Drug combination treatment in patients with ALS: current status and future directions.

Abstract

Although the cause of ALS remains enigmatic, plausible hypotheses have been generated and new facts are continuously presented to explain the disease process in ALS, as have been summarized in this colloquium. The likelihood that several drugs will be effective in treating ALS is a reality. At present, the first drug available by prescription for ALS, riluzole, appears to have only modest effects in prolonging survival. A consensus has developed that a key strategy for increasing benefit is the treatment of ALS patients with a combination of drugs that are effective individually to achieve additive or synergistic benefits. In fact, a combination of several drugs is the standard practice in the treatment of advanced cancers and infectious diseases. In this report, we review the preclinical data supporting combination treatment for ALS and discuss the issues that need to be addressed with drug combination treatment of patients with ALS. Motor neuron survival in chick embryonic tissue culture is only 4.8% in the control medium, whereas the percentage of the survival increases to 14.5% when insulin-like growth factor-I (IGF-I) is added, 51.9% with basic fibroblast growth factor (bFGF), and 60.7% with ciliary neurotrophic factor (CNTF). [1] When these trophic molecules are combined in the culture media, the percentage of motor neuron survival rises to 76.1% with a combination of bFGF and IGF-I, 87% with CNTF and IGF-I, and 98.2% with bFGF and CNTF. A combination of all three trophic factors (bFGF, IGF-I, and CNTF), however, does not increase the survival further. Concerning the survival of in vitro motor neurons, a combination of bFGF and CNTF appears to be most effective. [1] Although these studies demonstrate a partially additive effect of the combination, [1] similar studies have shown that a combination of CNTF and bFGF results in survival-promoting effects that are more than …