ASH: ARB Plus Thiazide Slashes Blood Pressure But Boosts CRP

NEW YORK, May 21 — Diovan HCT (valsartan + hydrochlorothiazide) significantly reduced blood pressure compared with Diovan monotherapy, but at the cost of a spike in an inflammatory marker, researchers reported here.

Diovan HCT treatment raised high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, whereas monotherapy with the Diovan reduced hsCRP, Paul M. Ridker, M.D., of Brigham and Women's Hospital in Boston reported at the American Society of Hypertension meeting.


There was no relationship between blood pressure and hsCRP, he said.


The finding suggested that Diovan may have additional anti-inflammatory effects in addition to lowering blood pressure, and thiazide diuretics may have adverse effects on hsCRP, Dr. Ridker said.


Diovan's anti-inflammatory action could additionally reduce the risk of cardiovascular events, although that has not been proven in a clinical trial, he said.


That was the take-home message from the 1,668-patient Val-MARC (Valsartan—Managing BP Aggressively and Evaluating Reductions in hsCRP) trial reported at a late-breaking clinical trials session and simultaneously published online in Hypertension, Journal of the American Heart Association.


However, some hypertension researchers were frankly dubious.


John M. Flack, M.D., M.P.H., of Wayne State in Detroit said that while Dr. Ridker's work is impressive, hsCRP does not trump blood pressure. "Getting the pressure down is what is important and diuretics drive down blood pressure," he said.


Dr. Flack said his concern is that the Val-MARC data will be misinterpreted as a reason to avoid combining angiotensin receptor blockers (ARBs) like Diovan with hydrochlorothiazide and that "would be a mistake because it would avoid what we know is a very effective treatment for reducing blood pressure."


Likewise, John Kostis, M.D., of the UMDNJ-Robert Wood Johnson School of Medicine in New Brunswick, N.J. Said, "I don't believe CRP is a factor in treating hypertension."


During a press conference Dr. Ridker stated that he is not recommending that hypertension treatment should be based on hsCRP. But he said that Val-MARC findings have implications for "future trials of hypertension prevention since [Diovan] was shown to reduce hsCRP in all subgroups."


Dr. Ridker has focused much of his research in the study of hsCRP and the impact of inflammation on the risk of cardiovascular events. Moreover, he developed and patented the blood test used to assess hsCRP.


Val-MARC randomized 1,668 patients with systolic pressure of 160 mm Hg or higher and diastolic pressure of 100 mm Hg or higher to 160 mg of Diovan or 160 mg of Diovan plus 12.5 mg of hydrochlorothiazide once daily for two weeks with forced titration to 320 mg of Diovan or 320 mg of Diovan plus 12.5 of hydrochlorothiazide for an additional four weeks.


The average age of patients was 50 and a little less than half of the patients were women.


After six weeks of treatment systolic pressure was reduced by a median of 25 mm Hg among patients randomized to Diovan HCT versus an 18 mm Hg reduction in systolic pressure for patients randomized to Diovan. Diastolic pressure was reduced by 14 mm Hg in the combination therapy arm versus 9 mmHg in the monotherapy arm (P<0.001 for both systolic and diastolic).


By contrast, the primary hsCRP endpoint at 6 weeks significantly favored Diovan which reduced hsCRP by a median 0.12 mg/L versus an increase of 0.05 mg/L in the DiovanHCT arm, which was a difference of 13% (P<0.001).


After six weeks, patients in the Diovan arm were allowed to receive 12.5 mg hydrochlorothiazide if blood pressure remained uncontrolled, but a cohort of 224 remained on Diovan monotherapy. At 12 weeks, the patients in the Diovan arm had hsCRP levels similar to those seen at six weeks, but for 385 patients who switched to Diovan HCT the reduction in hsCRP at six weeks was no longer present at 12 weeks.


Val-MARC was an investigator-initiated study funded by Novartis, the maker of Diovan.


Two days before he reported the Val-MARC results at ASH, a study by Dr. Ridker and colleagues was published in the Journal of the American Medical Association, which found that drug company-sponsored studies were more likely to report results that favored newer treatments. Moreover, the JAMA study stated that trials using surrogate markers as endpoints were usually positive when compared with trials that relied on clinical endpoints.


Dr. Ridker told a news conference in response to a question that he saw no contradiction between the Val-MARC study and his JAMA paper. He said the JAMA study recognized that industry plays a valuable role in sponsoring studies. Moreover, he said that using a biomarker such as hsCRP in this study paves the way for much larger studies that could finally determine whether lowering hsCRP could improve clinical outcome.

