TRIAL AGENTS

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose

Description:

Blueberry extract is an edible product which is available in health and grocery stores. It will be supplied in concentrated liquid extract form.

Mechanism of Action:

This product works as an antioxidant, stabilizing membrane function and promoting growth of new neurons.

Rationale for Use in HD:

This product has been shown to improve balance, coordination, and short-term memory and promote neurogenesis in the Alzheimer's rat model (Joseph et al., 2003).

Dosage:

The dosage is equivalent to 1 cup of blueberries per day. This corresponds to l tablespoon of the extract per day. This extract will remain more active if it is frozen.

Adverse effects:

There may be a laxative effect, but otherwise no adverse effects are expected.

References:

• Joseph, et al., Nutrition Neuroscience June 2003; 6 (3): 153-162

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose

Description:

Co-enzyme Q10 is a non-prescription dietary supplement that can be bought across the counter at health stores or pharmacies. It is a natural nutrient made in the human body which is involved in multiple cell processes. It is also found in meat and seafood.

Coenzyme-Q10 will be obtained from Tishcon.

Mechanism of Action:

Coenzyme-Q10 is a carrier for electron-transfer in the mitochondrial membrane and plays a vital role in mitochondrial ATP (energy) production. It acts as a free radical scavenging agent or "antioxidant".

Rationale for Use in HD:

Research studies have shown that Co-enzyme Q10 (1) reduces brain injury and improves HD symptoms in the mouse model (Ferrante, et al., 2001), and (2) improves energy metabolism in Huntington's people (Koroshetz et al., 1997) (3) demonstrated a "trend" toward benefit in a large trial of Huntington's people with the dosage of 600 mg/day (Huntington Study Group 2001). (4) benefits people with Parkinson's disease by slowing disease progression. This study showed that doses at 1200 mg per day were better.

Dosage:

Co-enzyme Q10 will be supplied in wafer form in dosage equivalent to 1200 mg dry powder used in the Parkinson's disease study.

Contraindications:

Coenzyme-Q10 has structural similarities to vitamin K, and should be used with care in those on coumadin or warfarin blood thinners.

Adverse effects:

Side effects include nausea, diarrhea, dyspepsia and loss of appetite. Insomnia and liver enzyme elevations have been reported with higher dosages.

References:

• Ferrante et al., Journal of Neuroscience, March 1, 2002, 22(5): 1592-1599
• Huntington Study Group, Neurology 2001, 57: 397-404
• Koroshetz et al., Annals of Neurology, February 1997, 41(2): 160-1655

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose

Description:

Creatine is a dietary supplement which can be bought over the counter. It is a natural chemical made in the human body by the kidney, liver, and pancreas and is an essential component of the energy system in muscle, brain, and other cells. It is found naturally in meat and fish. Normal dietary needs are about 2 gm/day. Creatine supplements have been used for many years to enhance athletic ability.

Avicena Group will supply creatine at a 60% discount to trial participants.

Mechanism of Action:

Creatine supplement acts as an "energy buffer". Creatine supplements increase the amount of the energy molecule, ATP, which is involved in normal metabolism. Researchers believe there are several different molecular mechanisms "by which creatine could be an effective treatment" (Crest-HD authors).

Rationale for Use in HD:

Research studies have shown that creatine supplements (1) improve ATP energy function that is impaired in the mouse and human brain in Huntington's disease (Ferrante, et al., 2000) (2) reduce brain injury and improve HD symptoms in the mouse model (Ferrante et al., 2000); (3) prevent progression for a year in HD people if given at the 10 gram per day dosage (Tabrizi et al., 2003).

Administration:

It will be taken in wafer form. Though creatine has been used safely for many years, the safety of lifetime use of this agent has not been established. It is presently in study with Amyotrophic Lateral Sclerosis (ALS) and has been well tolerated even when used in seriously ill patients.

Dosage:

The dosage is 10 grams per day.

Contraindications:

Creatine should be used cautiously in people with kidney disease or in diabetics with impaired renal function.

Adverse effects:

Side effects that you should report to your doctor include: diarrhea, severe muscle cramping or pain, and vomiting.

References:

• Ferrante et al., Journal of Neuroscience, June 15, 2000, 20(12):4389-4397
• Tabrizi et al., Neurology, (July 1 of 2) 2003, 61: 141-142

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose

Description:

Cysteamine bitartrate (Cystagon) is a drug that is available by prescription only. This drug is converted in the human body to cystamine. This drug is FDA approved for treatment of a disease called cystinosis. It is used in children and adults. This drug used in Huntington's would be "off label".

