Diclofenac poses similar risks as COX-2 Inhibitors

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has completed its review of diclofenac and concluded that the drug poses similar risks as selective COX-2 inhibitors, particularly when used in high doses (150 mg) or when used long term [1].

Still, committee says the benefits of diclofenac exceed the risks and that physicians should take the same precautions to minimize thromboembolic events as they do with patients treated with selective COX-2 inhibitors.

"Patients who have serious underlying heart or circulatory conditions, such as heart failure, heart disease, circulatory problems, or a previous heart attack or stroke, should not use diclofenac," according to PRAC. "Patients with certain cardiovascular risk factors (such as high blood pressure, raised blood cholesterol, diabetes, or smoking) should only use diclofenac after careful consideration. Healthcare professionals will also be advised to periodically reassess the need for patients to continue taking the medicine."

The review conducted by PRAC was launched in October 2012 after the EMA completed a report on published information assessing the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs). Like PRAC, the EMA concluded that there was a consistent but small increase in the risk of cardiovascular side effects with diclofenac compared with other NSAIDs and that this risk was on par with that observed with COX-2 inhibitors.

The current PRAC conclusions are based on all published and unpublished data. Its recommendations will now be forwarded to the Coordination Group for Mutual Recognition and Decentralized Procedures--Human (CMDh), a regulatory body representing member European Union states, which will adopt a final position.

Source: http://www.medscape.com/viewarticle/806308?nlid=31771_1301&src=wnl_edit_dail&uac=129655SZ

Silver enhances antibiotic activity against gram-negative bacteria in mice

The use of silver in medicine is as old as western medicine itself. Hippocrates is known to have used it to treat ulcers and wounds, the Romans almost certainly knew of its healing properties, its use continued through the middle ages and up to the present day. In the antibiotic age, interest in silver may have waned a little. But with urgent need to fight antibiotic-resistant bacteria, there is resurgence in its uses.

The reason is that silver can kill bacteria selectively and, more importantly, bacteria are unable to develop resistance against it. Despite silver’s long medical history, we do not know how it operates. A paper published last Thursday in the journal Science Translational Medicine sheds some light on silver’s success against bacteria. The most important find is that silver – unlike most antibiotics – works in more than one way. This is perhaps why bacteria are not able to build resistance to silver.

Here is silver’s multi-pronged approach: first, silver sticks very strongly to sulfur, found in parts of proteins. These sulfur groups normally bond to each other in proteins, holding them together and keeping the protein folded up in its correct shape. But if silver interacts with sulfur then the protein cannot fold correctly, and thus it cannot do its job. Next silver interferes with how bacteria use iron. Iron is often held in the places it is needed by binding to sulfur. And since silver also interacts with sulfur it stops the iron doing so. Finally, silver causes bacteria to produce extremely toxic substances called reactive oxygen species. These go on to cause damage inside the cell, harming the DNA, proteins and even the membranes that surround cells.

The net result of this silver onslaught is bacteria with severely damaged defences. Most importantly the membranes and walls that surround it are leakier after the silver treatment. Once weakened, they are much more susceptible to conventional antibiotics. James Collins, at Boston University, who led the research showed that with added silver, less antibiotic drug is needed to kill the bugs. A great result in itself, but it gets better. Silver also reverses antibiotic resistance of E. coli bacteria making them, once more, susceptible to tetracycline.

These experiments not only worked in a Petri dish. When silver was added to standard antibiotics such as gentamicin and vancomycin, Collins could treat E. coli infections in the bladder and abdomens of mice. Normally these drugs have little effect on E. coli infections because they are designed to attack a completely separate class of bacteria.

Bacteria are broadly classified into two groups called Gram-negative or Gram-positive. Gram-negatives have an extra cell membrane that protects the bacteria, which means that it is much more difficult for some antibiotics, such as gentamicin and vancomycin, to penetrate the cell. It seems that silver negates this advantage and allows even weaker drugs to do their jobs. Finally, Collins showed that the mice themselves remain unharmed by silver. If he is able to repeat this work in humans, then he may actually have a “silver bullet” for antibiotic resistance.

High intake of processed meat linked to cancer deaths

Bacon, sausage, and ham are once again being singled out as key culprits driving the association between meat consumption and the world's most common diseases.

