Targeting N-methyl-D-aspartate 2B receptor in painful diabetic neuropathy – mechanisms, challenges, and emerging therapeutics

Table 2 Success or failures of clinical investigations on N-methyl-D-aspartate receptor-2B antagonists from previous clinical trials

Ref.	NMDAR-2B antagonist	Clinical indication	Study phase/type of clinical trial	Outcome summary
Preskorn et al[44], 2008; Machado-Vieira et al[45], 2017	Traxoprodil (CP-101, 106)	Treatment-refractory major depressive disorder	Randomised, double-blind study	Traxoprodil produced an exceptional antidepressant response, well-tolerated without producing a dissociative reaction in patients. Nevertheless, further development of traxoprodil was not pursued due to concern for potential cardiovascular toxicity risk via QTc prolongation
Yurkewicz et al[46], 2005	Traxoprodil (CP-101, 106)	Severe traumatic brain injury	Randomised, double-blind study	Traxoprodil failed to demonstrate any mortality rate improvement or a favourable outcome that achieved statistical significance. No definitive claim of efficacy was made for traxoprodil for the treatment of severe TBI
Merchant et al[47], 1999	Traxoprodil (CP-101, 106)	Mild or acute moderate traumatic brain injury or hemorrhagic stroke	Double blind, placebo-controlled study	Minimal adverse effects of traxoprodil were reported in healthy subjects at 3 mg/kg/hour for 72 hours. The 72-hour-infused taxoprodil exerted no psychotropic effects in mild or moderate TBI or hemorrhagic stroke, but is well-tolerated by patients
Kotajima-Murakami et al[48], 2022	Ifenprodil	Methamphetamine use disorder	Exploratory, randomised, double-blind, placebo-controlled study	Ifenprodil at 120 mg/day showed safety and efficacy in reducing emotionality problems but exerted no effect on primary or secondary outcomes (such as drug use status, relapse risk, drug craving, and methamphetamine in urine)
Sugaya et al[49], 2018	Ifenprodil	Alcohol dependence	Prospective, randomised, controlled, rater-blinded study	Ifenprodil (60 mg/day for 3 months) significantly lowers the rate of heavy drinking in patients with alcohol dependence
Sasaki et al[50], 2022	Ifenprodil	Adolescent post-traumatic stress disorder (PTSD)	Randomised, double-blind, placebo-controlled trial	Ifenprodil can be a short-term, effective, safe alternative treatment for adolescent patients with PTSD
Danton et al[51], 2004	Ifenprodil	Stroke	Phase 2 clinical trial	Although eliprodil demonstrated a safer side-effect profile with promising findings in Phase 2 clinical trials; however, no considerable effect was observed in patients with stroke
Jain et al[52], 2000	Ifenprodil	Acute ischaemic stroke	Phase 3 clinical trial	Treatment of eliprodil in 8 hours (time window) for 14 14-day duration of treatment indicated no functional outcome improvement at 3 months. This clinical trial was discontinued, thus unpublished, due to lack of efficacy in sequential analysis
Branchereau and Rouffy[53], 1995	Ifenprodil	Chronic arterial occlusive disease of the legs (Fontaine stage II)	Double-blind randomised controlled trial	Ifenprodil tartrate (60 mg a.d.) improved maximum walking distance in patients. Nonetheless, no considerable evolution of ankle/brachial systolic post detected compared to placebo, ifenprodil exhibited excellent clinical and biological tolerance in the patients

PTSD: Post-traumatic stress disorder; TBI: Traumatic brain injury.