Inhaled Insulin Effective for Diabetes

Nov. 7, 2006 -- Although inhaled insulin is comparable to injected insulin in controlling high blood sugar, its use should be reserved for diabetic patients who cannot or will not use needles, according to a New study.

That's because its long-term safety has yet to be established, says Lisa Ceglia, MD, of the Tufts-New England Medical Center in Boston, a researcher on the study.

"For the time being, the most worrisome concern is the effect inhaled insulin may have on lung function," Ceglia tells WebMD. The review article shows that one of the most common side effects of such therapy is increased coughing and a mild decrease in test scores that measure lung function.

"Are there other things to worry about? Possibly," Ceglia says. "But pulmonary toxicity is the issue we focused on because of the way the therapy is administered."

The findings are published in the November issue of the Annals of Internal Medicine.

Short-Term Trials

Ceglia's team reviewed 16 trials of inhaled insulin involving 4,023 patients with type 1 or type 2 diabetes.

Most of the trials lasted only 12-24 weeks. The longest trial lasted two years. It evaluated Exubera, Pfizer Inc.'s inhaled insulin delivery system. Pfizer is a WebMD sponsor.

In January 2006, Exubera became the first New insulin delivery option to be approved by the FDA since insulin was discovered in the 1920s. Pfizer launched the drug in the U.S. Market in September 2006.

"All of the trials were open-label, meaning that the patients knew what they were getting," Ceglia says. None of the trials used the so-called "double-dummy" technique, in which patients receive an inhaler and injections without knowing which one contains insulin.

Although that other technique may have produced more definitive results, it was not used because the trial designers considered it "logistically difficult and cumbersome."

"What these trials were designed to do is prove non-inferiority," says Larry Deeb, MD, president of medicine and science at the American Diabetes Association in Alexandria, Va. Deed was not connected with the study. "All Pfizer had to do was prove that inhaled insulin was as good as subcutaneous insulin, not that it was superior."

Inhaled Insulin Worked

Ceglia's analysis showed that inhaled insulin was "comparable" to injected insulin in controlling blood sugar. Its effects were "just slightly less" than those of injected insulin, Ceglia says.

Though injected insulin had a small advantage over inhaled insulin in reducing blood sugar, the same number of patients on either therapy achieved a benchmark of diabetes control: a hemoglobin A1c level of less than 7%.

"Clearly, inhaled insulin is not an improvement over subcutaneous insulin, a drug [with] which we've had 80 years of experience," Deeb tells WebMD. "Doctors should tell patients who are already doing well on subcutaneous insulin that they shouldn't expect to do any better if they switch to inhaled insulin."

But Ceglia's analysis also showed high levels of patient satisfaction with inhaled insulin therapy.

She suggested this may be related to the "novelty of the New delivery method" and cautioned it remains to be seen if patients will be as enthusiastic and adherent to inhaled insulin therapy over the long term.

"It's exciting that this New therapy is out," Ceglia says. "It's been in development for a long time. We'll just have to wait and see how it goes."

Safety Concerns

Ceglia's analysis doesn't raise any immediate alarm. "Certainly there was nothing in the first two years that was frightening," she says.

But that doesn't mean there are no concerns. Leading the list is inhaled insulin's long-term effect on lung function.

Even in the short term, patients on inhaled insulin are more than three times as likely as those on injected insulin to develop a dry cough. "This appears to be an immediate reaction to the inhalation and doesn't seem to progress over time," Ceglia says.

Lung Damage?

More worrisome, patients on inhaled insulin were more likely than those on injected insulin to experience a mild decrease in lung function. The mild decrease in lung function happened early in the study and did not worsen over two years.

Another potential problem is severe hypoglycemic reactions, which were shown to be as likely with inhaled insulin as with injected insulin. That could be because inhaled insulin devices don't yet allow for finer dosing adjustments that may be necessary to avoid hypoglycemia, according to the study.

"Based on the trials we analyzed, we can't make any definitive conclusions about the safety of inhaled insulin," Ceglia says. "Like any New drug, however, inhaled insulin is going to have to be tested further and assessed for its long-term efficacy and safety."

Recommendations

Because of long-term safety concerns, Ceglia's team recommends that inhaled insulin be reserved for patients without pulmonary problems, who oppose injections and would otherwise not receive appropriate and timely therapy for their diabetes.

