Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials

Though considerable of research, both pre-clinical and clinical, has been conducted during recent Amyotrophic Lateral Sclerosis (ALS) remains one of the mysterious diseases of the 21st century. Great efforts have been made to develop pathophysiological models and to clarify the underlying pathology, and with novel instruments in genetics and transgenic techniques, the aim for finding a durable cure comes into scope. On the other hand, most pharmacological trials failed to show a benefit for ALS patients. In this book, the reader will find a compilation of state-of-the-art reviews about the etiology, epidemiology, and pathophysiology of ALS, the molecular basis of disease progression and clinical manifestations, the genetics familial ALS, as well as novel diagnostic criteria in the field of electrophysiology. An overview over all relevant pharmacological trials in ALS patients is also included, while the book concludes with a discussion on current advances and future trends in ALS research.


Introduction
There are several synonyms for Amyotrophic Lateral Sclerosis (ALS) which include Motor Neuron Disease (MND), Charcot's disease, and Lou Gehrig's disease. The latter is named after the American baseball professional Lou Gehrig, who died of ALS in the 1940s (Miller, 2011). The symptoms of motor neuron disease (MND) have first been described by several neurologists by the mid-19 th century. The French neurologist Charcot defined the nosological entity "amyotrophic lateral sclerosis" (ALS) some years later (historic aspects of ALS are reviewed in (Eisen, 2007;Mitsumoto et al., 2006;Oliveira & Pereira, 2009;Rowland, 2001;Wijesekera & Leigh, 2009)). In the present understanding, MND comprehends a spectrum of different neurodegenerative syndromes which show a common neuropathology, i. e. the progressive degeneration of motor neurons. These syndromes include the "classical" ALS, progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), flail arm syndrome (Vulpian-Bernhardt syndrome), flail leg syndrome, and ALS with multi-system involvement (e.g., Fronto-Temporal Dementia, FTD) ( Fig. 1) (reviewed in Lillo & Hodges, 2009;.

Diagnostic criteria 2.1 Clinical features
The diagnosis of ALS is based on a catalogue of criteria specified by the World Federation of Neurology (www.wfneurology.org). These criteria are known as the "El Escorial" criteria, named after the Spanish historic site El Escorial. The original criteria of 1994 (Brooks, 1994;Mitsumoto, 1997) have been revised in 1998 (Brooks et al., 2000;Ross et al., 1998), which are known as the "Airlie House" criteria, named after the conference site at Warrenton, VA, U.S.A. In 2006, a consensus conference at Awaji-shima defined criteria of electromyographic and nerve conduction measurements for the diagnosis of ALS (de Carvalho et al., 2008). The clinical features comprehend the presence of (i) lower motorneuron (LMN) signs such as the loss of muscle strength, muscular atrophy, fasciculations, hyporeflexia, hypotonicity or flaccidity, or muscle cramps, in at least two limbs; (ii) upper motorneuron (UMN) signs such as extensor plantar responses, spasticity, or pathologic hyperreflexia, in at least one region (bulbar, cervical, or lumbosacral), and (iii) the progression of the disease defined as increasing symptomatic impairment by history in the same region or new regions (Ferguson & Elman, 2007).
With regard to the diagnoses and prevalence of these in ALS patients, there are only few data available, which are summarized in Table 1.
In the following paragraphs, I will shortly describe the major psychiatric abnormalities in ALS patients and current findings.

Sleep
In the current understanding, it is difficult to distinguish whether psychiatric abnormalities in ALS patients are integral part of the CNS disease, or if they are a secondary phenomenon. For example, sleep disturbances are a common problem in ALS patients, but besides anxiety, they may also result from reduced mobility, muscle cramps, or swallowing problems (Hetta & Jansson, 1997).

Fatigue
Fatigue is also a common problem in ALS patients, which does not describe physical exhaustion, but a pathological state of mind (Jackson & Bryan, 1998;Lou, 2008).

Pathophysiological considerations in the planning of ALS treatment strategies
Most pre-clinical trials in ALS research started with the pathophysiological model of the disease. In counteracting the pathophysiology of the disease, motor neuron survival and stabilization of motor neuron function is increased (reviewed in Bedlack et al., 2007;Carlesi et al., 2011;Fornai et al., 2011;Ilieva et al., 2009;Pradat et al., 2010;. Current strategies for treatment concepts reach for counteracting the individual pathophysiological actors. They including the following groups of agents:  Anti-excitotoxicitory drugs. Excitotoxicity is mainly modulated by the release of glutamate and contributes to an acute toxicity.

