Michele G. Sullivan

Officials in charge of disclosing financial interests in research agree that disclosure is important, but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt, a psychiatrist at Duke University, Durham, N.C., and his coinvestigators.

"Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure," the researchers wrote. "There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making" (J. Law Med. Ethics 2006;34: 581–91).

The study was based on detailed personal interviews with eight investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision-making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source, but some said the name of the company or organization wasn't as important as a description—whether it was a nonprofit organization, pharmaceutical company, or government body, for instance.

They also differed on whether the amount of financial interest should be disclosed. Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure—the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships. Again, concern about overcomplicating the consent statement seemed to be at the root of these issues. Some respondents said the disclosure should include an explanation of how an unscrupulous investigator might alter the research results.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document—at the very beginning, for example.

"Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests," the researchers said. "Before we can resolve what counts as substantial understanding, there must be agreement about what risks are important for potential research participants to understand."

Officials in charge of disclosing financial interests in research agree that disclosure is important, but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt, a psychiatrist at Duke University, Durham, N.C., and his coinvestigators.

"Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure," the researchers wrote. "There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making" (J. Law Med. Ethics 2006;34: 581–91).

The study was based on detailed personal interviews with eight investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision-making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source, but some said the name of the company or organization wasn't as important as a description—whether it was a nonprofit organization, pharmaceutical company, or government body, for instance.

They also differed on whether the amount of financial interest should be disclosed. Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure—the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships. Again, concern about overcomplicating the consent statement seemed to be at the root of these issues. Some respondents said the disclosure should include an explanation of how an unscrupulous investigator might alter the research results.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document—at the very beginning, for example.

"Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests," the researchers said. "Before we can resolve what counts as substantial understanding, there must be agreement about what risks are important for potential research participants to understand."

Officials in charge of disclosing financial interests in research agree that disclosure is important, but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt, a psychiatrist at Duke University, Durham, N.C., and his coinvestigators.

"Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure," the researchers wrote. "There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making" (J. Law Med. Ethics 2006;34: 581–91).

The study was based on detailed personal interviews with eight investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision-making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source, but some said the name of the company or organization wasn't as important as a description—whether it was a nonprofit organization, pharmaceutical company, or government body, for instance.

They also differed on whether the amount of financial interest should be disclosed. Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure—the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships. Again, concern about overcomplicating the consent statement seemed to be at the root of these issues. Some respondents said the disclosure should include an explanation of how an unscrupulous investigator might alter the research results.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document—at the very beginning, for example.

"Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests," the researchers said. "Before we can resolve what counts as substantial understanding, there must be agreement about what risks are important for potential research participants to understand."

BOSTON — Intermittent intravenous ibandronate is at least as effective as daily oral ibandronate for increasing bone mineral density and may be preferable to oral dosing in patients with esophageal disease or compliance problems.

There are no fracture data for the intravenous dosing schedule, but the risk reduction that has been shown with oral ibandronate can probably be extrapolated to the intravenous form of the drug, Dr. Mone Zaidi said at the annual meeting of the Endocrine Society.

Oral ibandronate has been shown to reduce the risk of new vertebral fractures by up to 60% (Curr. Med. Res. Opin. 2005;21:391–401; J. Bone Miner. Res. 2004;19:1241–9). “If you can show equivalence or superiority in bone mineral density changes to [the form] with proven fracture data, which we have done, I think everyone would agree that you can extrapolate that data,” said Dr. Zaidi, director of the Mount Sinai Bone Program, Mount Sinai School of Medicine, New York.

Dr. Zaidi presented 2-year bone mineral density (BMD) data from the ibandronate Dosing Intravenous Administration trial, a Roche-sponsored phase III study that compared two doses of intravenous ibandronate (2 mg every 2 months and 3 mg every 3 months) with the approved oral dosing schedule (2.5 mg daily). The study group included 1,400 postmenopausal women with low bone mass (T scores of −3.3 for total spine and −2 for hip).

After 2 years, BMD at the lumbar spine increased significantly more in both intravenous groups than in the oral group (mean increase 6.4% for the 2-mg IV dose, 6.3% for the 3-mg IV dose, and 4.8% for the oral dose). BMD increased similarly at all other sites measured, with consistently greater gains in both intravenous groups than in the oral group, Dr. Zaidi said.

At 2 years, the incidence of adverse events was similar across all groups. There was no osteonecrosis of the jaw. Renal and urinary incidents were uncommon and similar across groups.

Fracture incidence, which was reported as an adverse event, was low and similar in all groups, although Dr. Zaidi stressed that the study was not powered to prove fracture risk reduction.

BOSTON — Intermittent intravenous ibandronate is at least as effective as daily oral ibandronate for increasing bone mineral density and may be preferable to oral dosing in patients with esophageal disease or compliance problems.

There are no fracture data for the intravenous dosing schedule, but the risk reduction that has been shown with oral ibandronate can probably be extrapolated to the intravenous form of the drug, Dr. Mone Zaidi said at the annual meeting of the Endocrine Society.

Oral ibandronate has been shown to reduce the risk of new vertebral fractures by up to 60% (Curr. Med. Res. Opin. 2005;21:391–401; J. Bone Miner. Res. 2004;19:1241–9). “If you can show equivalence or superiority in bone mineral density changes to [the form] with proven fracture data, which we have done, I think everyone would agree that you can extrapolate that data,” said Dr. Zaidi, director of the Mount Sinai Bone Program, Mount Sinai School of Medicine, New York.

Dr. Zaidi presented 2-year bone mineral density (BMD) data from the ibandronate Dosing Intravenous Administration trial, a Roche-sponsored phase III study that compared two doses of intravenous ibandronate (2 mg every 2 months and 3 mg every 3 months) with the approved oral dosing schedule (2.5 mg daily). The study group included 1,400 postmenopausal women with low bone mass (T scores of −3.3 for total spine and −2 for hip).

After 2 years, BMD at the lumbar spine increased significantly more in both intravenous groups than in the oral group (mean increase 6.4% for the 2-mg IV dose, 6.3% for the 3-mg IV dose, and 4.8% for the oral dose). BMD increased similarly at all other sites measured, with consistently greater gains in both intravenous groups than in the oral group, Dr. Zaidi said.

At 2 years, the incidence of adverse events was similar across all groups. There was no osteonecrosis of the jaw. Renal and urinary incidents were uncommon and similar across groups.

Fracture incidence, which was reported as an adverse event, was low and similar in all groups, although Dr. Zaidi stressed that the study was not powered to prove fracture risk reduction.

BOSTON — Intermittent intravenous ibandronate is at least as effective as daily oral ibandronate for increasing bone mineral density and may be preferable to oral dosing in patients with esophageal disease or compliance problems.

There are no fracture data for the intravenous dosing schedule, but the risk reduction that has been shown with oral ibandronate can probably be extrapolated to the intravenous form of the drug, Dr. Mone Zaidi said at the annual meeting of the Endocrine Society.

Oral ibandronate has been shown to reduce the risk of new vertebral fractures by up to 60% (Curr. Med. Res. Opin. 2005;21:391–401; J. Bone Miner. Res. 2004;19:1241–9). “If you can show equivalence or superiority in bone mineral density changes to [the form] with proven fracture data, which we have done, I think everyone would agree that you can extrapolate that data,” said Dr. Zaidi, director of the Mount Sinai Bone Program, Mount Sinai School of Medicine, New York.

Dr. Zaidi presented 2-year bone mineral density (BMD) data from the ibandronate Dosing Intravenous Administration trial, a Roche-sponsored phase III study that compared two doses of intravenous ibandronate (2 mg every 2 months and 3 mg every 3 months) with the approved oral dosing schedule (2.5 mg daily). The study group included 1,400 postmenopausal women with low bone mass (T scores of −3.3 for total spine and −2 for hip).

After 2 years, BMD at the lumbar spine increased significantly more in both intravenous groups than in the oral group (mean increase 6.4% for the 2-mg IV dose, 6.3% for the 3-mg IV dose, and 4.8% for the oral dose). BMD increased similarly at all other sites measured, with consistently greater gains in both intravenous groups than in the oral group, Dr. Zaidi said.

At 2 years, the incidence of adverse events was similar across all groups. There was no osteonecrosis of the jaw. Renal and urinary incidents were uncommon and similar across groups.

Fracture incidence, which was reported as an adverse event, was low and similar in all groups, although Dr. Zaidi stressed that the study was not powered to prove fracture risk reduction.

It is usually not necessary to eliminate dairy foods from the diets of lactose-intolerant children and adolescents, and doing so may compromise their long-term skeletal health.

Most of these patients still can consume enough dairy every day to meet their calcium and vitamin D needs, especially if they drink lactose-reduced milk and eat yogurt with live cultures and/or aged cheeses, like cheddar or Swiss, according to the American Academy of Pediatrics' new guidelines on lactose intolerance.

If dairy products are eliminated from the diet of these children, the AAP strongly recommends regular calcium supplements. However, the guidelines said, supplemental calcium is not as bioavailable as that contained in mammalian milk.

The report also noted that, although the gastrointestinal distress of true lactose intolerance is unpleasant, is not harmful. However, when such symptoms occur in newborns or children who are younger than 3 years old, they should be immediately investigated as they may signal a serious, even life-threatening, digestive disorder.

The document is the first AAP lactose guideline update since 1990 (Pediatrics 2006;118:1279–86).

A statement from the American Dairy Council hailed the AAP guidelines as a common sense approach to a problem that sometimes prevents children from getting milk's unique nutritional package of protein, vitamins, and minerals.

“Although calcium-fortified beverages and other foods can provide an alternative source of calcium, the report reinforces that they do not provide an equivalent nutrient package to dairy foods like milk, cheese, and yogurt,” Ann Marie Krautheim, a registered dietitian and an official on the council, said in a statement.

“We hope this report will further educate parents on how to continue to include dairy in the diets of children sensitive to lactose and also help improve their nutrient intake.”

Symptoms of lactose intolerance usually emerge slowly over several years and are most common among Asians and Native Americans, followed by blacks and Hispanics. The incidence is very low in whites, whose northern European heritage seems to be protective, according the guidelines. Among white children, symptoms typically don't develop until after age 4 or 5 years; they may manifest earlier in other groups.

Newborns who develop intractable diarrhea after consuming any mammalian milk product, including human milk, may have congenital lactase deficiency, a life-threatening inability to digest lactose. A biopsy of the small intestine will show normal histology but low or absent lactase concentrations. Unless this disorder is recognized and treated immediately, fatal dehydration from diarrhea is possible. Treatment is simple—feed the child a commercial lactose-free formula, the guidelines said.

When lactose-intolerance symptoms appear, the most common reaction is to remove dairy foods from the diet completely. However, that may be a mistake, the guidelines noted.

“The avoidance of milk products to control symptoms may be problematic for optimal bone mineralization. Children who avoid milk have been documented to ingest less than the recommended amounts of calcium needed for normal bone calcium accretion and bone mineralization.”

Most lactose-intolerant children can tolerate varying amounts of dairy, depending on their individual symptoms: One glass of milk may be fine, but two may provoke diarrhea.

Parents should be encouraged to feed children lactose-free or lactose-reduced milk, and to encourage them to enjoy cheese and yogurt with live bacterial cultures, according to the guidelines. Yogurt and cheese may be especially valuable for very sensitive children, since the firmer textures of these foods delay gastric emptying and intestinal transit time, which results in fewer symptoms.

The guidelines also pointed out that all mammalian milks contain lactose, so there is no advantage in switching from cow milk to goat milk.

In addition, they said, rice and soy milks are not good substitutes, because they are lacking in nutrients that are needed for bone growth.