When contacted by WebMD, Pfizer officials said they were reviewing Ceglia's analysis. They issued a statement reiterating their belief that Exubera "represents a major advance in the treatment of diabetes.

"In clinical trials, Exubera was found to be as effective as short-acting subcutaneous insulin injections, and to significantly improve blood sugar control when added to oral medications," the statement reads. "This is reflected in the Exubera product labeling in the United States and European Union."


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SOURCES: Lisa Ceglia, MD, division of endocrinology, diabetes, and metabolism, Tufts-New England Medical Center, Boston. Larry Deeb, MD, president of medicine and science, American Diabetes Association, Alexandria, Va. Pfizer statement from Rebecca Hamm, U.S. Pharmaceuticals Public Relations, Pfizer, New York. Ceglia, L. Annals of Internal Medicine, November 2006; vol 145: pp 665-675.

Reviewed by Louise Chang




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Cancer Patients May Not Benefit From Dietary Modifications

One study, a meta-analysis of 59 trials, found little evidence that diet is associated with survival or prognosis. The other study suggests that neither use of garlic nor vitamin supplements delays the progression of precancerous gastric lesions to cancer.

Numerous studies have linked dietary modifications and vitamins to cancer prevention and treatment. But researchers are worried that some dietary changes may not be harmless, a concern echoed by a European Union recommendation to tighten sales of supplements.

Steven Thomas, M.D., Ph.D., of the University of Bristol in the United Kingdom, and colleagues used database searches to identify 59 trials that investigated the effects of a diverse range of nutritional interventions on patients with a previous diagnosis of cancer or precancerous lesions. Trial results were combined using meta-analysis.

The authors suggest that the trials provide little evidence that specific interventions have any effect on disease-free survival, mortality, or recurrence. They say the impact of most nutritional interventions cannot be estimated reliably because of the limited number of trials, many of which are small or of low quality.

The authors write, "The large personal expenditure on supplements and dietary modifications by patients with cancer demonstrates an urgent need to understand their effects on cancer outcomes. This vulnerable group of people need to be better informed as diet is one of the few areas of their lives where they may feel that they have some control."

A second study of Chinese adults showed that garlic and vitamin supplements did not reduce the prevalence of precancerous lesions or gastric cancer, but treatment to kill Helicobacter pylori may limit the progression of these lesions to cancer and reduce their prevalence.

In Linqu County, China, gastic cancer causes 42% of all cancer deaths, and H. Pylori bacteria is present in 67% of adults. H. Pylori causes gastric cancer.

Wei-Cheng You, M.D., of the Beijing Institute for Cancer Research, Mitchell Gail, M.D., Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues tested 3,365 Chinese adults ages 35-64 in Linqu County. Beginning in 1995, the subjects were randomly assigned to receive various combinations of three interventions--one-time treatment with antibiotics for H. Pylori; long-term vitamin E, C, and selenium supplements; or long-term garlic supplements--or a placebo. The researchers reassessed the patients in 1999 and 2003.

The authors found that one-time use of the antibiotics amoxicillin and omeprazole to treat H. Pylori infection reduced the severity and progression of precancerous gastric lesions. The data also suggested, but did not prove, that antibiotic treatment reduced gastric cancer incidence. Long-term vitamin and garlic supplementation had no effect on the incidence of gastric cancer or progression of precancerous lesions.

The authors write, " H. Pylori treatment reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence [...] Long-term vitamin or garlic supplementation had no beneficial effects."

In an accompanying editorial examining both studies, John A. Baron, M.D., of Dartmouth Medical School in Lebanon, N.H., discusses reasons the two studies may have come to negative conclusions and suggests changes that could have been made to the study designs. He writes, "Together the two articles in this issue of the Journal well illustrate the contemporary status of chemoprevention: hard to summarize, many negative findings, but some nuggets of progress."

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Contacts:

* Article 1: Cherry Lewis, Cherry.Lewis@bristol.ac.uk, (44) 117 928 8086

* Article 2: NCI Press Officers, 301-496-6641, NCIPressOfficers@mail.nih.gov

* Editorial: John A. Baron, 603-650-3456, john.a.baron@dartmouth.edu

Citations:

* Article 1: Davies A, Smith GD, Harbord R, Bekkering GE, Sterne JAC, Beynon R, et al. Nutritional Interventions and Outcome in Patients with Cancer or Preinvasive Lesions: Systematic Review. J Natl Cancer Inst 2006; 98:961-973.