Programmed failure in clinical trials for ALS?
In the typical process of drug development, preclinical data such as biochemical assays, cellular assays, and rodent models for the disease, lead to positive results with regard to predefined outcome parameters, for example, the increase in muscle strength, or survival time. For all of the drugs listed in the next section, promising preclinical data have been provided and published (for review, see (Ludolph & Sperfeld, 2005)). But why did the majority of the clinical trials fail, when preclinical data have been so promising? Three major points came to my notice, when reviewing the literature: First, the animal models (mouse, rat, drosophila etc.) may either not sufficiently reflect the human pathology, or the animal pathology does not reflect human conditions (discussed in Green, 2002;Kiernan et al., 2011;Scott et al., 2008). Second, "ALS" is a clinical but not a pathophysiological entity. Thus, the inter-personal variability between patients is too big, and the inclusion criteria are too broad. Third, the design of the clinical trials may be insufficient (Aggarwal & Cudkowicz, 2008;Fornai et al., 2011;Kiernan et al., 2011;Maragakis, 2009), including:  the number of subjects is too small,  the time for follow-up is too short,  the power of the study is calculated too low,  the inclusion criteria are too broad,  the outcome measures are not well-defined and comparable, or insufficient. In future clinical trials, these issues should be discussed and included into the design of clinical ALS trials (Borasio, 1997).

Consensus guidelines for ALS trials
Therefore, a round table has been established to agree on minimal criteria for a "good" clinical trial (Miller et al., 1999). Of note, there have been substantial efforts also in other diseases such as stroke research to agree on clinical and pre-clinical guidelines for research, such as the "Stroke Therapy Academic Industry Roundtable (STAIR)" (STAIR -Stroke Treatment Academic Industry Roundtable, 2006). In the following paragraphs, I will shortly summarize the consensus guidelines for ALS trial. The prerequisite for any ALS trial should be a substantial diagnosis according to the criteria defined by the World Federation of Neurology (see above). Moreover, the inclusion criteria should be handled strictly, including that both sporadic and familial ALS can be entered into the trial. The age of the patients should be limited between 18 and 85 years of age. Symptoms should show a disease progression within the first six months after onset, but not more than five years. Additionally, also exclusion criteria have been defined, for example, the patients should not show sensory abnormalities, dementia, other neurological diseases, they should not suffer from any uncompensated medical illness, substance abuse, or psychiatric illness. Of note, the patients should not be taking any other investigational drug. The endpoints of the trial must be defined in advance, for example, survival time, muscle strength, or ventilator dependence are common endpoints. All trials should include a control group. The quality of life should be assessed in every efficacy trial. The statistical analysis must be sound and planned with sufficient power. Any co-medication must be carefully reconsidered.

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Since there has been an early release of information about the efficacy in clinical ALS trials, which had to be revoked after thorough analysis, any information with regard to the efficacy of an investigational drug should only be released when peer-reviewed publication is at least imminent (with the exception of scientific meetings). The investigator is responsible for any conflict of interest.
The design of ALS trials should comprehend three phases (Brooks, 1997). In phase I, toxicity and pharmacokinetics is tested. In phase II (pilot, exploratory, or screening trials) information is gathered about dose finding, preliminary efficacy, and further safety observations. In phase III, definitive efficacy and safety is evaluated. Phase I trials should incorporate a placebo control group and the follow-up should be at least six months. Phase II trials may use placebo controls, historic controls, or a crossover design. If the prospective therapeutic value aims at improvement of signs and symptoms, such as increased muscle strength or ameliorated function, the follow-up should be at least six months, whereas trials aiming at stabilization or slowing of deterioration should observe the patients' condition for at least 12 months (Bedlack, 2010). All phase III trials should be placebo-controlled. The endpoints should include at least the survival time, assessment of strength measured by maximum voluntary isometric contraction, pulmonary function, and functional performance by the ALS rating scale. Of course, an independent data and safety monitoring board should be established. Of note, since survival times are rather short, many patients feel desperate and take unapproved medication out of the reach of a clinical trial. By establishing these consensus guidelines, this potentially dangerous drug use may be reduced (Ross, 2009).

Overview over drug candidates in clinical ALS trials
In the following "inventory" of clinical trials in ALS, I will give an overview over drug candidates used in ALS trials. I have included all interventional clinical trials registered at Clinicaltrials.gov (http://clinicaltrials.gov/). Information on these trials can be obtained by accessing the website http://ClinicalTrials.gov/show/NCTxxx, where xxx stands for the registration number shown below. Since there have been various clinical trials in the era before Clinicaltrials.gov required registration, and before a consensus conference established criteria for ALS trials (Miller et al., 1999), I have included some information on earlier trials. On the other hand, I excluded case reports, trials with nutritional supplements, and non-pharmacological therapeutic procedures such as plasma exchange, whole-body irridation, hyperbaric oxygenation, balneotherapy, cervico-dorsal electroshock therapy, adrenal cortex injection or stem cell injection, even when the stem cells are used as vehicles and vectors for the expression of biologicals. Of note, this inventory is neither comprehensive, nor does it contain all available references due to space restriction. It is mainly based on a selective literature search in the PubMed database, and summarizes recent reviews in the field (Carlesi et al., 2011;Miller et al., 2005;Siciliano et al., 2010;Zinman & Cudkowicz, 2011;Zoccolella et al., 2009).

