Presentation on theme: "Pharmacology – A Class Act"— Presentation transcript:
1Pharmacology – A Class Act St. Louis, MOMarch 22, 2014
2Choosing a route of administration Remember—topical drugs CAN have systemic absorption and side effectsMost of the time this is NOT a problemA few exceptions to mention:
3Highly lipid-soluble and cross the blood-brain barrier Beta-blocker eye drops for glaucoma—second-line therapy--Lower intraocular pressure by 20-25% with once or twice daily dosingBetoxolol (Betoptic, Betoptic S), timolol (Betimol, Timoptic, Timoptic XE, Istalol, Timoptic Ocudose), levobunolol (Betagan), carteolol (Ocupress), metipranolol (Optipranolol)Highly lipid-soluble and cross the blood-brain barrierCan cause bradycardia and anhedoniaSo what can you use instead?
4The “oprosts”—first line therapy for glaucoma—Prostaglandin analogs The “oprosts”—bimatoprost (Lumigan, Latisse for thick, long eyelashes), latanoprost (Xalatan), travoprost (Travatan, Travatan Z)Prostaglandin analogues—lower Intraocular pressure by 25-30%
5Long-term use of topical prostaglandin analogs **Latisse (bimatoprost) for thick, long eyelashesConjunctival hyperemiaDarkening of the irisIncreasing the length and number of eyelashesIris pigment changes occur most frequently in patients with green-brown, yellow-brown, or blue-gray-brown irides
6Vaginal monistat and warfarin Check the INR within 4 days of adding or subtracting any drug, regardless of the route of administrationTELL your patients to let you know if they pick something up OTCVaginal monistat can double the INR
7Premarin vaginal cream/estrogen vaginal suppositories (Vagifem) If used within 2 hours of sex, can cross the male urethra and feminize the husband98.7% of vaginal estrogen stays in the vagina; only 1.3% can be absorbed systemically—not enough to cause systemic side effects
8Pre- and Post-menopausal females and hormones Use of a hormone patch does NOT increase fibrinogen or clotting factorsReduces risk of clotting complicationsEspecially useful in smokers, overweight, and older women
9Notes on “timing” of drugs Any drug that is given once a day works best in the first 12 hours—even tho’ drug “levels” are maintained throughout the 24 hour period (exception to rule, insulin glargine (Lantus) has a steady state for 24 hours)Once a day BP drugs—given in a.m.? Work best from 8 a.m. to 8 p.m. fine for most people; however, remember that BP rises fastest in the early a.m.—strokes and MIsDippers vs. non-dippersBID dosing or give anti-HBP drug at bedtime
10Notes on timing of drugs Proton Pump InhibitorsGive minutes before the first meal of the day or if given BID, give minutes before breakfast and dinnerThe PPIs STOP the acid pump that kicks in after you eatGiving the pill AFTER a meal defeats the purpose—the pump has already started
11ASA at nightSome new studies are showing that aspirin taken at night may decrease platelet aggregation in a.m. (American Heart Association Annual Meeting, November 2013)Separate low-dose aspirin from ibuprofen by 30 minutes)—don’t take together or the effect of aspirin on platelets will be negated (FDA Advisory, 9/2006)
12Notes on OTC drugsOTC famotidine (Pepcid) is the best H2 blocker –less drug interactions, more acid suppressionDouble the recommended OTC dose on the box for the best results—remember that the H2 blockers work best at suppressing vagally-induced histamine—i.e. histamine produced overnight.So give Pepcid at hs
13OTC Aspirin-- role in inflammation IN ADULTS:Preventing heart disease—arterial clots (not venous clots)—platelets play a major role in arterial clots, not DVTsPreventing colon polyps (triggered by production of prostaglandins) and other solid tumors; may also inhibit metastasis in cancer patients (Rothwell)Aspirin is no longer recommended for pain management or for hyperthermia
14OTC herbal productsSJW—interacts with 60% of all drugs and makes them LESS effective; dig, cyclosporin, tamoxifen, HAART, COCs…and the list continues…Ginseng—sodium and water retention with increased BP; estrogen-like properties (gynecomastia), platelet inhibition, (dysfunctional uterine bleeding in PMF, prolonged periods in younger women)Many herbal products elevate liver enzymes—KAVA, germander, skull cap, mistletoe, sassafrasMany herbal products interfere with platelet aggregation—gingko, grapeseed extract, garlic, SJW