It is usually not necessary to eliminate dairy foods from the diets of lactose-intolerant children and adolescents, and doing so may compromise their long-term skeletal health.

Most of these patients still can consume enough dairy every day to meet their calcium and vitamin D needs, especially if they drink lactose-reduced milk and eat yogurt with live cultures and/or aged cheeses, like cheddar or Swiss, according to the American Academy of Pediatrics' new guidelines on lactose intolerance.

If dairy products are eliminated from the diet of these children, the AAP strongly recommends regular calcium supplements. However, the guidelines said, supplemental calcium is not as bioavailable as that contained in mammalian milk.

The report also noted that, although the gastrointestinal distress of true lactose intolerance is unpleasant, is not harmful. However, when such symptoms occur in newborns or children who are younger than 3 years old, they should be immediately investigated as they may signal a serious, even life-threatening, digestive disorder.

The document is the first AAP lactose guideline update since 1990 (Pediatrics 2006;118:1279–86).

A statement from the American Dairy Council hailed the AAP guidelines as a common sense approach to a problem that sometimes prevents children from getting milk's unique nutritional package of protein, vitamins, and minerals.

“Although calcium-fortified beverages and other foods can provide an alternative source of calcium, the report reinforces that they do not provide an equivalent nutrient package to dairy foods like milk, cheese, and yogurt,” Ann Marie Krautheim, a registered dietitian and an official on the council, said in a statement.

“We hope this report will further educate parents on how to continue to include dairy in the diets of children sensitive to lactose and also help improve their nutrient intake.”

Symptoms of lactose intolerance usually emerge slowly over several years and are most common among Asians and Native Americans, followed by blacks and Hispanics. The incidence is very low in whites, whose northern European heritage seems to be protective, according the guidelines. Among white children, symptoms typically don't develop until after age 4 or 5 years; they may manifest earlier in other groups.

Newborns who develop intractable diarrhea after consuming any mammalian milk product, including human milk, may have congenital lactase deficiency, a life-threatening inability to digest lactose. A biopsy of the small intestine will show normal histology but low or absent lactase concentrations. Unless this disorder is recognized and treated immediately, fatal dehydration from diarrhea is possible. Treatment is simple—feed the child a commercial lactose-free formula, the guidelines said.

When lactose-intolerance symptoms appear, the most common reaction is to remove dairy foods from the diet completely. However, that may be a mistake, the guidelines noted.

“The avoidance of milk products to control symptoms may be problematic for optimal bone mineralization. Children who avoid milk have been documented to ingest less than the recommended amounts of calcium needed for normal bone calcium accretion and bone mineralization.”

Most lactose-intolerant children can tolerate varying amounts of dairy, depending on their individual symptoms: One glass of milk may be fine, but two may provoke diarrhea.

Parents should be encouraged to feed children lactose-free or lactose-reduced milk, and to encourage them to enjoy cheese and yogurt with live bacterial cultures, according to the guidelines. Yogurt and cheese may be especially valuable for very sensitive children, since the firmer textures of these foods delay gastric emptying and intestinal transit time, which results in fewer symptoms.

The guidelines also pointed out that all mammalian milks contain lactose, so there is no advantage in switching from cow milk to goat milk.

In addition, they said, rice and soy milks are not good substitutes, because they are lacking in nutrients that are needed for bone growth.

It is usually not necessary to eliminate dairy foods from the diets of lactose-intolerant children and adolescents, and doing so may compromise their long-term skeletal health.

Most of these patients still can consume enough dairy every day to meet their calcium and vitamin D needs, especially if they drink lactose-reduced milk and eat yogurt with live cultures and/or aged cheeses, like cheddar or Swiss, according to the American Academy of Pediatrics' new guidelines on lactose intolerance.

If dairy products are eliminated from the diet of these children, the AAP strongly recommends regular calcium supplements. However, the guidelines said, supplemental calcium is not as bioavailable as that contained in mammalian milk.

The report also noted that, although the gastrointestinal distress of true lactose intolerance is unpleasant, is not harmful. However, when such symptoms occur in newborns or children who are younger than 3 years old, they should be immediately investigated as they may signal a serious, even life-threatening, digestive disorder.

The document is the first AAP lactose guideline update since 1990 (Pediatrics 2006;118:1279–86).

A statement from the American Dairy Council hailed the AAP guidelines as a common sense approach to a problem that sometimes prevents children from getting milk's unique nutritional package of protein, vitamins, and minerals.

“Although calcium-fortified beverages and other foods can provide an alternative source of calcium, the report reinforces that they do not provide an equivalent nutrient package to dairy foods like milk, cheese, and yogurt,” Ann Marie Krautheim, a registered dietitian and an official on the council, said in a statement.

“We hope this report will further educate parents on how to continue to include dairy in the diets of children sensitive to lactose and also help improve their nutrient intake.”

Symptoms of lactose intolerance usually emerge slowly over several years and are most common among Asians and Native Americans, followed by blacks and Hispanics. The incidence is very low in whites, whose northern European heritage seems to be protective, according the guidelines. Among white children, symptoms typically don't develop until after age 4 or 5 years; they may manifest earlier in other groups.

Newborns who develop intractable diarrhea after consuming any mammalian milk product, including human milk, may have congenital lactase deficiency, a life-threatening inability to digest lactose. A biopsy of the small intestine will show normal histology but low or absent lactase concentrations. Unless this disorder is recognized and treated immediately, fatal dehydration from diarrhea is possible. Treatment is simple—feed the child a commercial lactose-free formula, the guidelines said.

When lactose-intolerance symptoms appear, the most common reaction is to remove dairy foods from the diet completely. However, that may be a mistake, the guidelines noted.

“The avoidance of milk products to control symptoms may be problematic for optimal bone mineralization. Children who avoid milk have been documented to ingest less than the recommended amounts of calcium needed for normal bone calcium accretion and bone mineralization.”

Most lactose-intolerant children can tolerate varying amounts of dairy, depending on their individual symptoms: One glass of milk may be fine, but two may provoke diarrhea.

Parents should be encouraged to feed children lactose-free or lactose-reduced milk, and to encourage them to enjoy cheese and yogurt with live bacterial cultures, according to the guidelines. Yogurt and cheese may be especially valuable for very sensitive children, since the firmer textures of these foods delay gastric emptying and intestinal transit time, which results in fewer symptoms.

The guidelines also pointed out that all mammalian milks contain lactose, so there is no advantage in switching from cow milk to goat milk.

In addition, they said, rice and soy milks are not good substitutes, because they are lacking in nutrients that are needed for bone growth.

The optimal treatment for gout requires both pharmacologic and nonpharmacologic therapy to reduce the severity of acute attacks and prolong the period between them, according to new gout management guidelines issued by the European League Against Rheumatism.

The guidelines and accompanying set of diagnostic recommendations are similar to the quality care indicators for gout published in 2004 (Arthritis Rheum. 2004;50:937–43), said Dr. Kenneth Saag, director of the University of Alabama's Center for Education and Research on Therapeutics of Musculoskeletal Disorders, Birmingham. The indicators are used mostly by researchers of quality of care issues.

Dr. Saag said that clinical guidelines for gout treatment are needed because, with more people using long-term thiazide diuretics and people with chronic illness generally living longer, the incidence of gout is increasing.

EULAR commissioned a 20-member panel that included 11 rheumatologists and 1 expert in evidence-based medicine to develop the guidelines. It drew its management recommendations from a review of 181 studies published from 1945 to 2005.

The recommendations are graded according to a formula that includes risk/benefit tradeoffs. Expert commentary accompanies those recommendations that reflect standard clinical practice but lack significant supporting research (Ann. Rheum. Dis. 2006;65:1312–24).

Treatment in all stages of gout should be tailored to specific risk factors (serum urate level, radiographic evidence), clinical phase (acute, intercritical, or chronic), and general risk factors (gender, age, obesity, alcohol use, urate elevating drugs, and other comorbidities), according to the guidelines. Nonpharmacologic treatments are also important, because they can potentiate drugs' effectiveness, are inexpensive, and do not cause harmful or distressing side effects.

The EULAR panel's recommendations for managing gout include the following:

▸ Patients should reduce alcohol and purine-rich food consumption and lose weight if they are obese.

▸ Hyperlipidemia, hypertension, hyperglycemia, obesity, and smoking should also be addressed. The link between metabolic syndrome and elevated serum uric acid has been proved in clinical studies. There is no direct evidence linking smoking to gout, but smoking has been associated with increased alcohol consumption, thereby having an association with gout.

▸ During acute gout, oral colchicine and/or nonsteroidal anti-inflammatory drugs should be the first-line treatment. Patients who cannot tolerate the GI effects of colchicine, however, can be treated with NSAIDs which provide gastroprotection.

▸ A 1-g loading dose of colchicine followed by 0.5 mg every 2–3 hours relieves symptoms in acute attacks, but even this level may cause serious GI side effects. A lower dose (0.6 mg three times per day) may be appropriate and effective, but there are no studies addressing this.

▸ Neither intra-articular aspiration nor injection of long-acting steroids has been studied in controlled trials. However, case reports and uncontrolled trials indicate that the treatments are well tolerated and effective in reducing pain. They may be especially important for patients who cannot tolerate pharmacotherapy.

▸ Only patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes should receive urate-lowering drugs. There is little agreement on whether less severe patients should have long-term urate-lowering therapy. However, all gout patients should make urate-lowering lifestyle changes through diet modification.

▸ A uric acid level of less than 6 mg/dL—below the saturation point for monosodium urate—should be the target serum level. Many patients with serum uric acid in the normal range can still have joint damage. Maintaining the lower level keeps crystals from precipitating into the joints.

▸ “Start low, go slow” with allopurinol for long-term urate-lowering therapy. To avoid the rare but potentially life-threatening allopurinol hypersensitivity sydrome, begin with 100 mg/day and increase by 100 mg/day every 2–4 weeks.

▸ Patients with normal renal function who cannot tolerate allopurinol may do well with a uricosuric drug such as probenecid or sulphinpyrazone. For renal patients, benzbromarone can be tried, but liver function should be carefully monitored.

▸ Low-dose colchicine (0.5–1.0 mg daily) and/or NSAIDs may have a place in preventing additional attacks. One placebo-controlled trial suggested that colchicine could prevent half of acute attacks, although all colchicine-treated patients experienced diarrhea. Evidence suggests that NSAIDs are not as effective.

▸ If possible, stop diuretic therapy in gout patients. Replace the diuretic with another antihypertensive; losartan and fenofibrate are effective and have modest uricosuric effects.

Diagnostic Criteria Draw On Research and Expert Opinion

The presence of monosodium urate monohydrate crystals in synovial fluid remains the gold standard for gout diagnosis, with a sensitivity of 84% and a specificity of 100%, according to new gout diagnostic guidelines issued by the European League Against Rheumatism.

But the crystals may be present only during an acute attack, and their identification requires a clinician who is both well trained and experienced, the document notes. Additionally, the cost-effectiveness of the test has not been fully demonstrated (Ann. Rheum. Dis. 2006;65:1301–11).

The guidelines put forth 10 diagnostic criteria for gout, ranked not only upon extant research but also on benefit and risk, cost, and the clinical expertise required to effectively use the criteria.

“This seems a better system, reflecting both research evidence and expert opinion, than the traditional semiautomatic estimation based on category of research data alone,” wrote Dr. Weiya Zhang of the University of Nottingham (England), who led a 20-person panel in developing the document.

The recommendations were drawn from the same 181 studies, published from 1945 to 2005, from which the EULAR panel drew its 12 gout management recommendations (see accompanying story).

