**5.3.7 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).

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials 13

The rationale of celecoxib treatment is the reduction of PGE2 in the cerebrospinal fluid

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 (Cudkowicz et al., 2006). Moreover, PGE2 levels in the CSF were not elevated at baseline and did not decline during treatment (Cudkowicz et al., 2006). In this trial, celecoxib was combined with creatinine and/or minocycline

The immunosuppressant cyclosporine A did not show a benefit in ALS patients (Appel et

It has been tested in two clinical trials finding no effect on disease progression (ALS CNTF Treatment Study Group, 1996; Miller et al., 1996), but an increased trend of adverse effects

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

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

A phase IIa study (NCT01089010) was completed in 2010 and showed a trend towards

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

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).

future comparability to other medications and effectiveness of different preparations.

short-term improvements in grip-strength and respiration parameters.

futility trial (NCT00243932) (Kaufmann et al., 2009; Levy et al., 2006).

Creatine acts as anti-oxidant and is a mitochondrial co-factor.

(CSF), thus preventing neuroinflammation and neuronal loss.

CNTF is a neurotrophic factor with neuroprotective properties.

(Gordon et al., 2008).

**5.3.16 Ciclosporine A** 

(Miller et al., 1996).

**5.3.19 CK-2017357** 

**5.3.20 Coenzyme Q10** 

**5.3.21 Creatine** 

delayed (von Haehling et al., 2010).

**5.3.17 Ciliary neurotrophic factor (CNTF)** 

**5.3.18 Cistanche total glycosides (CTGs)** 

al., 1988).

### **5.3.8 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).