One of the largest studies to address this question, published online March 7 in BMC Medicine, found a moderate positive association between processed meat consumption and mortality. This was particularly true for cardiovascular diseases (CVDs), but was also true for cancer.

Over a mean of 12 years, high consumption of processed meat was associated with a near doubling of the risk for all-cause mortality in adults, compared with low consumption. The risk for cancer death was 43% higher and the risk for cardiovascular death was 70% higher in people eating more than 160 g/day of processed meats than in those eating 10.0 to 19.9 g/day.

"The clinical message [is] to limit consumption of processed meat — not every day and not in high amounts," said lead author Sabine Rohrmann, PhD, MPH, head of the Department of Epidemiology and Prevention at the University of Zurich in Switzerland, in an interview.

EPIC data
The new data come from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which involved 10 countries and almost half a million men and women.

A signal of increased mortality was seen in the highest consumers of red meat in general; however, the risk was much lower with red meat than with processed meats, and lost statistical significance after correction for measurement error, the researchers report. In fact, the high consumption of processed meat was associated with an 18% increased risk for all-cause mortality.

After multivariate adjustment, the consumption of more than 160 g/day of red meat was related to higher all-cause mortality than the consumption of 10.0 to 19.9 g/day (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01 to 1.28). The HR was higher for more than 160 g/day of processed meat (1.44; 95% CI, 1.24 to 1.66).

After correction for measurement error, all-cause mortality remained significantly higher only for the consumption of 50 g/day of processed meat (HR, 1.18; 95% CI, 1.11 to 1.25).

A very high consumption of red meat was nonsignificantly associated with increased cancer mortality, but not with deaths caused by CVD or respiratory diseases, diseases of the digestive tract, or any other disease.

As the researchers point out, processed meats tend to contain more saturated fat than unprocessed meat (where the fat is often trimmed off) and more cholesterol and additives (which are part of the smoking or curing process). Some of these are believed to be carcinogenic or precursors to carcinogenic processes.

When the researchers re-examined the association between processed meat intake and cancer risk using the lowest consumption category (0.0 to 9.9 g/d) as a reference, they observed a statistically significantly increased risk for cancer mortality in people who consumed 80.0 to 159.9 g/day (HR, 1.12; 95% CI, 1.01 to 1.24). There was also a nonsignificantly increased risk in the highest consumption category (HR, 1.19; 95% CI, 0.93 to 1.51).

"Another factor is the salt in processed meat products, which is linked to hypertension — a CVD risk factor," noted Dr. Rohrmann. Heme iron also links meat consumption to CVD risk, "but that's not limited to processed meat," she explained.

Dr. Rohrmann and colleagues point out that the high consumption of processed meat typically goes hand in hand with other unhealthy behaviors, including smoking, low levels of physical activity, and low consumption of fruit and vegetables.

"Overall, we estimate that 3% of premature deaths each year could be prevented if people ate less than 20 g of processed meat per day," she said in a press statement.

What about red meat?
Other studies have singled out processed meats as being particularly hazardous to health. Two large long-running American studies have documented the link between meat consumption and CVD and cancer deaths. However, the stronger association with processed meats that Dr. Rohrmann and colleagues found in their European cohort is somewhat at odds with the American data.

A number of studies have examined the link between meat consumption and cancer. For example, one large prospective trial linked the consumption of processed meat to an increased risk for bladder cancer. Another study found that the consumption of red and processed meats increases the risk for colorectal cancer.

"Although we did not find a statistically significant association between unprocessed red meat consumption and mortality in our studies, we would not say that there is definitely no association" between red meat consumption and CVD, Dr. Rohrmann explained.

"Our studies show it that it's okay to eat a moderate amount of meat (300 to 600 g per week), as recommended by many nutrition societies," she said. However, "a balanced vegetarian diet is okay as well," she added.

Significant association with processed meat
In their study, Dr. Rohrmann and colleagues examined the association between risk for early death and the consumption of red meat, processed meat, and poultry. The 448,568 study participants were 35 to 69 years of age, and had no prevalent cancer, stroke, or myocardial infarction, and had complete information on diet, smoking, physical activity, and body mass index.

A total of 26,344 study participants (11,563 men and 14,781 women) died during the median follow-up period of 12.7 years; 5556 died of CVD, 9861 of cancer, 1068 of respiratory diseases, 715 of digestive tract diseases, and 9144 of other causes.