N-acetylcysteine
The anti-oxidant N-acetylcysteine did not show efficacy in a phase II clinical trial (Louwerse et al., 1995).

AEOL-10150
AEOL-10150 is a metalloporphyrin scavenging reactive oxygen species (ROS) (Orrell, 2006). It has been tested for safety and tolerability in three phase I trials, but further development has been halted.

Amantadine (1-adamantylamine, 1-aminoadamantane)
Amantadine shows a weak NMDA receptor antagonism and anti-cholinergic effects. In a cross-over study with guanidine, no benefits for ALS patients have been described (Munsat et al., 1981).

Anakinra
Anakinra is a recombinant antibody directed against the interleukin-1 receptor (IL-1R). IL-1 is involved in sustaining the neuroinflammatory process. Treatment with anakinra in the G93A-SOD1 transgenic mouse model of ALS extended the lifespan of the animals and decreased neuroinflammation (Meissner et al., 2010). Thus blocking of the IL-1R may be a potential target in decreasing the speed of ALS progression (van der Meer & Simon, 2010). Currently, a phase II study (NCT01277315), designed as a riluzole add-on study, investigates the safety and tolerability of anakinra in ALS.

Antioxidants
In a systematic review, no evidence for a benefit of anti-oxidant treatment with regard to survival, neither alone, nor in combination, has been described (Orrell et al., 2008). The antioxidants administered in ALS patients included vitamin E, acetylcysteine, L-methionine, and selenium.

Arimoclomol (BRX-220)
The small molecule arimoclomol is a co-inducer of heat-shock proteins (Phukan, 2010), namely of HSP70 (Brown, 2007). Thus it may be used to increase endogenous cellular protein repair and to prevent misfolding, or aggregation, of proteins by activating molecular chaperones (Kalmar & Greensmith, 2009). Arimoclomol was tested in two phase II studies to evaluate safety and efficacy in ALS patients (NCT00561366) and to find a dose range and to determine pharmacokinetic parameters (NCT00244244) (Cudkowicz et al., 2008;Lanka et al., 2009). Currently, arimoclomol is tested in a phase II/III trial in patients with SOD1-positive fALS (NCT00706147).

Arundic acid (ONO-2506)
Arundic acid is an enantiomeric, three carbon atom homolog of valproic acid, with antiinflammatory and anti-glutamatergic effects (de Paulis, 2003). It was tested in two phase II studies, designed as riluzole add-on, in clinical ALS trials for long-term safety (NCT00694941) and safety and efficacy (NCT00403104). The original evaluation of the trials did not show statistically significant differences between groups, but the subgroup analysis showed a possible positive effect for patients in early stages, namely within 14 months after onset of symptoms. On the other hand, patients with longer disease onset showed negative outcome (Thomas Meyer, 2005).

AVP-923 (Zenvia)
AVP-923 is a combinational formulation containing dextromethorphan hydrobromide, which is an NMDA antagonist and sigma-1 receptor agonist, and quinidine sulphate, which inhibits the cytochrome P450 2D6 (CYP2D6) enzyme. Dextromethorphan hydrobromide shows a high first pass metabolism in the liver, where it is metabolized by CYP2D6. Thus the addition of quinidine sulphate increases the bioavailability of dextromethorphan hydrobromide (Olney & Rosen, 2010). AVP-923 was tested in two phase III trials in ALS patients with pseudobulbar affect (PBA), which is characterized by emotional dysregulation, such as uncontrollable outbursts of laughing or crying that are inappropriate to the emotions being experienced (Garnock-Jones, 2011;Olney & Rosen, 2010). The study showed that AVP-923 ameliorates symptoms of PBA in ALS patients and improved quality of life and quality of relationships (Brooks et al., 2004).

Azathioprine
The immunosuppressant azathioprine in combination with prednisolone did not show a benefit in ALS patients (Werdelin et al., 1990).

Brain-derived neurotrophic factor (BDNF)
The neuroprotective growth factor BDNF has been evaluated in a phase I/II clinical trial which reported a trend for prolonged survival after subcutaneous infusion (The BDNF Study Group & Bradley, 1995), a result which could not be reproduced in the subsequent phase III clinical trial (The BDNF Study Group (Phase III), 1999). The intrathecal administration was safe and well-tolerated (Ochs et al., 2000).