* Article 2: You W-C, Brown LM, Zhang L, Li J-Y, Jin M-L, Chang Y-S, et al. Randomized Double-Blind Factorial Trial of Three Treatments to Reduce the Prevalence of Precancerous Gastric Lesions. J Natl Cancer Inst 2006; 98:974-983.

* Editorial: Baron JA. (Nutritional) Chemoprevention of Cancer: What's Up? J Natl Cancer Inst 2006; 98:945-946.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at http://jncicancerspectrum.oxfordjournals.org/.

Contact: Ariel Whitworth
Journal of the National Cancer Institute




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Life And Death In The Basal Forebrain

Marta Volosin, Wenyu Song, Ramiro D. Almeida, David R. Kaplan, Barbara L. Hempstead, and Wilma J. Friedman

The p75 neurotrophin receptor (p75NTR) and Trk receptor tyrosine kinases elicit opposite cellular consequences: apoptosis and survival, respectively. This week, Volosin et al. Compared the actions of proneurotrophins, selective activators of p75NTR, with neurotrophins on basal forebrain neurons. These cholinergic neurons express p75NTR throughout life as well as all three Trk receptors. The results suggest that Trk receptor activation cannot overcome apoptosis triggered by activation of p75NTR in these cells. Forty percent of cultured basal forebrain neurons died after treatment with pro-nerve growth factor (pro-NGF), but not after mature NGF treatment. Pro-NGF-induced apoptosis required p75NTR and its coreceptor sortilin. After kainic acid-induced seizures, pro-NGF was detected in basal forebrain astrocytes, lysates from these animals induced cell death of cultured basal forebrain neurons, and neuronal loss was less in p75-/- mice. In contrast to previous studies in sympathetic ganglion neurons, activation of Trk receptors did not protect against pro-NGF-mediated apoptosis.

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News Tips from The Journal of Neuroscience

Contact: Sara Harris
Society for Neuroscience





Saludos Cordiales
Dr. José Manuel Ferrer Guerra

ADULT MALE CIRCUMCISION SIGNIFICANTLY REDUCES RISK OF ACQUIRING HIV

Trials in Kenya and Uganda Stopped Early

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), announced an early end to two clinical trials of adult Male circumcision because an interim review of trial data revealed that medically performed circumcision significantly reduces a man's risk of acquiring HIV through heterosexual intercourse. The trial in Kisumu, Kenya, of 2,784 HIV-negative men showed a 53 percent reduction of HIV acquisition in circumcised men relative to uncircumcised men, while a trial of 4,996 HIV-negative men in Rakai, Uganda, showed that HIV acquisition was reduced by 48 percent in circumcised men.

"These findings are of great interest to public health policy makers who are developing and implementing comprehensive HIV prevention programs," says NIH Director Elias A. Zerhouni, M.D. "Male circumcision performed safely in a Medical environment complements other HIV prevention strategies and could lessen the burden of HIV/AIDS, especially in countries in sub-Saharan Africa where, according to the 2006 estimates from UNAIDS, 2.8 million New infections occurred in a single year."

"Many studies have suggested that Male circumcision plays a role in protecting against HIV acquisition," notes NIAID Director Anthony S. Fauci, M.D. "We now have confirmation -- from large, carefully controlled, randomized clinical trials -- showing definitively that medically performed circumcision can significantly lower the risk of adult males contracting HIV through heterosexual intercourse. While the initial benefit will be fewer HIV infections in men, ultimately adult Male circumcision could lead to fewer infections in women in those areas of the world where HIV is spread primarily through heterosexual intercourse."

The findings from the African studies may have less impact on the epidemic in the United States for several reasons. In the United States, most men have been circumcised. Also, there is a lower prevalence of HIV. Moreover, most infections among men in the United States are in men who have sex with men, for whom the amount of benefit provided by circumcision is unknown. Nonetheless, the overall findings of the African studies are likely to be broadly relevant regardless of geographic location: a man at sexual risk who is uncircumcised is more likely than a man who is circumcised to become infected with HIV. Still, circumcision is only part of a broader HIV prevention strategy that includes limiting the number of sexual partners and using condoms during intercourse.