Primary source: Hypertension, Journal of the American Heart Association
Source reference:
Ridker, PM et al "Valsartan, Blood Pressure Reduction, and C-Reactive Protein Primary Report of the Val-MARC Trial" Hypertension 2006;48:1-7.

Additional source: American Society of Hypertension
Source reference:
Ridker, PM et al "Effects of Blood Pressure Reduction on High Sensitivity C-Reactive Protein (hsCRP): The Val-MARC Trial" Late breaking clinical trials.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

ASH: Hypertension Associated With Sexual Dysfunction in Women

NEW YORK, May 20 — More than 40% of women with hypertension report sexual dysfunction, which is twice the rate reported by women with normal blood pressure, according to research reported here.

And that's not all. Women who are taking antihypertensive medications, but are not treated to goal, are even more likely to have sexual dysfunction than women with treatment-naïve hypertension, said Michael Doumas, M.D., of the University of Athens at the American Society of Hypertension meeting.


Dr. Doumas and colleagues assessed sexual function in 417 sexually active women treated at an outpatient clinic. Nineteen percent of normotensive women reported sexual dysfunction, versus 42% of women with hypertension (P<0.001), he said.


Women who were receiving treatment for hypertension had slightly higher blood pressure than hypertensive women who were treatment naïve and were also significantly more likely to report sexual dysfunction, he said. Thirty-three percent of the treatment, naïve women had sexual dysfunction, versus 48% of women receiving treatment for hypertension (P=0.027).


Sexual dysfunction was defined as persistent or recurring decrease in sexual desire and in sexual arousal, difficulty in achieving or inability to achieve orgasm, and pain during sexual intercourse.


Two hundred and sixteen women were hypertensive with an average systolic blood pressure of 156.4±15.5 mm Hg and average diastolic pressure of 87.7±6.9 mm Hg versus 121±10.6 mm Hg average systolic and 70.9±8.5 mm Hg average diastolic pressure in the 201 controls.


Women in both groups were in their mid-40s to mid-50s.


In an interview, Dr. Doumas said the poorly controlled hypertension observed in this study reflects not only a "failure to treat to goal, but also the failure to use newer drugs and combination therapy in order to achieve significant reductions in blood pressure." He said that most women were taking receiving ACE inhibitors or angiotensin receptor blockers.


Dr. Doumas said that Male and female sexual dysfunction may be related, in that both may be triggered by reduced circulation to sexual organs—penis in the man and the clitoris, labia and vagina in women. But he said that larger studies are needed to confirm this hypothesis.


Sexual dysfunction was also associated with older age and longer duration of hypertension, he said.

Primary source: American Society of Hypertension
Source reference:
Doumas, M et al "The Effect of Antihypertensive Treatment and Adequate Blood Pressure Control on Female Sexual Function" P173.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

DDW: Hepatitis Patients at Risk for Accidental Acetaminophen Toxicity

LOS ANGELES, May 22 — Over-the-counter flu remedies such as Nyquil or Theraflu are often used for relief of the flu-like symptoms of acute hepatitis, a choice that may trigger acute liver failure because those agents contain acetaminophen.

Serum samples from 72 patients with fulminant hepatitis detected evidence of acetaminophen toxicity in 12.5% of patients, said William M. Lee M.D., of the University of Texas Southwester Medical Center in Dallas, who reported the findings at Digestive Disease Week sessions here today.


Dr. Lee and colleagues used a high-pressure liquid chromatography with electrochemical detection to assess acetaminophen levels. They studied 10 patients with liver failure due to confirmed acetaminophen overdose as a positive control group.


The average serum concentration of acetaminophen adducts was 0.45 nmol/mL versus 5.58 nmol/mL in the control group. Nonetheless, Dr. Lee said the evidence of acetaminophen adducts was "a second insult to the liver cells on top of hepatitis."


Importantly, the toxicity occurred when the patients used the over-the-counter flu medicines at therapeutic doses. "None reported doses that would exceed 4 g/day," he said. That is lower than previously reported toxic doses, he said.


Acetaminophen toxicity occurs in a dose-related fashion. Seven or eight grams consumed over the course of three to four days can be fatal, Dr. Lee said.


An online check of ingredients in cold and flu products found acetaminophen listed as an ingredient in 26 OTC remedies, including Coricidin D, Triaminic, NyQuil, DayQuil, and Dristan as well as Midol and Pamprin.