Branched-chain amino acids (BCAA)
The branched-chain amino acids comprehend leucine, isoleucine, and valine. In clinical trials, branched chain amino acids did not show a beneficial effect in ALS patients (Tandan et al., 1996).

Bromocriptine
The dopamine agonist bromocriptine did not show a benefit in ALS patients (Szulc-Kuberska et al., 1990).

Buspirone
The anxiolytic agent buspirone did not show a benefit in ALS patients (The ALS Association, 2010).

Ceftriaxone
Ceftriaxone is a ß-lactam antibiotic which also shows anti-oxidant and anti-excitotoxity effects (Traynor et al., 2006). Currently, ceftriaxone is evaluated in a phase III clinical trial in patients with ALS (NCT00349622).

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The rationale of celecoxib treatment is the reduction of PGE2 in the cerebrospinal fluid (CSF), thus preventing neuroinflammation and neuronal loss. In a phase II clinical trial (NCT00355576), celecoxib did not show a beneficial effect on the decline in muscle strength, motor unit number estimates, vital capacity, ALS Functional Rating Scale-Revised, and overall survival . Moreover, PGE2 levels in the CSF were not elevated at baseline and did not decline during treatment . In this trial, celecoxib was combined with creatinine and/or minocycline (Gordon et al., 2008).

Ciclosporine A
The immunosuppressant cyclosporine A did not show a benefit in ALS patients (Appel et al., 1988).

Ciliary neurotrophic factor (CNTF)
CNTF is a neurotrophic factor with neuroprotective properties. It has been tested in two clinical trials finding no effect on disease progression (ALS CNTF Treatment Study Group, 1996;, but an increased trend of adverse effects .

Cistanche total glycosides (CTGs)
The glycosidic extract of the plant Cistanche spp. has a long tradition in its medicinally use in Traditional Chinese Medicine (TCM). It has been described as a neuroprotective agent in a mouse model of Parkinson's Disease (PD) (Li et al., 2008). Currently, Cistanche Total Glycosides are investigated in a phase II trial (NCT00753571). Of note, the CTGs are the only agents in registered ALS trials without a defined chemical composition, which may impose problems in future comparability to other medications and effectiveness of different preparations.

CK-2017357
With regard to the loss of skeletal muscle strength, the substituted urea derivative CK-2017357 is claimed to activate the muscle protein troponin in fast skeletal muscle fibres. A proposed mode-of-action is sensitizing the sarcomere to calcium, thus the neuro-muscular transmission is amplified, thus muscle power increases and the time to musclular fatigue is delayed (von Haehling et al., 2010). A phase IIa study (NCT01089010) was completed in 2010 and showed a trend towards short-term improvements in grip-strength and respiration parameters.

Coenzyme Q10
Coenzyme Q10 has been proposed to inhibit neurodegeneration. In a phase II clinical trial, it was well tolerated and safe (Ferrante et al., 2005), but showed no efficacy in a phase II futility trial (NCT00243932) (Kaufmann et al., 2009;Levy et al., 2006).

Creatine
Creatine acts as anti-oxidant and is a mitochondrial co-factor. It has been evaluated in several phase II clinical trials (NCT00070993, NCT00005674, NCT00005766) which reported no beneficial effect in ALS patients (Groeneveld et al., 2003;Shefner et al., 2004), as well as a phase III clinical trial (NCT00069186) (Rosenfeld et al., 2008).
Creatine supplementation temporarily increased maximal isometric power in ALS patients (Mazzini et al., 2001). In a phase I dose-escalation trial, creatine concentrations in the brain increased after oral administration (Atassi et al., 2010). Currently, creatine is evaluated in a phase II clinical trial (NCT01257581) in combination with tamoxifen in ALS patients.

Cyclophosphamide
The immunosuppressant cyclophosphamide showed only a temporary amelioration of symptoms in ALS patients without a long-term benefit (Gourie-Devi et al., 1997).

Dronabinol
Dronabinol is a synthetic Δ9-tetrahydrocannabinol (Delta-9-THC, Δ9-THC, THC). It has been tested in a phase II study (NCT00812851) in ALS patients suffering from muscular cramps, where no subjective improvement of cramp intensity has been seen (Weber et al., 2010).

Edaravone (MCI-186; NSC 2629)
Edavarone is an anti-oxidant free radical scavenger (Takahashi, 2009). It has been tested in several phase II/III clinical trials (NCT00330681, NCT00415519, NCT00424463) for safety and efficacy. A phase II study found a possible delay in the progression of functional motor symptoms in ALS patients (Yoshino & Kimura, 2006).

