News and Articles on Health. Medical research topics.

Though Cialis (Tadalafil) does not merit the title of a groundbreaker in the sphere of ED remedies due to Viagra’s all-time unbeaten popularity, it is still a much sought-after pharmaceutical product bringing the Eli Lilly Company, USA, over whopping $2 billion in revenue annually. Infusing ED sufferers with a hope that they would perform as in their glory days, Cialis is among the best 100 selling medicines in the world. Impressive statistics, isn’t it?

Meant to address erectile dysfunction (and some other ailments like enlarged prostate and pulmonary arterial hypertension) in men over 18, Cialis refers to the same drug family as the other hyped ED oral solutions (Viagra, Levitra, and so forth) – they all are selective PDE5 inhibitors. However, Cialis is a bit different from its competitors – they usually last up to 6 hours while Cialis preserves its action up to 36 hours. Maybe that is why Cialis is so popular and demanded. Nevertheless, Cialis is not the safest drug in the world (are there any?). Here is what you should know before turning to Cialis to manage your erectile frustration.

How Much Does It Take Cialis To Work And How Long Its Effects Last?

Cialis is known to start working earlier compared to its rivals. Its onset of effect is obtained in mere 20-30 minutes after taking while other ED drugs are prescribed to be used 1 hour prior to an anticipated intimacy. Cialis’s effect lasts from 24 up to 36 hours owing to which Cialis is also called a “weekend peel” as a man can take one dose of Cialis at Friday’s night and enjoy its benefits throughout Sunday. The long-lasting action of Tadalafil eliminates any guesswork about when to take the drug – because sex is often a very spontaneous event.

Two Ways to Take Cialis

There are two approaches to consume Cialis: on an as-needed routine or on a daily routine with a lower strength. The as-needed regimen involves taking Cialis in the strength of 10 mg (on the market, the drug is dispensed at the doses of 5 mg and 20 mg) which is not very convenient.

The daily intake requires 2.5 mg of Cialis. A daily therapy with Tadalafil tends to be more efficacious at fixing impotence during a course of treatment. If you choose a daily routine with Cialis to improve your ED, it is better to take the medicine at the same time every day. Should a 2.5.mg dosage fail to work, your doctor may recommend you to switch to a 5 mg daily dose.

Mixing Cialis with Food and Alcohol

Unlike its direct competitors, Cialis has no strict gastronomic restrictions – you can take it both with or without food. However, there is still one product which can seriously interact with Tadalafil (the key ingredient of Cialis) – it is grapefruit juice. The matter is that a blend of grapefruit juice with Cialis results in an increased concentration of Tadalafil in the blood – a phenomenon which actually is not very desired as it may sound, because a higher blood level of Cialis is fraught with a higher risk of bad effects.

Since Cialis is known for its vasodilatory properties (it can make blood vessels expand), the combination with alcohol is not recommended as well because it can cause an abrupt drop in blood pressure and its unpleasant symptoms including dizziness, rapid heartbeat, a migraine, etc, especially when you get up from a sitting or lying position.

How to Take Cialis Safely?

Prior applying to Cialis to improve your ED, make sure to let your doctor know about all other medications/supplements/vitamins/herbs you currently use. Any PDE5 inhibitor including Cialis or its generic versions must not be used by men taking nitroglycerin, riociguat or other drugs containing nitrates for the heart or chest pain management because such a mix can result in serious, if not to say, life-threatening side effects like a heart failure or a critical drop in pressure. There are also some other medicines that can interact with Tadalafil including other PDE5 inhibitors and lifestyle drugs, antibiotics, antifungal agents, antiviral solutions, anti-seizure drugs.

Always follow your doctor’s instructions to enjoy all benefits of Cialis and avoid any associated complications. Before taking Cialis, be sure you do not have any of the following conditions:

• A severely impaired kidney or liver function
• Bleeding or blood cell disorders
• Chest pain
• Heart or blood pressure problems
• Inherited eye diseases
• Pulmonary veno-occlusive disease

Cialis Dosage

The As-Needed regimen with Cialis

The standard dose of Cialis for the as-needed basis is 10 mg taken 20-30 minutes before an intercourse not oftener than once in a day, but better every 36 hours owing to a longer half-life of Cialis. The doctor may advise to lower this dose to 5 mg or enhance up to 20 mg depending on a patient’s tolerability and response to the drug.

