By Ronald Steriti, NMD, PhD
Various medications can be given to the patient as ALS progresses.
Baclofen (Lioresal) is used to relieve stiffness in the limbs and throat. Patients with seizure disorder or impaired renal function should use caution. Serious adverse reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression. Common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, and increased perspiration. Excessive dosing may lead to weakness. Baclofen may interact with alcohol, antipsychotics, MAOIs, narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin.
Tizanidine (Zanaflex) is a centrally acting muscle relaxant. Zanaflex may interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance.) Zanaflex can increase hypotensive effects when administered concurrently with diuretics. Elderly patients and patients with impaired renal function should use caution. Serious reactions include hallucinations, severe bradycardia, and liver toxicity. Common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension.
Tricyclic antidepressants may be used to control the production of excess saliva.
Riluzole, the only FDA-approved drug to treat ALS, reduces the presynaptic release of glutamate. Riluzole is metabolized in the liver. It is contraindicated with active liver disease or elevated liver function tests (SGPT or ALT and GTT.) Theophylline and caffeine may affect rate of elimination. Riluzole treatment may be associated with mild blood pressure elevation. 
Unfortunately Riluzole, although described in medical journals as an effective treatment for ALS, provides almost no benefit and is associated with significant side effects in most patients. One journal noted It is often said that the benefits of riluzole are marginal but the side effects are major. One writer commented that Clearly, riluzole does succeed at one important task. It allows treating physicians to end the day assured that the did something for the ALS patients they were treating since a prescription was written an obligation was thus fulfilled. [47-49]
Several new drugs are being studied for treatment of ALS. These include: 
Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been approved for use in the treatment of dementia in Germany for over ten years. NMDA receptor antagonists have therapeutic potential in numerous central nervous system (CNS) disorders. Memantine does not have the side effects common to other NMDA receptor antagonists such as dizocilpine.  
Dextramethorphan is an N-methyl-D-aspartate receptor antagonist that is being explored for use in ALS. Preliminary studies, however, did not find positive effect. 
Some authors have reported decreased insulin-like growth factor 1 (IGF-1) in patients with ALS.   
Insulin-like growth factor-I (IGF-I) receptors are present in the spinal cord where they mediate signal transduction via tyrosine kinase. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Clinical trials of recombinant human IGF-I have been initiated for patients with amyotrophic lateral sclerosis. 
One study examined the cost effectiveness of treatment with recombinant insulin-like growth factor 1 (rhIGF-I) in patients with ALS. They conclude that treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favorably with treatments for other chronic progressive diseases. 
A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. The authors concluded that recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.  
An European placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis, however, showed no significant difference between treatment groups. 
A moderate reduction in beta-NGF (nerve growth factor) levels was seen in the serum of patients with ALS and multiple sclerosis. There was a statistically significant reduction in the patients who were carriers of Parkinsons disease and Huntingtons chorea. 
Leukemia inhibitory factor (LIF) was named after its effect on hemopoietic (blood-forming) cells. Studies have demonstrated a powerful effect of LIF in the survival of both motor and sensory neurons, while reducing denervation induced muscle atrophy. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. A human recombinant form of LIF (AM424), entered human clinical trials during 1998. 
Ciliary neurotrophic factor is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis. 
Pigment epithelium-derived factor (PEDF), a natural substance produced by the body, was located for the first time in the spinal cord and skeletal muscles of humans, monkeys, and rats. Previously, scientists believed that PEDF was found only in the pigmented layer of cells beneath the retina. Using slices of rat spinal cords kept alive in culture, PEDF showed a dramatic ability to protect cells from the toxic effects of threohydroxyaspartate (THA), a chemical that mimics the effects ALS, causing slow death of motor neurons. The PEDF-treated sections showed a near-normal neuron count compared with untreated cultures. According to Dr. Ralph Kuncl, who led the Johns Hopkins research team, protection of the spinal cord nerves in culture by PEDF was nearly complete. He went on to state that ...If we had this same level of protection in patients with ALS, theyd experience slight muscle weakness at most. The effectiveness of PEDF will be tested next on transgenic mouse models.
The same research team recently reported in the May issue of Molecular and Cellular Neuroscience on another natural compound known as neurturin, a neurotrophic substance that will stimulate regeneration of damaged nerve cells. Neurotrophic factors including PEDF and neurturin are believed to protect healthy cells from the damaging effects of glutamate, a neurotransmitter that gluts the spaces between motor nerve cells causing over-stimulation and contributing to the progression of the disease. Although riluzole mildly restrains the immediate release of glutamate, it provides minimal protection to motor neurons as do PEDF and neurturin. The researchers predict the development of an ALS cocktail, drug combinations containing neurotrophic factors, each working at a different point in the process. 
In an commentary published in the November issue of the journal Nature Neuroscience, authors Richard J Miller and Clifton W Ragsdale of the University of Chicago discuss the function of transforming growth factor-beta, or TGF-beta in the programmed death, or apoptosis, of nerve cells. TGF-beta is part of a family of growth factors by the same name that are involved in many biological functions in all of the body's tissues, such as embryonic development, reproduction and wound healing. 
In a study reported in the same in the same issue, chick embryos were immunized to neutralize the three forms of TGF-beta during the restricted period of embryonic development in which 50% of the neurons that have formed experience apoptosis. Neuron death was halted in all of the cells that were destined to die, which included central nervous system motor neurons and peripheral nervous system autonomic neurons. It is possible that TGF-beta works only on those neurons that will die, acting in a way that permits rather than instructs the cells to die. In other circumstances TGF-betas may enhance neuron survival. The researchers, led by Kerstin Krieglstein of the University of Saarland at Homburg, Germany conclude that TGF-beta could function as a molecular switch, which determines the life and death of neurons. 
The authors of the commentary state that the findings may have important implication for diseases such as amyotrophic lateral sclerosis (ALS) which is characterized by the death of motorneurons and may involved programmed cell death. Spinal cord trauma may involve neuron death by apoptosis as well. The removal of TGF-betas may be able to reduce the death of neurons and prevent some of the disability associated with this and other conditions.
TR500, a glutathione-repleting agent, is being studied for use in ALS. 
Deprenyl (Eldepryl, Selegiline hydrochloride), a selective monoamine oxidase B inhibitor, is effective in Parkinson's disease, and can slow the cognitive deterioration in Alzheimer's disease. Studies of its use in ALS however did not show any significant improvement.  
Pimozide is a voltage-dependent calcium channel blocker that is being explored for use in ALS. One study showed a significant decrease of the index of progression of the disease in pimozide treated patients as compared to selegiline and vitamin E. In a randomized trial of 44 patients diagnosed as either definite or possible ALS, were treated with 1 mg per day of pimozide for 3-12 months. Statistical analysis showed a significant decrease of the index of progression of the disease in pimozide treated patients as compared to the others. 
Gabapentin (Neurontin) is derived from gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. [71, 72]
Unfortunately Gabapentin was found to provide no evidence of a beneficial effect on disease progression or symptoms in patients with ALS in a Phase III randomized double-blind placebo trial. 
Continue to Part 3 of the ALS Article