In this series, 67% of patients who had detectable acetaminophen-protein adducts in their blood died within three weeks of hospital admission versus 27% of patients who had no evidence of acetaminophen use (P=0.017).


Liver toxicity is a well known side-effect of acetaminophen, he said, noting that acetaminophen overdose is a leading cause of liver failure and liver transplants "I am surprised it is still on the market," Dr. Lee said.


He later qualified that statement saying that but the drug is so popular, and is sold under so many different brands—the most popular being Tylenol—that he doubts it would ever be removed from the market.


That said, he noted that people with liver disease are frequently unaware that they are using acetaminophen-containing compounds, which could put them at risk for liver failure.


"Vicodin and Percocet are the two most popular prescription compounds containing acetaminophen and these are often prescribed for pain relief in people with liver disease," he said. "Unbundling of both of these drugs, which might be done at some point, would be significant in terms of reducing accidental acetaminophen overdose."


He said that in 2002 a FDA advisory committee recommended that labels of over-the-counter cold and flu medicines be changed so that the front label would list acetaminophen as an ingredient. "But that was in 2002 and the FDA has yet to act on that recommendation."


John M. Vierling, M.D., president of the American Society for the Study of Liver Diseases, a professor of medicine at Baylor in Houston, said the hallmarks of acetaminophen toxicity are "a change in mental state and alteration in clotting ability."


Dr. Vierling called acetaminophen an "excellent drug" but added that Dr. Lee's study suggests the need to advise patients with chronic liver disease to avoid not only Tylenol and other acetaminophen products but also to be cautious when selecting cold and flu medicines.


The patients were included in the National Institutes of Health Acute Liver Failure Study (1999-2004), a national registry of acute liver failure cases. Dr. Lee said there are roughly 2,000 cases of acute liver failure annually and about 500 of those are fatal.

Primary source: Digestive Disease Week
Source reference:
Lee, WM et al "Acetaminophen as a co-factor in acute liver failure due to viral hepatitis determined by measurement of acetaminophen-protein adducts" Abstract S1002.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Parental Smoking Linked to Allergic Rhinitis in One-Year-Olds

CINCINNATI, May 18 — In susceptible infants, second-hand cigarette smoke from a parent may lead to allergic rhinitis by the age of 12 months, a study here suggested.

With infants who had at least one parent with allergies, exposure to environmental tobacco smoke nearly tripled the risk of developing allergic rhinitis by age one year, according to Jocelyn Biagini, a doctoral student at the University of Cincinnati here, and colleagues.


Although similar findings have been reported in older children, "to our knowledge, this is the first report of this association at that early age," Biagini and colleagues reported online in Pediatric Allergy and Immunology.


Household mold, also thought to be a cause of allergic rhinitis, did not appear significantly linked with it in this patient group, but mold was associated with more upper respiratory tract infections, the researchers said.


The Cincinnati Childhood Allergen and Air Pollution Study (CCAAPS) involved 633 children born from 2001 through 2003. All children had at least one parent with a positive allergy skin prick test and so were more susceptible to allergies themselves, the investigators said. Parental smoking was determined by questionnaire, household mold was assessed by a home visit, and children were evaluated by a clinical exam when they reached 12 months of age.


The infants of parents who smoked 20 or more cigarettes daily had an increased risk of developing allergic rhinitis at age one (odds ratio=2.7; 95% confidence interval=1.04 to 6.8). Allergic rhinitis was confirmed by a skin prick test.


These infants also had nearly double the risk of non-allergic rhinitis symptoms (OR=1.9; 95% CI=1.1 to 3.2), the study found.


High levels of household mold were also associated with allergic rhinitis, regardless of parental smoking, but the results were not statistically significant (OR=3.2; 95% CI=0.7 to 14.8).


However, high levels of household mold increased risk of upper respiratory tract infections by more than fivefold (OR=5.1; 95% CI=2.2 to 12.1). Even low levels of household mold were linked to a 50% higher URI risk (OR=1.5; 95% CI=1.1 to 2.3).


"This study suggests that environmental tobacco smoke exposure, rather than visible mold, is associated with rhinitis and allergic rhinitis in infants," the authors concluded.


Previous research found that about 43% of children in the United States are exposed to tobacco smoke in their homes, the authors noted. "There are clear associations with environmental tobacco smoke and wheezing, asthma, and otitis media in children," they said.