The Daily Regimen with Cialis

The initial daily dose of Cialis, in this case, is 2.5 mg used at the same time each day, but this dosage may be stepped up to 5 mg every day depending on individual tolerance and response to the drug.

Cialis in Specific Populations

Geriatric Patients (65 and older): no differences in efficacy or safety can be observed, which means dose adjustments are not necessary based on age alone.

People with mild to moderate hepatic impairment: no exposure to Tadalafil can be observed with a dose of 10 mg. It is not known whether higher doses of Cialis are safe in people with liver conditions. Patients with a severely impaired liver function should refrain from using Cialis to treat ED.

People with renal impairment should ask their doctor to adjust the right dose of Cialis for them because it will vary depending on the creatinine clearance. Notably, subjects with renal disorders are not recommended taking Cialis on the daily basis, but only on as-needed.

Side Effects of Cialis

Like any other drug, Cialis along with beneficial effects can trigger some unpleasant reactions. The most common of them include:

• Cardiovascular system: increased heartbeat, flushing, blood pressure swings, chest pain;
• Gastrointestinal system: stomach upset, diarrhea, nausea, vomiting, abdominal pain, constipation, dry mouth, rectal bleeding, acid or sour stomach;
• Musculoskeletal system: pain in different parts of a body and extremities, musculoskeletal stiffness, joints swelling;
• Nervous system: migraines, lightheartedness, sudden tiredness, sleep disorder, tremor, seizures (in people with pre-existing conditions);
• Respiratory system: shortness of breath, infections of the upper and lower respiratory tracts, rhinitis, cough, nasal blockage;
• Urogenital system: bloody urine, infections of the urinary tract, penile bleeding, prolonged and painful erections, spontaneous erections;
• Other: skin reactions (redness, itching, sweating, scaling, cracks), abnormal vision, loss of hearing, conjunctivitis, eyelids swelling, Quincke’s disease, inadequate liver function tests, reduced sensitivity to touch, voice changes.

Read also: Cialis Professional: Advanced ED Treatment with Advanced Medication

The ASR is a class III device — the FDA’s highest risk classification. Clearance through the 510(k) process is especially inappropriate for such risky devices. Congress envisioned that class III devices would be approved through the more stringent premarket approval (PMA) process, which does require clinical testing, and the Safe Medical Devices Act of 1990 requires that the FDA either use the PMA process for class III devices or reclassify them in a lower-risk category. Despite the clear intent of Congress, high-risk devices continue to slip by this requirement.

On July 20, 2011, the U.S. House Energy and Commerce Subcommittee on Oversight and Investigations held a hearing entitled “Medical Device Regulation: Impact on American Patients, Innovation, and Jobs.” The subcommittee’s chairman, Congressman Cliff Stearns (R-FL), argued that FDA regulation of medical devices is too burdensome, stifles innovation, and drives device manufacturers overseas. But the disastrous outcomes of the use of DePuy ASRs show that rushing untested and potentially dangerous medical devices into the marketplace carries serious risks; our regulators should not be in the business of creating jobs in the manufacture of dangerous devices.

On July 29, 2011, the Institute of Medicine (IOM) released an FDA-commissioned report on the 510(k) clearance process.4,5 The report concluded that it was impossible for 510(k) clearance to assure safety and effectiveness, because it assesses neither, instead establishing only “substantial equivalence” to an existing device. The report therefore recommended that 510(k) clearance be eliminated. In addition, it recommended monitoring medical devices throughout their life cycle, especially during the postmarketing period. Despite its reasonable (and relatively modest) recommendations, the report has been aggressively attacked by the device industry and by politicians from states where device companies are located. In fact, the attacks began even before the report was released, which is highly unusual for an IOM report.

We believe that the IOM report is insightful, judicious, sensible, and long overdue. The 510(k) clearance process was established 35 years ago, and although it may have been a reasonable approach then, it surely is not today. We support the IOM committee’s recommendation that the 510(k) process be replaced with an evaluation of safety and effectiveness. It is important to maintain and encourage innovation in medical devices. But true innovation requires that safety and effectiveness be proven by scientific study in clinical trials.

Unfortunately, the FDA leadership has already suggested that it does not intend to implement this key recommendation of the report, although it may be open to other changes. As the best long-term improvements are contemplated, there are important steps that the agency can take now.