The researchers note that, according to their estimates, "3.3% (95% CI, 1.5% to 5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g/day."

The consumption of poultry was not related to all-cause mortality.

Source: http://www.medscape.com/viewarticle/780553?nlid=29163_1301&src=wnl_edit_dail

Domperidone under scrutiny in Europe for cardiac risks

European Union (EU) drug regulators announced yesterday that they have begun a review of domperidone, an antiemetic, because of concerns about adverse cardiac events, including QT prolongation and arrhythmias.

Domperidone-containing antiemetics, sold under brand names such as Motilium (Janssen), Mirax (Berlin), and Domper(Opalia, YSP, and Yung Shin), are widely available over the counter or by prescription in a number of European countries. The drugs also have been used on an off-label basis to increase lactation in breast-feeding mothers.

The US Food and Drug Administration (FDA) has not approved domperidone for any indication. In 2004, the FDAwarned clinicians and breast-feeding mothers not to use domperidone to boost milk production because of the risk for adverse events. The agency cited reports of cardiac arrhythmias, cardiac arrest, and sudden death in patients receiving an intravenous form of domperidone that has been discontinued in several countries. However, the European Medicines Agency (EMA) — the EU equivalent of the FDA — continued to receive reports of these adverse events with other forms of the drug.

The FDA noted in 2004 that breast-feeding women in the United States were buying the drug from Internet pharmacies and US compounding pharmacies. The FDA sent warning letters to 6 such compounding pharmacies about the illegal trade in domperidone. A similar letter was issued in 2010 to a compounding pharmacy in Virginia. However, Internet pharmacies still continue to advertise the drug.

The EMA said yesterday that it began its review of domperidone at the request of drug regulators in Belgium, who learned of new cases of cardiotoxicity. Those regulators have proposed that the drug be contraindicated for patients with QT prolongation, significant electrolyte disturbances, or underlying cardiac diseases such as congestive heart failure.

The EMA said that its Pharmacovigilance Risk Assessment Committee will study domperidone-containing drugs, assess whether their benefits outweigh their risks, and recommend possible regulatory action, which could include withdrawing the drugs from the market or revising their label instructions.

Male-pattern baldness linked with heart disease

Vertex baldness, more commonly known as male-pattern baldness, is associated with an increased risk of coronary heart disease, according to the results of a new meta-analysis[1]. The severity of male pattern baldness increased the risk of coronary disease even in younger subjects, report investigators.

A receding hairline, on the other hand, was not associated with an increased risk of heart disease (relative risk 1.11, 95% CI 0.92–1.32; p=0.28).

"These findings suggest that vertex baldness is more closely associated with systemic atherosclerosis than . . . frontal baldness [is]," say Dr Kazuo Hara (University of Tokyo, Japan) and colleagues in their report, published online April 3, 2013 in BMJ Open. "Thus, cardiovascular risk factors should be reviewed carefully in men with vertex baldness, especially younger men, and they probably should be encouraged to improve their cardiovascular risk profile."

The researchers included six studies with 36 990 participants in the meta-analysis, including three cohort studies and three case-control studies. In the three cohort studies, the adjusted risk of coronary heart disease was 32% higher among individuals with severe vertex baldness compared with men with full hair. In the case-control studies, the risk of coronary heart disease was 70% higher among bald subjects compared with those without baldness. The increased relative risk of coronary disease was statistically significant in both analyses. When the analysis was restricted to younger subjects, those <55 or <60 years at baseline, the association between vertex baldness and coronary heart disease remained.

Three studies classified the severity of baldness. In this analysis, the risk of coronary heart disease was 48%, 36%, and 18% higher among subjects with severe, moderate, and mild vertex baldness compared with subjects without baldness. "When baldness was classified by the Hamilton-Norwood scale, which is the most commonly used classification of pattern baldness worldwide, the relationship between coronary heart disease and baldness was shown to be dependent on the severity of baldness," state the researchers.

The reason for the association between vertex baldness and coronary heart disease is not known. The current working hypothesis is that insulin resistance can impair the supply of nutrients to the hair follicles or a proinflammatory state could increase the inflammatory cytokines in the hair follicles. The researchers state that further studies are needed to confirm these findings, as well as to identify mechanisms for the association.