The co-principal investigators of the Kenyan trial are Robert Bailey, Ph.D., M.P.H., of the University of Illinois at Chicago, and Stephen Moses, M.D., M.P.H., University of Manitoba, Canada. In addition to NIAID support, the Kenyan trial was funded by the Canadian Institutes of Health Research and included Kenyan researchers Jeckoniah Ndinya-Achola, M.B.Ch.B., and Kawango Agot, Ph.D., M.P.H. The Ugandan trial is led by Ronald Gray, M.B.B.S., M.Sc., of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Additional collaborators in the Ugandan trial were David Serwadda, M.Med., M.Sc., M.P.H., Nelson Sewankambo, M.B.Ch.B., M.Med.M.Sc., Stephen Watya, M.B.Ch.B., M.Med., and Godfrey Kigozi, M.B.Ch.B., M.P.H.

Both trials involved adult, HIV-negative heterosexual Male volunteers assigned at random to either intervention (circumcision performed by trained Medical professionals in a clinic setting) or no intervention (no circumcision). All participants were extensively counseled in HIV prevention and risk reduction techniques.

Both trials reached their enrollment targets by September 2005 and were originally designed to continue follow-up until mid-2007. However, at the regularly scheduled meeting of the NIAID Data and Safety Monitoring Board (DSMB) on December 12, 2006, reviewers assessed the interim data and deemed medically performed circumcision safe and effective in reducing HIV acquisition in both trials. They therefore recommended the two studies be halted early. All men who were randomized into the non-intervention arms will now be offered circumcision.

"It is critical to emphasize that these clinical trials demonstrated that Medical circumcision is safe and effective when the procedure is performed by medically trained professionals and when patients receive appropriate care during the healing period following surgery," notes Dr. Fauci.

Researchers have noted significant variations in HIV prevalence that seemed, at least in certain African and Asian countries, to be associated with levels of Male circumcision in the community. In areas where circumcision is common, HIV prevalence tends to be lower; conversely, areas of higher HIV prevalence overlapped with regions where Male circumcision is not commonly practiced.

Results of the first randomized clinical trial assessing the protective value of Male circumcision against HIV infection, conducted by a team of French and South African researchers in South Africa, were reported in 2005. That trial of more than 3,000 HIV-negative men showed that circumcision reduced the risk of acquiring HIV by 60 percent. The trial was funded by the French Agence Nationale de Recherches sur le Sida (ANRS) ().

For more information on the Kenyan and Ugandan trials of adult male circumcision, see the NIAID Questions and Answers document at .

The World Health Organization (WHO) press statement in response to the NIAID DSMB recommendation is available on the WHO web site, .

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at .

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .
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Reference: B Auvert et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 trial. "PLoS Medicine". DOI: 10.1371/journal.pmed.0020298 (2005).

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Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Mental Health America Release: FDA Meeting on Antidepressants, Suicidal Thoughts and Behaviors

FOR IMMEDIATE RELEASE

December 13, 2006

FDA Meeting on Antidepressants, Suicidal Thoughts and Behaviors
A Statement by David Shern, Ph.D., President and CEO of Mental Health America

Heather Cobb (703) 797-2588 or
hcobb@mentalhealthamerica.net

ALEXANDRIA, Va. (December 13, 2006) — Mental Health America, the country’s leading nonprofit advocacy organization, appreciates the U.S. Food and Drug Administration’s review of suicidality data for various antidepressant drugs in adults living with depression and other mental disorders. Above all else, people’s safety is paramount. It is important, however, to emphasize the inherent risk of untreated depression.

Without treatment, this disorder can be fatal – 15 percent of people who live with untreated depression take their own lives. Any knee-jerk or pressure-based actions by the FDA may put an untold number of Americans at risk of the tragedy the agency aims to avoid – suicide. The risk associated with not treating depression is far greater than any potential risk of adverse effects of medication.

Mental Health America believes that black box labeling may increase the already troubling number of people who go without adequate Medical care. Historically undertreated, fewer than half of those who need treatment for depression receive any and even fewer get appropriate care.

It is critical that access to treatment is maintained and that consumers and families are not unnecessarily scared away from seeking treatment. Dissuading people from treatments will only lead to serious consequences. In fact, it could certainly behoove the FDA to do an analysis of the effects of the black box issued for youth in 2004 on identification, treatment and outcomes before taking any action related to adults.

