Remacemide
Drug Summary: Remacemide (RMC) is a drug that HD researchers hope can alleviate glutamate toxicity in the brains of HD patients. Remacemide is an NMDA antagonist – it inhibits the binding of glutamate to NMDA receptors, preventing glutamate from exerting its toxic effects on the nerve cell. Although, it has been shown to transiently improve motor performance in mouse models of HD, the few human clinical trials that have been performed have not produced statistically significant improvements in brain or motor function. Patients have also experienced side effects such as lightheadedness, dizziness, vomiting, nausea, and gastrointestinal disturbance.
The lowered amount of energy available in the nerve cells of patients with HD is thought to cause NMDA receptors to be oversensitive to glutamate. Therefore, normal physiological levels of glutamate can cause overexcitation of the NMDA receptor, leading to the influx of calcium ions into the cell. Excess calcium ion entry can lead to cell death through a combination of events. (For more information, click here.)
Remacemide, sometimes referred to as Remacemide Hydrochloride, is under investigation as a treatment for HD because it acts as a non-competitive inhibitor of the NMDA receptor. This means that remacemide decreases the receptor’s ability to bind glutamate by docking to a site on the receptor other than the glutamate binding site, and changing the shape of the receptor such that glutamate has a difficult time binding. Researchers hope that by inhibiting the NMDA receptor, the toxic effects of glutamate in the neurons of patients with HD can be lessened.
Clinical trials have examined the effectiveness of remacemide in curbing or stopping the neurodegenerative effects of HD in humans. Although remacemide treatment has not produced statistically significant improvement in these trials, in some patients it seems to transiently improve certain motor symptoms caused by HD such as chorea. Side effects such as dizziness, nausea, vomiting, lightheadedness, and gastrointestinal disturbances tended to accompany treatment.
Experiments done on mouse models of HD have been more positive.
Research on Remacemide^
Kieburtz, et al. (1996) conducted a study on the effects of remacemide in 31 participants in the early-stages of HD. The study was conducted over a 5-week period and the participants were divided into three treatment groups:
• 10 received 200 mg of remacemide per day
• 10 received 600 mg of remacemide per day
• 11 received a placebo (no medication at all)
The total functional capacity (TFC) of the participants was used as the criteria of the drug’s effectiveness. TFC is a standardized scale used to assess capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The TFC scale ranges from 13 (normal) to 0 (severe disability). The HD Motor Rating Scale (HDMRS) was also used to assess the motor capabilities of the participants. The HDMRS consists of 14 items that assess the relevant motor features of HD including chorea and other motor functions. Other psychological tests were also conducted to measure the effectiveness of the drug in improving cognitive function.
Following treatment, the researchers concluded that there was no statistically significant difference between the three treatment groups. However, a trend towards improvement in chorea was observed among the participants who received 200 mg of remacemide per day. No major side effects were observed in most of the participants. However, one of the participants who received 600 mg/day did not complete the study due to persistent nausea and vomiting, which was believed to be a result of the medication.
The researchers concluded that remacemide could have short-term effects in improving chorea experienced by people in the early stages of HD. No statistically significant changes in cognitive performances were seen in the treatment groups. Larger, long-term controlled studies of remacemide are needed to determine the duration of tolerability and potential benefits of remacemide and other NMDA blockers.
The Huntington Study Group (2001) conducted a clinical trial involving 347 early-stage HD patients at 23 sites in the United States and Canada, monitored between July 1997 and June 1998. Participants in the study were assigned to four different treatments:
• 25% received remacemide (200 mg thrice a day)
• 25% received CoQ10 (300 mg twice a day)
• 25% received a combination of remacemide and CoQ10
• 25% received a placebo (no medication at all)
The primary measure of the drug’s effectiveness was change in total functional capacity (TFC) of the people with HD. A score of 13 represents a normal degree of function and a score of 0 represents a severely disabled state. The average TFC score of the participants before the study was 10.2. None of the treatments significantly altered the decline in TFC.
The condition of the participants who were treated with remacemide worsened by 2.3 points on the TFC scale, showing that the drug had no beneficial effect on slowing the functional decline experienced by people with HD. However, there was a trend toward an improvement in the degree of chorea in the participants treated with remacemide. Although this effect was not statistically significant, the effect was seen during the patient’s first visit after treatment began, suggesting that remacemide may decrease chorea. These findings suggest that antiglutamate therapies could be useful in controlling chorea even if they have no impact on slowing functional decline. However, remacemide was associated with side effects that included dizziness, lightheadedness and nausea. A trend towards a decrease in TFC decline was seen in the participants treated with CoQ10. (For information on CoQ10, click here.)
Ferrante et al. (2002) studied the potential therapeutic effects of remacemide, coenzyme Q10, and the combination of the two drugs on transgenic mouse models of Huntington’s Disease. They found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using CoQ10 and remacemide together, was even more effective than either compound alone.
For further reading^
- Kieburtz, et al. “A controlled trial of remacemide hydrochloride in Huntington’s disease.” Movement Disorders. 1996, May; 11(3): 273-7.
This article contains the full details on the study by Kieburtz, et al. - The Huntington Study Group. “A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease.” Neurology. 2001, Aug 14; 57(3): 397-404.
This article contains details on the study done by The Huntington Study Group. - Schilling, et al. “Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model.” Neuroscience Letters. 2001, Nov 27; 315(3): 149-153.
- Ferrante, et al. “Therapeutic Effects of Coenzyme Q10 and Remacemide in Transgenic Mouse Models of Huntington’s Disease.” Journal of Neurosience. 2002, Mar 1; 22(5): 1592-1598.
-P. Chang, 7/5/04