Source: http://www.medscape.com/viewarticle/781931?nlid=30099_1301&src=wnl_edit_dail

Omega-3 plasma levels predict mortality and heart disease

The highest levels of plasma phospholipid omega-3 polyunsaturated fatty acids (PUFA), as measured in over 2,500 older adults initially without coronary heart disease or a history of stroke, predicted the lowest mortality in the observational, prospective Cardiovascular Health Study(CHS)[1].

In comparisons of the highest quintile of omega-3 PUFA levels vs the lowest quintile, all-cause mortality fell by 27%, with most of the benefit due to a reduction in cardiovascular death. The rate of arrhythmic death, in particular, fell by nearly one-half.

Such cardiovascular-outcome effects are consistent with abundant evidence from laboratory and clinical studies that omega-3 PUFA intake may benefit heart rate, blood pressure, myocardial contractile function and electrical stability, and endothelial, autonomic, and hemostatic function, write the study's authors, led by Dr Dariush Mozaffarian (Harvard School of Public Health, Boston, MA). Their analysis was published in the April 2, 2013 issue of the Annals of Internal Medicine.

The CHS longitudinal data allowed the group not only to link plasma omega-3 PUFA levels with survival, Mozaffarian told heartwire , it allowed them to estimate the benefit: in this population, starting at age 65, he said, about 2.2 extra years for people in the highest compared with the lowest plasma-level quintile.

Outcomes also varied by individual omega-3 PUFAs. For a number of end points, importantly heart-disease mortality and arrhythmic mortality, there was a pattern of greater benefit from highest levels of docosahexaenoicacid (DHA) vs highest levels of eicosapentaenoic acid (EPA) and an even greater benefit from highest levels of total omega-3 PUFA.

For the end point of heart-disease death, "DHA seems to have stronger association" than EPA, according to Mozaffarian; the effect, he noted, appears to be dominated by a difference in arrhythmic death. But EPA at the highest levels vs the lowest levels showed a weakly significant trend (p=0.04) of benefit for nonfatal MI, while DHA and total omega-3 PUFA were unquestionably nonsignificant. Still, he said, given the "borderline" p value for EPA, "maybe none of them are significantly associated" with respect to nonfatal MI.

That outcomes varied by type of omega-3 PUFA has implications for dietary recommendations as well as therapeutic preparations of omega-3 PUFA.

"I think that our results support DHA, in particular, being important for heart-disease death and leaves open the question of whether EPA . . . [has] additional benefit." Consuming both together is probably wise, as there appear to be "complementary effects," Mozaffarian said. Based on the current analysis, "If you're going to consume omega-3s, you should at least be sure you're getting DHA. EPA alone might not have the same benefit; I think that's fair to say."

The CHS enrolled 5201 adults aged >65 years in four US communities, two in the East and one in California from 1989 to 1990, plus 687 additional African Americans from 1992 to 1993. The current analysis includes 2692 without CHD, stroke, or heart failure at baseline who were not taking fish-oil supplements and in whom levels of plasma phospholipid omega-3 PUFA were measured in 1992–1993. Their mean age at baseline was 74 years, 64% were women, and 88% were white; they were followed until 2000.

The adjusted hazard ratio (HR) for total mortality was 0.83 for the highest quintile of EPA vs the lowest quintile (p=0.005), 0.80 for DHA (p=0.006), and 0.73 for total omega-3 PUFA (p<0.001).

Decreases in HR for total heart-disease mortality were significant only for DHA (p=0.003) and total omega-3 PUFA (p=0.002). The same was true for arrhythmic death: DHA (p=0.028) and total omega-3 PUFA (p=0.008).

Acknowledging that "this is an observational study--it doesn't prove cause and effect," Mozaffarian said that it at least supports high plasma levels of omega-3 PUFAs as directly affecting survival. "If there was confounding--if it was just that people were more educated or had healthy lifestyles--you'd expect that higher [omega-3 PUFA plasma levels] would relate very similarly to a lower risk of every kind of death: [including] respiratory death, infectious death, cancer death, and stroke death. But the bulk of the association seems to be from heart-disease death, and [especially] heart disease death from arrhythmia."

