The purpose of the study is to determine the safety and the efficacy of Tretinoin and Pioglitazone HCL in patients with ALS who are currently on Riluzole.

Physicians at Phoenix Neurological Associates (PNA) are looking for individuals diagnosed with ALS to participate in a double-blind, placebo controlled study of Tretinoin and Pioglitazone HCL, used in combination with Riluzole, for treating ALS. This investigator initiated trial conducted by Dr. Todd Levine and Dr. David Saperstein will help determine whether Tretinoin and Pioglitazone HCL, in combination, can slow the progression of ALS.

At present, there is little to no effective therapy for ALS, nor is there a known cause. Therefore there is a tremendous unmet need for more effective therapy for this disease and that is why the physicians at PNA have been very interested in the role of developing a more active anti-excitotoxic cocktail for patients with ALS. Since recent data have suggested that inflammatory mechanisms may interact with and promote neurodegeneration (where cells in the spinal cord and brain are lost), there have been a number of anti-inflammatory treatment strategies that have been evaluated in animal models. Some studies have shown that mice that were given Pioglitazone HCL demonstrated improved muscle strength and body weight, exhibited a delayed disease onset as well as had a longer survival rate compared to non treated mice.

In addition to these studies, retinoic acids have been studied extensively in various models of the injured nervous system. These studies have shown that retinoic acids, such as Tretinoin may be neuroprotective and support axonal growth, which could in turn slow disease progression.

The purpose of this study is to determine if such a drug "cocktail" could offer the best chance of attaining a significant reduction in disease progression by utilizing currently available FDA-approved agents

Inclusion Criteria:

• El Escorial Classification of laboratory supported probable, probable, or definite ALS
• Age 18 - 85 years
• Male or female
• FVC greater than or equal to 70% predicted

Exclusion Criteria:

• Patients with FVC below 1.5 L or below 70% predicted
• History of liver disease
• Severe renal failure (CrCl<30)
• History of coronary artery disease requiring placement of stents, bypass surgery or previous myocardial infarction
• EKG at baseline with evidence for previous myocardial infarction, cardiomyopathy, or arrhythmia
• History of intolerance to Riluzole, Tretinoin, or Pioglitazone HCL
• History of diabetes
• Any other comorbid condition which would make completion of trial unlikely