5-HT3 receptor antagonists 1365
Drug–Drug Interactions
Acetylsalicylic acid
In eight healthy men who took a total of 485 mg of aspirin
over 3 days before beginning 2 weeks of fish oil supple-
mentation (4.5 g of n-3 fatty acids/day), aspirin alone
prolonged the bleeding time by 34% and fish oil alone
prolonged it by only 9%; however, aspirin þ fish oil pro-
longed the bleeding time by 78% (13). Although fish oil
alone did not significantly raise aggregation thresholds for
collagen, arachidonic acid, or platelet activating factor, it
did reduce the extent of aggregation with collagen. When
challenged by single or dual agonists, the combination of
fish oil and aspirin did not make platelets less sensitive
than aspirin alone.
However, in 18 healthy men randomly allocated to N-3
polyunsaturated fatty acids 10 g/day or placebo for
14 days, the addition of a single intravenous dose of
acetylsalicylic acid 100 mg did not alter the small effect of
polyunsaturated fatty acids on platelet aggregation (14).
In four subjects given a single oral dose of aspirin 37.5 mg
before and after a natural stable fish oil daily for 1 week,
serum thromboxane A2 fell by 40% after aspirin alone, but
by 62% after fish oil þ aspirin, and leukotriene B4 rose by
19% after aspirin and fell by 69% after fish oil þ aspirin;
serum prostacyclin fell equally in both cases (15).
In healthy subjects who took either fish oil or olive oil
(control) daily for 3 weeks before exposure to aspirin or no
aspirin, fish oil had no significant effect on mucosal prosta-
glandin E2 or F2a content or on the damaging effect of
aspirin on the stomach, despite the fact that fish oil reduced
serum triglyceride concentrations significantly (16).
Warfarin
In a placebo-controlled, randomized, double-blind study
of the effect of fish oil supplements 3–6 g/day for 4 weeks
on the International Normalized Ratio (INR) in 16
patients taking chronic warfarin therapy there was no
statistically significant effect on anticoagulation (17).
However, fish oils can affect hemostasis, and there has
been an anecdotal report of a possible interaction.
 A 67-year-old white woman who had been taking war-
farin for 18 months doubled her dose of fish oil from
1000 to 2000 mg/day. The INR increased from 2.8 to 4.3
within 1 month and fell to 1.6 within 1 week of reduc-
tion of the dose of fish oil (18).
References
1. Sanders TA. Marine oils: metabolic effects and role in
human nutrition. Proc Nutr Soc 1993;52(3):457–72.
2. Sanders TA, Roshanai F. The influence of different types of
omega 3 polyunsaturated fatty acids on blood lipids and
platelet function in healthy volunteers. Clin Sci (Lond)
1983;64(1):91–9.
3. Harris WS. Dietary fish oil and blood lipids. Curr Opin
Lipidol 1996;7(1):3–7.
4. Wander RC, Du SH, Ketchum SO, Rowe KE. Effects of
interaction of RRR-alpha-tocopheryl acetate and fish oil on
low-density-lipoprotein oxidation in postmenopausal
women with and without hormone-replacement therapy.
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ª 2006 Elsevier B.V. All rights reserved.
5. Ritter JM, Taylor GW. Fish oil in asthma. Thorax
1988;43(2):81–3.
6. Dawson JK, Abernethy VE, Graham DR, Lynch MP. A
woman who took cod-liver oil and smoked. Lancet
1996;347(9018):1804.
7. Vessby B, Boberg M. Dietary supplementation with n-3
fatty acids may impair glucose homeostasis in patients with
non-insulin-dependent diabetes mellitus. J Intern Med
1990;228(2):165–71.
8. Tracy RP. Diet and hemostatic factors. Curr Atheroscler
Rep 1999;1(3):243–8.
9. Clarke JT, Cullen-Dean G, Regelink E, Chan L, Rose V.
Increased incidence of epistaxis in adolescents with familial
hypercholesterolemia treated with fish oil. J Pediatr
1990;116(1):139–41.
10. Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S,
Miglioli M. Effect of an enteric-coated fish-oil preparation
on relapses in Crohn’s disease. N Engl J Med
1996;334(24):1557–60.
11. Cairns JA, Gill J, Morton B, Roberts R, Gent M, Hirsh J,
Holder D, Finnie K, Marquis JF, Naqvi S, Cohen E. Fish
oils and low-molecular-weight heparin for the reduction of
restenosis after percutaneous transluminal coronary angio-
plasty. The EMPAR Study. Circulation 1996;94(7):1553–60.
12. Rothman KJ, Moore LL, Singer MR, Nguyen US,
Mannino S, Milunsky A. Teratogenicity of high vitamin A
intake. N Engl J Med 1995;333(21):1369–73.
13. Harris WS, Silveira S, Dujovne CA. The combined effects
of N-3 fatty acids and aspirin on hemostatic parameters in
man. Thromb Res 1990;57(4):517–26.
14. Svaneborg N, Kristensen SD, Hansen LM, Bullow I,
Husted SE, Schmidt EB. The acute and short-time effect
of supplementation with the combination of N-3 fatty acids
and acetylsalicylic acid on platelet function and plasma
lipids. Thromb Res 2002;105(4):311–16.
15. Engstrom K, Wallin R, Saldeen T. Effect of low-dose
aspirin in combination with stable fish oil on whole blood
production of eicosanoids. Prostaglandins Leukot Essent
Fatty Acids 2001;64(6):291–7.
16. Faust TW, Redfern JS, Podolsky I, Lee E, Grundy SM,
Feldman M. Effects of aspirin on gastric mucosal prosta-
glandin E2 and F2 alpha content and on gastric mucosal
injury in humans receiving fish oil or olive oil.
Gastroenterology 1990;98(3):586–91.
17. Bender NK, Kraynak MA, Chiquette E, Linn WD,
Clark GM, Bussey HI. Effects of marine fish oils on the
anticoagulation status of patients receiving chronic warfarin
therapy. J Thromb Thrombolysis 1998;5(3):257–61.
18. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with
warfarin. Ann Pharmacother 2004;38(1):50–2.
5-HT3 receptor antagonists
General Information
The 5-HT3 antagonists, alosetron, granisetron, ondansetron,
and tropisetron (all rINNs), are effective antiemetics used in
treating cytotoxic-induced and postoperative vomiting.
There have been several reviews of the pharmacology
and use of alosetron (1–5). In patients with irritable bowel
syndrome, alosetron increases colonic transit time and
colonic compliance. It produces significant improvement
in abdominal pain, stool consistency, and frequency and