Clinical evaluation of ALS drugs

During the past several years there has been a dramatic increase in the number of clinical trials investigating new treatments for amyotrophic lateral sclerosis (ALS). Among the reasons for this intense activity are new insights into the pathogenesis of the disease; the availability of a new assortment of drugs, a number created by recombinant techniques, that are available for clinical evaluation; newly issued standards for the conduct of clinical trials, making them more reproducible and efficient; and improved assessment and measurement techniques for following the natural history of ALS and drug treatment effects on the course of the disease. ^[1] Increased determination on the part of physicians, patients, their families, and voluntary health organizations to enroll patients in clinical trials makes the goal of finding an effective treatment for ALS much more attainable. ^[1]

Pathogenesis of ALS.

The pathogenesis of ALS can be divided into initiating events, propagating events, and terminal events. Oxidative stress is believed to be an initiating event in ALS. ^[2] The identification of patients with familial ALS who have been found to have mutations in Cu/Zn superoxide dismutase (SOD1) supports this hypothesis. ^[3] This defect may render motor neurons more susceptible to glutamate-induced toxicity. Propagating events are involved in the spread of the disease process. Glutamate is the principal excitatory neurotransmitter in the brain, mediating many neurologic functions, and there is evidence that glutamate excitotoxicity may be an important factor in the propagation of ALS. ^[4] Decreased uptake of glutamate may lead to over-stimulation of glutamate receptors which, via increased intracellular calcium, can lead to the activation of a series of enzymes, such as protein kinase C, phospholipases, proteases, protein phosphatases, and nitric oxide synthetase, which contribute to injury of the neuronal cell membrane. ^[5] Autoimmune mechanisms, such as the formation of anticalcium channel antibodies, are also believed to …