Disease Modifying Agents in the Treatment of Multiple Sclerosis

Numerous agents have been tested in multiple sclerosis and the vast majority of these have either failed to show a beneficial effect or produced undesirable side effects. In some cases, there was worsening of disease activity. Treatment strategies for multiple sclerosis over the last 16 years have undergone a profound change. Several treatment options are now available primarily targeting the inflammatory phase of the disease [clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS) with relapses]. All currently approved disease-modifying agents (DMA) are moderately effective in reducing relapses and MRI activity. The treatment effect appears to be greater when these drugs are used soon after onset of symptoms. The effect on long-term disability seems to be modest if any. This post reviews both currently used agents (both FDA approved and off-label) and also discusses several promising agents in various phases of development. Disease Modifying Agents in the Treatment of Multiple Sclerosis: Currently Approved Agents Treatment of Radiologically Isolated Syndrome Several recent studies have raised awareness of patients with incidentally discovered Read more [...]

Other Off-Label Agents Used in the Treatment of RRMS

Corticosteroids Corticosteroids are considered as standard treatment for acute relapses. Corticosteroids decrease inflammation and stabilize the blood brain barrier, resulting in more rapid recovery from relapses. The standard dose is 1 g of methylprednisolone (MP) daily for 3-5 days through I/V infusion, although other regimens also have been used. Some studies have suggested that oral forms are also equally effective. One randomized study noted decrease brain atrophy, decreased T1 lesion volume, and decreased progression in patients treated with pulse steroids for 5 years. Pulse steroids may also have a beneficial effect on disease activity when used in combination with interferons. Corticosteroids are also safe to use during pregnancy and may have a role in the postpartum period. Treatment with steroids may reduce the development of neutralizing antibodies to IFN. Corticosteroids when used as short-term or long-term pulse therapy seem to be well tolerated. Unusual but serious side effects may include steroid-induced psychosis, mood disorders, reversible memory disturbance, and aseptic vascular necrosis. Cyclophosphamide Cyclophosphamide is an alkylating agent that binds to DNA and suppresses both B and T Read more [...]

Mitoxantrone in Multiple Sclerosis

Mitoxantrone () was developed in the 1970s and is an antineoplastic agent. It is an anthracenedione derivative related to the anthracyclins doxorubicine and daunorubicine. It interacts with topoisomerase-2, stabilizes its cleavable complex with DNA, thus prevents the ligation of DNA strands, and consecutively delays the cell-cycle progression. Mitoxantrone is used to effectively treat malignancies such as breast and advanced prostate cancer, lymphoma, and leukemia. Furthermore, in common with other antineoplastic agents, strong immunosuppressive properties of mitoxantrone have been observed providing a rationale for its use in autoimmune disorders. Evidence Leading To The Approval Of Mitoxantrone For Use In Multiple Sclerosis Mitoxantrone in Experimental Autoimmune Encephalomyelitis In the 1980s, mitoxantrone was proven effective in both actively and passively induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ridge et al. observed a dose-dependent inhibitory effect as determined by clinical evaluation and histopathology in rat EAE. Interestingly, mitoxantrone was 10 to 20 times more effective than cyclophosphamide in suppressing the development of EAE. Moreover, Read more [...]

Treatment of the epilepsy patient with renal disease

Seizures may occur in uraemic encephalopathy, dialysis disequilibrium syndrome and dialysis encephalopathy. In addition, renal insufficiency and dialysis may both have effects on anti-epileptic drug pharmacokinetics. Renal impairment can alter the fraction of anti-epileptic drug absorbed, volume of distribution, protein binding and renal drug clearance. Renal impairment may alter the gastric pH, cause small intestinal bacterial overgrowth, gastrointestimal tract oedema and impaired gastrointestinal motility. These factors may cause reduced ionization of some drugs and reduce drug absorption. The volume of distribution of drugs may be increased in patients with end-stage renal failure, resulting in lower total plasma levels. However, protein binding of acidic drugs may be significantly reduced in renal impairment; total plasma levels of anti-epileptic drugs may therefore be misleading. A total drug level may appear within the therapeutic range, despite a toxic-free level. For anti-epileptic drugs metabolized by the liver, changes in protein binding will affect the steady-state plasma concentration, but the free concentration will remain unchanged. For these reasons, it is often more useful to measure free concentrations Read more [...]

Treatment Of Breakthrough Disease

There is consensus that therapy in relapsing-remitting multiple sclerosis (MS) in the pediatric age group should be initiated with first-line treatments approved for adult multiple sclerosis (MS), namely one of the three forms of interferon-beta or glatiramer acetate (GA). However, as in adults with multiple sclerosis (MS), the disease remains clinically or radiologically active in some children despite first-line therapies even 6-12 months after initiation of an appropriate regimen. In adult breakthrough disease, treatment strategies include switching to another first-line agent, adding another agent to the on-going therapy (combination therapy), or switching to a second-line drug such as natalizumab or immunosuppression. Although very few data are available regarding tolerability and efficacy of these therapeutic strategies in pediatric multiple sclerosis (MS), there is anecdotal evidence from several pediatric multiple sclerosis centers that a variety of treatments are being used for the treatment of breakthrough disease in this age group. Most of the drugs considered are either approved for the treatment of multiple sclerosis in the adult age group (natalizumab, mitoxantrone) or approved for other indications than Read more [...]

Treatment Of Breakthrough Disease: Combination Therapies

Combination therapy of either first-line drugs (interferon beta and glatiramer acetate) or first-line drugs with a second-line agent is sometimes used as an approach to obtain better disease control in breakthrough multiple sclerosis (MS). Similar treatment strategies combining drugs with different mechanisms of action have provided utility in other autoimmune diseases, such as rheumatoid arthritis where early, aggressive combination therapy is considered the best treatment paradigm for ensuring adequate disease control and optimizing long-term outcome. The goal of combination therapy should be to improve disease control without aggravating adverse events. Very few studies have appropriately looked at the effect of combining therapies in adult multiple sclerosis patients with breakthrough disease on first-line agents, and none in children. Interferon beta and glatiramer acetate An obvious combination treatment would be glatiramer acetate and interferon beta. The two first-line treatments have quite different mechanisms of action and thus could, in theory, have additive or synergistic effects. However, studies on the mechanism of action of glatiramer acetate and interferon beta have indicated that a combination of both Read more [...]

Side Effects of Mood Stabilizers and Atypical Antipsychotics

This post provides an overview of developmental issues related to side effects, and then reviews the most common adverse events and concerns related to mood stabilizers and atypical antipsychotics. There are clear developmental differences in adverse event expression or side effects risks when mood stabilizers and antipsychotics are used in children and adolescents. All the mood stabilizers and antipsychotic medications produce adverse events. Each mood stabilizer and each atypical antipsychotic medication has its own adverse events profile. Prescribing physicians need to be familiar with the spectrum of risks for each of these medications. Currently, concerns with cardiovascular and metabolic complications take center stage in current mood stabilizing and antipsychotic treatments. Children and adolescents are more vulnerable to these risks. Sudden-death risk with the use of atypical antipsychotics is due to cardiovascular and metabolic risks, or the result of pancreatitis or liver failure. Females have an increased risk for these complications. Polypharmacy increases the risk of side effects. Increase in pediatric psychotropic polypharmacy is on the rise. Caution must be exercised when initiating these practices. Read more [...]