Denosyl (Canada)

(S-Adenosylmethionine)

Denosyl, a nutritional supplement, is the pure and stabilized salt of S-Adenosylmethionine for veterinary use only. It is the only brand researched in U.S. trials for veterinary use in dogs and cats. Denosyl is available in two strengths: as an enteric coated 90 mg and 225 mg tablet of active S-Adenosylmethionine. Because S-Adenosylmethionine is extremely sensitive to moisture, tablets are individually sealed in specialized moisture-resistant blister packs.

Background

S-Adenosylmethionine is an endogenous molecule synthesized by cells throughout the body and is formed from the amino acid methionine and ATP. It is an essential part of three major biochemical pathways: transmethylation, transsulfuration and aminopropylation. As part of these pathways, S-Adenosylmethionine is essential to all cells and is particularly important in hepatocytes because of their central role in metabolism. A deficiency of S-Adenosylmethionine, therefore, may initiate or contribute to abnormalities of cellular structure and function in the liver as well as many other body tissues.

Conversely, exogenous administration of S-Adenosylmethionine has been shown to result in improvements in hepatocellular function in both in-vivo and in-vitro studies, without cytotoxicity or significant side effects. ^1-9Precursors of S-adenosylmethionine do not have similar effects. Administration of methionine to animals with decreased liver function may not increase hepatic S-adenosylmethionine levels and may be toxic. ⁶ The best way to increase S-adenosylmethionine levels is by direct supplementation with S-adenosylmethionine.

Purpose

Denosyl has been shown to increase hepatic glutathione levels in cats and dogs ^1,7. Glutathione is a potent antioxidant that protects hepatic cells from toxins and death. A study found that low liver glutathione concentrations are common in dogs and cats with decreased hepatobiliary function. ¹⁰ Denosyl is recommended to improve hepatic glutathione levels in patients to help maintain and protect liver function. Denosyl may also be used in other areas of tissue oxidant injury and RBC fragility caused by certain toxins or drugs which are related to reduced glutathione concentrations ⁶. Denosyl, however, goes beyond increasing glutathione levels and has been shown to protect liver cells from cell death ^2,8 and may be useful in cell regeneration. ⁶

Pharmacokinetics

In a pharmacokinetic study with fasted dogs given Denosyl, peak plasma levels were recorded in most dogs within 4 hours of administration. ¹ A pharmacokinetic study in fasted cats showed peak plasma levels at 2-4 hours post Denosyl administration. ^7,11

Safety

Denosyl demonstrates an exceptionally wide margin of safety. Oral acute toxicity studies in rats indicated an LD₅₀ greater than 4,640 mg/kg. ⁶ Clinically healthy dogs administered 20 mg/kg/day of Denosyl for 6 weeks, and clinically healthy cats administered Denosyl at 2 times the recommended daily amount for 113 days remained healthy with no adverse effects from administration of Denosyl. ^1-7

Administration As A Nutritional Supplement

Because the tablet must be kept intact to prevent destruction by stomach acid, administration range is based on the nearest whole-tablet. The chart below is provided as a guide for administration. Daily administration may also be calculated based on 20 mg/kg of body weight and rounded to the closest tablet size of combination of sizes.

For optimal absorption, tablets should be given on an empty stomach, at least one hour before feeding, as the presence of food decreases the absorption of S-Adenosylmethionine. For those owners who have difficulty administering tablets to their pets, Denosyl tablet(s) may be disguised in a small bite of food. Studies have shown that, in many cases, tablets or capsules given as a “dry swallow” do not pass into the stomach in cats but may become lodged in the esophagus. It is recommended for pet owners to administer 3-6 cc of water immediately following any tablet administration to speed passage of the tablet into the stomach. ^12,13Denosyl 90 mg tablets are ideal for cats because of their small size. If the pet is to receive more than one tablet daily, the total number of tablets may be divided between morning and evening for ease of administration. For example, a daily administration of three tablets could be divided into two tablets in the morning and one tablet in the evening.

Storage

Store in a cool dry place. Keep tablets in original blister pack until used. Tablets are sensitive to moisture and extreme heat and should not be split or crumbled.

FELINE AND CANINE Denosyl ADMINISTRATION GUIDE

The number of tablets can be gradually reduced or may be increased at any time depending on the pet's needs. Many pets may be maintained long-term on every-other-day or every-third-day administration.

REFERENCES

1. Center SA, Warner K, Hoffman WE, et al. Evaluation of the influence of S-adenosylmethionine on systemic and hepatic effects of prednisolone in dogs. AJVR 2005;66(2):330-341.

2. Webster CRL, Boria P, Usechak P, Answer MS. S-Adnosylmethionine and cAMP confer differential cytoprotection against bile acid-induced apoptosis in canine renal tubular cells and primary rat hepatocytes. Vet Therapeutics 2002;3(4):474-484.

3. Wallace KP, Center SA, Hickford FH, et al. S-adenosyl-l-methionine (SAMe) in the treatment of acetaminophen toxicity in a dog. J Am Anim Hosp Assoc 2002;38:246-254.

4. Webb CB, Twedt DC, Fettman MJ, Mason G. S-Adenosylmethionine (SAMe) in a feline acetaminophen model of oxidative injury. J Fel Med & Surg 2003;5:69-75.

5. Center SA, Warner KL. Influence of chronic oral S-adnosylmethionine (SAMe) on biliary glutathione and bile acid concentrations in healthy cats. Proceedings of the 22^nd ACVIM, Minneapolis, MN:867-868, 2004.

6. Center SA. S-Adenosyl-methionine an antioxidant and anti-inflammatory nutraceutical. Proccedings of the 18th ACVIM, Seattle, WA: 550-552, 2000

7. Center SA, Randolph JF, Warner K, et al. The effects of s-adenosylmethionine on clinical pathology and redox potential in the red blood cell, liver, and bile of clinically normal cats. J Vet Intern Med 2005; 19;303-314.

8. McCool J, Johnston A, Webster CRL. Effect of hepatoprotective agents in an in vivo model of cholestatic liver disease. Proceeding of the 21^st ACVIM, Charlotte, NC, 2003; abstract #134.

9. Watson PJ, Scott L, Smith N, Mariln DJ. The use of S-adenosylmethionine in cats and dogs with liver disease. Proc. ECVIM-CA/ESVIM, Munich;178, 2002.

10. Center SA, Warner KL, Erb HN. Liver glutathionoine concentrations in dogs and cats with naturally occuring liver disease. AJVR 2002,63(8):1187-1197.

11. Center SA, Warner KL Pharmacokinetics of S-Adenosylmethionine delivered in enteric coated tablets to healthy cats: acute and chronic oral dosing study. World Veterinary Congress, 2002.

12. Westfall DS, Twedt DC, Steyn PF, et al. Evaluation of esophageal transit of tablets and capsules in 30 cats. J Vet Intem Med 2001;15(5):467-470.

13. Graham JP, Lipman AH, Newell SM, Roberts GD. Esophageal transit of capsules in clinically normal cats. Am J Vet Res 2000;61(6):655-657.

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