15Generics vs. Brand names As a general rule, classes of drugs have the same generic “last” name“Statins”—Lower LDL-cholesterol“Prils”—ACE inhibitors (BP + more)“Triptans”—treatment of acute migraine headache“Sartans”—ARBs (angiotensin receptor blockers)—BP + more“Prazoles”—Proton Pump Inhibitors, GERDThe “afils” – pulmonary hypertensionThe “conazoles”—antifungalThe “olols”, “alols”, “ilols”“Dipines”—calcium channel blockers (BP+)The “coxibs”—COX-2 inhibitorsThe “cyclovirs”—antiherpetic drugs
17“Sartans”—Angiotensin II Receptor Blockers—the ARBS Angiotensin receptor blockers (bypass ACE) and work by blocking the angiotensin II receptors on tissuesWho are they? The “Sartan Sisters”…losartan—Cozaar; yes, peds; 6 and overvalsartan—Diovan—yes; 6 and overcandesartan—Atacand—peds, yes. Ages 1 and overirbesartan—Avapro—peds, nopetelmisartan—Micardis—no in kidsolmesartan—Benicar; yes in kidseprosartan –Tevetan—peds? nopeazilsartan – Edarbi; no kids
18ACES and ARBSACE inhibitors = ARBS for blood pressure control and they are both relatively safe.The side effect of angioedema is less likely with the ARBs.The ARBs may be better after a myocardial infarction, whereas both ACE inhibitors and ARBs protect after strokes.There is absolutely no evidence to support combining ACE inhibitors with ARBs. (American Society of Hypertension, March 2013)
19Is there a “better” ACE inhibitor? Good question…yes, and it has nothing to do with reducing systemic blood pressureEvidence suggests that centrally acting ACE inhibitors (i.e. ramipril, trandolopril, captopril, fosinopril, and lisinopril), all cross the blood brain barrier (ie, lipid-soluble), and have been shown to slow cognitive decline in patients with dementia. (Gao Y et al. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. BMJ Open 2013 Jul 22)
20Pediatric hypertension Primary hypertension in children has been shown to correlate with family history of hypertension, low birth weight, and excess weight.With the increasing prevalence of childhood weight problems, increased attention to weight-related health conditions including hypertension is warranted.And the weight is not just about blood pressure!
21Pediatric Type 2 diabetes The incidence of Type 2 diabetes in kids is increasing exponentiallyThere’s NO good news about thisThe combination of obesity and type 2 diabetes = more rapid progression to long-term side effects—HBP, CAD and …Progression to chronic kidney disease (CKD) much faster than kids with Type 1 diabetes
22Three “prils” approved for kids over 6 Fosinopril (Monopril)—approved for kids over 6 and weight greater than 50 kgLisinopril (Prinivil, Zestril)—kids 6 and overBenazepril (Lotensin)—kids 6 and over
23New BP recommendations – primary (old name—essential) hypertension Chlorthalidone (Thalitone), amlodipine (Norvasc), and lisinopril (Prinivil, Zestril) all lower blood pressure equally and outcomes are similar between these three drugs (ALLHAT Study)
24Chlorthalidone vs. HCTZ Chlorthalidone (Thalitone) is superior to hydrochlorothiazide (HCTZ); decreases cardiovascular riskWorks in patients with lower glomerular filtration rates than HCTZ. HCTZ has no effect with GFRs less than 45 mL/min; chlorthalidone is okay with GFRs down to 30 mL/min.Downside: more hospitalizations for hypokalemia and hyponatremia with chlorthalidone vs. HCTZ.(Dhalla LA et al. Chlorthalitone vs. hydrochlorothiazide for the treatment of hypertension in older adults. Ann Intern Med 2013 Mar 19;158:447)
25“Stacking” diuretics is the new trend When spironolactone is add-on therapy in CHF (chronic heart failure) patients, hyperkalemia is a high risk. If spironolactone is added to a diuretic that “wastes” potassium, the results improve—so chlorthalidone or furosemide can be stacked with spironolactone. Metazolone (Indapamide) can also be stacked with spironolactone in patients with a low GFR.