Many Americans benefit from the implantation of medical devices, such as artificial joints and lifesaving defibrillators. Tragically, many also suffer or even die from complications related to medical devices that were never studied in clinical trials before being implanted in patients. As devices have evolved and become more complex, our device-approval system has become incapable of assuring safety and effectiveness. The system we use today was created 35 years ago in an era of much simpler and fewer devices, and it is now outdated.

A recent, but not rare, example provides a cautionary tale about the challenges of ensuring that complex medical devices are both effective and safe. Osteoarthritis of the hip joint is a common and debilitating disorder. Each year, nearly a quarter of a million patients with advanced painful arthritis receive a total hip replacement in the hope that it will restore mobility and improve their quality of life. Conventional artificial hip implants consist of a metal ball inserted into a plastic cup. In 2005, a new metal-on-metal design was introduced in which both components were made from a metal alloy. The design was touted as a major innovation that would improve durability and reduce the risk of hip dislocation — advantages that were especially appealing to younger patients but were never tested.

One metal-on-metal design is the DePuy (Johnson & Johnson) ASR XL Acetabular System, which was introduced into the U.S. market in 2005. The ASR was cleared by a Food and Drug Administration (FDA) process known as 510(k), which refers to the section of the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act that created it. Under that section, the criterion for clearance of a new medical device is that it be “substantially equivalent” to an already-marketed device (a “predicate”); clinical data are not required.

The ASR was constructed by borrowing a metal alloy cup from a different hip device known as the ASR Hip Resurfacing System and retrofitting it onto a standard hip implant. The manufacturer successfully made the case that the re-engineered implant was “substantially equivalent” to a predicate device. Its marketing clearance was therefore based not on clinical trials or other clinical data but on bench testing in a laboratory, which was inadequate to simulate the stresses that would be placed on it in patients’ bodies.

It soon became clear that the device failed at the astonishing rate of at least one in eight. According to a recent report presented at the British Hip Society Annual Conference, 21% of these hips have had to be replaced (revised) by 4 years after implantation, and the revision rate rises to 49% at 6 years, as compared with 12 to 15% at 5 years for other devices. Failure appears to be due to erosion of the metal in the articular surfaces and migration of metallic particles into the surrounding tissues and the bloodstream. Thus, the innovation led to tragedy for many patients. Before it was recalled in 2010, the ASR had been implanted in nearly 100,000 patients, and the result was a public health nightmare.

Interactions
Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.

Interactions with Drugs

In theory, glucosamine may decrease the effectiveness of insulin or other drugs used to control blood sugar levels. However, there is limited human research to suggest that glucosamine may not have significant effects on blood sugar. Nonetheless, caution is advised when using insulin or drugs for diabetes by mouth. Patients with diabetes or hypoglycemia should be monitored closely by a qualified healthcare provider, and medication adjustments may be necessary. Based on limited evidence, the combination of glucosamine with diuretics (water pills), such as furosemide (Lasix®), may cause an increased risk of glucosamine side effects.

In theory, glucosamine may increase the risk of bleeding when taken with drugs that increase the risk of bleeding. Some examples include aspirin, anticoagulants (“blood thinners”) such as warfarin (Coumadin®) or heparin, anti-platelet drugs such as clopidogrel (Plavix®), and non-steroidal anti-inflammatory drugs such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®).

Interactions with Herbs and Dietary Supplements

In theory, glucosamine may decrease the effectiveness of herbs or supplements that lower blood sugar levels. Caution is advised when using herbs or supplements that may alter blood sugar.

Based on limited human study, side effects of glucosamine may be increased when used at the same time as diuretic herbs or supplements.

In theory, glucosamine may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding

There are preliminary reports that use of glucosamine with vitamin C, bromelain, chondroitin sulfate, or manganese may lead to increased beneficial glucosamine effects on osteoarthritis. Simultaneous use with fish oil may have additive beneficial effects in the treatment of psoriasis, based on preliminary research.

Safety
The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies
Since glucosamine can be made from the shells of shrimp, crab, and other shellfish, people with shellfish allergy or iodine hypersensitivity may have an allergic reaction to glucosamine products. However, some research suggests that there is not enough shrimp allergen in glucosamine supplements to trigger reactions in patients who are allergic to shrimp. Nevertheless, caution is warranted. A serious hypersensitivity reaction including throat swelling has been reported with glucosamine sulfate. There are reported cases suggesting a link between glucosamine/chondroitin products and asthma exacerbations.