The recommendations address clinical, biochemical, and radiographic diagnostic techniques for the disease:

1.IClinical symptoms of rapidly developing severe joint pain and swelling, especially with overlying erythema, are highly indicative of crystal formation but have low sensitivity (23%) for a gout diagnosis without further evidence.

2.IMonosodium urate monohydrate (MSU) crystals in synovial aspirate have both high sensitivity and high specificity, although variability in lab expertise may affect the accuracy of the sample findings.

3.IA clinical diagnosis of classic recurrent podagra with hyperuricemia can be reasonably assumed to be gout but requires MSU crystal confirmation.

4.IAll patients with inflamed joints should have their synovial fluid examined for MSU crystals.

5.IMSU testing can also be performed between bouts of inflammation, because urate crystals persist in intercritical periods in up to 70% of patients.

6.IBecause gout and sepsis may occur simultaneously, all possible gout patients should also have Gram staining and culture of synovial fluid. The test should be performed even if the fluid is positive for MSU crystals, because septic arthritis can progress rapidly and carries a significant risk of morbidity and mortality.

7.ISerum uric acid can't be used exclusively as a diagnostic tool. Many people with high serum uric acid don't develop gout, and some patients with confirmed MSU crystals have normal serum uric acid.

8.IGout patients under age 25 years who have a family history of the disease or who have renal calculi should have a 24-hour urinary uric acid/creatinine ratio done. The 24-hour screen appears to be more accurate and cost effective than an early morning spot sample.

9.IRadiographs might be useful for a differential diagnosis, but they can't confirm gout. There are radiographic changes in all stages of gout, but many affected joints can be radiographically normal. Patients with intradermal tophi are more likely to show severe radiographic changes.

10.IMale gender, diet, alcohol use, and diuretics increase the risk of gout, but don't ignore other important risk factors. These include hypertension (relative risk of 4, compared with controls), coronary heart disease (odds ratio, 1.75), chronic renal failure (odds ratio, up to 5), and obesity (odds ratio, 3.8).

The optimal treatment for gout requires both pharmacologic and nonpharmacologic therapy to reduce the severity of acute attacks and prolong the period between them, according to new gout management guidelines issued by the European League Against Rheumatism.

The guidelines and accompanying set of diagnostic recommendations are similar to the quality care indicators for gout published in 2004 (Arthritis Rheum. 2004;50:937–43), said Dr. Kenneth Saag, director of the University of Alabama's Center for Education and Research on Therapeutics of Musculoskeletal Disorders, Birmingham. The indicators are used mostly by researchers of quality of care issues.

Dr. Saag said that clinical guidelines for gout treatment are needed because, with more people using long-term thiazide diuretics and people with chronic illness generally living longer, the incidence of gout is increasing.

EULAR commissioned a 20-member panel that included 11 rheumatologists and 1 expert in evidence-based medicine to develop the guidelines. It drew its management recommendations from a review of 181 studies published from 1945 to 2005.

The recommendations are graded according to a formula that includes risk/benefit tradeoffs. Expert commentary accompanies those recommendations that reflect standard clinical practice but lack significant supporting research (Ann. Rheum. Dis. 2006;65:1312–24).

Treatment in all stages of gout should be tailored to specific risk factors (serum urate level, radiographic evidence), clinical phase (acute, intercritical, or chronic), and general risk factors (gender, age, obesity, alcohol use, urate elevating drugs, and other comorbidities), according to the guidelines. Nonpharmacologic treatments are also important, because they can potentiate drugs' effectiveness, are inexpensive, and do not cause harmful or distressing side effects.

The EULAR panel's recommendations for managing gout include the following:

▸ Patients should reduce alcohol and purine-rich food consumption and lose weight if they are obese.

▸ Hyperlipidemia, hypertension, hyperglycemia, obesity, and smoking should also be addressed. The link between metabolic syndrome and elevated serum uric acid has been proved in clinical studies. There is no direct evidence linking smoking to gout, but smoking has been associated with increased alcohol consumption, thereby having an association with gout.

▸ During acute gout, oral colchicine and/or nonsteroidal anti-inflammatory drugs should be the first-line treatment. Patients who cannot tolerate the GI effects of colchicine, however, can be treated with NSAIDs which provide gastroprotection.

▸ A 1-g loading dose of colchicine followed by 0.5 mg every 2–3 hours relieves symptoms in acute attacks, but even this level may cause serious GI side effects. A lower dose (0.6 mg three times per day) may be appropriate and effective, but there are no studies addressing this.

▸ Neither intra-articular aspiration nor injection of long-acting steroids has been studied in controlled trials. However, case reports and uncontrolled trials indicate that the treatments are well tolerated and effective in reducing pain. They may be especially important for patients who cannot tolerate pharmacotherapy.

▸ Only patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes should receive urate-lowering drugs. There is little agreement on whether less severe patients should have long-term urate-lowering therapy. However, all gout patients should make urate-lowering lifestyle changes through diet modification.

▸ A uric acid level of less than 6 mg/dL—below the saturation point for monosodium urate—should be the target serum level. Many patients with serum uric acid in the normal range can still have joint damage. Maintaining the lower level keeps crystals from precipitating into the joints.

▸ “Start low, go slow” with allopurinol for long-term urate-lowering therapy. To avoid the rare but potentially life-threatening allopurinol hypersensitivity sydrome, begin with 100 mg/day and increase by 100 mg/day every 2–4 weeks.

▸ Patients with normal renal function who cannot tolerate allopurinol may do well with a uricosuric drug such as probenecid or sulphinpyrazone. For renal patients, benzbromarone can be tried, but liver function should be carefully monitored.

▸ Low-dose colchicine (0.5–1.0 mg daily) and/or NSAIDs may have a place in preventing additional attacks. One placebo-controlled trial suggested that colchicine could prevent half of acute attacks, although all colchicine-treated patients experienced diarrhea. Evidence suggests that NSAIDs are not as effective.

▸ If possible, stop diuretic therapy in gout patients. Replace the diuretic with another antihypertensive; losartan and fenofibrate are effective and have modest uricosuric effects.

Diagnostic Criteria Draw On Research and Expert Opinion

The presence of monosodium urate monohydrate crystals in synovial fluid remains the gold standard for gout diagnosis, with a sensitivity of 84% and a specificity of 100%, according to new gout diagnostic guidelines issued by the European League Against Rheumatism.

But the crystals may be present only during an acute attack, and their identification requires a clinician who is both well trained and experienced, the document notes. Additionally, the cost-effectiveness of the test has not been fully demonstrated (Ann. Rheum. Dis. 2006;65:1301–11).

The guidelines put forth 10 diagnostic criteria for gout, ranked not only upon extant research but also on benefit and risk, cost, and the clinical expertise required to effectively use the criteria.

“This seems a better system, reflecting both research evidence and expert opinion, than the traditional semiautomatic estimation based on category of research data alone,” wrote Dr. Weiya Zhang of the University of Nottingham (England), who led a 20-person panel in developing the document.

The recommendations were drawn from the same 181 studies, published from 1945 to 2005, from which the EULAR panel drew its 12 gout management recommendations (see accompanying story).

The recommendations address clinical, biochemical, and radiographic diagnostic techniques for the disease:

1.IClinical symptoms of rapidly developing severe joint pain and swelling, especially with overlying erythema, are highly indicative of crystal formation but have low sensitivity (23%) for a gout diagnosis without further evidence.

2.IMonosodium urate monohydrate (MSU) crystals in synovial aspirate have both high sensitivity and high specificity, although variability in lab expertise may affect the accuracy of the sample findings.

3.IA clinical diagnosis of classic recurrent podagra with hyperuricemia can be reasonably assumed to be gout but requires MSU crystal confirmation.

4.IAll patients with inflamed joints should have their synovial fluid examined for MSU crystals.

5.IMSU testing can also be performed between bouts of inflammation, because urate crystals persist in intercritical periods in up to 70% of patients.

6.IBecause gout and sepsis may occur simultaneously, all possible gout patients should also have Gram staining and culture of synovial fluid. The test should be performed even if the fluid is positive for MSU crystals, because septic arthritis can progress rapidly and carries a significant risk of morbidity and mortality.

7.ISerum uric acid can't be used exclusively as a diagnostic tool. Many people with high serum uric acid don't develop gout, and some patients with confirmed MSU crystals have normal serum uric acid.

8.IGout patients under age 25 years who have a family history of the disease or who have renal calculi should have a 24-hour urinary uric acid/creatinine ratio done. The 24-hour screen appears to be more accurate and cost effective than an early morning spot sample.

9.IRadiographs might be useful for a differential diagnosis, but they can't confirm gout. There are radiographic changes in all stages of gout, but many affected joints can be radiographically normal. Patients with intradermal tophi are more likely to show severe radiographic changes.

10.IMale gender, diet, alcohol use, and diuretics increase the risk of gout, but don't ignore other important risk factors. These include hypertension (relative risk of 4, compared with controls), coronary heart disease (odds ratio, 1.75), chronic renal failure (odds ratio, up to 5), and obesity (odds ratio, 3.8).

The optimal treatment for gout requires both pharmacologic and nonpharmacologic therapy to reduce the severity of acute attacks and prolong the period between them, according to new gout management guidelines issued by the European League Against Rheumatism.

The guidelines and accompanying set of diagnostic recommendations are similar to the quality care indicators for gout published in 2004 (Arthritis Rheum. 2004;50:937–43), said Dr. Kenneth Saag, director of the University of Alabama's Center for Education and Research on Therapeutics of Musculoskeletal Disorders, Birmingham. The indicators are used mostly by researchers of quality of care issues.

Dr. Saag said that clinical guidelines for gout treatment are needed because, with more people using long-term thiazide diuretics and people with chronic illness generally living longer, the incidence of gout is increasing.

EULAR commissioned a 20-member panel that included 11 rheumatologists and 1 expert in evidence-based medicine to develop the guidelines. It drew its management recommendations from a review of 181 studies published from 1945 to 2005.

The recommendations are graded according to a formula that includes risk/benefit tradeoffs. Expert commentary accompanies those recommendations that reflect standard clinical practice but lack significant supporting research (Ann. Rheum. Dis. 2006;65:1312–24).

Treatment in all stages of gout should be tailored to specific risk factors (serum urate level, radiographic evidence), clinical phase (acute, intercritical, or chronic), and general risk factors (gender, age, obesity, alcohol use, urate elevating drugs, and other comorbidities), according to the guidelines. Nonpharmacologic treatments are also important, because they can potentiate drugs' effectiveness, are inexpensive, and do not cause harmful or distressing side effects.

The EULAR panel's recommendations for managing gout include the following:

▸ Patients should reduce alcohol and purine-rich food consumption and lose weight if they are obese.

▸ Hyperlipidemia, hypertension, hyperglycemia, obesity, and smoking should also be addressed. The link between metabolic syndrome and elevated serum uric acid has been proved in clinical studies. There is no direct evidence linking smoking to gout, but smoking has been associated with increased alcohol consumption, thereby having an association with gout.

▸ During acute gout, oral colchicine and/or nonsteroidal anti-inflammatory drugs should be the first-line treatment. Patients who cannot tolerate the GI effects of colchicine, however, can be treated with NSAIDs which provide gastroprotection.

▸ A 1-g loading dose of colchicine followed by 0.5 mg every 2–3 hours relieves symptoms in acute attacks, but even this level may cause serious GI side effects. A lower dose (0.6 mg three times per day) may be appropriate and effective, but there are no studies addressing this.

▸ Neither intra-articular aspiration nor injection of long-acting steroids has been studied in controlled trials. However, case reports and uncontrolled trials indicate that the treatments are well tolerated and effective in reducing pain. They may be especially important for patients who cannot tolerate pharmacotherapy.