26A note on the CCBsThe majority of CCBs, including amlodipine (Norvasc) can cause significant peripheral edema (felodipine /Plendil is the worst offender)Irsradipine (DynaCirc) does not. Switch if the patient is non-compliant due to the edema. You can combine calcium channel blockers together—isradipine and verapamil for example but watch out for gingival hypertrophy.And always watch for constipation with verapamil—regardless of age
27An interesting side effect of the CCBs Fertility issues
28Beta-blockers no longer recommended for primary hypertension Beta-blockers have become obsolete for cardiovascular protection in hypertensive patients. Their “era” did not include percutaneous interventions, statins, platelet therapies and ACE inhibitors or Angiotensin Receptor Blockers (ARBs).Studies show that adding a beta-blocker to current anti-hypertensive therapies does NOT improve outcomes.P.S. beta blockers are still useful for nonhypertensive indications—like inhibition of remodeling in patients with systolic heart failure. (REACH Registry JAMA 2012;308:1340)
29Beta-blockersAll antihypertensive agents are NOT created equal…case in point—the beta blockersThe beta blocker atenolol (Tenormin) is the worst of the bunch as a beta blocker used for hypertension. Atenolol raises the central blood pressure (the pressure experienced by the heart, brain, and kidneys) DESPITE lower brachial pressure. This paradoxical effect is a bad one. Atenolol has a risk ratio of for cardiovascular disease compared to all of the other beta blockers.
30Beta-blocker-plus drugs The beta-blocker “plus” drugs. The term means that beta blockade is accompanied by other important actions. Carvedilol (Coreg) provides alpha-one blocking effects with peripheral vasodilation. Nebivolol (Bystolic) also boosts nitric oxide production and is a potent vasodilator. As a result of the “plus” factor, carvedilol and nebivolol do not increase central blood pressure (as does Atenolol).So, choosing one of these as an “add-on” or first-line therapy for hypertension may be useful
31Important clinical note… The ASCOT-LLA trial compared atorvastatin/placebo with atorvastatin/beta-blocker for cardioprotection. Significant endpoints were better in the statin-placebo group compared with the statin/beta-blocker group.The results suggest that the beta blockers interfere with the statins effects on cardiovascular protection.
33Side effects, of course… Hypotension—start low and go slowHypoglycemia (low blood sugar)—only in diabetics on antiglycemic agents; not a problem in normoglycemic patients; instruct your patients to carry some extra hard candy with them for any initial hypoglycemic episodes
34Side effects, of course… Hyperkalemia (high potassium) (excreting sodium and water and retaining potassium)Add a thiazide diuretic to the ACE inhibitorCapozide (captopril + thiazide)Prinizide (lisinopril + thiazide)Zestorectic (as above)Lotensin HCT (benazepril + hydrochlorothiazide)
35ACE, ARBs and serum creatinine levels Serum creatinine may rise 10% to 30% from baseline within the first two weeks of starting therapy with either an ACE inhibitor or ARB (angiotensin-receptor blocker). Pts with normal renal function starting either class of angiotensin blocking drugs experience a rise of about 0.2 mg/dL over a two- to three-week period, returning to baseline in the 4th week.(Greene JH. Restricting dietary sodium and potassium intake: a dietitian’s perspective. In Daugirdas JT. Handbook of Chronic Kidney Disease Management. Philadelphia, PA: Lippincott Williams & Wilkins;2011:81-96)
36ACE, ARBs and serum creatinine levels If the patient has renal insufficiency to begin with, expect a rise in serum creatinine of 0.5 mg/dL over a four-week period. Patients with renal artery stenosis, extensive atherosclerotic cardiovascular disease, or dehydration may experience a progressive increase in serum creatinine to 2.0 mg/dL. Discontinuing the ACE or the ARB is the appropriate course of action.(Greene JH. Restricting dietary sodium and potassium intake: a dietitian’s perspective. In Daugirdas JT. Handbook of Chronic Kidney Disease Management. Philadelphia, PA: Lippincott Williams & Wilkins;2011:81-96)
37Since ACE inhibitors conserve potassium…What about K+ containing foods? May contribute to hyperkalemia and cardiac arrhythmias but usually only in patients with renal insufficiency or in patients who are also on K+ sparing diuretics such as spironolactone (Aldactone) and eplerenone (Inspra)Avoid excessive potassium intake when on the above drugs or with renal insufficiencyAdvise patients to decrease potassium intake until they can get their potassium checked