Erythropoietin (EPO)
EPO is a hematopoietic growth factor with neuroprotective properties (Maurer et al., 2008). Moreover, EPO exhibited anti-inflammatory and anti-apoptotic effects. It has been evaluated in a phase II trial, finding no effects on survival and functional outcome (Lauria et al., 2009).

Escitalopram
Escitalopram is a selective serotonin reuptake inhibitor (SSRI) and used clinically as an antidepressant. It has been tested in a phase III clinical trial (NCT00965497) for the improvement of depressive symptoms and the quality of life in ALS patients.

Gabapentin
Gabapentin is an anti-convulsant with anti-glutamatergic effects, which have been proposed to slow down neuronal pathology (Welty et al., 1995). It has been tested in a phase II trial finding a smaller slope in arm strength decrase , but a subsequent phase III trial has not shown beneficial effects of (Miller et al., 2001). No effects on neuronal integrity have been found in an MR spectroscopy study (Kalra et al., 2003).

Gangliosides
Gangliosides are derivatives of sialylated glycosphingolipids containing one to five sialic acids at various anomeric linkage sites to the core glycan. They modulate the effect of nerve growth factor and activate protein kinase (DeFelice & Ellenberg, 1984;Rapport, 1990). Gangliosides have been tested in several clinical trials without benefit for ALS patients (Bradley et al., 1984;Harrington et al., 1984;Lacomblez et al., 1989).

Glatiramer acetate
Glatiramer acetate is a random polymer composed of four amino acids that are found in myelin basic protein (MBP). It has been proposed that it inhibits neuroinflammation, stimulates anti-glutamatergic growth factor effects. In a phase II clinical trial (NCT00326625), glatiramer acetate has not shown any beneficial effect in ALS patients (Meininger et al., 2009).

Granulocyte colony stimulating Factor (G-CSF; AX200)
G-CSF is a hematopoietic growth and maturation factor with neuroprotective and neuroregenerative effects (reviewed in Maurer et al., 2008). G-CSF has been evaluated in a phase II study (NCT00298597) in ALS patients, finding no differences with regard to functional outcome between study groups, but slowing the progression of white matter tract destruction (Duning et al., 2011). In a second phase II trial (NCT00397423), the authors reported preliminary data on 13 patients with slower disease progression . Another clinical trial did not report statistically significant differences between study and control group (Nefussy et al.), but a trend towards slowing down disease progression.

Growth hormone (GH, Somatropin)
Human growth hormone (hGH) stimulates the production and release of insulin-like growth factor I (IGF-1) which induces cell proliferation and differentiation (Rosenbloom, 2009). GH has evaluated in a phase II trial (NCT00635960) with no effects on disease progression (Sacca et al., 2011).

GSK1223249
GSK1223249 is a humanised monoclonal antibody which counteracts the inhibition of neurite outgrowth by Nogo-A. Currently, GSK1223249 is evaluated in a phase I study (NCT00875446) for safety in ALS patients.

Guanidine
In a clinical trial, guanidine caused severe side effects such as acute paralysis . In a cross-over study with amantadine, no benefits for ALS patients have been described (Munsat et al., 1981).

Indinavir
The antiviral drug indinavir did not show a benefit in ALS patients (Scelsa et al., 2005).

Insulin-like growth factor-1 (IGF-1)
IGF-1 is a growth factor stimulated by the human growth hormone (hGH). It induces cell proliferation and differentiation (Rosenbloom, 2009). Whereas a first trial of IGF-1 in ALS patients reported a slower disease progression of functional impairment and a higher quality of life score (Lai et al., 1997), a subsequent study did not find beneficial effects after 9 months of treatment (Borasio et al., 1998). A phase III clinical trial (NCT00035815) found no beneficial effects after 2 years of treatment in ALS patients .

Lamotrigine
Lamotrigine is an anti-epileptic drug with anti-excitotocicity effects. It has been tested in two clinical trials (Eisen et al., 1993;Ryberg et al., 2003) showing no effects on disease progression.

Lecithin
The term lecithin describes a group compounds consisting of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids. Typical members comprehend phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. In a clinical trial, lecithin did not show a benefit in ALS patients (Kelemen et al., 1982). www.intechopen.com

Leuprorelin (Leuprolide)
Leuprorelin is a is a nonapeptide and a GnRH analog. It has been tested in a phase II study in combination with testosterone (NCT00004771), the results are awaited.

Levamisole
Levamisole is a synthetic imidazothiazole derivative with anti-helmintic and immunomodulatory effects. In a clinical trial, no beneficial effects have been seen for ALS patients (Olarte & Shafer, 1985).

