who received non-modified cells. The new procedure was particularly effective in restoring visual acuity. About 40% of patients experienced a gradual return of disabilities after five years.
Paclitaxel. Paclitaxel is derived from the Pacific yew tree and is the active ingredient in Taxol, a leading ovarian and breast cancer drug. It also may act as an immunosuppressant, preventing white blood cells from damaging myelin. A small, preliminary 1999 study found that paclitaxel benefited patients with advanced MS. It is used in lower doses for MS patients than for cancer patients and so side effects, such as hair loss or nausea, do not occur or are not as severe. Further research is needed.
Stem Cell Transplantation. Some investigators are studying the benefits of stem-cell transplantation procedures. Stem cells are produced in the bone marrow and are the early forms for all blood cells in the body (including red, white, and immune cells). Early studies indicate that it may slow progression, although at this point it is not a cure.
Immunosuppressants
Many drugs being investigated for chronic progressive multiple sclerosis are immunosuppressants, which block certain factors in the immune system that contribute to the inflammatory process. Each of these drugs can produce serious side effects, including susceptibility to infection and many others. Evidence on their benefits is uncertain, mainly because of study limitations. Still, they may help some patients with severe MS. Among immunosuppressant agents or procedures that have been investigated with little or no obvious benefits or unacceptably high side effects are total lymphoid irradiation, sulfasalazine, cyclosporine, acyclovir, and oral bovine myelin.
Mitoxantrone. Mitoxantrone (Novantron) has been approved for secondary progressive MS. Two studies suggested that it may be of some help in reducing progression and relapse rates. Cumulative doses can have toxic effects on the heart, however, and so the drug is only used for a limited period.
Methotrexate. In some patients, low doses of the immunosuppressant methotrexate may slow the course of chronic-progressive MS, particularly in those with secondary progressive MS. To date, studies have found beneficial effects only on the upper body, however. Although this drug, like all immunosuppressants, can have toxic side effects, it may be taken in low doses for MS and so side effects are generally minimal.
Azathioprine. Azathioprine (Imuran) is designed to suppress the immune system and reduce the number of cells attacking the CNS myelin. It is used with or without steroids and is sometimes used as an alternative to patients with relapsing-remitting MS who do not respond to either interferon beta or glatiramer acetate. One study reported that 40% of patients had not experienced a relapse after taking the drug for three years, although others report only modest benefits. The drug has no effect on progression of disability.
Cyclophosphamide. Cyclophosphamide (Cytoxan) blocks cell growth and also suppresses the immune system. Some studies, but not all, have reported benefits for patients with chronic progressive MS. Two small 2001 studies suggested that monthly intravenous administration or a combination with interferon-beta may help some patients with rapidly deteriorating MS. Cyclophosphamide has many side effects, including hair loss, nausea, vomiting, infertility, lung scarring, and blood abnormalities, and should be used for patients who do not respond to methotrexate.
Cladribine. Cladribine (Leustatin) may be effective in delaying progression in patients with chronic progressive MS. It has no significant effect on relapsing-remitting MS.
Experimental Agents
Monoclonal Antibodies. Monoclonal antibodies are specially designed antibodies directed against a specific substance. They are being developed to target immune factors thought to be responsible for MS. Early studies on one of the monoclonal antibodies, natalizumab (Antegren), have reported fewer relapses and fewer new lesions on MRI scans in patients. At six months there were no changes in disability. Common side effects include headache and stomach pain.
Aminopyridines. Aminopyridines are potassium-blocking compounds that appear to improve nerve conduction through demyelinated areas. In small, preliminary trials, 4-aminopyridine, or AP, has been associated with mild to marked improvement in vision, strength, and coordination and was well tolerated. Beneficial effects, however, lasted only a few hours. A related compound, 3,4-diaminopyridine, or DAP, has also produced temporary improvements in nerve conduction without harmful side effects, even when taken for several weeks. One study comparing the two drugs, however, found that AP was superior in improving walking, fatigue, and overall function. Side effects of AP are more apt to include dizziness and confusion. DAP may cause abdominal pain, numbness, or tingling. Overdose can occur at relatively low doses in both drugs and may cause epileptic seizures.
Cannabis. Cannabis, the source of marijuana, has been found to improve tremor and spasticity in animal studies. In one study of MS patients, a third reported improvements in pain, spasms, tremor, mood, appetite, fatigue, vision, sexual and urinary function, and memory. Cannabis may, however, worsen balance and posture in patients with spasticity due to MS. Four studies of cannabis used in capsules or in an oral spray are currently underway in England.
Plasmapheresis. Plasmapheresis with plasma exchange is a procedure in which blood is removed from the body. Blood cells are separated from plasma (the liquid portion of blood) and mixed with replacement plasma, which is then returned to the body. The replacement plasma is thought to dilute antibodies and other immunologically active substances that may trigger MS. Small investigative studies are suggesting this procedure may have significant benefits for certain patients with severe MS, particularly if they are younger and have any early response to this treatment. Side effects include risk of infection and blood clotting problems.
Oligodendrocyte Implants. A newly developed, minimally invasive method to transplant modified oligodendrocyte cells directly into the brain is under investigation. Such cells stimulate nerve and axon growth. In one 2000 study, 75% of patients treated with the new therapy improved significantly compared with 34% who received non-modified cells. The new procedure was particularly effective in restoring visual acuity. About 40% of patients experienced a gradual return of disabilities after five years.
Paclitaxel. Paclitaxel is derived from the Pacific yew tree and is the active ingredient in Taxol, a leading ovarian and breast cancer drug. It also may act as an immunosuppressant, preventing white blood cells from damaging myelin. A small, preliminary 1999 study found that paclitaxel benefited patients with advanced MS. It is used in lower doses for MS patients than for cancer patients and so side effects, such as hair loss or nausea, do not occur or are not as severe. Further research is needed.
Stem Cell Transplantation. Some investigators are studying the benefits of stem-cell transplantation procedures. Stem cells are produced in the bone marrow and are the early forms for all blood cells in the body (including red, white, and immune cells). Early studies indicate that it may slow progression, although at this point it is not a cure.