38Risk factors for moderate hyperkalemia (≥ 5.6 mmol/L) Patients older than 65CHFSCr greater than 1.6 mg/dLBUN greater than 18 mg/dLDOSING REDUCTION or D/C with the following:Hyperkalemia greater than 5.6 mmol/LAge greater than 70BUN greater than 25 mg/dLSerum K+ greater than 6 mmol/L
39High K+ containing foods≥200 mg/serving AvocadoArtichokeBroccoliCarrotsCantaloupePotatoesDried beans, canned mushroomsApricotsBananasPumpkinSpinachOrangesHealth.harvard.edu/heartextra for K+ content of 1,200 foods
40Bummer.Unfortunately chocolate also fits into the category of high-potassium foods, as does peanut butter, nuts, seeds, milk, and yogurt.(Greene JH. Restricting dietary sodium and potassium intake: a dietitian’s perspective. In Daugirdas JT. Handbook of Chronic Kidney Disease Management. Philadelphia, PA: Lippincott Williams & Wilkins;2011:81-96)
41Other potential K+ boosters… Check K+ level no later than one week after starting spironolactone (low risk patients check at 7 days; moderate and high risk patients check at 4 and 10 days, after a dose increase or if diuretic doses are increased)Stop taking any K+ supplementsGo easy on the NSAIDS (decrease GFR) with retention of fluids and electrolytesHerbal or natural remedies with hefty doses of potassium include noni juice, Siberian ginseng, hawthorn berries, (Harvard Heart Letter, December 2004)
42One last note…drugs and herbal products that increase potassium Don’t use Bactrim/Septra for UTIs when patients are on ACE inhibitors—it also increases K+ and can lead to life-threatening arrhythmiasNSAIDS conserve K+ due to vasoconstriction of the afferent arteriole (ibuprofen, piroxicam, and naproxen are the biggest offenders)KCl supplements (as salt substitutes)
43Side effects, continued… Cough (gender differences with F > M)ACE inhibitors block angiotensin converting enzyme; but as ACE is inhibited, bradykinin goes UP…bradykinin is a potent bronchospastic agentWomen have more bradykinin to begin with, therefore the gender disparity in the cough
44Side effects, continued… Life-threatening angioedema (“Does my voice sound funny to you?”)Usually within the first month (but not the first week); almost all cases within the first yearAn exception or two
45ARBs as a safe haven for the side effects of the “prils” Are the “sartans” safe for patients with a history of angioedema from the “prils”?Appears to be about an 5 to 8% rate of cross-reactivityGiven this limited percentage, switching to an ARB should not be considered an absolute contraindication in all patients with ACE-inhibitor induced angioedemaSwitch cautiously(Prescriber’s Letter 2004; 11(7))
46ACE vs. ARBNew and important info from American Society of Hypertension meeting 2013All ACE are = in lowering BPACE = ARB and both relatively safe; ARBs with less angioedemaARBs may be better after MIBoth protect after strokesNo evidence to support combing ACE + ARB
47ACA/AHA new recommendations for prevention and treatment of high cholesterol The American College of Cardiology/American Heart Association guideline on the Treatment of Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults has been released and it basically uses the KISS method—KEEP IT SIMPLE, STUPID. In other words, instead of a plethora of cholesterol-lowering drugs, a long-list of recommendations, and never-ending caveats, the focus is now on just 4 at-risk groups: (P.S. this has stirred up quite the controversy)
48The NEW recommendations for statin therapy 1) The so-called “secondary” prevention group consisting of individuals who have already experienced a cardiovascular event—TIA, PAD, Angina, ACS, ischemic stroke2) The population of individuals with an LDL-cholesterol level of ≥190 mg/dL
49New recommendations for statin therapy 3) Individuals with type 2 diabetes aged without a history of a prior cardiovascular event and a LDL-cholesterol level between 70 and 189 mg/dL, and,
50New recommendations for statin therapy Individuals with a 10-year or greater risk of a cardiovascular event as calculated by the Cardiovascular Risk Calculator. Log on to the Framingham Heart Study online and click on the cardiovascular risk assessment calculator to determine risk.Based on blood pressure, gender, total cholesterol, and HDL cholesterol…so have all of that information handy to determine the likelihood of having a major coronary event in the next 10 years.
