Newer Treatments for Myasthenia Gravis

By George Small, MD - Notes from the 2005 MGA Educational Seminar

Anticholinesterase Inhibition

TYPES

• Mestinon (Prodistigmine)
• Neostigmine (Prostigmine)

CHARACTERISTICS

• Improves muscle strength by blocking the enzyme that degrades acetylcholine at the neuromuscular junction
• Mainstays of treatment for myasthenia gravis

Steroids

TYPES

• Solumedrol
• Prednisone
• Hydrocortisone

CHARACTERISTICS

• Non-specific immunotherapy
• Targets multiple areas of the immune response from interleukin production to macrophage inhibition
• Works well, reliably, but also has severe long term side-effects

SIDE EFFECTS

• Hypertension, diabetes, osteoporosis, hip fracture, glaucoma, cataracts, ulcer, bleeding, bruising, weight gain, psychiatric (anxiety/depression), insomnia, tremor, fatal addisonian crisis, immune suppression

IVIG

Pooled immunoglobulin / long term benefits not established

ADVANTAGES

• Excellent short term results
• Good benefits in comparison to Plasmapheresis
• Ease of administration and few serious side effects (low incidence of transient high blood pressure, rash, headache.  No clear pathological immunosuppression or carcinogenic potential.
• Aseptic meningitis - transient

DISADVANTAGES

• Expensive, requires time and nursing supervision
• Questionable association with DVT, MI, CVA
• Clearly demonstrated reversible renal dysfunction in at-risk patients

MECHANISMS OF ACTION

• Down regulation of IL-1 production
• Decreased complement production
• Reduced macrophage chemotaxis
• Anti-Idiotype antibody function
• ↓ Bone
• ↓ ICAM expression/recognition
• IL-1 ↑ lymphocyte adhesiveness to the endothelial wall
• Acts as an endogenous pyrogen
• Like TNF → causes weight loss

PLASMAPHERESIS

The removal of blood with return of red cells – plasma is discarded.  Supplement with human albumin and normal saline solution.  Long term results not established.

ADVANTAGES

• Good short term results

DISADVANTAGES

• Expensive, requires inpatient administration
• Potential coagulopathy and line sepsis issues

LONG TERM IMMUNOMODULATION

NOTES

• No generally accepted blinded studies
• Nonetheless these drugs are in general use
• Most interfere with nuclear chromatin to down regulate production of T or B cells
• Occasionally, cytokine production affected
• Long term risk of cancer

ANTI-SENSE DRUGS

NOTES

• Concept depends upon the sight of action
• Nuclear DNA →RNA→tRNA→protein end product
• Rather than targeting the protein end product, the new idea is to prevent the protein end product from being ‘built’
• Targeting mRNA with RNA or DNA that has a complimentary nucleotide sequence would abort the production of protein end products that affect neuromuscular transmission

MONARSEN (EN101) – AN ANTI-SENSE DRUG

CLINICAL AND REGULATORY STATUS

• Ester Neurosciences
• Phase I Clinical Trial examining safety and efficacy in myasthenia gravis
• Above demonstrated improvement in severity in MG symptoms
• 14/16 had improved symptoms (28% - 54%)
• Phase II trial underway comparing placebo to varying doses of Monarsen to gauge improvement in life quality scores and quantitative MG scores

SMALL MOLECULAR WEIGHT COMPOUNDS

• Potential for use in other disorders such as Alzheimer’s Disease
• Target acetylcholinesterase inhibitors ‘upstream’, rather than at the level that current drugs work
• Exploit the ‘antisense’ technology through the synthesis of small molecular weight compounds to affect protein synthesis

ORPHAN DRUG STATUS

• Granted for Monarsen in November 2003 by FDA
• Grants exclusivity in marketing to Ester Neurosciences for seven years in the US
• Also potentially allows access to other government funds and grants
• Also granted exclusivity by the European Regulatory Authority (EMEA)

CONCLUSION

• Based upon number of patients with Alzheimer type dementia and myasthenia gravis worldwide, antisense technology blocking acetylcholinesterase may be useful
• Availability – latter part of decade at best

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