By Sergei A. Grando, MD, PhD, DSci
Professor of Dermatology
University of California Davis
The Need for Alternative Therapies for Pemphigus. In autoimmune pemphigus, systemic glucocorticosteroid treatment is life saving but may cause severe side effects. Pemphigus patients therefore need drugs that will provide safer treatment of their disease by replacing systemic use of glucocorticoid hormones such as Prednisone. Development of non-hormonal treatment is hampered by a lack of clear understanding of the mechanisms leading to pemphigus lesions. Pemphigus can be associated with myasthenia gravis, and in both diseases the autoantibodies to acetylcholine receptors are produced, suggesting a common mechanism of disease development.
First experience of treatment with Mestinon and azathioprine without systemic glucocorticoids. In a 33 year old female patient from New York, pemphigus vulgaris developed on the background of myasthenia gravis which was treated for approximately four years with the cholinergic drug Mestinon and a topical glucocorticoid cream. During worsening, azathioprine was added and the treatment was continued without need for using systemic glucocorticosteroids. The intriguing aspect of management of this patient is that the conventional glucocorticoid therapy has never been instituted. Although it is possible to maintain pemphigus patients in remission using immunosuppressive drugs only, initial treatment of pemphigus vulgaris usually relies on the high dose of systemic glucocorticoids. Since control of pemphigus in this patient was achieved without using systemic glucocorticoids, Mestinon should be considered as a therapeutic agent that could ameliorate the natural course of pemphigus.
How could Mestinon ameliorate pemphigus? Mestinon inhibits the destruction of acetylcholine by acetylcholinesterase and thereby permits stronger adhesion of the skin cells keratinocytes. Acetylcholine competes with the disease-causing pemphigus antibodies preventing them from attachment to keratinocytes, and reverses pemphigus antibody-induced detachment of keratinocytes in cell culture. Although it has been postulated that pemphigus vulgaris is caused by autoantibodies to the adhesion molecules desmogleins 1 and 3, the results obtained in my research laboratory show that the pool of disease-causing pemphigus antibodies includes the autoantibodies to keratinocyte acetylcholine receptors in approximately 85% of patients.
An opportunity to test the therapeutic efficacy of Mestinon in pemphigus. Each Mestinon tablet contains 60 mg of the reversible acetylcholinesterase inhibitor pyridostigmine bromide, which is used to treat muscle weakness in patients with myasthenia gravis. Pyridostigmine bromide is FDA approved for use in myasthenia gravis, but is experimental for the treatment of patients with pemphigus without myasthenia gravis. The Human Subjects Review Committee of University of California-Davis has recently approved the protocol of clinical trail of Mestinon in pemphigus. The study will be conducted in my dermatology clinic at the University of California-Davis Medical Center in Sacramento. Upon my request, ICN Pharmaceuticals has furnished Mestinon tablets for this clinical trial.
Description of the clinical trial of mestinon in pemphigus. The preliminary trial will be carried out in a limited number of patients with acute pemphigus vulgaris and pemphigus foliaceous. If the results are encouraging, we will extend the trial. Patients who are willing to participate in the study will not receive the standard treatment for pemphigus. Instead, they will receive Mestinon tablets orally from one to six per day, that is from 60 À 360 mg of pyridostigmine bromide per day. The dose of Mestinon will be adjusted for each particular patient based on his or her response to treatment. Experience with the use of Mestinon in myasthenia gravis patients indicates that failure of patients to show clinical improvement may reflect underdosage, by analogy with a lack of therapeutic effect of low-to-mid doses of Prednisone in acute pemphigus vulgaris.
Adverse reactions to Mestinon and contraindications. The side effects of Mestinon are most commonly related to overdose. These side effects may include nausea, vomiting, diarrhea, abdominal cramps, frequent passing of flatus and/or a need to have a stool, increased production of saliva, increased bronchial secretion, excessive sweating, muscle cramps and twitching, and muscle weakness. Mestinon is contraindicated in mechanical intestinal or urinary obstruction, and in patients with bronchial asthma. If you are willing to participate in the clinical trial of Mestinon in pemphigus, you may inquire about enrollment eligibility by contacting me:
Messagerie: [email protected]
Dr. Sergei A. Grando
UC Davis, Department of Dermatology
Ambulatory Care Center
4860 Y Street, Suite #3400
Sacramento, CA 95817