▸ Only patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes should receive urate-lowering drugs. There is little agreement on whether less severe patients should have long-term urate-lowering therapy. However, all gout patients should make urate-lowering lifestyle changes through diet modification.

▸ A uric acid level of less than 6 mg/dL—below the saturation point for monosodium urate—should be the target serum level. Many patients with serum uric acid in the normal range can still have joint damage. Maintaining the lower level keeps crystals from precipitating into the joints.

▸ “Start low, go slow” with allopurinol for long-term urate-lowering therapy. To avoid the rare but potentially life-threatening allopurinol hypersensitivity sydrome, begin with 100 mg/day and increase by 100 mg/day every 2–4 weeks.

▸ Patients with normal renal function who cannot tolerate allopurinol may do well with a uricosuric drug such as probenecid or sulphinpyrazone. For renal patients, benzbromarone can be tried, but liver function should be carefully monitored.

▸ Low-dose colchicine (0.5–1.0 mg daily) and/or NSAIDs may have a place in preventing additional attacks. One placebo-controlled trial suggested that colchicine could prevent half of acute attacks, although all colchicine-treated patients experienced diarrhea. Evidence suggests that NSAIDs are not as effective.

▸ If possible, stop diuretic therapy in gout patients. Replace the diuretic with another antihypertensive; losartan and fenofibrate are effective and have modest uricosuric effects.

Diagnostic Criteria Draw On Research and Expert Opinion

The presence of monosodium urate monohydrate crystals in synovial fluid remains the gold standard for gout diagnosis, with a sensitivity of 84% and a specificity of 100%, according to new gout diagnostic guidelines issued by the European League Against Rheumatism.

But the crystals may be present only during an acute attack, and their identification requires a clinician who is both well trained and experienced, the document notes. Additionally, the cost-effectiveness of the test has not been fully demonstrated (Ann. Rheum. Dis. 2006;65:1301–11).

The guidelines put forth 10 diagnostic criteria for gout, ranked not only upon extant research but also on benefit and risk, cost, and the clinical expertise required to effectively use the criteria.

“This seems a better system, reflecting both research evidence and expert opinion, than the traditional semiautomatic estimation based on category of research data alone,” wrote Dr. Weiya Zhang of the University of Nottingham (England), who led a 20-person panel in developing the document.

The recommendations were drawn from the same 181 studies, published from 1945 to 2005, from which the EULAR panel drew its 12 gout management recommendations (see accompanying story).

The recommendations address clinical, biochemical, and radiographic diagnostic techniques for the disease:

1.IClinical symptoms of rapidly developing severe joint pain and swelling, especially with overlying erythema, are highly indicative of crystal formation but have low sensitivity (23%) for a gout diagnosis without further evidence.

2.IMonosodium urate monohydrate (MSU) crystals in synovial aspirate have both high sensitivity and high specificity, although variability in lab expertise may affect the accuracy of the sample findings.

3.IA clinical diagnosis of classic recurrent podagra with hyperuricemia can be reasonably assumed to be gout but requires MSU crystal confirmation.

4.IAll patients with inflamed joints should have their synovial fluid examined for MSU crystals.

5.IMSU testing can also be performed between bouts of inflammation, because urate crystals persist in intercritical periods in up to 70% of patients.

6.IBecause gout and sepsis may occur simultaneously, all possible gout patients should also have Gram staining and culture of synovial fluid. The test should be performed even if the fluid is positive for MSU crystals, because septic arthritis can progress rapidly and carries a significant risk of morbidity and mortality.

7.ISerum uric acid can't be used exclusively as a diagnostic tool. Many people with high serum uric acid don't develop gout, and some patients with confirmed MSU crystals have normal serum uric acid.

8.IGout patients under age 25 years who have a family history of the disease or who have renal calculi should have a 24-hour urinary uric acid/creatinine ratio done. The 24-hour screen appears to be more accurate and cost effective than an early morning spot sample.

9.IRadiographs might be useful for a differential diagnosis, but they can't confirm gout. There are radiographic changes in all stages of gout, but many affected joints can be radiographically normal. Patients with intradermal tophi are more likely to show severe radiographic changes.

10.IMale gender, diet, alcohol use, and diuretics increase the risk of gout, but don't ignore other important risk factors. These include hypertension (relative risk of 4, compared with controls), coronary heart disease (odds ratio, 1.75), chronic renal failure (odds ratio, up to 5), and obesity (odds ratio, 3.8).

Officials in charge of disclosing financial interests in research agree that disclosure is important but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt, a psychiatrist at Duke University, Durham, N.C., and his coinvestigators.

“Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure,” the researchers wrote. “There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making” (J. Law Med. Ethics 2006;34:581–91).

The study was based on detailed personal interviews with 8 investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source. But some said the name of the company or organization wasn't as important as a description.

They also differed on whether the amount of financial interest should be disclosed.

Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure—the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document—at the very beginning, for example. Many also emphasized that the informed consent process should include a discussion of conflict of interest, not just a read-through of the document.

“Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests,” the researchers concluded.

Officials in charge of disclosing financial interests in research agree that disclosure is important but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt, a psychiatrist at Duke University, Durham, N.C., and his coinvestigators.

“Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure,” the researchers wrote. “There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making” (J. Law Med. Ethics 2006;34:581–91).

The study was based on detailed personal interviews with 8 investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source. But some said the name of the company or organization wasn't as important as a description.

They also differed on whether the amount of financial interest should be disclosed.

Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure—the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document—at the very beginning, for example. Many also emphasized that the informed consent process should include a discussion of conflict of interest, not just a read-through of the document.

“Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests,” the researchers concluded.

Officials in charge of disclosing financial interests in research agree that disclosure is important but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt, a psychiatrist at Duke University, Durham, N.C., and his coinvestigators.

“Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure,” the researchers wrote. “There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making” (J. Law Med. Ethics 2006;34:581–91).

The study was based on detailed personal interviews with 8 investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source. But some said the name of the company or organization wasn't as important as a description.

They also differed on whether the amount of financial interest should be disclosed.

Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure—the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document—at the very beginning, for example. Many also emphasized that the informed consent process should include a discussion of conflict of interest, not just a read-through of the document.

“Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests,” the researchers concluded.

BOSTON — Brothers of women with polycystic ovary syndrome share with their sisters similar metabolic features that indicate they may be at increased risk for decreased insulin sensitivity and glucose tolerance, high triglycerides, and dyscoagulability, Dr. Jean-Patrice Baillargeon said at the annual meeting of the Androgen Excess Society.

These characteristics, which are independent of both fat percentage and body mass index, suggest that polycystic ovary syndrome (PCOS) may represent an inherited constellation of symptoms that are expressed differently in men and women, said Dr. Baillargeon of the University of Sherbrooke (Que.).

He compared insulin sensitivity and other metabolic measures in 17 brothers of women with PCOS and 28 men who had no first-degree relatives with PCOS. Their average age was 28 years. There were no significant differences in body mass index (average 26.5 kg/m

At baseline, brothers had slightly, but not significantly, higher diastolic blood pressures (74 vs. 68 mm/Hg). However, they had significantly higher levels of triglycerides (1.66 vs. 0.99 mmol/L), plasminogen activator inhibitor-1 (27 vs. 16 nmol/L), and factor VIII (27 vs. 16 nmol/L). “The increased PAI-1 and factor VIII show a dyscoagulability in the brothers.”

Three of the brothers (18%) had decreased insulin sensitivity after an oral glucose tolerance test; insulin sensitivity values were normal in all controls. The 2-hour glucose levels, insulin area under the curve, and glucose area under the curve were also significantly higher in brothers of women with PCOS. “The insulin sensitivity of the brothers was 38% less than that of the controls. This was primarily due to a 65% decrease in insulin-stimulated nonoxidative carbohydrate metabolism.”

All of these factors remained significant, even after adjusting for anthropomorphic measures. They were also significant in two matched-pair analyses, one of 13 pairs and one of only 7 pairs.

BOSTON — Brothers of women with polycystic ovary syndrome share with their sisters similar metabolic features that indicate they may be at increased risk for decreased insulin sensitivity and glucose tolerance, high triglycerides, and dyscoagulability, Dr. Jean-Patrice Baillargeon said at the annual meeting of the Androgen Excess Society.

These characteristics, which are independent of both fat percentage and body mass index, suggest that polycystic ovary syndrome (PCOS) may represent an inherited constellation of symptoms that are expressed differently in men and women, said Dr. Baillargeon of the University of Sherbrooke (Que.).

He compared insulin sensitivity and other metabolic measures in 17 brothers of women with PCOS and 28 men who had no first-degree relatives with PCOS. Their average age was 28 years. There were no significant differences in body mass index (average 26.5 kg/m

At baseline, brothers had slightly, but not significantly, higher diastolic blood pressures (74 vs. 68 mm/Hg). However, they had significantly higher levels of triglycerides (1.66 vs. 0.99 mmol/L), plasminogen activator inhibitor-1 (27 vs. 16 nmol/L), and factor VIII (27 vs. 16 nmol/L). “The increased PAI-1 and factor VIII show a dyscoagulability in the brothers.”

Three of the brothers (18%) had decreased insulin sensitivity after an oral glucose tolerance test; insulin sensitivity values were normal in all controls. The 2-hour glucose levels, insulin area under the curve, and glucose area under the curve were also significantly higher in brothers of women with PCOS. “The insulin sensitivity of the brothers was 38% less than that of the controls. This was primarily due to a 65% decrease in insulin-stimulated nonoxidative carbohydrate metabolism.”

All of these factors remained significant, even after adjusting for anthropomorphic measures. They were also significant in two matched-pair analyses, one of 13 pairs and one of only 7 pairs.

BOSTON — Brothers of women with polycystic ovary syndrome share with their sisters similar metabolic features that indicate they may be at increased risk for decreased insulin sensitivity and glucose tolerance, high triglycerides, and dyscoagulability, Dr. Jean-Patrice Baillargeon said at the annual meeting of the Androgen Excess Society.

These characteristics, which are independent of both fat percentage and body mass index, suggest that polycystic ovary syndrome (PCOS) may represent an inherited constellation of symptoms that are expressed differently in men and women, said Dr. Baillargeon of the University of Sherbrooke (Que.).

He compared insulin sensitivity and other metabolic measures in 17 brothers of women with PCOS and 28 men who had no first-degree relatives with PCOS. Their average age was 28 years. There were no significant differences in body mass index (average 26.5 kg/m

At baseline, brothers had slightly, but not significantly, higher diastolic blood pressures (74 vs. 68 mm/Hg). However, they had significantly higher levels of triglycerides (1.66 vs. 0.99 mmol/L), plasminogen activator inhibitor-1 (27 vs. 16 nmol/L), and factor VIII (27 vs. 16 nmol/L). “The increased PAI-1 and factor VIII show a dyscoagulability in the brothers.”

Three of the brothers (18%) had decreased insulin sensitivity after an oral glucose tolerance test; insulin sensitivity values were normal in all controls. The 2-hour glucose levels, insulin area under the curve, and glucose area under the curve were also significantly higher in brothers of women with PCOS. “The insulin sensitivity of the brothers was 38% less than that of the controls. This was primarily due to a 65% decrease in insulin-stimulated nonoxidative carbohydrate metabolism.”

All of these factors remained significant, even after adjusting for anthropomorphic measures. They were also significant in two matched-pair analyses, one of 13 pairs and one of only 7 pairs.

MADRID – Leuprolide acetate may help forestall functional decline in patients with mild to moderate Alzheimer's disease, Christopher W. Gregory, Ph.D., reported in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders.

