Acute Therapy Showdown

Posted by Sam Maddox in Research News on December 01, 2015 # Research

The idea of any acute therapy for spinal cord injury is to limit the damage that occurs secondary to the initial trauma. As a result of inflammation, edema and general cellular chaos, the injury process continues for hours and even days. But that process, which is becoming better understood, can be manipulated. There are new tools to protect the surviving nerve cells.

Here’s a paper, a sort of smackdown between three animal study acute SCI therapies, riluzole, cooling and glibenclamide: “A Direct Comparison of Three Clinically Relevant Treatments in a Rat Model of Cervical Spinal Cord Injury.”

Riluzole has been spoken about often here; it is a drug already FDA-approved for ALS. Given in the first eight hours after injury, by pill form, riluzole is thought to protect spinal cord tissue by blocking sodium channels, thus blocking release of the neurotransmitter glutamate, which in excess can be toxic. Riluzole is still being tested, in part by the Reeve Foundation’s North American Clinical Trials Network® (NACTN); early trial data shows a clear but modest benefit, especially for patients with some spared function.

Cooling, or hypothermia, has been explored in depth by Miami Project researchers. It makes intuitive sense that lower temperatures at the injury site would reduce swelling and thus preserve function. The timing and methods haven’t been fully worked out, but results are promising.

Regarding glibenclamide, this neuroprotective strategy starts with Marc Simard, a neurosurgeon scientist at the University of Maryland. His studies, which in years past were supported by Reeve Foundation grants, have shown that initial impact to the spinal cord busts open blood vessels, causing an immediate “primary hemorrhage.” In the hours following trauma, this hemorrhage enlarges progressively, he says, to double its volume.

Simard calls this “progressive hemorrhagic necrosis” (PHN) and ties it to “catastrophic failure of the structural integrity of capillaries.” He discovered a specific ion channel, Sur1-Trpm4, triggers PHN. But by inhibiting this channel, using glibenclamide, he showed it is possible to prevent capillary fragmentation and thus preserve function.

Glibenclamide is already approved to treat diabetes. In recent months it has been administered intravenously in human trials for stroke and brain injury. A company called Remedy Pharmaceuticals, licensing Simard’s patents and indeed, adding him as a shareholder and scientific consultant, reported data last month showing that its formulation of glibenclamide -- they call it Cirara -- reduced mortality in stroke patients, particularly when administered in the first eight hours. Cirara has also been tested in brain injury; no data has been reported but the company says it is coming soon.

Simard, FYI, is the primary author of the three-way comparison. He says no support, direct or indirect, was provided by Remedy.

On to the paper:

... we performed a direct comparison of riluzole, systemic hypothermia and glibenclamide. Despite the high quality of the published research on these treatments, there previously was no reliable way to compare them in terms of efficacy (i.e., to judge which might be better) since different models were used, different laboratories were involved, and different outcomes may have been evaluated. Similarly, there was no way to compare the three in terms of safety, given that each has its own treatment-associated complications or untoward side-effects, especially in the context of injury.

Here, we directly compared riluzole, systemic hypothermia, and glibenclamide in a single experiment; moreover, a wide variety of treatment and safety outcome measures were evaluated by investigators who were blinded to treatment group identity during all but the first week after trauma.

So what’s the score?

All three treatments showed overall favorable results, compared with controls, in keeping with previously published reports. On the outcome measure that is used routinely in preclinical SCI research—the BBB score—the three treatments demonstrated similar efficacy at six weeks, with all three being significantly better than controls.

The hypothermia- and glibenclamide-treated animals were largely indistinguishable throughout the entire study. Riluzole-treated rats underperformed for the first two weeks but then joined the hypothermia and glibenclamide groups, and the three treatments became almost indistinguishable by six weeks. However, on beam balance, which assesses cervical lower motor neuron function, as well as lower extremity function, hypothermia and glibenclamide treatments showed significant advantages over riluzole. A better performance with glibenclamide also was found in our previous study comparing riluzole and glibenclamide, in which a larger impact force, lower doses of both drugs, and an earlier treatment time were used.

The comparison didn’t pick a winner. Lesion volume was reduced with all three but moreso with cooling and glibenclamide. Three rats on riluzole died, compared to one with cooling and none with glibenclamide -- and including three control animals. Simard suggests riluzole's toxicity profile relative to dose should be monitored.

Glibenclamide had one unexpected advantage. Spinal cord injury is often accompanied by malnutrition and thus prolonged post-injury loss of body weight. But not with this treatment:

An intriguing observation from the present study is that rats in the glibenclamide group lost comparatively little weight and rapidly returned to a normal pattern of weight gain, a finding that differed markedly and significantly from all other groups.

Bottom line: Simard likes his drug.

In summary, the data reported here reaffirm that riluzole, systemic hypothermia, and glibenclamide are strong candidates for translation to clinical trials in SCI. With regard to safety and efficacy (lesion volume), systemic hypothermia and glibenclamide appear to be superior to riluzole. With regard to safety, efficacy, general well-being, and ease of administration, glibenclamide appears to be superior to riluzole and systemic hypothermia.

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