Early data testing three compounds in the ALS mouse model presented at the International Symposium on ALS/MND in Milan.
Early test data on Ceftriaxone, one of three compounds tested in an ALS mouse model, appears to show a trend toward increasing the survival of mice, according to a report presented at the International Symposium on ALS/MND in Milan, Italy by Dr. Lucie Brujn, science director and vice president of The ALS Association.
The FDA-approved antibiotic Ceftriaxone - along with Promethazine, an FDA-approved antihistamine and Ebselen, an experimental anti-oxidant and anti-inflammatory - are part of an initiative funded by ALSA, The National Institute of Neurological Disorders and Stroke (NINDS), The Packard Center for ALS Research at Johns Hopkins and Project A.L.S. The three compounds were tested in an ALS mouse model at PsychoGenics, Inc, Hawthorne, NY and were selected from a series of FDA-approved compounds that showed positive effects in a variety of assays (modeling a disease mechanism in a dish) for ALS.
Mice were treated with compounds at 6 weeks of age, before onset of symptoms and at 90 days when symptoms had already begun" said Bruijn. "The study is in progress and results are currently inconclusive. One of the compounds, Ceftriaxone appears to show a trend towards increasing the survival of the mice."
Ceftriaxone is a member of the cephalosporin family. Other members of the family were tested and several of these compounds were also positive in as many as four ALS assays strengthening the rationale for selecting this compound for further testing in the animal model. Ceftriaxone appeared to increase levels of glutamate transporter EAAT2 (excitatory amino acid transporter 2). Increased glutamate surrounding motor neurons is believed to be one potential mechanism leading to cell death and improving removal of glutamate via the transporter is a potential therapeutic approach. Furthermore, ceftriaxone appeared to prevent SOD1-mediated cell death in cells expressing the mutant protein.
Promethazine demonstrated a positive effect in a mitochondrial assay. The role of mitochondria in the disease is receiving increased attention and compounds that restore mitochondrial function may be of therapeutic value for ALS. One such compound, minocycline is currently in clinical trials.
Ebselen showed a positive effect in an assay measuring increased glutamate uptake via the glutamate transporter (EAAT2) and previous publications have demonstrated a beneficial effect in a stroke model.
Questions and Answers
1. Are human studies of these drugs available?
Early efforts are underway to possibly develop a clinical trial of ceftriaxone in people with ALS based on the rationale that this drug increases the amount of EAAT2. At this time, it is too early to have a timetable for a possible trial or for patients to inquire about enrollment.
2. Will these drugs be available if they are proven effective?
Currently, ceftriaxone and promethazine are FDA-approved drugs for medical indications other than ALS. Ebselen is in clinical trial for medical indications other than ALS. The results of the assay study and the progress report of the mouse study presented above are "works in progress" and have not shown evidence sufficient to determine that the drugs in taken combination would be safe. In addition, there is, as yet, no evidence that these compounds taken either individually or in combination are effective for use by people with ALS. If any or all of these compounds are proven safe and effective, they should become readily available.
