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Aspartame for Type II or III Cryoglobulinemia?

Some recent studies have found that Aspartame (Nutrasweet) binds to the part of the immunoglobulin molecule that is involved in rheumatoid arthritis and Type II and III cryoglobulinemia. The studies, cited below, found that ingestion of Aspartame could clinically reduce the symptoms of arthritis. The dosage in this study was 76 to 152 mg of Aspartame, which is about what is contained in a typical diet soft drink or yogurt.

This research has gotten some media interest.

While not everyone is convinced of the safety of ingesting Aspartame, the medical consensus is that Aspartame is safe for most people.

In Type II or III cryoglobulinemia due to hepatitis C virus (HCV) infection, the cryoglobulins bind to the HCV virus itself. Aspartame would hypothetically interfere with the binding of rheumatoid factor antibodies (monoclonal [Type II] or polyconal [Type III] IgM) to these anti-HCV antibodies. Whether this would affect the body's immune response to HCV is unknown. It also remains unexplored whether ingestion of Aspartame by Type II or III cryoglobulinemia patients can reduce their symptoms by interfering with the formation of the cryoglobulin immune complexes.

J Mol Recognit 1999 Sep-Oct;12(5):249-57

Corrected and republished with original paging, article originally printed in J Mol Recognit 1999 Jul-Aug;12(4):249-57

Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester.

Ramsland PA, Movafagh BF, Reichlin M, Edmundson AB

Crystallography Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.

Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints. Copyright 1999 John Wiley & Sons, Ltd.

Clin Pharmacol Ther 1998 May;63(5):580-93

Treatment of osteoarthritis with aspartame.

Edmundson AB, Manion CV

Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.

OBJECTIVE: The binding of sweet-tasting compounds in a human (Mcg) Bence-Jones dimer has been characterized by x-ray crystallography. Aspartame binding in this immunoglobulin fragment is remarkable. Unexpected pain relief noted by A.B.E., a crystallographer with diagnosed osteoarthritis, suggested that the accommodation of aspartame in the active site of the dimer may represent surrogate binding by other proteins, with analgesia as the outcome. METHODS: X-ray analysis of the complex of aspartame and the Bence-Jones dimer was conducted with crystalline Mcg protein and pure aspartame. A single-blind (n = 1) study to confirm analgesia was completed by administration of aspartame to A.B.E. A controlled double-blind trial was performed in patients with x-ray-documented osteoarthritis. Pain and performance changes were evaluated with use of two doses of placebo and two doses of aspartame. Effects on bleeding time were then evaluated by determination of template bleeding times in 34 normal volunteers. Finally, antipyretic effects were studied in Sprague-Dawley rats given intramuscular turpentine injections. RESULTS: Aspartame binding in the Bence-Jones dimer was verified by x-ray crystallography. Improvements in performance and pain relief were observed in A.B.E. at p < 0.001. Decreased pain and improved performance were also observed in patients with osteoarthritis (p < 0.001). Mild antihemostatic responses were observed in bleeding times after aspartame treatment. Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile responses in the treated rats (p < 0.01). CONCLUSIONS: L-Aspartyl-L-phenylalanine methyl ester is biologically active and appears to relieve pain, induce mild antithrombotic effects in humans, and decrease fever in animals.