51The #1 oral drug for Type 2 DM Metformin (Glucophage, Glucophage ER, Fortamet, Glumetza, Riomet ) (1995)--does not have any direct effect on insulin release from the pancreas—doesn’t require insulin to work—hypoglycemia is NOT a side effectPrimary action: DECREASE hepatic glucose production; decreases glucose absorption via the GI tract, and increases insulin receptor sensitivityProblem? GI blues; need functioning organs--kidneys and heart especially (check serum creatinine before starting metformin; caution with heart failure)Se Creatinine--Cut-off is 1.4 (50-90 mmol/L) in females and 1.5 ( mmol/L) in males
52Metformin (Glucophage,Glumetza, Fortamet, Glucophage ER) Metformin and breast and prostate cancer reduction (54%)—Diabetes Care December 2010Metformin and slowing the aging process (slows down the shortening of telomeres + fish oil)Metformin and neurogenesisMetformin and anti-psychotic drugs and weight gainMetformin and HD-Prednisone and weight gainMetformin and NASH (Hepatology Vol. 55 (6): 2012)Metformin and PCOS
53Downside to MetforminB12 deficiency (the peripheral neuropathy of diabetes may actually be due to a B12 deficiency neuropathy—give diabetics B12—improves any neuropathy they have) (have the patient take 1000 mcg B12 daily)Increase in BFR (basal flatal rate)Diarrhea (nighttime dosing, take with food; switch to long-acting metformin— glucophage ER, Glumetza, Fortamet)D/C for 48 hours after a contrast dye procedure
54The “gliptins” Weight neutral Sitagliptin (Januvia) inhibits enzymes in the intestine responsible for breaking down incretins;What are incretins? Incretins are responsible for approx. 60% of the post-meal insulin secretion, but the action of the incretins is impaired in diabeticsincretins potentiate insulin releaseSaxagliptin (Onglyza)Linagliptin (Tradjenta)Alogliptin (Nesina)Side Effects? acute pancreatitis (possible increased risk of pancreatic cancer????—not sure, diabetes increases your risk of pancreatic cancer as does chronic pancreatitis)
55Better…oral drug combinations Metaglip (glipizide and metformin)Glucovance (glyburide and metformin)Janumet (sitagliptin and metformin)Kombiglyze (saxagliptin + metformin)Kazano (alogliptin + metformin)Sitagliptin (JANUVIA)+ simvastatin (ZOCOR)--JuvisyncMore, more, more…
56Incretin mimetics (April 28, 2005)— Remember: Incretins are responsible for approx. 60% of the post-meal insulin secretion, but the action of the incretins is impaired in diabetics)Exenatide (Byetta and Bydureon—longer lasting/once a week)—isolated from saliva of a Gila Monster—”lizard spit”..Generally added on to Type 2 diabetics who are already receiving metformin, a sulfonylurea, or both and do not have optimal control
57Incretin mimeticsActs at the GLP-1 receptor, promoting insulin releaseWeight loss is a + side effect (due to slowing of gastric emptying and “feeling full”)2nd generation—liraglutide (Victoza)--qdBydureon (long-acting Byetta once a week)Better than Byetta as it reduces HgA1C 1.6% vs. 0.9% for ByettaBydureon with weight loss greater than Byetta but less than liraglutideBydureon nausea 14% vs. Byetta at 35%
58The “prazoles”—Proton Pump Inhibitors* Who are they?Omeprazole (Prilosec)(first released as Losec in U.S., Losec* )—yes in kids for GERDLansoprazole (Prevacid) –approved for kids 1 and overDeXlansoprazole (old-Kapidex)(new-Dexilant) not in kidsRabeprazole (Aciphex)—kids 12 and olderPantoprazole (Protonix, Pantoloc*)Esomeprazole (Nexium)-- “the purple pill”—yes in kids based on weight or ageBIG Exception: Aripiprazole/Abilify—antipsychotic—a dopamine system stabilizer
59GER and GERD in kidsGER is also called acid reflux or acid regurgitation because the stomach’s digestive juices contain acid. Infants with GER spit up liquid mostly made of saliva and stomach acids. GER is common in infants under 2 years of age. About half of all infants spit up, or regurgitate, many times a day in the first 3 months of life. Most healthy infants experience few to no symptoms and stop spitting up between the ages of 12 and 14 months.