The study also found a protective effective of having two or more older siblings against allergic rhinitis (OR=0.70; 95% CI=0.4 to 0.99). Previous research has found this "sibling effect" in older children, they noted. The biological mechanisms behind this effect are unknown, but one hypothesis is that larger family size increases the number of infections a child is exposed to earlier in life, thereby helping to ensure a properly functioning immune system, they said.

Primary source: Pediatric Allergy and Immunology
Source reference:
Jocelyn Biagini et al. "Environmental risk factors of rhinitis in early infancy." Pediatric Allergy and Immunology. Advanced online publication May 17, 2006.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra
CERTIFICADO CONTRA VIRUS POR BIT DEFENDER PROFFESIONAL PLUS 8

HRS: Thyroxine Levels Correlate with Atrial Fibrillation in Older Patients

BOSTON, May 18 — In older patients, even mildly elevated levels of thyroid hormones may be an independent risk factor for atrial fibrillation, British researchers reported here.

Among 5,784 men and women ages 65 and over, there was a "striking association" between atrial fibrillation on resting electrocardiogram and serum free thyroxine (T4) concentrations, reported Michael D. Gammage, M.D., and colleagues from the University of Birmingham in England.

"There is increasing evidence from cross-sectional studies that subclinical hyperthyroidism is associated with the finding of atrial fibrillation, as well as evidence that subclinical hyperthyroidism predicts increased all-cause and vascular mortality over a 10-year period of followup," they said in a poster presentation at the Heart Rhythm Society meeting.

The investigators looked at a cohort of 2,934 women and 2,850 men who were not being treated for thyroid dysfunction. The patients were identified from primary care practices by serum free T4 and serum thyrotropin (TSH) levels, and by resting 12-lead ECG.

They found that on resting ECG, 4.78% of all patients had atrial fibrillation. The prevalence was higher among men (6.57%) compared with women 3.04%. The prevalence of atrial fibrillation varied significantly with serum TSH concentrations.

Among the 128 patients with subclinical hyperthyroidism, the prevalence of atrial fibrillation was 3.7 among those with undetectable serum TSH, compared with 10.9% of those with low but detectable levels of the hormone.

They also found among the entire cohort that the median serum free T4 concentrations were higher in patients with atrial fibrillation compared with those without atrial fibrillation. Median free T4 was 14.6 pmol/L (interquartile range 13.4-16.4) in patients with atrial fibrillation, compared with 14.2 pmol/L in those without atrial fibrillation (interquartile range 12.9-15.7, P<0.001).

When they controlled in a logistic regression analysis for risk factors associated with atrial fibrillation-smoking, diabetes, hypertension, heart failure, ischemic heart disease-they found that the atrial fibrillation was still positively associated with serum free T4 concentration, Male gender, and age.

In a subanalysis of 5,380 patients with neither overt hyper- nor hypothyroidism, 280 (4%) turned out to have atrial fibrillation. In this group, serum free T4 concentrations were also significantly higher among the patients with atrial fibrillation compared with those without the arrhythmia.

"Furthermore, when the analysis of the cohort was further restricted to those classified euthyroid (those with normal serum TSH), this independent relationship between serum free T4 concentration and atrial fibrillation was sustained," the authors wrote.
Their finding of an association between atrial fibrillation and small but measurable changes in thyroid function suggests that patients should be screened and treated for subclinical hyperthyroidism, Dr. Gammage and colleagues said.

"The association of atrial fibrillation with free T4 within the normal range raises intriguing New questions about reducing risk of this important and prevalent dysrhythmia," they concluded.

Primary source: 2006 Heart Rhythm Society Meeting
Source reference:
Gammage MD et al. "Absolute value of free thyroxine predicts atrial fibrillation in relation to age and sex in elderly patients." Abstract P1-27, presented May 17 2006.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

First European Product Containing Delta Biotechnology's Recombumin Receives Marketing Approval from the EMEA

First European Product Containing Delta Biotechnology's Recombumin Receives Marketing Approval from the EMEA


NOTTINGHAM, England, May 22, 2006 - Delta Biotechnology Ltd announced today that the European Medicines Agency (EMEA) has granted a Marketing Authorisation for Sanofi Pasteur MSD's M-M-RVAXPRO(tm) childhood vaccine (measles, mumps and rubella virus (live)). The vaccine is manufactured using and containing Recombumin(r); a recombinant human albumin produced by Delta Biotechnology. Recombumin(r) is a biosynthetic, animal-free material for use in vaccine production and biopharmaceutical formulation.