Side Effects and Warnings
In most human studies, glucosamine sulfate has been well tolerated for 30 to 90 days.
Side effects may include upset stomach, drowsiness, insomnia, headache, skin reactions, sun sensitivity, and nail toughening. There are rare reports of abdominal pain, loss of appetite, vomiting, nausea, flatulence (gas), constipation, heartburn, and diarrhea. Based on several human cases, temporary increases in blood pressure and heart rate, as well as palpitations, may occur with glucosamine/chondroitin products. Based on animal research, glucosamine theoretically may increase the risk for eye cataract formation.
It remains unclear if glucosamine alters blood sugar levels. Several human studies suggest that glucosamine taken by mouth has no effects on blood sugar, while other research reports mixed effects on insulin. When glucosamine is injected, it appears to cause insulin resistance and endothelial dysfunction. Preliminary studies show no effect on mean hemoglobin A1c concentrations in patients with type 2 diabetes mellitus. Caution is advised in patients with diabetes or hypoglycemia and in those taking drugs, herbs, or supplements that affect blood sugar. Serum glucose levels may need to be monitored by a healthcare provider and medication adjustments may be necessary.
In theory glucosamine may increase the risk of bleeding. Caution is advised in patients with bleeding disorders or taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary.
In several human cases, abnormally high amounts of protein were found in the urine of patients receiving glucosamine/chondroitin products. The clinical meaning of this is unclear. Glucosamine is removed from the body mainly in the urine, and elimination of glucosamine from the body is delayed in people with reduced kidney function. Acute interstitial nephritis, a condition that causes the kidneys to become swollen and possibly dysfunctional, has been reported in a patient taking glucosamine. Increased blood levels of creatine phosphokinase may occur with glucosamine/chondroitin, which may be due to impurities in some products. This may alter certain laboratory tests measured by healthcare providers.
Early data suggest that glucosamine may modulate the immune system, although the clinical relevance of this is not clear.
One patient developed liver inflammation (acute cholestatic hepatitis) after taking glucosamine forte.

Pregnancy and Breastfeeding
Glucosamine is not recommended during pregnancy or breastfeeding due to lack of scientific evidence.

Tradition/Theory
The below uses are based on tradition, scientific theories, or limited research. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider. There may be other proposed uses that are not listed below.
AIDS, athletic injuries, back pain, bleeding esophageal varices (blood vessels in the esophagus), cancer, congestive heart failure, depression, fibromyalgia, kidney stones, migraine headache, immunosuppression, osteoporosis, pain, psoriasis, skin rejuvenation, spondylosis deformans (growth of bony spurs on the spine), topical hypopigmenting agent (combination product containing multiple ingredients), wound healing

Dosing
The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Adults (18 years and older)
In most available studies, 500 milligrams of glucosamine sulfate has been taken by mouth as tablets or capsules three times daily for 30 to 90 days. Once daily dosing as 1.5 grams (1,500 milligrams) has also been used. Limited research has used 1,500 milligrams daily as a crystalline powder for oral solution or 500 milligrams of glucosamine hydrochloride three times daily. Dosing of 20 milligrams per kilogram of body weight daily has also been recommended in some publications. One study used a dose of 2,000 milligrams per day for 12 weeks.
Another kind of glucosamine that has been used is a topical form in combination with chondroitin for a four-week period. Safety and effectiveness of these formulations are not clearly proven.
Glucosamine hydrochloride provides more glucosamine than glucosamine sulfate, although this difference likely does not matter when products are prepared to provide a total of 500 milligrams of glucosamine per tablet.

Children (younger than 18 years)
There is not enough scientific evidence to recommend the use of glucosamine in children.
Research in children has shown that there could be a relationship between the ingestion of MSM (methylsulfonylmethane) and autism; whether it is beneficial or harmful is unclear. MSM is often marketed with glucosamine as a dietary supplement and at this time should be avoided in children.

Design
One hundred twenty patients with polycystic ovarian syndrome (PCOS) and 14–16 months of infertility were studied in this randomized, controlled clinical trial. Patients were randomly assigned to receive either 1,500 mg/day metformin or 4 grams of myo-inositol plus 400 mcg folic acid daily. In patients where in whom pregnancy occurred, patients underwent ovulation induction with recombinant follicle stimulating hormone (r-FSH) (37.5 units/day) for a maximum of 3 attempts. The primary endpoint was restoration of spontaneous ovulation (measured by monitoring serum progesterone levels weekly and transvaginal ultrasound to confirm). Secondary endpoints included resistance to treatment (percentage of patients who did not restore spontaneous ovulation), pregnancy rate, and abortion rate.

