Study 1 highlights:

• Just two weeks on a high-fructose diet raises blood pressure in men.

• A drug used to treat gout seems to protect against that blood pressure increase and some aspects of metabolic syndrome.

Study 2 highlights:

• A study in mice finds that the time of day when fructose is consumed is linked to abnormalities in blood pressure, weight gain and behavior.

Abstract P127

A high-fructose diet raises blood pressure in men, while a drug used to treat gout seems to protect against the blood pressure increase, according to research reported at the American Heart Association’s 63rd High Blood Pressure Research Conference.

“This is the first evidence of a role of fructose in raising blood pressure and a role for lowering uric acid to protect against that blood pressure increase in people,” said Richard Johnson, M.D., co-author of the study and professor and head of the division of Renal Diseases and Hypertension at the University of Colorado-Denver medical campus in Aurora, Colo.

In the study, excessive fructose consumption seemed to increase new onset of metabolic syndrome, a cluster of risk factors associated with the development of cardiovascular disease and type 2 diabetes. On the other hand, the gout drug seemed to halt it - most likely by lowering uric acid, which affects blood pressure.

Fructose, one of several dietary sugars, makes up about half of all the sugar molecules in table sugar and in high-fructose corn syrup, a sweetener often used in packaged products because it’s relatively cheap and has a long shelf life. Glucose makes up the other half. Fructose is the only common sugar known to increase uric acid levels.

Patients with high blood pressure, diabetes and kidney disease often have high uric acid levels and gout. But all the ways in which those conditions might contribute to the development or worsening of the others isn’t completely understood, Johnson said.

Johnson and co-author Santos Perez-Pozo, M.D., a nephrologist at Mateo Orfila Hospital in Minorca, Spain who led the study, evaluated 74 adult men, average age 51, who consumed a diet that included 200 grams (g) of fructose per day in addition to their regular diet. The amount is much higher than the estimated U.S. daily intake of 50 g to 70 g of fructose consumed by most U.S. adults. Half of the men were randomly assigned to get the gout drug allopurinol and the other half acted as controls.

After only two weeks on the diet, the high-fructose plus placebo group experienced significant average blood pressure increases of about 6 millimeters of mercury (mm Hg) in systolic blood pressure (the pressure when the heart beats) and about a 3 mm Hg rise in diastolic blood pressure (the pressure between heartbeats). They were measured with strap-on monitors that record blood pressure periodically around the clock.

In contrast, men on the high-fructose diet plus allopurinol had significantly lower uric acid levels and virtually no increase in systolic blood pressure (only 1 mm Hg). The blood pressure levels of most of the men returned to normal within two months of the study’s conclusion when the participants returned to their normal dietary intake, Johnson said.

The study also found changes in the incidence of metabolic syndrome. The United States and the international community define the syndrome slightly differently, so researchers used both criteria in the study. In general, metabolic syndrome is defined as having three or more of these five risk factors:

• Increased waist circumference;

• High triglyceride levels;
• Low levels of high-density lipoprotein (HDL), a component of total cholesterol thought to have a protective effect;
• High blood pressure; and
• High fasting blood sugar.

After just two weeks, the incidence of metabolic syndrome more than doubled in the men who consumed a heavy fructose diet and took the placebo pill. The incidence went from 19 percent at baseline to 44 percent at the study’s end, according to the U.S. National Cholesterol Education Program-ATP III (NCEP-ATP III) definition, and from 25 percent to 58 percent under the International Diabetes Federation (IDF) definition.

Among men consuming fructose plus allopurinol, virtually no change in the rate of metabolic syndrome occurred - perhaps because the gout drug prevented the blood pressure rise associated with increased fructose consumption.

The study should be viewed as a pilot and more investigations are needed before doctors consider lowering uric acid in the clinical setting, said Johnson, noting that allopurinol can have rare but serious side effects.

Men in both groups had an increase in fasting triglycerides and an indication of insulin resistance by a method called homeostatic model assessment (HOMA), while on the increased fructose diet. The HOMA method is used to quantify insulin resistance and beta-cell function. Allopurinol treatment appeared to lower low-density lipoprotein cholesterol (LDL), a component of total blood cholesterol linked to the development of cardiovascular disease, compared to placebo, the researchers reported.

“These results suggest that fructose may be a cause of metabolic syndrome,” Johnson said. “They also suggest that excessive fructose intake may have a role in the worldwide epidemic of obesity and diabetes.”

Fruit, which has just 4 g to 10 g of fructose per serving, also contains many beneficial substances including antioxidants, vitamin C, potassium and fiber that are believed to counter the effects of fructose alone. The main risk for excessive fructose consumption in the Western diet comes from sweetened drinks and foods rich in sugar or high fructose corn syrup, he said.

“When you give fructose to animals, they absolutely develop every feature of metabolic syndrome: they get abdominal fat, high triglycerides, low HDL, their blood pressure goes up and they get insulin resistance,” Johnson said. “However, you must give massive amounts of fructose to rats to raise uric acid levels, because rats and most other animals have an enzyme that breaks down uric acid. Humans lack that enzyme. It turns out humans get gout but other animals don’t.”

If you inhibit the enzyme in rats that breaks down uric acid, it takes only a small amount of fructose to cause uric acid to rise and the symptoms of metabolic syndrome to appear in the animals, he said.