As for the possible advantage high plasma DHA levels may have over high EPA levels with respect to total and heart-disease mortality, which would conceivably conflict with the higher elevations in LDL cholesterol observed with DHA vs EPA supplementation, Mozaffarian said doesn't see a paradox.

"The LDL-raising effect of omega-3s is very modest." If there is any such effect, he said, "it's to make the particles larger and fluffier and therefore potentially less atherogenic." According to Mozaffarian, "it's just hype" to say that an omega-3 PUFA supplement that delivers only EPA should be preferred over a mixed EPA/DHA supplement because of a difference in LDL effects.

In addition to many brands of nonprescription mixed EPA/DHA supplements on the market, in the US there is the prescription-only mixed formulation Lovaza (GlaxoSmithKline); and just last year, the FDAapproved the synthetic EPA-only preparation Vascepa (Amarin), which contains ethyl eicosapentaenoic acid.

Source: http://www.medscape.com/viewarticle/781931?nlid=30099_1301&src=wnl_edit_dail

Dietary nitrate in beet lowers blood pressure

A small, proof-of-principle study has demonstrated that the blood-pressure lowering effects of dietary nitrates--already documented in normotensives--are also seen in subjects with established hypertension[1].

Dr Amrita Ahluwalia (Barts and the London School of Medicine and Dentistry, UK) and colleagues have a track record of studying the interaction between dietary sources of biologically inert nitrate (NO3) and oral microflora, which converts the NO3 into bioactive nitrite (NO2). Circulating NO2 is known to cause vasodilation and lower blood pressure. Ahluwalia et al have previously proposed a pathway for nitrate-nitrite conversion, showing that beet juice, after coming into contact with human saliva, increases levels of plasma nitrate and nitrite, and leads to significant blood-pressure decreases in healthy volunteers.

In their latest study, published online April 15, 2013 in Hypertension, Ahluwalia and colleagues, including senior author Dr Suborno Ghosh (Queen Mary University of London, UK) turned again to beetroot, which, along with green leafy vegetables, has high concentrations of inorganic nitrate. In a mouse model of hypertension, investigators first established a threshold nitrite dose at which blood pressure decreased in the hypertensive mice, but not in normotensive control mice. At higher doses, however, both strains of mice saw blood-pressure decreases.

The authors then tested the beet-juice effects in 15 hypertensive, drug-naive patients, randomized to either 250ml of inorganic nitrate-rich beetroot juice or an equal volume of water. The "dose" of juice elevates nitrite levels approximately 1.5 fold--a rise previously shown to have no significant BP-lowering effect in subjects with normal blood pressure.

In patients who drank the juice, systolic blood pressure dropped by a mean of 11.2 mm Hg between three and six hours after consumption (vs 0.7 mm Hg in subjects who drank water). By 24 hours, clinic systolic BP remained significantly lower in the beet-juice group and roughly 7.2 mm Hg lower than baseline. Peak drop in diastolic BP also occurred within the first six hours, dropping by a mean of 9.6 mm Hg. Pulse-wave velocity also decreased in the beet-juice group, but not in the controls.

"Our observations . . . support the concept of dietary nitrate supplementation as an effective, but simple and inexpensive, antihypertensive strategy," the authors conclude.

Ahluwalia underscored the finding that nitrate in beets appears to be even more potent in hypertensives than in normotensives. "In this new study we used a dose that had little to no effect upon blood pressure in healthy volunteers; in contrast, this dose caused a substantial decrease in blood pressure (~12 mm Hg) in the patients, suggesting that dietary nitrate is more potent, and therefore potentially one needs less to produce an important blood-pressure–lowering effect."

She added: "It is also true that while we all know that eating fruits and vegetables is good for the cardiovascular system, exactly why this is the case is not certain. Studies have shown that of all the different fruit and vegetables out there it is the green leafy vegetables that provide the greatest protection against heart attacks and strokes. What is true about these vegetables is that they represent the major source of nitrate in our diet."

She also stressed the limitations of the study: while "impressive," the BP-lowering effects of beet juice consumption were measured only over 24 hours and in very small numbers. "Whether this effect can be sustained in the long term is not yet known, and further clinical studies that assess the effects over longer periods of time and in larger cohorts are needed," she said.

Source: http://www.medscape.com/viewarticle/782590?nlid=30483_1301&src=wnl_edit_dail