The drug, most frequently used for prostate cancer, endometriosis, and precocious puberty, decreases levels of luteinizing hormone–an action that has been shown to decrease the rate of cognitive decline and amyloid accumulation in an Alzheimer's mouse model. Anecdotal evidence has suggested that leuprolide acetate also boosts cognition in some men taking it for prostate cancer, said Dr. Gregory, vice president of research for Voyager Pharmaceutical Corp.

“Our hypothesis is that elevations in luteinizing hormone levels, which are a result of normal aging, may contribute to several of the pathologic processes that foster the development of Alzheimer's” including promoting tau phosphorylation and amyloidogenic processing of the amyloid precursor protein, Dr. Gregory said in an interview. “Therefore, reducing luteinizing hormone levels may help to improve the symptoms of Alzheimer's.”

He presented the results of a phase II pooled data analysis in which 106 men and women with mild to moderate Alzheimer's received either leuprolide acetate (22.5-mg injections given every 12 weeks) or placebo for 48 weeks. About 75% of the patients were on acetylcholinesterase inhibitors, which were continued throughout the study.

After 48 weeks, compared with placebo patients, those in the active group retained significantly more function in both activities of daily living (mean change from baseline −5.4 placebo vs. −3.5 leuprolide) and global function (unchanged or improved from baseline, 34% placebo vs. 51% leuprolide acetate).

Leuprolide patients also experienced less cognitive decline than did placebo patients (about 2 points), although the difference was not statistically significant.

The results were encouraging enough for the Raleigh, N.C., company to launch two 56-week phase III trials of leuprolide implants vs. placebo. Each study will need 555 patients with mild to moderate disease. All patients must have been taking an acetylcholinesterase inhibitor for at least 120 days prior to baseline.

The conference was presented by the Alzheimer's Association.

MADRID – Leuprolide acetate may help forestall functional decline in patients with mild to moderate Alzheimer's disease, Christopher W. Gregory, Ph.D., reported in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders.

The drug, most frequently used for prostate cancer, endometriosis, and precocious puberty, decreases levels of luteinizing hormone–an action that has been shown to decrease the rate of cognitive decline and amyloid accumulation in an Alzheimer's mouse model. Anecdotal evidence has suggested that leuprolide acetate also boosts cognition in some men taking it for prostate cancer, said Dr. Gregory, vice president of research for Voyager Pharmaceutical Corp.

“Our hypothesis is that elevations in luteinizing hormone levels, which are a result of normal aging, may contribute to several of the pathologic processes that foster the development of Alzheimer's” including promoting tau phosphorylation and amyloidogenic processing of the amyloid precursor protein, Dr. Gregory said in an interview. “Therefore, reducing luteinizing hormone levels may help to improve the symptoms of Alzheimer's.”

He presented the results of a phase II pooled data analysis in which 106 men and women with mild to moderate Alzheimer's received either leuprolide acetate (22.5-mg injections given every 12 weeks) or placebo for 48 weeks. About 75% of the patients were on acetylcholinesterase inhibitors, which were continued throughout the study.

After 48 weeks, compared with placebo patients, those in the active group retained significantly more function in both activities of daily living (mean change from baseline −5.4 placebo vs. −3.5 leuprolide) and global function (unchanged or improved from baseline, 34% placebo vs. 51% leuprolide acetate).

Leuprolide patients also experienced less cognitive decline than did placebo patients (about 2 points), although the difference was not statistically significant.

The results were encouraging enough for the Raleigh, N.C., company to launch two 56-week phase III trials of leuprolide implants vs. placebo. Each study will need 555 patients with mild to moderate disease. All patients must have been taking an acetylcholinesterase inhibitor for at least 120 days prior to baseline.

The conference was presented by the Alzheimer's Association.

MADRID – Leuprolide acetate may help forestall functional decline in patients with mild to moderate Alzheimer's disease, Christopher W. Gregory, Ph.D., reported in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders.

The drug, most frequently used for prostate cancer, endometriosis, and precocious puberty, decreases levels of luteinizing hormone–an action that has been shown to decrease the rate of cognitive decline and amyloid accumulation in an Alzheimer's mouse model. Anecdotal evidence has suggested that leuprolide acetate also boosts cognition in some men taking it for prostate cancer, said Dr. Gregory, vice president of research for Voyager Pharmaceutical Corp.

“Our hypothesis is that elevations in luteinizing hormone levels, which are a result of normal aging, may contribute to several of the pathologic processes that foster the development of Alzheimer's” including promoting tau phosphorylation and amyloidogenic processing of the amyloid precursor protein, Dr. Gregory said in an interview. “Therefore, reducing luteinizing hormone levels may help to improve the symptoms of Alzheimer's.”

He presented the results of a phase II pooled data analysis in which 106 men and women with mild to moderate Alzheimer's received either leuprolide acetate (22.5-mg injections given every 12 weeks) or placebo for 48 weeks. About 75% of the patients were on acetylcholinesterase inhibitors, which were continued throughout the study.

After 48 weeks, compared with placebo patients, those in the active group retained significantly more function in both activities of daily living (mean change from baseline −5.4 placebo vs. −3.5 leuprolide) and global function (unchanged or improved from baseline, 34% placebo vs. 51% leuprolide acetate).

Leuprolide patients also experienced less cognitive decline than did placebo patients (about 2 points), although the difference was not statistically significant.

The results were encouraging enough for the Raleigh, N.C., company to launch two 56-week phase III trials of leuprolide implants vs. placebo. Each study will need 555 patients with mild to moderate disease. All patients must have been taking an acetylcholinesterase inhibitor for at least 120 days prior to baseline.

The conference was presented by the Alzheimer's Association.

MADRID – Even though they appear cognitively intact, carriers of the apo E4 gene show significant longitudinal decline on measures of frontally mediated cognitive skills and memory, Dr. Richard Caselli reported at the 10th International Conference for Alzheimer's Disease and Related Disorders.

“This shows that decline can occur in carriers even when it cannot be detected clinically,” said Dr. Caselli, chairman of neurology at the Mayo Clinic, Scottsdale, Ariz. “If these changes reflect early stage Alzheimer's disease, they suggest that Alzheimer's may have a preclinical phase that lasts for years and occurs even before the onset of mild cognitive impairment.”

His prospective study followed 35 apo E4 carriers and 33 noncarriers for at least 6 years, during which time all study participants received neuropsychological testing every other year. To ensure that only cognitively intact carriers were followed, Dr. Caselli excluded any patient who developed mild cognitive impairment, Alzheimer's disease, or any other form of symptomatic cognitive impairment during the study.

At baseline, the patients were a mean 56 years old, with 16 years of education; 63% were female. The testing included the revised Weschler Adult Intelligence Scale (WAIS-R) digit span, mental arithmetic, digit symbol substitution, freedom from distractibility, and controlled oral word association as measures of frontally mediated cognition.

At baseline, carriers performed slightly better than noncarriers on the auditory verbal learning test, as well as on short-term recall, long-term recall, and percent recall. However, by the end of the study period, carriers had declined significantly more than noncarriers in short-term recall as well as in mental arithmetic, digit symbol substitution, and freedom from distractibility–all frontal mediated cognitive domains.

“Aging is normally accompanied by modest declines in memory and executive skills, but in apo E4 carriers, this 'age effect' appears to be exaggerated,” Dr. Caselli said in an interview.

'Alzheimer's may have a preclinical phase that lasts for years' before onset of cognitive impairment. DR. CASELLI

MADRID – Even though they appear cognitively intact, carriers of the apo E4 gene show significant longitudinal decline on measures of frontally mediated cognitive skills and memory, Dr. Richard Caselli reported at the 10th International Conference for Alzheimer's Disease and Related Disorders.

“This shows that decline can occur in carriers even when it cannot be detected clinically,” said Dr. Caselli, chairman of neurology at the Mayo Clinic, Scottsdale, Ariz. “If these changes reflect early stage Alzheimer's disease, they suggest that Alzheimer's may have a preclinical phase that lasts for years and occurs even before the onset of mild cognitive impairment.”

His prospective study followed 35 apo E4 carriers and 33 noncarriers for at least 6 years, during which time all study participants received neuropsychological testing every other year. To ensure that only cognitively intact carriers were followed, Dr. Caselli excluded any patient who developed mild cognitive impairment, Alzheimer's disease, or any other form of symptomatic cognitive impairment during the study.

At baseline, the patients were a mean 56 years old, with 16 years of education; 63% were female. The testing included the revised Weschler Adult Intelligence Scale (WAIS-R) digit span, mental arithmetic, digit symbol substitution, freedom from distractibility, and controlled oral word association as measures of frontally mediated cognition.

At baseline, carriers performed slightly better than noncarriers on the auditory verbal learning test, as well as on short-term recall, long-term recall, and percent recall. However, by the end of the study period, carriers had declined significantly more than noncarriers in short-term recall as well as in mental arithmetic, digit symbol substitution, and freedom from distractibility–all frontal mediated cognitive domains.

“Aging is normally accompanied by modest declines in memory and executive skills, but in apo E4 carriers, this 'age effect' appears to be exaggerated,” Dr. Caselli said in an interview.

'Alzheimer's may have a preclinical phase that lasts for years' before onset of cognitive impairment. DR. CASELLI

MADRID – Even though they appear cognitively intact, carriers of the apo E4 gene show significant longitudinal decline on measures of frontally mediated cognitive skills and memory, Dr. Richard Caselli reported at the 10th International Conference for Alzheimer's Disease and Related Disorders.

“This shows that decline can occur in carriers even when it cannot be detected clinically,” said Dr. Caselli, chairman of neurology at the Mayo Clinic, Scottsdale, Ariz. “If these changes reflect early stage Alzheimer's disease, they suggest that Alzheimer's may have a preclinical phase that lasts for years and occurs even before the onset of mild cognitive impairment.”

His prospective study followed 35 apo E4 carriers and 33 noncarriers for at least 6 years, during which time all study participants received neuropsychological testing every other year. To ensure that only cognitively intact carriers were followed, Dr. Caselli excluded any patient who developed mild cognitive impairment, Alzheimer's disease, or any other form of symptomatic cognitive impairment during the study.

At baseline, the patients were a mean 56 years old, with 16 years of education; 63% were female. The testing included the revised Weschler Adult Intelligence Scale (WAIS-R) digit span, mental arithmetic, digit symbol substitution, freedom from distractibility, and controlled oral word association as measures of frontally mediated cognition.

At baseline, carriers performed slightly better than noncarriers on the auditory verbal learning test, as well as on short-term recall, long-term recall, and percent recall. However, by the end of the study period, carriers had declined significantly more than noncarriers in short-term recall as well as in mental arithmetic, digit symbol substitution, and freedom from distractibility–all frontal mediated cognitive domains.

“Aging is normally accompanied by modest declines in memory and executive skills, but in apo E4 carriers, this 'age effect' appears to be exaggerated,” Dr. Caselli said in an interview.

'Alzheimer's may have a preclinical phase that lasts for years' before onset of cognitive impairment. DR. CASELLI

MADRID – Donepezil appears to decrease the risk of death among patients with severe Alzheimer's disease by about 50% but may be dangerous for patients with vascular dementia, Dr. Lon Schneider said at the 10th International Conference on Alzheimer's Disease and Related Disorders.

“The unexpected benefit of donepezil means we should be looking at this drug more carefully for those with severe Alzheimer's,” said Dr. Schneider, professor of psychiatry, neurology, and gerontology at the University of Southern California, Los Angeles. “The magnitude of this effect implies that for every 41 such patients treated with donepezil, 1 death could be prevented.”

Conversely, he said, statistical variability among the vascular dementia trials indicates a potential for an increased risk of death as high as three times among vascular dementia patients taking the drug, which should alert physicians to be more cautious when prescribing it in that population.