In any event, better monitoring of individuals taking antidepressant medications and better education of family members and caregivers about the risks and benefits of treatment is preferable to any actions that could negatively affect the millions of people who need treatment.

Depression affects approximately 34 million American adults in their lifetime and the World Health Organization has projected depression to be the second leading cause of disability for all ages and both sexes worldwide by the year 2020. However, people do not need to suffer; there is wide availability of effective treatments – including antidepressant medications – that prove successful in three-fourths of people.

Depression is by far the leading cause of suicide. Treatment – including medications, psychotherapy and other “talk” therapies or a combination of the two – lessens this risk. In fact, recent research shows a 30 percent decrease in suicide rates since the development of selective serotonin reuptake inhibitors.

Mental Health America is deeply committed to reducing the fear and misinformation surrounding mental disorders, such as depression, and its treatments. It is our hope that the Food and Drug Administration will consider these issues in a broad context, recognizing the public health crisis already facing our nation in untreated depression. Far too many people already suffer needlessly – we need to work harder to identify additional treatments to help people recover and break down stigma and other barriers to care. We need to clear the way for people with depression to recover – not build all-together New obstacles.

Mental Health America is the country’s leading nonprofit dedicated to helping ALL people live mentally healthier lives. With our more than 320 affiliates nationwide, we represent a growing movement of Americans who promote mental wellness for the health and well-being of the nation – everyday and in times of crisis.

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Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Genetic imprinting

Genetic imprinting causes different expressions of the same gene. It is dependent upon which parent the gene is inherited from.

The imprinting itself involves chemical reactions taking place with the DNA that alter not the genes but the expressions of genes (specifically: 'methylation', another term for another day).

Genetic imprinting is the cause for the difference between Prader-Willi syndrome and Angelman syndrome. Both occur due to the same problem (a 'deletion' on chromosome 15), but Prader-Willi is caused by a faulty gene passed down by the father; Angelman from the mother.

Evolutionarily speaking, these diffences occur because of interest differences between the genders.

For example, genetic imprinting is linked with over- and under-expression of genes (think enhancement vs. Suppression). A female (mouse) passing on a suppressed growth-linked gene, and thereby giving birth to smaller young, is more likely to survive and have a high rate of reproduction, while a Male (mouse) 'wants' larger young, so is more likely to be genetically successful if he passes on an enhanced gene.



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Mid-Life Metabolic Syndrome Increases Heart Failure Risk at Older Age

NEW YORK (Reuters Health) Oct 06 - The presence of metabolic syndrome in middle-aged men is associated with an increased risk for heart failure after 20 years, according to a report in the October issue of Heart.

"Metabolic risk factors tend to cluster, and this cluster increases the risk for cardiovascular disease," Dr. Erik Ingelsson from Uppsala University, Sweden told Reuters Health. "This is true, no matter which position you take in the ongoing debate regarding the definitions and use of the metabolic syndrome as a concept."

Dr. Ingelsson and colleagues investigated whether metabolic syndrome predicted later heart failure in some 2300 50-year-old men who were free from heart failure, prior acute myocardial infarction, and valvular disease in 1970-74. The men were followed up until the age of 70.

The risk for heart failure among participants with metabolic syndrome (5.3/1000 person years) was more than three times higher than that for subjects without metabolic syndrome (1.7/1000 person years), the researchers report.

Metabolic syndrome persisted as an independent predictor of heart failure after adjustment for established heart failure risk factors, the results indicate.

When myocardial infarction was included among the heart failure risk factors, metabolic syndrome was still associated with a 1.74-fold increased risk for heart failure, the researchers note.

"Metabolic syndrome can be considered as a clinical proxy for insulin resistance," Dr. Ingelsson said. "We have previously shown that insulin resistance is a strong risk factor for heart failure, independent of established risk factors, including obesity and diabetes. Therefore, the mechanisms behind the current findings surely include insulin resistance."

Dr. Ingelsson concluded: "As a doctor, you should urge your patients to decrease this risk by making lifestyle changes, such as diet modification, smoking cessation, and regular exercise."

Heart 2006;92:1409-1413.




Related Links
Resource Centers
Cardiometabolic Risk Factor Management (Metabolic Syndrome)





Saludos Cordiales
Dr. José Manuel Ferrer Guerra