Lithium
Lithium has been described as inductor of autophagy and anti-oxidant. Clinically, it is used as mood stabilizer. In a phase II study (EudraCT ), lithium did not show efficacy with regard to survival and keeping of patient autonomy (Chio et al.). In another phase II study, lithium was reported to delay disease progression (Fornai et al., 2008), but in a follow-up, riluzole add-on phase II study (NCT00818389), lithium has been proven to be safe and well tolerated in ALS patients, but did not slow disease progression (Aggarwal et al.). Due to these findings, two other studies of lithium are currently not recruiting patients (NCT00925847, NCT00790582).

Memantine
Memantine non-competitive antagonist at the NMDA and AMPA glutamate receptors with low affinity. In two phase II/III clinical trials (NCT01020331, NCT00409721), memantine was safe and tolerated, but no efficacy has been found in ALS patients .

Methylcobalamin (E0302, mecobalamin)
Methylcobalamin is an analog of vitamin B12, which reduces the concentration of homocystein, an excitatory amino acid which showed toxic effects on motor neurons by inducing apoptosis. ALS patients treated with high doses of methylcobalamin (MeCbl) showed an increase in compound muscle action potential amplitudes (CMAPs) after 4 weeks of treatment (Kaji et al., 1998). It increased the decline in ALS patients with regard to becoming respirator-bound (Izumi & Kaji, 2007). Methylcobalamin is currently evaluated in two phase III studies (NCT00445172, NCT00444613) in ALS patients

Minocycline
Minocycline has been described as anti-apoptotic and anti-inflammatory. In a phase III study (NCT00047723), minocycline showed harmful effects of minocycline in ALS patients (Gordon et al., 2007).

Modafinil
Modafinil is a psychostimulant clinically used for the treatment of narcolepsy and other sleep disorders.
It is currently evaluated in a phase IV study (NCT00614926) for the treatment of fatigue in ALS patients.

Naloxone
The µ opioid receptor antagonist naloxone did not show a benefit in ALS patients (Silani et al., 1983).

Neostigmine
The cholinesterase inhibitor did not show a benefit in ALS patients (Aquilonius et al., 1986).

Nimodipine
The calcium channel antagonist nimodipine showed no beneficial effect in a clinical trail in ALS patients .

NP001
NP001 is a small molecule regulator of macrophage activation, which aims at restoring the neuroprotective state of macrophages, reducing inflammation, and normalizing the neuronal microenvironment. NP001 has been tested in a phase I trial (NCT01091142) for safety and tolerability. It is currently evaluated in a subsequent phase II clinical trial (NCT01281631).

Olanzapine
Olanzapine is an atypic neuroleptic drug used in psychiatry for the treatment of schizophrenia and other psychoses. One of its effects is also weight gain. In ALS patients, an involuntary weight loss of more than 10 percent of the original body weight correlates with an increased mortality. Thus treatment with olanzapine might increase the body weight, or, at least, keep it constant. Currently, olanzapine is evaluated in a phase II/III study (NCT00876772) in ALS patients.

Olesoxime (TRO19622)
Olesoxime is a neuroprotective agent with a cholesterol-like structure which is thought to act at the mitochondrial membrane (Bordet et al., 2010;Martin, 2010). Currently, olesoxime is evaluated in a phase II/III trial (NCT00868166) as add-on to riluzole and a phase II/III safety extension study (NCT01285583).

Penicillamine
The metal ion chelating agent penicillamine did not show a benefit in ALS patients (Conradi et al., 1982).

Pentoxifylline
Pentoxifylline is an anti-apoptotic drug. It has been tested in a riluzole add-on phase II clinical trial, which did not show efficacy, but increased mortality (Meininger et al., 2006).

Phthalazine
The inhibitor of cyclic adenosine monophosphate (cAMP) phosphodiesterase and cyclic guanine monophosphate (cGMP) phosphodiesterase phthalazinol did not show a benefit in ALS patients (Engel & Brooks, 1980).

Physostigmine
The acetylcholine esterase inhibitor physostigmine did not show a benefit in ALS patients (Norris et al., 1993).

Pioglitazone
Pioglitazone activates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) (Gillies & Dunn, 2000;Kiaei, 2008). It has been used as anti-diabetic drug in diabetes type 2. In phase II clinical trial (NCT00690118), pioglitazone was found to be save and welltolerated, but showed no effect on ALS disease progression (Ludolph et al., 2010). In a riluzole add-on phase II study (NCT00919555), pioglitazone is currently evaluated in combination with tretinoin.

Prednisolone
The immunosuppressant prednisolone in combination with azathioprine did not show a benefit in ALS patients (Werdelin et al., 1990).