Johnson’s other co-authors are Jesse Schold, Ph.D., and Julian Lopez Lillo, M.D. Author disclosures are on the abstract.

The National Institutes of Health funded the study.

SEE ALSO:

Abstract P237

Timing of fructose intake affects weight gain, blood pressure and behavior

Researchers found that abnormalities in blood pressure and weight gain were linked to the timing of the availability of fructose, a dietary sugar, in a study conducted in mice. When sugary liquids were consumed during the day (the usual sleeping period for mice), mice showed greater weight gain and a reversal in blood pressure rhythms.

Researchers implanted small ambulatory monitors to measure blood pressure around the clock in mice. Mice were given either continuous access to fructose water (10 percent) or restricted access for 12 hours during the day (light) or 12 hours at night (dark).

“The first thing we noticed was that the mice on restricted access rushed to their drinking bottles to load up on the sweetened beverage, similar to teenagers who drink too many soft drinks,” said Mariana Morris, Ph.D., study co-author and vice president for graduate studies and chair of the Pharmacology and Toxicology Department, in the Boonshoft School of Medicine at Wright State University in Dayton, Ohio.

Researchers reported that groups consuming fructose continuously or during the dark period, showed an increase in blood pressure with a characteristic spike during the night when mice are usually active.

However, in mice that consumed fructose during the day, the blood pressure pattern was reversed, high in the day and low in night. The blood pressure change was also associated with higher stress hormone levels.

“The reversal in the day/night rhythm is similar to the pattern seen in human diabetics, suggesting the timing of fructose intake may be important in cardiovascular pathologies,” Morris said.

Researchers also observed increased weight gain in mice given fructose during the light period. This weight gain occurred even though total calorie consumption (fructose water and solid food) was similar.
“This model may be similar to the human condition of night time binging of fructose laden foods and beverages,” Morris said. “The results indicate that consideration must be given not only to the amount of calories consumed but also the timing of intake.”

Co- authors are Swapnil V. Shewale, a master’s degree candidate and Danielle Senador, Ph.D., a postdoctoral associate. Author disclosures are on the abstract.

Source:
Karen Astle

American Heart Association

Consumption of alcohol may interfere with controlled-release drugs, potentially sending an excess of active ingredient into the bloodstream, researchers say.

In a meta-analysis, ethanol tended to impair the release mechanism, sending the drug more quickly into the small intestine, Hans Lennernas, PharmD, of Uppsala University in Sweden, reported online in Molecular Pharmaceutics.

The finding is particularly worrisome in the case of controlled-release opioids, Lennernas concluded.

“An absorption ethanol-drug interaction is a very serious safety concern when substantially the entire dose from a controlled-release product is rapidly emptied into the small intestine in an uncontrolled manner, having been largely dissolved in a strong alcohol beverage in the stomach during a sufficient lag-time in gastric emptying,” Lennernas wrote.

• Explain that in a meta-analysis, ethanol tended to impair the controlled-release mechanism on some pills, sending the drug more quickly into the small intestine.
• Note that the author calls for in vivo testing of all controlled-release formulas that appear to be susceptible to alcohol.

He suggested that controlled-release pills that tend toward such “dose dumping” in vitro should be withheld from the market until they’ve passed safety tests in vivo.

It’s well-known that ethanol enhances the pharmacodynamic effects of opioids on the central nervous system, Lennernas noted. And more recently, it’s been shown that consumption of alcohol will affect the plasma pharmacokinetics of some controlled-release drugs.

Currently, the FDA suggests testing the effects of different concentrations of ethanol on dissolution in vitro to investigate whether alcohol affects the kinetics of a controlled-release drug. However, the agency does not require tests in humans.

Lennernas said the latter is important because the gastric emptying rate can vary. Other important factors include the pharmaceutical formulation of the compound, its absorption rate, and the amount of alcohol a patient ingests.

One study included in the review, for example, found that an oral hydromorphone formulation was withdrawn from the U.S. market after in vivo testing revealed that drinking strong alcohol while taking the drug increased plasma exposure in some patients.

It had passed in vitro testing, although even that had foreshadowed an interaction with ethanol, Lennernas said.

He added that another key factor is product formulation. One in vitro study cited in the review suggested that alcohol-soluble excipients should not be used in controlled-release formulations.

Based on his review, Lennernas concluded that controlled-release formulations should be subject to a two-hour in-vitro screening of dissolution in ethanol concentrations of up to 40%.

“It may be considered as the absolute minimum standard,” he said.

Any of these products that show a vulnerability to ethanol during those two hours, he said, “should be required to demonstrate clinical safety by going through in vivo testing with an alcoholic beverage of up to 40% ethanol and of a sufficient volume, consumed in a relatively short period of time.”

Lennernas concluded that controlled-release drugs “by definition contain large amount of drug in most cases. Thus, the release mechanisms must be sufficiently robust to prevent any possibility of uncontrolled rapid release rate in the presence of ethanol.”

He added that this is especially important for opioid drugs “such as hydromorphone, tramadol, oxycodone, and morphine because opioids can prolong gastric emptying, which in turn increases the risk of a sufficiently long exposure to high concentrations of ethanol in the stomach.”