The study demonstrated a statistically significant difference in restoration of spontaneous ovulation in patients taking myo-inositol over metformin.

Key Findings
Fifty percent of the patients who received metformin restored spontaneous ovulation, and 18.3% of these achieved pregnancy. Sixty-five percent of patients treated with myo-inositol restored spontaneous ovulation, and 30% of these achieved pregnancy. In the remaining patients who did not respond to monotherapy, r-FSH was added. In each of the 2 groups (metformin plus r-FSH group or myo-inositol and folic acid plus r-FSH group), 11 pregnancies occurred. The total pregnancy rates were 36.6% for patients receiving metformin and 48.4% for patients receiving myo-inositol. The study demonstrated a statistically significant difference in restoration of spontaneous ovulation in patients taking myo-inositol over metformin. There was an overall higher rate of pregnancy in the myo-inositol group, but the effect was not significant.

Practice Implications
One metabolic feature often observed in patients with PCOS is a defect in inositol metabolism. Inositol plays an important role in insulin and glucose metabolism. Inositol accelerates the dephosphorylation of glycogen synthase and pyruvate dehydrogenase, both rate-limiting enzymes of non-oxidative and oxidative glucose disposal. Supplying myo-inositol can accelerate glucose disposal and sensitize insulin action. This may decrease the hyperinsulinemic state that can prohibit proper luteinizing hormone (LH) secretion.

Previous studies have demonstrated that myo-inositol is capable of restoring spontaneous ovarian activity, and consequently fertility, in patients with PCOS. This study is the first to compare the effectiveness of 2 insulin-sensitizing agents, inositol and metformin, in the treatment of chronic anovulation and infertility secondary to PCOS.

In this study, myo-inositol offered a significant advantage over metformin in restoration of spontaneous ovulation in patients with PCOS. This also resulted in a non-significant increase in pregnancy rate. In addition, patients on myo-inositol reported no side effects during the course of treatment. Myo-inositol should be considered as a first-line treatment in patients with PCOS experiencing chronic anovulation or infertility secondary to anovulation.

The potential health implications caused by the nuclear disaster in Japan may extend beyond Japanese citizens. The wind and water currents have carried radioactive materials to many parts of the world. Furthermore, concerns are arising regarding consumable goods exported from Japan. Included in this category are dietary supplement ingredients and their finished products. In this issue, you will find several commentaries from manufacturers about some of the proactive steps that they are taking to ensure the continued safety of their products. These manufacturers, along with other dietary supplement manufacturers, are to be lauded for their timely and quick accountability to this situation.

On March 25, 2011, the US Food and Drug Administration (FDA) began detaining all shipments of FDA-regulated products imported from the Japanese prefectures (sub-national jurisdictions) that are in the closest proximity to the Fukushima Daiichi nuclear plant, specifically Fukushima, Gunma Ibaraki, and Tochigi. This is a result of the fact that in mid-March, the Japanese Ministry of Health, Labour and Welfare confirmed the presence of radioactive iodine contamination in dairy and fresh produce from these regions. The FDA’s Import Alert further explains that radioactive iodine has a short half-life of about 8 days and naturally decays, but does pose risk to human health if contaminated food is absorbed into the body prior to its decay. In addition to produce, other at-risk Japanese exports, such as seafood, are being tested by the FDA prior to release into the US market.

It is not clear at this time what degree of risk is represented by dietary supplements with ingredients sourced from Japan. One would presume that there is risk associated with products containing raw materials sourced from, or processed in, the prefectures with proximity to the nuclear power plant. Michael McGuffin, president of the American Herbal Products Association (AHPA), recently released this statement: “AHPA will keep its membership apprised of any additional information of interest that may impact raw materials and ingredients, supply chains, distribution, and members’ ability to market products.” This statement summarizes the current state of watchfulness and caution.