60GER and GERD in kidsGastroesophageal reflux disease (GERD) is a more serious, chronic—or long lasting—form of GER. If an infant’s GER progresses to GERD, additional symptoms—such as vomiting and poor feeding—occur and can adversely affect the child’s overall health and temperament. Infants with severe symptoms or with GER that lasts beyond 12 to 14 months may actually have GERD
61The “prazoles”—Proton Pump Inhibitors MOA—Inhibition of the proton pump at the lumenal surface of the stomach…especially after a mealPPIs work hereH+, Intrinsic Factor-B12Lumenal surfaceParietal cellBasilar surfaceH2H2 receptorsH2 blockers work here
62The “prazoles”Work within 4-7 days to reduce all acid in the stomach; take 30’-60’ before the first meal of the day or before the dinner meal (especially if nocturnal GERD is a problem)BUT suppressing acid has been shown to have significant side effects:Increased risk of hospital-acquired pneumonia and community acquired pneumonia (PPI use might be associated with 33,000 preventable deaths due to pneumonia in hospitalized patients)(Herzig)Increased food-borne illnessIron deficiency anemia over the long term (need acid to absorb iron)Increased risk of B12 deficiency due to blocking the release of intrinsic factor
63**Use of PPIs and clostridium difficile Daily PPI use associated with an estimated 74% increase in Clostridium difficile infectionPeople using PPIs while being treated for C. difficile had a 42 % increased risk of recurrence Archives of Internal Medicine 2010;170: ,Should all patients be put on PPIs upon admission to the hospital? NO, it’s NOT necessary…ICU patients? YES, because they have been shown to have the highest risk for a GI bleed from stress-induced gastric ulcers; but not for every bunionectomy, hemorrhoidectomy, or tonsillectomy
64PPIs and Inappropriate subscribing in hospital patients Reid M et all. Inappropriate prescribing of proton pump inhibitors in hospitalized patients. J Hosp Med 2012 May/Jun 7:421Herzig SJ et al. Acid-suppressive medication use and the risk for nosocomial gastrointestinal tract bleeding. Arch Intern Med 2011 Jun 13;171:991.
65Clinical implications of B12 deficiency B12 is necessary for the healthy production of RBCs and for the maintenance of the central and peripheral nervous system (cognitive function in the CNS and motor/sensory function of spinal cord and peripheral nerves)B12 deficiency is the number one cause of nutritional dementiaB12 deficiency is one of the top 3 causes of peripheral neuropathy in the elderlyB12 deficiency causes macrocytic anemia (MCV greater than 120)B12 is stored in the liver for ~ 5 years—takes a long time of PPI use to cause B12 deficiency
66Combine long-term use of PPIs with other risk factors… 39% of the population over 50 has a B12 deficiencyPatients on glucophage (Metformin) for longer than 3 years should also have B12 levels measuredPatients with malabsorption (kids with Crohn’s disease, celiac disease; gastrectomy; gastric by-pass surgery; atrophic gastritisVegetarians, vegans
67Should we all be taking B12? Keep B12 above 350 pg/mL (“normal range” – pg/mLIf so, how can we take it? Supplements?The 4 S’s…How much? For dementia? Injections (patients with dementia and levels less than 300 pg/mL should be given a trial of B12);For peripheral neuropathy?For daily maintenance?Can you overdose on B12? The one dreaded side effect is…
68BibliographyAnnibale B, Capurso G, Delle Fave G. The stomach and iron deficiency anemia: a forgotten link. Dig Liver Dis 2003;35:Cayley WE. Are beta blockers effective first-line treatments for hypertension? Am Fam Phys 2007 Nov 1; 76(9);Gardiner P, Phillips R, Shaughnessy AF. Herbal and dietary supplement-drug interactions in patients with chronic illnesses. Am Fam Phys 2008 Jan 1; 77(1):73-78.Herzig SJ et al. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA 2009 May 27;301:2120.
69BibliographyRothwell PM et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death. Lancet 2012 Mar 21.Rothewell PM et al. Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet 2012, Mar 21.Tatro DS, ed. Drug Interaction Facts: Herbal supplements and Food. St. Louis, MO. A. Walters Kluwer Co; 2004; also available at
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