Pyrimethamine
The anti-malaria drug pyrimethamine was found to reduce SOD1 levels in vitro and in vivo in rodents as well as in humans (Lange, 2008). Pyrimethamine is currently evaluated in a phase I/II trial (NCT01083667) for tolerability, safety, and efficacy in familial ALS.

Rasagiline
Rasagiline is a monoamine oxidase type B inhibitor with neuroprotective effects. Rasagiline is currently evaluated in a phase II clinical trial (NCT01232738).

Riluzole
Riluzole is an anti-glutamatergic drug (Cheah et al., 2010;. In two clinical trials, riluzole showed a moderate increase of about two months in survival after 21 and 18 months of treatment, respectively (Bensimon et al., 1994;Lacomblez et al., 1996). An open-label phase IV study (NCT00542412) found a longer survival in riluzoletreated patients of 92 days in median. In subsequent population-based trials, older patients and patients with bulbar-onset had the biggest beneficial effect of riluzole, but the effects were transient and lost after longer periods of observation (Traynor et al., 2003;Zoccolella et al., 2007).

SB-509
SB-509 is an engeineered zinc finger protein which up-regulates the transcription of the proangiogenic vascular entothelial growth factor A (VEGF-A) (Liu et al., 2001), which is also neuroprotective and neuroregenerative (Maurer et al., 2008) SB-509 is currently evaluated in a phase II clinical trial (NCT00748501). www.intechopen.com

Selegiline
The anti-depressant drug selegiline is an inhibitor of monoamino oxidase B. It has been tested in several clinical trials without benefit for ALS patients (Jossan et al., 1994;Lange et al., 1998;Mazzini et al., 1994).

Snake venom
Modified snake venom as neurotoxin did not show a benefit in ALS patients (Rivera et al., 1980).

Sodium phenylbutyrate
Sodium phenylbutyrate acts as a histone deacetylase inhibitor, therefore it improves transcription and stimulates post-transcriptional pathways. In a phase II study (NCT00107770), sodium phenylbutyrate was safe and well tolerated ).

Sodium valproate
Valproic acid (VPA) is a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity. It is used as antiepileptic drug. In a phase II clinical trial (NCT00136110), VPA has been found safe but not effective with regard to survival and disease progression (Piepers et al., 2009).

Talampanel (GYKI 53405)
Talampanel is a derivated benzodiazepine which is a non-competitive antagonist at the AMPA glutamate receptor. It has been evaluated in a phase II trial (NCT00982150) which showed safety and tolerability (Pascuzzi et al., 2010), whereas a subsequent phase II study (NCT00696332) did not show efficacy in ALS patients (reviewed in Carlesi et al., 2011).

Tamoxifen
The selective estrogen receptor modulator tamoxifen is an inhibitor of protein kinase C, which is a mediator in neuroinflammation. It has been evaluated in a phase II study (NCT00214110) in ALS patients (Brooks et al., 2005) and was recommended for a phase III trial (mentioned in Traynor et al., 2006). Currently, tamoxifen is evaluated in a phase II clinical trial (NCT01257581) in combination with creatine in ALS patients.

Tauroursodeoxycholic acid (TUDCA)
In preclinical data, tauroursodeoxycholic acid (TUDCA) has been found to be neuroprotective, antioxidative, and antiapoptotic in rat models of neurodegenerative diseases such as stroke  and Huntington's disease (Keene et al., 2002). TUDCA is currently evaluated in a phase II study (NCT00877604) for safety and efficacy.

Testosterone
The sexual hormone testosterone has been tested in a phase II study in combination with leuprolide (NCT00004771), the results are awaited.

Tetrahydroaminoacridine (Tacrine, THA)
The reversible inhibitor of cholinesterase THA did not show a benefit in ALS patients (Askmark et al., 1990).

Thalidomide
Thalidomide is a small molecule which has been used as a sedative drug in the 1950s-1960s. Due to its teratogenic and neuropathic adverse effects, its use was discontinued until the 1990s, when thalidomide was introduced in oncology for its anti-angiogenic effects. With regard to clinical trials in ALS, thalidomide was tested in a phase II clinical trial (NCT00140452) (Stommel et al., 2009), with no improvement in the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment. Moreover, thalidomide showed severe side effects, and did not affect anti-inflammatory cytokine levels. A second phase II clinical trial (NCT00231140) was terminated after severe adverse effects (Thomas Meyer, 2005).

L-Threonine
The hydroxylated essential amino acid L-threonine did not show a benefit in ALS patients (Blin et al., 1992;Tandan et al., 1996).

Tilorone
The antiviral drug tilorone did not show a benefit in ALS patients (Olson et al., 1978).