Both risk analyses emerged as part of an ongoing Cochrane database review of mortality associated with the use of drugs approved for Alzheimer's disease.

The study was sparked by reports of increased death among patients with mild cognitive impairment taking galantamine (an almost fivefold increased risk compared with placebo), and by a recent phase III clinical trial of donepezil as a possible treatment for vascular dementia. In the phase III trial, there were 11 deaths in the active group, but none in the placebo group.

The review found no evidence of an overall increased risk of death for any of the cholinesterase inhibitors or memantine. The differences emerged only when the researchers stratified the results by disease type or severity. The four trials of donepezil in moderate to severe Alzheimer's showed a decreased risk of death in active patients compared with placebo. Two of the three trials of donepezil in vascular dementia showed an increased risk of death, while one showed a decreased risk.

“We can speculate that patients with vascular dementia have underlying cardiovascular disease which donepezil and other cholinesterase inhibitors may adversely affect,” Dr. Schneider said in an interview. “In patients with severe Alzheimer's who have the most severe cholinergic deficits, the drug may have beneficial effects on parasympathetic function, or may so substantially improve their levels of attention that they can be better cared for.”

Donepezil is not approved for vascular dementia or severe Alzheimer's, but Eisai Inc. has submitted a supplemental new drug application for use in severe Alzheimer's.

The conference was presented by the Alzheimer's Association.

MADRID – Donepezil appears to decrease the risk of death among patients with severe Alzheimer's disease by about 50% but may be dangerous for patients with vascular dementia, Dr. Lon Schneider said at the 10th International Conference on Alzheimer's Disease and Related Disorders.

“The unexpected benefit of donepezil means we should be looking at this drug more carefully for those with severe Alzheimer's,” said Dr. Schneider, professor of psychiatry, neurology, and gerontology at the University of Southern California, Los Angeles. “The magnitude of this effect implies that for every 41 such patients treated with donepezil, 1 death could be prevented.”

Conversely, he said, statistical variability among the vascular dementia trials indicates a potential for an increased risk of death as high as three times among vascular dementia patients taking the drug, which should alert physicians to be more cautious when prescribing it in that population.

Both risk analyses emerged as part of an ongoing Cochrane database review of mortality associated with the use of drugs approved for Alzheimer's disease.

The study was sparked by reports of increased death among patients with mild cognitive impairment taking galantamine (an almost fivefold increased risk compared with placebo), and by a recent phase III clinical trial of donepezil as a possible treatment for vascular dementia. In the phase III trial, there were 11 deaths in the active group, but none in the placebo group.

The review found no evidence of an overall increased risk of death for any of the cholinesterase inhibitors or memantine. The differences emerged only when the researchers stratified the results by disease type or severity. The four trials of donepezil in moderate to severe Alzheimer's showed a decreased risk of death in active patients compared with placebo. Two of the three trials of donepezil in vascular dementia showed an increased risk of death, while one showed a decreased risk.

“We can speculate that patients with vascular dementia have underlying cardiovascular disease which donepezil and other cholinesterase inhibitors may adversely affect,” Dr. Schneider said in an interview. “In patients with severe Alzheimer's who have the most severe cholinergic deficits, the drug may have beneficial effects on parasympathetic function, or may so substantially improve their levels of attention that they can be better cared for.”

Donepezil is not approved for vascular dementia or severe Alzheimer's, but Eisai Inc. has submitted a supplemental new drug application for use in severe Alzheimer's.

The conference was presented by the Alzheimer's Association.

MADRID – Donepezil appears to decrease the risk of death among patients with severe Alzheimer's disease by about 50% but may be dangerous for patients with vascular dementia, Dr. Lon Schneider said at the 10th International Conference on Alzheimer's Disease and Related Disorders.

“The unexpected benefit of donepezil means we should be looking at this drug more carefully for those with severe Alzheimer's,” said Dr. Schneider, professor of psychiatry, neurology, and gerontology at the University of Southern California, Los Angeles. “The magnitude of this effect implies that for every 41 such patients treated with donepezil, 1 death could be prevented.”

Conversely, he said, statistical variability among the vascular dementia trials indicates a potential for an increased risk of death as high as three times among vascular dementia patients taking the drug, which should alert physicians to be more cautious when prescribing it in that population.

Both risk analyses emerged as part of an ongoing Cochrane database review of mortality associated with the use of drugs approved for Alzheimer's disease.

The study was sparked by reports of increased death among patients with mild cognitive impairment taking galantamine (an almost fivefold increased risk compared with placebo), and by a recent phase III clinical trial of donepezil as a possible treatment for vascular dementia. In the phase III trial, there were 11 deaths in the active group, but none in the placebo group.

The review found no evidence of an overall increased risk of death for any of the cholinesterase inhibitors or memantine. The differences emerged only when the researchers stratified the results by disease type or severity. The four trials of donepezil in moderate to severe Alzheimer's showed a decreased risk of death in active patients compared with placebo. Two of the three trials of donepezil in vascular dementia showed an increased risk of death, while one showed a decreased risk.

“We can speculate that patients with vascular dementia have underlying cardiovascular disease which donepezil and other cholinesterase inhibitors may adversely affect,” Dr. Schneider said in an interview. “In patients with severe Alzheimer's who have the most severe cholinergic deficits, the drug may have beneficial effects on parasympathetic function, or may so substantially improve their levels of attention that they can be better cared for.”

Donepezil is not approved for vascular dementia or severe Alzheimer's, but Eisai Inc. has submitted a supplemental new drug application for use in severe Alzheimer's.

The conference was presented by the Alzheimer's Association.

Investigational drugs that decrease the body's load of both soluble and fibrillar amyloid β (Aβ) could change a diagnosis of Alzheimer's disease from a death sentence to that of a chronic but manageable illness.

All of these compounds are still in preclinical or clinical trials, but their potential to redefine the prognosis of Alzheimer's patients is remarkable, researchers say–akin to the benefits that protease inhibitors have wrought for those with HIV-AIDS.

“The first protease inhibitor for AIDS was not a very good drug, but it provided a proof of principle that paved the way for the current drugs, which have revolutionized HIV-AIDS treatment,” said Michael Wolfe, Ph.D., of Brigham and Women's Hospital and Harvard Medical School, Boston.

Similarly, although these first Aβ-modulating agents that target proteases “are not perfect right now, I believe they will pave the way for more effective drugs that will completely change the way we view Alzheimer's therapy.”

Perhaps the most exciting component of drugs that modify Aβ is their potential to change the course of Alzheimer's, according to Dr. Samuel Gandy, chief scientific adviser for the Alzheimer's Association. “We're on the verge of knowing whether antiamyloid strategies will slow or prevent cognitive decline,” he told this news organization.

Methods of Action

The drugs all aim to decrease levels of Aβ peptides, but they do so in different ways, Dr. Wolfe said in an interview.

Aβ–some forms of which aggregate into the characteristic Alzheimer's brain plaques–is produced when the enzymes β- and γ-secretase cut the amyloid precursor protein into different lengths. Inhibitors of γ-secretase stop that cleavage, lowering Aβ levels by keeping the precursor protein intact. Selective amyloid-lowering agents (SALAs) also work on γ-secretase: They change the point where the protein is cut, preventing the formation of the toxic, longer-chain Aβ-42. Both γ-secretase inhibitors and SALAs are designed to reduce soluble Aβ levels, with the aim of preventing plaque formation.

The third agent under development–an Aβ antagonist–is designed to maintain Aβ peptides in a soluble state. It apparently stops heparin from binding to Aβ, an interaction thought to trigger Aβ aggregation, Dr. Wolfe said. This compound, which is furthest along the developmental pipeline, not only reduces soluble Aβ, but has been shown in animal models to reduce the load of already-formed Aβ-42 plaques.

Safety and Efficacy

Some serious safety issues plagued the γ-secretase inhibitors during early preclinical development, Dr. Wolfe said. The enzyme also plays a key role in cell signaling from the Notch receptor: Blocking it entirely had significant effects on this pathway, which mediates cell differentiation and proliferation. Immune cells and tissues with high cellular turnover–including gut tissue–were most severely affected.

The SALAs don't block γ-secretase, but rather modify the enzyme's activity in a way that avoids the Notch problem. But, Dr. Wolfe said, early SALAs just weren't very effective in cell cultures. “Even the one in clinical trials requires very high doses,” to achieve a significant effect. “They're apparently very safe, however,” he added.

The Aβ antagonists have likewise shown little or no toxicity in humans, even at very high doses, he said.

Tramiprosate: A β Antagonist

Of all the Aβ modulators, tramiprosate (Alzhemed, Neurochem Inc.) is closest to clinical use. Its initial 18-month phase III trial, which includes 1,052 North American patients with mild to moderate Alzheimer's, is set to conclude in January 2007. A similarly sized European trial is underway.

Findings from in vitro experiments have shown that the drug inhibited Aβ-42-induced cell death by 38%. In animal studies, it reduced Aβ-42 plasma levels by 31% and plaque burden by 24% (Neurobiol. Aging 2006, May 1;[Epub ahead of print]doi:10.1016/j.neurobiolaging.2006.02.015).

The findings of a phase II study of 58 patients with mild to moderate Alzheimer's, who were followed for almost 3 years, are consistent with those early results. Over the first 3 months of that trial, patients on the highest dose of tramiprosate had a significant decrease in mean levels of Aβ-42 in cerebrospinal fluid compared with placebo patients.

“The reductions varied depending on the dose given, but the average decrease was up to 30%, which reproduced quite nicely what we saw in the animal studies,” said Denis Garceau, Ph.D., Neurochem's senior vice president of drug development.

Tramiprosate also has some ability to stabilize disease progression and perhaps even modify its course, he said. After 20 months on the drug, about 70% of the patients with mild Alzheimer's who were still receiving tramiprosate showed either stabilized or slightly improved cognitive measures.

There were no significant adverse effects; the most frequent were mild to moderate gastrointestinal symptoms that resolved spontaneously.

Both phase III trials are testing two, twice-daily doses (100 mg and 150 mg) against placebo, and will be followed by an 18-month open-label extension. About 350 patients have already completed the North American trial, and 85% of them have signed onto the extension study.

Some of the phase III study patients will have pre- and posttherapy MRI to help evaluate the drug's effect on brain atrophy.

R-Flurbiprofen: SALA

Myriad Genetics Inc. is just revving up its phase III trials for this drug (Flurizan). The U.S. trial is in its last stage of recruitment, looking for 1,600 Alzheimer's patients with mild disease. A global study will enroll 800 patients. Both are 18-month trials that pit R-flurbiprofen (800 mg twice a day) against placebo.

R-flurbiprofen rode an efficacy seesaw during its phase II trials. Preliminary results showed no significant effects in any of the three end points (activities of daily living, dementia score, and cognitive function) for the overall group of 207 patients with mild to moderate disease. However, patients with mild AD who were taking the 1,600-mg/day dosage showed a statistically significant benefit at 12 months in activities of daily living and global function, with a positive trend in the Alzheimer's Disease Assessment Scale with the cognitive function subscale (ADAS-cog) (Neurology 2006;66 [Suppl 2]:A347).

The 12-month follow-up study showed that patients with mild disease who stayed on the drug continued to improve, actually regaining up to 2 points on the ADAS-cog. “Although not statistically significant, we saw that the less advanced the patients' disease, the bigger the response they get from the drug,” said Adrian Hobden, Ph.D., president of Myriad.

