**5.3.61 Prednisolone**

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

### **5.3.62 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.

### **5.3.63 Rasagiline**

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

### **5.3.64 Riluzole**

Riluzole is an anti-glutamatergic drug (Cheah et al., 2010; R.G. Miller et al., 2007).

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).

### **5.3.65 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).

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials 21

The sexual hormone testosterone has been tested in a phase II study in combination with

The reversible inhibitor of cholinesterase THA did not show a benefit in ALS patients

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

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

A second phase II clinical trial (NCT00231140) was terminated after severe adverse effects

The hydroxylated essential amino acid L-threonine did not show a benefit in ALS patients

TRH has been tested in a larger number of clinical trials, but none of them showed a benefit in ALS patients (Brooke et al., 1986; Brooks et al., 1987; Caroscio et al., 1986; Congia et al., 1991; Hawley et al., 1987; Imoto et al., 1984; Klimek et al., 1989; Klimek et al., 1988; Miller & Warnick, 1989; Mitsumoto et al., 1986; Munsat et al., 1992; Patrignani et al., 1992; Serratrice

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

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

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

1990s, when thalidomide was introduced in oncology for its anti-angiogenic effects.

**5.3.74 Testosterone** 

(Askmark et al., 1990).

**5.3.76 Thalidomide** 

(Thomas Meyer, 2005).

**5.3.77 L-Threonine** 

**5.3.79 Tilorone** 

**5.3.81 Topiramate** 

**5.3.80 Tocopherol (Vitamin E)** 

side effects (Cudkowicz et al., 2003).

leuprolide (NCT00004771), the results are awaited.

**5.3.75 Tetrahydroaminoacridine (Tacrine, THA)** 

affect anti-inflammatory cytokine levels.

(Blin et al., 1992; Tandan et al., 1996).

**5.3.78 Thyreotropin releasing hormone (TRH, Protirelin)** 

et al., 1985; Stober et al., 1985; Thielen et al., 1987; Yamane et al., 1986).

tocopherol decreased the risk of developing ALS (Veldink et al., 2007).

### **5.3.66 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).

### **5.3.67 Snake venom**

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

### **5.3.68 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 (Cudkowicz et al., 2009).

### **5.3.69 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).

### **5.3.70 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).

### **5.3.71 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.

### **5.3.72 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 (Rodrigues et al., 2002) and Huntington's disease (Keene et al., 2002). TUDCA is currently evaluated in a phase II study (NCT00877604) for safety and efficacy.

### **5.3.73 TCH346**

TCH 346 showed neuroprotective effects by binding glyceraldehydes-3-phosphate dehydrogenase (GAPDH) (Mück-Seler & Pivac, 2000).

It has been evaluated in three phase II studies (NCT00230074, NCT00072709, NCT00036413), where it showed no beneficial effects in ALS (R. Miller et al., 2007).