Emerson Ecologics is in the process of soliciting information from each of its suppliers any raw materials that present risk of radioactive contamination and how they are mitigating this risk. Thus far, several companies whose operations are based in Japan have noted that their manufacturing facilities are located in the southern region of Japan, hundreds of miles away from the nuclear reactors, and areas which have not evidenced significant radioactive contamination. These companies continue to monitor the situation. Other companies with raw materials at risk for contamination are subjecting their raw materials to testing. Testing for radioactive iodine and cesium can be done by FDA-certified methodology. This test analyzes Cesium-134/137 and Iodine-131 by means of gamma-spectrometry using a Germanium-detector. Sample quantities of about 1 kg are typically required which effectively restricts the use of this test to raw materials as opposed to finished products. One qualified independent analytical laboratory charges $160 for this test.

At this point in time, the radiation risk to dietary supplements appears to be minimal. That being said, continued vigilance is required on the part of dietary supplement manufacturers to ensure that is parameter of supplement safety remains a non-issue for consumers.

Adenoma recurrence is already widely accepted as a surrogate end point for colorectal cancer. However, our data on initial adenoma, taken together with our earlier findings in this cohort, which demonstrated an inverse relationship between use of aspirin and colorectal cancer, provide additional evidence to substantiate the protective effect of aspirin on colorectal neoplasia. In our previous study, the relative risk for cancer after 20 years of consistent aspirin use was 0.56 (CI, 0.36 to 0.90). The influence of duration on risk for colorectal cancer (but not adenoma risk) seems plausible because there may be a dwell period of a decade or longer within which an adenomatous polyp becomes invasive cancer. Our results also demonstrate that optimal chemoprevention requires substantially higher doses of aspirin than those previously considered. These findings may have clinical implications related to potential adverse events associated with prolonged use of aspirin. Gastrointestinal bleeding, the most common major toxicity of aspirin, occurs in approximately 1 in 100 people taking aspirin over at least 2 years, and considerable evidence suggests that this toxicity, as well the severity of bleeding, is strongly dependent on increasing dose. In a large, randomized trial of aspirin in the secondary prevention of cerebrovascular events, the annual rate of upper gastrointestinal bleeding was 0.6% in patients taking 1200 mg/d, 0.3% for those assigned to 300 mg/d, and 0.1% for those taking placebo. Another rare but potentially devastating adverse consequence of aspirin use, intracerebral bleeding, may also be related to increasing dose. In our cohort, participants tak ing the highest dose of aspirin (_2 tablets/d) had a 2-fold higher risk for subarachnoid hemorrhage. Treatment of large numbers of healthy persons to prevent colorectal cancer in a small percentage requires a high standard of safety as well as efficacy. For example, the U.S. Preventive Services Task Force presently recommends routine use of low-dose aspirin as primary prophylaxis against myocardial infarction only in those at high risk for coronary heart disease. Thus, it has been suggested that any agent requires a safety profile that meets or exceeds that of low-dose aspirin before it can be recommended for widespread use in colorectal cancer prevention.

Moreover, 2 cost-effectiveness analyses concluded that present colorectal cancer screening strategies were generally superior to daily use of 325 mg of aspirin. Although the overall cost-effectiveness of aspirin improves if cardiovascular benefits are incorporated, our findings suggest that the optimal doses for cardiovascular and neoplasia prevention differ considerably. Because our study is observational, the results are not as definitive as an intervention trial designed to directly examine the effects of daily administration of low-dose, standard-dose, or 2 standard-dose aspirin tablets on subsequent risk for initial adenoma, as well as adverse outcomes in a healthy population. However, such a trial is probably not feasible given the need for a large number of patients to examine relatively rare outcomes and even more infrequent toxicities. Moreover, the cost of surveillance colonoscopy would be prohibitive, and ethical concerns about adverse consequences related to high doses of aspirin may be considerable. In summary, our results demonstrate that both shortand long-term aspirin use reduces the risk for adenoma in an average-risk population. However, chemoprevention efforts using aspirin may require substantially greater doses of aspirin than those currently recommended for the prevention of cardiovascular disease. The potential of regular use of moderate aspirin doses to prevent colorectal neoplasia necessitates further evaluation. The risk–benefit profile must be thoroughly considered, especially when compared with other potential strategies.