Tocopherol (Vitamin E)
The anti-oxidant tocopherol has been evaluated in two phase II clinical trials, where tocopherol has been as add-on medication to riluzole in ALS patients. Both studies reported safe and well-tolerated drug administration, but no beneficial effect for ALS patients (Desnuelle et al., 2001;Graf et al., 2005). In a retrospective case-control study, high dosage of tocopherol decreased the risk of developing ALS (Veldink et al., 2007).

Topiramate
Topiramate is an anti-convulsant with anti-glutamatergic effects. It has been tested in a clinical trial without benefit for ALS patients, but with an increased rate of life-threatening side effects (Cudkowicz et al., 2003).

Transfer factor
The antiviral agent transfer factor did not show a benefit in ALS patients (Jonas et al., 1979;Olarte et al., 1979).

Tretinoin (all-trans retinoic acid)
Tretinoin is the all-trans form of retinoic acid. It has various effects in the nervous system, including neuroprotection and neuroregeneration (for review, see ). In a riluzole add-on phase II study (NCT00919555), tretinoin is currently evaluated in combination with pioglitazone.

Trypan blue and trypan red
The antimicrobial agents trypan blue and trypan red did not show a beneficial effect in ALS patients (Montanari & Pessina, 1955;Schwob & Bonduelle, 1952).

Vascular endothelial growth factor (VEGF, sNN0029)
VEGF is a neuroprotectice and angiogenic growth factor (Maurer et al., 2008). It is currently tested in a phase I/II clinical trial (NCT00800501) for safety and tolerability. Of note, VEGF must be administered into the CSF.

Verapamil
The calcium channel antagonist verapamil showed no beneficial effect in a clinical trail in ALS patients .

Xaliproden (SR57746)
The 5HT1R agonist xaliproden is neurotrophic and neuroprotective. It has been evaluated in phase II/III trials, which showed modest effects on vital capacity, but not on survival of ALS patients Meininger et al., 2004).

YAM80
There is no drug information available for YAM80 searching literature and chemical databases. YAM80 is evaluated in a phase II study (NCT00886977) for safety and efficacy in ALS patients.

Zidovudine
The antiviral drug zidovudine did not show a benefit in ALS patients (Westarp et al., 1993).

"Alternative" therapeutic approaches
Since most clinical trials in ALS did not show a benefit for ALS patients, a number of "alternative" or off-label cures have been propagated. Besides severe ethical issues, these treatments are of experimental nature, but not in the sense of a registered trial. Some ALS patients who are desperately looking for a relief, tend to participate in these treatments, although they have to pay large amounts of money by themselves, and no proven, or replicable outcome has been reported in a peer-reviewed journal. To evaluate some of these treatments, the ALSUntangled group (www.alsuntangled.com), which is based on social networking of patients, clinicians, and scientists (Bedlack & Hardiman, 2009), reports sporadically on these treatments (see homepage for open and completed investigations).

Outlook
ALS remains a mysterious disease with a limited life expectancy and a deteriorating condition, although efforts in basic and clinical research brought some light in the understanding of pathophysiological aspects of MND. With dozens of failed neuropharmacological trials in ALS, the current concept of the design of clinical trials in ALS patients must be reevaluated, as well as the pre-clinical models. Future research may concentrate on the definition of ALS, maybe by the use of biomarkers, and on translational aspects, that is, how to transfer pre-clinical results into successful clinical treatment.

Acknowledgments
The author has been supported by grants of the European Union within the Framework Program 7, the Germany Ministry of Research and Education (BMBF) within the National Genome Research Network NGFN-2, the German Research Foundation DFG, the intramural program of the Medical Faculty of the University of Heidelberg, the Steuben-Schurz Society, and the Estate of Friedrich Fischer. www.intechopen.com

Publisher InTech
Published online 20, January, 2012 Published in print edition January, 2012 Though considerable amount of research, both pre-clinical and clinical, has been conducted during recent years, Amyotrophic Lateral Sclerosis (ALS) remains one of the mysterious diseases of the 21st century. Great efforts have been made to develop pathophysiological models and to clarify the underlying pathology, and with novel instruments in genetics and transgenic techniques, the aim for finding a durable cure comes into scope.
On the other hand, most pharmacological trials failed to show a benefit for ALS patients. In this book, the reader will find a compilation of state-of-the-art reviews about the etiology, epidemiology, and pathophysiology of ALS, the molecular basis of disease progression and clinical manifestations, the genetics familial ALS, as well as novel diagnostic criteria in the field of electrophysiology. An overview over all relevant pharmacological trials in ALS patients is also included, while the book concludes with a discussion on current advances and future trends in ALS research.