IF THE ANTIPLATELET
EFFECTS OF ASPIRIN PERSIST FOR 7 DAYS, WHY IS IT DOSED EVERY DAY?
This is an interesting question, and the concept is applicable to more than aspirin. The answer is sometimes simple: drugs are dosed according to how they are studied in clinical trials. Although the initial dosing interval studied is usually dependent on drug half-life and pharmacodynamic effects, it is certainly true that some drugs are likely to be effective for longer than the approved dosing interval. Once-weekly fluoxetine (Prozac) and bisphosphonates are examples of drugs that underwent a change in labeling after being available as a once-daily formulation.
With aspirin, the explanation is a little different. Unlike other NSAIDs, aspirin irreversibly inhibits the cyclo-oxygenase (COX) enzyme in platelets. Because platelets cannot synthesize new proteins, the effect of aspirin lasts for the life of the platelet (approximately 7-10 days). It is somewhat deceiving to say that the effects of aspirin last for 7 days because new platelets are made every day that are not exposed to aspirin. Approximately 10% of the total platelet number is produced daily (about 153109 to 403109 platelets). Therefore, noticeable changes in platelet aggregation can occur within a few days of discontinuing aspirin.
WHAT IS THE ROLE OF
NATTOKINASE AS A BLOOD THINNER?
Natto is a traditional Japanese food of boiled soybeans fermented with the bacteria Bacillus natto. It contains the enzyme nattokinase (NK), which is known to have thrombolytic effects. Nattokinase is available as an oral supplement that is used for many conditions, including cardiovascular disease and deep vein thrombosis (DVT). Its mechanism as a fibrinolytic is thought to be due to inactivation of plasminogen activator inhibitor 1 (PAI-1), which ultimately leads to an increase in endogenous tissue plasminogen activator (tPA).
Animal studies have shown that nattokinase has potent fibrinolytic activity.1 In three dogs with experimentally induced thrombi, orally administered NK resulted in complete clot dissolution within 5 hours, as measured by angiography. None of the six dogs in the control group had clot resolution. Nattokinase given orally to rats also had favorable effects on femoral intimal wall thickness after exposure to chemically induced endothelial injury. One criticism of these studies is that the dosage used was much higher than the recommended human dose.
In a small human trial of nattokinase, 1,300 mg taken orally 3 times daily, fibrin degradation products and endogenous tPA were increased in plasma. However, results were not reported for all study subjects, and the dose appeared to be higher than what is commercially available.1 In perhaps the most compelling study involving nattokinase to date, 224 patients at high risk for DVT were randomized to receive either Flite Tabs or placebo during long-haul airline flights (7-8 hours).2 Ultrasound administered before and after the flight revealed that patients given Flite Tabs had a significantly decreased risk of thrombosis (5 DVTs and 2 superficial thromboses occurred in the placebo group, none in the treatment group).2 However, Flite Tabs are a combination product of nattokinase and pycnogenol (an herbal product with antiedematous properties), and effects of pycnogenol cannot be ruled out.
The question is: when can nattokinase be used clinically? The supplement was met with excitement among patients interested in alternative medicine, particularly as a substitute for antiplatelets and anticoagulants. However, NK has received an equal amount of criticism. No outcomes data are available regarding this agent as an alternative to aspirin, clopidogrel, or warfarin. Additionally, there is controversy over oral bioavailability. Although NK is available as an enteric coated tablet, how much of this enzyme is destroyed by gastric acid is unknown. It seems premature to recommend the use of nattokinase in patients most eager to take it (as a replacement for warfarin, aspirin, or clopidogrel). Additionally, taking NK in combination with the aforementioned medications may increase the risk of bleeding and should be avoided. According to the Natural Medicine Comprehensive Database, taking Flite Tabs as two separate doses during long haul airplane rides is "possibly safe."3 However, there is insufficient evidence to rate the effectiveness of nattokinase. JAAPA
Larissa DeDea, PharmD, BCPS, PA-C, completed a pharmacy practice residency at Gallup Indian Medical Center, Gallup, New Mexico, and has worked on the Navajo Reservation as a pharmacist for the Public Health Service. In addition to being board certified in pharmacotherapy, she is a recent graduate of the Yale University PA Program.
REFERENCES
1. Tai MW, Sweet BV. Nattokinase for prevention of thrombosis. Am J Health-Syst Pharm. 2006;63(12):1121-1123.
2. Cesarone MR, Belcaro G, Nicolaides AN, et al. Prevention of venous thrombosis in long-haul flights with Flite Tabs: the LONFLIT-FLITE randomized controlled trial. Angiology. 2003;54(5):531-539.
3. Nattokinase. Natural Medicines Comprehensive Database monograph. www.naturaldatabase.com. Accessed November 18, 2010.