Because most women in our study used aspirin for reasons other than cardiovascular prevention, it is likely that most women were consuming standard 325-mg tablets. However, to address potential secular changes in the pattern of consumption, we specified both low-dose and standard-dose tablets in subsequent questionnaires. A limitation of our study is that we cannot directly assess the relationship of risk to more refined categories of dose (for example, number of milligrams) or more frequent categories of use (for example, daily). Nonetheless, we believe that the number of tablets used per week is a relevant measure of a range of aspirin intake that has been previously associated with other dose-related outcomes in this cohort. Moreover, any misclassification of dosage would have tended to bias the observed dose relationship to the null. Because adenomas are essentially diagnosed only through endoscopy, a potential limitation of a populationbased analysis is differential exposure to endoscopy, resulting in a bias in ascertaining our outcome.

To minimize this detection and selection bias, we restricted our cohort to patients who underwent endoscopy during the study period, an approach that is consistent with other observational analyses and clinical trials assessing the risk for adenomatous polyps. Although we acknowledge that this restriction may limit the generalizability of our findings to the remaining cohort, our previous analyses of colorectal cancer in the larger cohort compared with analyses of adenoma in the endoscopy cohort have yielded complementary results. Furthermore, because most adenomas are asymptomatic, discontinuation of aspirin due to symptoms attributable to adenomas or differential bleeding is unlikely to explain our results. Most important, our findings remained unchanged despite stratification by the indication for endoscopy, including bleeding. Because we assumed that many screening endoscopies performed in this cohort were sigmoidoscopies rather than colonoscopies, we restricted our analysis to adenomas of the distal colon and rectum to minimize detection bias. Therefore, women with only proximal adenomas were classified as non–case participants.

Nonetheless, we believe that our results can be generalized to proximal adenomas. In a secondary analysis in which we defined cases as proximal adenomas without distal findings, we observed a similar effect of aspirin on the risk for proximal adenomas. Moreover, a recently completed intervention trial demonstrated comparable effect for aspirin on proximal and distal adenomas, and our previous analysis in this cohort observed a similar effect for aspirin on the risk for proximal and distal cancer. Our results may have potential implications for population- based colorectal cancer prevention strategies using aspirin. Because existing screening efforts using endoscopy and polypectomy are costly, invasive, and not widely used, there is substantial enthusiasm for aspirin chemoprevention of colorectal cancer.

Although low-dose aspirin is sufficient to inhibit colonic prostaglandins and constitutively expressed cyclooxygenase- 1 isoenzymes in anucleated platelets, higher doses are needed to inhibit the cyclooxygenase-2 inducible isoenzymes in nucleated cells, such as those found in the colonic epithelium. The cyclooxygenase-2 pathway seems to be more directly relevant to colorectal neoplasia, because expression of cyclooxygenase-2 but not cyclooxygenase- 1 is upregulated in colorectal adenoma and carcinoma compared with normal colonic mucosa. Furthermore, increasing experimental data suggest that aspirin works through several other potential antineoplastic mechanisms that are maximized at higher doses. Consequently, our findings seem to be biologically plausible and support current understanding of aspirin’s known mechanisms. Our data support an effect of aspirin use in a primary prevention cohort that has a lower risk for adenoma than patients with a history of adenoma or cancer enrolled in recurrence trials. Overall, about 5% of our participants received a diagnosis of distal adenoma compared with up to 45% diagnosed with either recurrent proximal or distal adenoma in the aspirin intervention trials. Our proportion of cases is also lower than that of other average-risk populations. This may be due to the lower median age of our cohort, a higher proportion of women of premenopausal status, and a lower prevalence of other adenoma risk factors among potentially health-conscious nurses.

Furthermore, our main analyses focused on distal adenomas, and we required strict pathologic confirmation of all cases. Hence, women with only proximal adenomas or adenomas that were endoscopically ablated or not retrieved for pathologic examination were not classified as case-participants. In addition, self-report of polyps may have led to underascertainment. However, studies of other population-based cohorts have confirmed the validity of self-reports of lower endoscopy, and a parallel study of a similarly educated cohort of health professionals has validated our method of self-report of polyps. Most important, misclassification or underascertainment of adenoma cases would have probably diluted the protective benefit we observed. The strengths of our study include its prospective design, repeated assessments of aspirin use, detailed data on potential confounders, long-term follow-up, and consistently high response rate. Since the participants were all nurses, the accuracy of self-reported aspirin use is likely to be high. Moreover, because aspirin use was recorded before endoscopy, errors in recall of aspirin use would not be influenced by knowledge of the presence or absence of adenoma. Hence, nondifferential misclassification of aspirin dose or frequency would have tended to attenuate rather than exaggerate a true association.