The only supplier of cysteamine (cystagon) is Mylan who is not offering any discount.

Mechanism of Action:

Cystamine decreases the activity of an enzyme called transglutamase. It is thought that this enzyme helps abnormal Huntington molecules to bind, which may be an early event in disease causation. Cystamine also increases levels of chemicals that protect the nerve cell from injury. This type of drug is also used to decrease injury in Tylenol over dosage and radiation exposure.

Rationale for Use in HD:

This drug has been shown to decrease brain injury and improve symptoms in the Huntington's mouse model (Karpuj et al., 2002) and (Dedeoglu, et al., 2002). It is being studied for use in Infantile Neuronal Ceroid Lipofuscinosis which is a rare brain disorder of children. In this situation, the researchers have documented the drug in brain. (Anil Mukherjee, Principal Investigator.)

Dosage:

Dosage will be the same as that used in cystinosis in adults: 2 gm/day given in 4 divided doses. This drug comes in tablet form and must be taken frequently to maintain adequate blood level of this drug.

Adverse effects:

This drug causes nausea and GI upset. This side effect is common, and is greatly helped drugs that prevent acid secretion in the stomach, such as omeprazole (prilosec). As such, this drug will be required when cysteamine is used. Skin rash, headache, dehydration, low white blood cell count and elevated liver function tests occur much less frequently. Seizures have been reported in children with cystinosis, but it is not clear whether seizures are due to the primary disease or to the cysteamine use. This drug is bitter tasting and foul smelling. It will take some getting used to.

References:

• Karpuj et al., Nature Medicine: Feb. 2002, 8 (2) 143-149
• Dedeoglu et al., Journal of Neuroscience, Oct. 2002, 22 (20) 8942-8950

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose

Description:

Omega 3 fatty acids are non-prescription dietary supplements that can be bought over the counter at health stores or pharmacies. Omega 3 fatty acids, EPA and DHA are polyunsaturated fats that are not made in the human body, but must be obtained from food intake. They are found in highest concentrations in cold water fish.

Omegabrite will supply this agent free of charge to study participants. Mercury contaminants have been removed from this product.

Mechanism of Action:

Omega 3 fatty acids are found naturally in mitochondria where they act as coenzymes or helpers in chemical reactions which stabilize membrane function at several levels.

Rationale for Use in HD:

Research studies have shown that Omega-3 fatty acids (1) reduce brain injury and improve HD symptoms in the mouse model (Clifford, et al., 2002). (2) reduce brain inury and improve neurologic function in people in small pilot studies in late stage disease (Vaddadi, et al., 2002). Preliminary results in a human study by Amarin suggest delay of progression in midstage disease (Laxdale public announcement).

Dosage:

The Omega-3 fatty acids tablet contains EPA and DHA and is taken orally at a dosage 2 gm/day taken in divided dosage. It may be taken with or without food.

Adverse effects:

Side effects include a fish odor/ fish after taste and belching. Diarrhea has been reported as a rare side effect.

References:

• Clifford, et al., Neuroscience, Jan 18, 2002; 109(2), 81-89
• Vaddadi, et al., Neuroreport, 2002; 13, 29-33

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose

Description:

Trehalose is a disaccharide edible product that is used as a sugar substitute. It is found naturally in mushrooms. It is not (yet) sold retail in stores, at least in North America. However, we will have this agent available to us in our trials.

Trehalose is used in commercial baking because it does not turn brown with high temperatures. It is also used for medical purposes such as preserving cells in blood for transfusions and organs for transplantation.

Mechanism of Action:

This agent works by stabilizing protein structure.

Rationale for Use in HD:

Researchers have shown that this agent decreases the ability of proteins with polyglutamine stretches (like Huntington's) to aggregate. These same researchers have shown that trehalose decreases brain damage and Huntington's symptoms in the mouse model (Tanaka, et al., 2004).

Dosage:

Dosage will be 20-25 grams three times per day. This dose of sugar is similar to the amount you would get in three soda drinks per day. Trehalose is only 50% as sweet, and does not increase blood sugar or insulin level nearly as much as the same dose of regular sugar.

Adverse effects:

Side effects include bloating and diarrhea. This is a safe agent even at very high dosage.

References:

• Tanaka, et al., Nature Medicine; Jan. 2004

Blueberry extract | Co-Enzyme Q10 | Creatine | Cysteamine | Omega 3 | Trehalose