An additional benefit of R-flurbiprofen may be its ability to delay the onset of psychiatric symptoms in Alzheimer's patients, according to data presented in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders, held in Madrid. In a secondary analysis of the phase II trial, Dr. Jacobo Mintzer, of the Medical University of South Carolina in Charleston, showed that by 1 year, about 90% of patients on the 1,600-mg/day dosage were free of psychiatric symptoms, compared with about 70% of those on placebo.

The European trial will collect cerebrospinal fluid at baseline and at 18 months for exploratory biomarker studies, once reliable markers have been identified.

Myriad also is contemplating separate imaging studies to examine hippocampal and whole-brain volume changes associated with the drug. An exploration of the drug's effect on amyloid plaque deposition with PET imaging using Pittsburgh Compound B is also a possibility. Such studies may be key to showing whether the drug has any effect on existing brain plaques in humans.

LY450139 Dihydrate: γ-Secretase Inhibitor

Eli Lilly & Co. will get its first glimpse of this drug's effect in cognitive and functional domains from a 29-week phase IIB study, launched at six U.S. sites earlier in 2006. The trial will include 45 patients with mild to moderate Alzheimer's randomized to placebo or LY450139.

Two previous human trials demonstrated the compound's ability to significantly lower total Aβ levels in plasma, but were unable to show a significant decrease in cerebrospinal fluid levels.

Both studies provoked concern among the research community for adverse events that could be tied to Notch signaling toxicity. In the 2004 dose-ranging trial (Clin. Neuropharmacol. 2005;28:126–32), two of seven healthy volunteers who took the 50-mg/day dosage for 2 weeks withdrew: one for an increase in serum amylase and lipase concentrations and exacerbation of previous gallbladder and biliary disease, and the other for nausea, vomiting, weakness, and diarrhea accompanied by elevation in white blood cell count.

A single death occurred during the 2005 trial (Neurology 2006;66:602–4). In this study, 70 patients with mild to moderate Alzheimer's took placebo or a titrated lower dose of the drug (1 week of drug at 30 mg/day followed by 5 weeks at 40 mg/day). One patient in the active group died from endocarditis 5 months after withdrawing from the trial as a result of gastrointestinal bleeding from Barrett's esophagus. Neither the endocarditis nor the Barrett's was associated with the drug, according to the study.

Other patients may have shown mild Notch toxicity. Diarrhea was more common among the active group (six subjects vs. none taking placebo), but reports of “loose stool” were more common among placebo-treated subjects (in one subject vs. six taking placebo). Active patients also had small but significant increases in T lymphocyte and eosinophil counts.

The short half-life of LY450139–only 2.5 hours–may be its saving grace in this area, Dr. Eric Siemers, medical advisor for Lilly, said in an interview. “Based on our data thus far, in adults you can apparently inhibit Notch signaling for up to 12 hours a day and not really see any Notch-related toxicity.”

The Future

The biggest bang of LY450139 and similar compounds will probably be in their ability to forestall cognitive decline, Dr. Siemers said. He and other researchers envision a time when advances in imaging and biomarkers will foster the advent of a regular dementia screen as people approach old age–something akin to today's colorectal-screening process.

Those who screen positive–perhaps by a brain imaging study showing amyloid plaque deposition–will immediately receive a disease-modifying drug, or perhaps a cocktail of remedies including Aβ-modulators and immunotherapy. “These things could be used presymptomatically to catch people before they experience significant decline,” Dr. Siemers said.

Drug research will combine in a very powerful way with advances in markers and imaging technology to improve social acceptance of early diagnosis, predicted Dr. Paul Aisen, of Georgetown University Medical Center in Washington. “Today at diagnosis, you are basically giving them a death sentence, so right now there is a great deal of reluctance to diagnose someone early,” said Dr. Aisen, Neurochem's principal U.S. investigator of tramiprosate. “But if you have a way to detect early changes and drugs that will prevent progression, that will change our entire outlook on early diagnosis.”

Investigational drugs that decrease the body's load of both soluble and fibrillar amyloid β (Aβ) could change a diagnosis of Alzheimer's disease from a death sentence to that of a chronic but manageable illness.

All of these compounds are still in preclinical or clinical trials, but their potential to redefine the prognosis of Alzheimer's patients is remarkable, researchers say–akin to the benefits that protease inhibitors have wrought for those with HIV-AIDS.

“The first protease inhibitor for AIDS was not a very good drug, but it provided a proof of principle that paved the way for the current drugs, which have revolutionized HIV-AIDS treatment,” said Michael Wolfe, Ph.D., of Brigham and Women's Hospital and Harvard Medical School, Boston.

Similarly, although these first Aβ-modulating agents that target proteases “are not perfect right now, I believe they will pave the way for more effective drugs that will completely change the way we view Alzheimer's therapy.”

Perhaps the most exciting component of drugs that modify Aβ is their potential to change the course of Alzheimer's, according to Dr. Samuel Gandy, chief scientific adviser for the Alzheimer's Association. “We're on the verge of knowing whether antiamyloid strategies will slow or prevent cognitive decline,” he told this news organization.

Methods of Action

The drugs all aim to decrease levels of Aβ peptides, but they do so in different ways, Dr. Wolfe said in an interview.

Aβ–some forms of which aggregate into the characteristic Alzheimer's brain plaques–is produced when the enzymes β- and γ-secretase cut the amyloid precursor protein into different lengths. Inhibitors of γ-secretase stop that cleavage, lowering Aβ levels by keeping the precursor protein intact. Selective amyloid-lowering agents (SALAs) also work on γ-secretase: They change the point where the protein is cut, preventing the formation of the toxic, longer-chain Aβ-42. Both γ-secretase inhibitors and SALAs are designed to reduce soluble Aβ levels, with the aim of preventing plaque formation.

The third agent under development–an Aβ antagonist–is designed to maintain Aβ peptides in a soluble state. It apparently stops heparin from binding to Aβ, an interaction thought to trigger Aβ aggregation, Dr. Wolfe said. This compound, which is furthest along the developmental pipeline, not only reduces soluble Aβ, but has been shown in animal models to reduce the load of already-formed Aβ-42 plaques.

Safety and Efficacy

Some serious safety issues plagued the γ-secretase inhibitors during early preclinical development, Dr. Wolfe said. The enzyme also plays a key role in cell signaling from the Notch receptor: Blocking it entirely had significant effects on this pathway, which mediates cell differentiation and proliferation. Immune cells and tissues with high cellular turnover–including gut tissue–were most severely affected.

The SALAs don't block γ-secretase, but rather modify the enzyme's activity in a way that avoids the Notch problem. But, Dr. Wolfe said, early SALAs just weren't very effective in cell cultures. “Even the one in clinical trials requires very high doses,” to achieve a significant effect. “They're apparently very safe, however,” he added.

The Aβ antagonists have likewise shown little or no toxicity in humans, even at very high doses, he said.

Tramiprosate: A β Antagonist

Of all the Aβ modulators, tramiprosate (Alzhemed, Neurochem Inc.) is closest to clinical use. Its initial 18-month phase III trial, which includes 1,052 North American patients with mild to moderate Alzheimer's, is set to conclude in January 2007. A similarly sized European trial is underway.

Findings from in vitro experiments have shown that the drug inhibited Aβ-42-induced cell death by 38%. In animal studies, it reduced Aβ-42 plasma levels by 31% and plaque burden by 24% (Neurobiol. Aging 2006, May 1;[Epub ahead of print]doi:10.1016/j.neurobiolaging.2006.02.015).

The findings of a phase II study of 58 patients with mild to moderate Alzheimer's, who were followed for almost 3 years, are consistent with those early results. Over the first 3 months of that trial, patients on the highest dose of tramiprosate had a significant decrease in mean levels of Aβ-42 in cerebrospinal fluid compared with placebo patients.

“The reductions varied depending on the dose given, but the average decrease was up to 30%, which reproduced quite nicely what we saw in the animal studies,” said Denis Garceau, Ph.D., Neurochem's senior vice president of drug development.

Tramiprosate also has some ability to stabilize disease progression and perhaps even modify its course, he said. After 20 months on the drug, about 70% of the patients with mild Alzheimer's who were still receiving tramiprosate showed either stabilized or slightly improved cognitive measures.

There were no significant adverse effects; the most frequent were mild to moderate gastrointestinal symptoms that resolved spontaneously.

Both phase III trials are testing two, twice-daily doses (100 mg and 150 mg) against placebo, and will be followed by an 18-month open-label extension. About 350 patients have already completed the North American trial, and 85% of them have signed onto the extension study.

Some of the phase III study patients will have pre- and posttherapy MRI to help evaluate the drug's effect on brain atrophy.

R-Flurbiprofen: SALA

Myriad Genetics Inc. is just revving up its phase III trials for this drug (Flurizan). The U.S. trial is in its last stage of recruitment, looking for 1,600 Alzheimer's patients with mild disease. A global study will enroll 800 patients. Both are 18-month trials that pit R-flurbiprofen (800 mg twice a day) against placebo.

R-flurbiprofen rode an efficacy seesaw during its phase II trials. Preliminary results showed no significant effects in any of the three end points (activities of daily living, dementia score, and cognitive function) for the overall group of 207 patients with mild to moderate disease. However, patients with mild AD who were taking the 1,600-mg/day dosage showed a statistically significant benefit at 12 months in activities of daily living and global function, with a positive trend in the Alzheimer's Disease Assessment Scale with the cognitive function subscale (ADAS-cog) (Neurology 2006;66 [Suppl 2]:A347).

The 12-month follow-up study showed that patients with mild disease who stayed on the drug continued to improve, actually regaining up to 2 points on the ADAS-cog. “Although not statistically significant, we saw that the less advanced the patients' disease, the bigger the response they get from the drug,” said Adrian Hobden, Ph.D., president of Myriad.

An additional benefit of R-flurbiprofen may be its ability to delay the onset of psychiatric symptoms in Alzheimer's patients, according to data presented in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders, held in Madrid. In a secondary analysis of the phase II trial, Dr. Jacobo Mintzer, of the Medical University of South Carolina in Charleston, showed that by 1 year, about 90% of patients on the 1,600-mg/day dosage were free of psychiatric symptoms, compared with about 70% of those on placebo.

The European trial will collect cerebrospinal fluid at baseline and at 18 months for exploratory biomarker studies, once reliable markers have been identified.

Myriad also is contemplating separate imaging studies to examine hippocampal and whole-brain volume changes associated with the drug. An exploration of the drug's effect on amyloid plaque deposition with PET imaging using Pittsburgh Compound B is also a possibility. Such studies may be key to showing whether the drug has any effect on existing brain plaques in humans.

LY450139 Dihydrate: γ-Secretase Inhibitor

Eli Lilly & Co. will get its first glimpse of this drug's effect in cognitive and functional domains from a 29-week phase IIB study, launched at six U.S. sites earlier in 2006. The trial will include 45 patients with mild to moderate Alzheimer's randomized to placebo or LY450139.

Two previous human trials demonstrated the compound's ability to significantly lower total Aβ levels in plasma, but were unable to show a significant decrease in cerebrospinal fluid levels.

Both studies provoked concern among the research community for adverse events that could be tied to Notch signaling toxicity. In the 2004 dose-ranging trial (Clin. Neuropharmacol. 2005;28:126–32), two of seven healthy volunteers who took the 50-mg/day dosage for 2 weeks withdrew: one for an increase in serum amylase and lipase concentrations and exacerbation of previous gallbladder and biliary disease, and the other for nausea, vomiting, weakness, and diarrhea accompanied by elevation in white blood cell count.

