Obscure and Unknown: Aptiganel

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

Hello, for today's installment we will be looking at Aptiganel, aka Cerestate, or CNS-1102, an aborted pharmaceutical intended for treatment of strokes whose failure led to the collapse of its development company, Cambridge Neuroscience inc. It may not be obscure for anyone who was involved in that company. Its failure was due to it doing pretty much the opposite of what it was designed for, in addition to some side effects. Considering it is an NMDA antagonist those side effects end up being very interesting!

A problem child

Aptiganel is basically an amino-naphthalene (or naphthylamide if you will (If you're not familiar with the molecules, naphthalene is the chemical used in mothballs, naphthylamide just means that with a nitrogen and 2 hydrogens stuck onto it)) joined to a 3-ethyl-Methyalaniline (with an extra amino group mixed in). As far as I know this isn't structurally analagous to any known psychoactive chemicals, though it could perhaps be a base that could be expanded upon. 

Aptiganel was first developed as a treatment for ischemic stroke, based on the observation that high levels of gluatamate are released in the event of a stroke, further exacerbating the problem. Thus it stands that an NMDA (glutamate) antagonist should soften the blow a little1. This hypothesis was laid out in "Cerestat and other NMDA antagonists in ischemic stroke" by KR Lees, who notes
"The competitive and noncompetitive glutamate antagonists share a propensity to cause confusion, agitation, or hallucinations. Moreover, progression to catatonia has been noted with Aptiganel hydrochloride at high doses. These effects have been dose limiting."
Exciting!

A phase II study published around the same time as this observed the effects of prolonged infusions2. Total doses of 15, 32, 50, and 72 μg/kg were used (for a 62 kg (137 lb) person this comes out to doses of 930, 1984, 3100, 4464 μg total).
Really interesting results- one volunteer who had received 66 μg/kg before the doses were stopped had vivid open eyed hallucinations of domestic animals, which were received amusingly. He also stated he "believed his fingers and toes were disappearing and repeatedly counted them". This is consistent with the loss of proprioception from dissociatives and the anesthesia of extremities. He also stated having an unclear memory of these events after he had recovered. These effects first appeared 30 minutes after initial dose and persisted for 90 minutes, after which the volunteer felt sedation and drowsiness. Another volunteer had vivid recollection of memories. Many patients also noted a tingling sensation on their skin and through their extremities, also reminiscent of dissociatives.
All in all, there was a low proportion of volunteers that experienced these effects, and they were in the upper dosage ranges. It is possible that the upper dose ranges used in this experiment (lets just say 3-4.5 mg for simplicity sake) would form the lower bounds of a psychoactive dose.

Another study went into further detail on the side effects3. This delved into higher doses, at 4.5 and 6 mg. Patients in the higher dose ranges consistently developed marked sedation, with occasional agitation and hallucinations. This is perhaps reminiscent of a "hole".

These were published concurrent to the running of phase III clinical trials. So what happened next? Phase 3 trials determined that Aptiganel did nothing to abate the damage caused by strokes4. In fact a higher mortality was seen in stroke patients treated with Aptiganel vs. those treated with Placebo. Add a litany of concerning side effects and you get a failed drug. The trials were not even run to completion due to the mortality rate. Cambridge Neuroscience had invested a lot in this drug, and it turns out that it was likely even worse for patients than taking nothing. Oof. Tough break. They were forced to lay off half of their staff and sell off a great deal of their equipment, eventually selling the entire company to CeNeS Pharmaceuticals5.

So what do we have here? Aptiganel certainly won't help you if you have a stroke. However, in doses <10 mg, there are notable CNS effects that resemble that of "recreational" NMDA antagonists, with the capability of even producing vivid open eyed visuals. Perhaps someone more experienced with the world of dissociatives would have been able to provide a meatier description of the effects, but it is clear that Aptiganel is psychoactive to some degree.

But is it safe? Trials showed an increase in heart rate and blood pressure, but this is seen with most dissociatives already in safe ranges. Other side effects like nausea and headache are also fairly common and unalarming in dissociatives- thus it is probably not TOO dangerous, though if you dare to go out and seek this, effects should be clinically monitored, titrated up from a very low dose. Also if you have had a stroke recently, this drug is probably very unadvised.

Sources and Further Reading:
1-Lees KR, (1997) Cerestat and other NMDA antagonists in ischemic stroke. Neurology 49(5 Suppl 4):S66-69
2-Muir KW., Grosset DG., Lees KR. Effects of prolonged infusion of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers. Clin Neuropharmacol. 1997;20:311–321
3-Dyker AG, Edwards KR, Fayad PB, Hormes JT, Lees KR, (1999) Safety and Tolerability Study of Aptiganel Hydrochloride in Patients With an Acute Ischemic Stroke. Stroke 30:2028-2042
4-Albers GW, Goldstein LB, Hall D, Lesko LM (2001) Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286:2673–2682
5-https://www.bizjournals.com/boston/stories/1998/05/04/daily8.html