A single death occurred during the 2005 trial (Neurology 2006;66:602–4). In this study, 70 patients with mild to moderate Alzheimer's took placebo or a titrated lower dose of the drug (1 week of drug at 30 mg/day followed by 5 weeks at 40 mg/day). One patient in the active group died from endocarditis 5 months after withdrawing from the trial as a result of gastrointestinal bleeding from Barrett's esophagus. Neither the endocarditis nor the Barrett's was associated with the drug, according to the study.

Other patients may have shown mild Notch toxicity. Diarrhea was more common among the active group (six subjects vs. none taking placebo), but reports of “loose stool” were more common among placebo-treated subjects (in one subject vs. six taking placebo). Active patients also had small but significant increases in T lymphocyte and eosinophil counts.

The short half-life of LY450139–only 2.5 hours–may be its saving grace in this area, Dr. Eric Siemers, medical advisor for Lilly, said in an interview. “Based on our data thus far, in adults you can apparently inhibit Notch signaling for up to 12 hours a day and not really see any Notch-related toxicity.”

The Future

The biggest bang of LY450139 and similar compounds will probably be in their ability to forestall cognitive decline, Dr. Siemers said. He and other researchers envision a time when advances in imaging and biomarkers will foster the advent of a regular dementia screen as people approach old age–something akin to today's colorectal-screening process.

Those who screen positive–perhaps by a brain imaging study showing amyloid plaque deposition–will immediately receive a disease-modifying drug, or perhaps a cocktail of remedies including Aβ-modulators and immunotherapy. “These things could be used presymptomatically to catch people before they experience significant decline,” Dr. Siemers said.

Drug research will combine in a very powerful way with advances in markers and imaging technology to improve social acceptance of early diagnosis, predicted Dr. Paul Aisen, of Georgetown University Medical Center in Washington. “Today at diagnosis, you are basically giving them a death sentence, so right now there is a great deal of reluctance to diagnose someone early,” said Dr. Aisen, Neurochem's principal U.S. investigator of tramiprosate. “But if you have a way to detect early changes and drugs that will prevent progression, that will change our entire outlook on early diagnosis.”

Investigational drugs that decrease the body's load of both soluble and fibrillar amyloid β (Aβ) could change a diagnosis of Alzheimer's disease from a death sentence to that of a chronic but manageable illness.

All of these compounds are still in preclinical or clinical trials, but their potential to redefine the prognosis of Alzheimer's patients is remarkable, researchers say–akin to the benefits that protease inhibitors have wrought for those with HIV-AIDS.

“The first protease inhibitor for AIDS was not a very good drug, but it provided a proof of principle that paved the way for the current drugs, which have revolutionized HIV-AIDS treatment,” said Michael Wolfe, Ph.D., of Brigham and Women's Hospital and Harvard Medical School, Boston.

Similarly, although these first Aβ-modulating agents that target proteases “are not perfect right now, I believe they will pave the way for more effective drugs that will completely change the way we view Alzheimer's therapy.”

Perhaps the most exciting component of drugs that modify Aβ is their potential to change the course of Alzheimer's, according to Dr. Samuel Gandy, chief scientific adviser for the Alzheimer's Association. “We're on the verge of knowing whether antiamyloid strategies will slow or prevent cognitive decline,” he told this news organization.

Methods of Action

The drugs all aim to decrease levels of Aβ peptides, but they do so in different ways, Dr. Wolfe said in an interview.

Aβ–some forms of which aggregate into the characteristic Alzheimer's brain plaques–is produced when the enzymes β- and γ-secretase cut the amyloid precursor protein into different lengths. Inhibitors of γ-secretase stop that cleavage, lowering Aβ levels by keeping the precursor protein intact. Selective amyloid-lowering agents (SALAs) also work on γ-secretase: They change the point where the protein is cut, preventing the formation of the toxic, longer-chain Aβ-42. Both γ-secretase inhibitors and SALAs are designed to reduce soluble Aβ levels, with the aim of preventing plaque formation.

The third agent under development–an Aβ antagonist–is designed to maintain Aβ peptides in a soluble state. It apparently stops heparin from binding to Aβ, an interaction thought to trigger Aβ aggregation, Dr. Wolfe said. This compound, which is furthest along the developmental pipeline, not only reduces soluble Aβ, but has been shown in animal models to reduce the load of already-formed Aβ-42 plaques.

Safety and Efficacy

Some serious safety issues plagued the γ-secretase inhibitors during early preclinical development, Dr. Wolfe said. The enzyme also plays a key role in cell signaling from the Notch receptor: Blocking it entirely had significant effects on this pathway, which mediates cell differentiation and proliferation. Immune cells and tissues with high cellular turnover–including gut tissue–were most severely affected.

The SALAs don't block γ-secretase, but rather modify the enzyme's activity in a way that avoids the Notch problem. But, Dr. Wolfe said, early SALAs just weren't very effective in cell cultures. “Even the one in clinical trials requires very high doses,” to achieve a significant effect. “They're apparently very safe, however,” he added.

The Aβ antagonists have likewise shown little or no toxicity in humans, even at very high doses, he said.

Tramiprosate: A β Antagonist

Of all the Aβ modulators, tramiprosate (Alzhemed, Neurochem Inc.) is closest to clinical use. Its initial 18-month phase III trial, which includes 1,052 North American patients with mild to moderate Alzheimer's, is set to conclude in January 2007. A similarly sized European trial is underway.

Findings from in vitro experiments have shown that the drug inhibited Aβ-42-induced cell death by 38%. In animal studies, it reduced Aβ-42 plasma levels by 31% and plaque burden by 24% (Neurobiol. Aging 2006, May 1;[Epub ahead of print]doi:10.1016/j.neurobiolaging.2006.02.015).

The findings of a phase II study of 58 patients with mild to moderate Alzheimer's, who were followed for almost 3 years, are consistent with those early results. Over the first 3 months of that trial, patients on the highest dose of tramiprosate had a significant decrease in mean levels of Aβ-42 in cerebrospinal fluid compared with placebo patients.

“The reductions varied depending on the dose given, but the average decrease was up to 30%, which reproduced quite nicely what we saw in the animal studies,” said Denis Garceau, Ph.D., Neurochem's senior vice president of drug development.

Tramiprosate also has some ability to stabilize disease progression and perhaps even modify its course, he said. After 20 months on the drug, about 70% of the patients with mild Alzheimer's who were still receiving tramiprosate showed either stabilized or slightly improved cognitive measures.

There were no significant adverse effects; the most frequent were mild to moderate gastrointestinal symptoms that resolved spontaneously.

Both phase III trials are testing two, twice-daily doses (100 mg and 150 mg) against placebo, and will be followed by an 18-month open-label extension. About 350 patients have already completed the North American trial, and 85% of them have signed onto the extension study.

Some of the phase III study patients will have pre- and posttherapy MRI to help evaluate the drug's effect on brain atrophy.

R-Flurbiprofen: SALA

Myriad Genetics Inc. is just revving up its phase III trials for this drug (Flurizan). The U.S. trial is in its last stage of recruitment, looking for 1,600 Alzheimer's patients with mild disease. A global study will enroll 800 patients. Both are 18-month trials that pit R-flurbiprofen (800 mg twice a day) against placebo.

R-flurbiprofen rode an efficacy seesaw during its phase II trials. Preliminary results showed no significant effects in any of the three end points (activities of daily living, dementia score, and cognitive function) for the overall group of 207 patients with mild to moderate disease. However, patients with mild AD who were taking the 1,600-mg/day dosage showed a statistically significant benefit at 12 months in activities of daily living and global function, with a positive trend in the Alzheimer's Disease Assessment Scale with the cognitive function subscale (ADAS-cog) (Neurology 2006;66 [Suppl 2]:A347).

The 12-month follow-up study showed that patients with mild disease who stayed on the drug continued to improve, actually regaining up to 2 points on the ADAS-cog. “Although not statistically significant, we saw that the less advanced the patients' disease, the bigger the response they get from the drug,” said Adrian Hobden, Ph.D., president of Myriad.

An additional benefit of R-flurbiprofen may be its ability to delay the onset of psychiatric symptoms in Alzheimer's patients, according to data presented in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders, held in Madrid. In a secondary analysis of the phase II trial, Dr. Jacobo Mintzer, of the Medical University of South Carolina in Charleston, showed that by 1 year, about 90% of patients on the 1,600-mg/day dosage were free of psychiatric symptoms, compared with about 70% of those on placebo.

The European trial will collect cerebrospinal fluid at baseline and at 18 months for exploratory biomarker studies, once reliable markers have been identified.

Myriad also is contemplating separate imaging studies to examine hippocampal and whole-brain volume changes associated with the drug. An exploration of the drug's effect on amyloid plaque deposition with PET imaging using Pittsburgh Compound B is also a possibility. Such studies may be key to showing whether the drug has any effect on existing brain plaques in humans.

LY450139 Dihydrate: γ-Secretase Inhibitor

Eli Lilly & Co. will get its first glimpse of this drug's effect in cognitive and functional domains from a 29-week phase IIB study, launched at six U.S. sites earlier in 2006. The trial will include 45 patients with mild to moderate Alzheimer's randomized to placebo or LY450139.

Two previous human trials demonstrated the compound's ability to significantly lower total Aβ levels in plasma, but were unable to show a significant decrease in cerebrospinal fluid levels.

Both studies provoked concern among the research community for adverse events that could be tied to Notch signaling toxicity. In the 2004 dose-ranging trial (Clin. Neuropharmacol. 2005;28:126–32), two of seven healthy volunteers who took the 50-mg/day dosage for 2 weeks withdrew: one for an increase in serum amylase and lipase concentrations and exacerbation of previous gallbladder and biliary disease, and the other for nausea, vomiting, weakness, and diarrhea accompanied by elevation in white blood cell count.

A single death occurred during the 2005 trial (Neurology 2006;66:602–4). In this study, 70 patients with mild to moderate Alzheimer's took placebo or a titrated lower dose of the drug (1 week of drug at 30 mg/day followed by 5 weeks at 40 mg/day). One patient in the active group died from endocarditis 5 months after withdrawing from the trial as a result of gastrointestinal bleeding from Barrett's esophagus. Neither the endocarditis nor the Barrett's was associated with the drug, according to the study.

Other patients may have shown mild Notch toxicity. Diarrhea was more common among the active group (six subjects vs. none taking placebo), but reports of “loose stool” were more common among placebo-treated subjects (in one subject vs. six taking placebo). Active patients also had small but significant increases in T lymphocyte and eosinophil counts.

The short half-life of LY450139–only 2.5 hours–may be its saving grace in this area, Dr. Eric Siemers, medical advisor for Lilly, said in an interview. “Based on our data thus far, in adults you can apparently inhibit Notch signaling for up to 12 hours a day and not really see any Notch-related toxicity.”

The Future

The biggest bang of LY450139 and similar compounds will probably be in their ability to forestall cognitive decline, Dr. Siemers said. He and other researchers envision a time when advances in imaging and biomarkers will foster the advent of a regular dementia screen as people approach old age–something akin to today's colorectal-screening process.

Those who screen positive–perhaps by a brain imaging study showing amyloid plaque deposition–will immediately receive a disease-modifying drug, or perhaps a cocktail of remedies including Aβ-modulators and immunotherapy. “These things could be used presymptomatically to catch people before they experience significant decline,” Dr. Siemers said.

Drug research will combine in a very powerful way with advances in markers and imaging technology to improve social acceptance of early diagnosis, predicted Dr. Paul Aisen, of Georgetown University Medical Center in Washington. “Today at diagnosis, you are basically giving them a death sentence, so right now there is a great deal of reluctance to diagnose someone early,” said Dr. Aisen, Neurochem's principal U.S. investigator of tramiprosate. “But if you have a way to detect early changes and drugs that will prevent progression, that will change our entire outlook on early diagnosis.”