This development results from collaborative efforts between Delta and Sanofi Pasteur MSD and Merck & Co. To define and test the use of recombinant albumin in the measles, mumps and rubella vaccine production process. Recombumin(r) replaces the human serum albumin currently used in Sanofi Pasteur MSD's MMR vaccine. Following this announcement, Recombumin(r) is the only animal-free, commercially available, recombinant human albumin approved by both the EMEA and FDA for use in the manufacture of human therapeutics. It is a structurally identical, yeast-derived alternative to HSA, which has the potential to improve product acceptance by the regulatory authorities.


Recombumin(r) is manufactured at Delta's cGMP-compliant, Health Canada and FDA inspected facility in Nottingham, UK by a team with over 20 years of leadership and expertise in the development of an animal free biomanufacturing process for the commercial production of recombinant human albumin.


"We are very proud to have gained regulatory approval for the use of Recombumin(r) from both the EMEA and FDA", commented Werner Merkle, CEO of Delta Biotechnology. "Recombumin(r) has passed the strictest regulatory standards and we are now looking forward to global rollout of our premier recombinant albumin product".


"Our customers can now reap the proven benefits of using animal component free recombinant human albumin in their vaccine production and drug formulation. Recombumin(r) provides the industry with an animal-free alternative to human serum albumin. We have approximately 30 healthcare companies evaluating its use in their products with several in clinical development in Europe and the US", added Dermot Pearson, Commercial Operations Director of Delta Biotechnology.


See: http://ec.europa.eu/enterprise/pharmaceuticals/register/2006/20060505112 95/dec_11295_en.pdf for a list of approved products manufactured using and containing Recombumin(r).




For a high resolution image of Recombumin(r), please contact Ben Routley at Northbank Communications on: +44 (0) 1260 296 500 or b.routley@northbankcommunications.com


M-M-RVAXPRO(tm) is the Sanofi Pasteur MSD registered trademark for measles, mumps and rubella virus vaccine live.


About Delta Biotechnology:

Delta Biotechnology Ltd develops and manufactures its lead product, Recombumin(r) using highly engineered, proprietary Saccharomyces cerevisiae yeast strains. The Company also undertakes flexible licensing of its yeast based expression system to offer its pharmaceutical, healthcare and biotech partners customised solutions to their recombinant protein needs. Delta's capabilities range from state of the art molecular biology manipulation of yeast, through to fermentation, process development and analytics to commercial-scale manufacture of proteins in a Health Canada and FDA-inspected, cGMP-compliant facility with an 8000L fermentation capacity.


The Company's proprietary yeast based expression technologies and accompanying Intellectual Property portfolio has resulted in animal component free, high-yielding systems for the production of recombinant proteins at an extremely competitive cost of goods. Delta's protein expression abilities include both the production of native or modified polypeptides and the secretion of proteins genetically fused to albumin using albufuse(tm), the proprietary albumin fusion technology. Fusing proteins to albumin has been shown to significantly enhance circulatory half-life.


Established in 1984, Delta is a wholly-owned subsidiary of Sanofi-Aventis SA, operated as a self-contained business unit with both its R&D and manufacturing facilities based in Nottingham, UK.

For more information on Recombumin(r) or Delta Biotechnology, visit www.deltabiotechnology.com


Media enquiries:

At Delta Biotechnology Ltd:

Dermot Pearson, Commercial Operations Director

Tel: + 44 (0) 115 955 3355

dermot.pearson@deltabiotechnology.com dermot.pearson@deltabiotechnology.com>


At Northbank Communications:

Ben Routley, Account Manager

Tel: +44 (0) 1260 296500

b.routley@northbankcommunications.com b.routley@northbankcommunications.com>



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

New study data co nfirm excellent speed of eradication by Avelox (moxifloxacin HCl)

Complete eradication of pathogens in acute bacterial sinusitis after only three days of treatment New study data confirm excellent speed of eradication by Avelox (moxifloxacin HCl)


LEVERKUSEN, Germany, May 22, 2006 - A recently published study in the peer-reviewed online Journal BMC Ear, Nose and Throat disorders found that Avelox® (moxifloxacin HCl) eradicated all pathogens in patients suffering from acute bacterial sinusitis (ABS) within only three days.

The purpose of the study was to specifically investigate in the real world setting of a doctor_s office, how quickly bacteria are eradicated from the sinuses through antibiotic treatment with moxifloxacin. Knowing how long it takes to remove the cause of infection makes it easier to evaluate the potential of antibiotic treatments to relieve the symptoms of sinusitis.

"Acute bacterial sinusitis is a painful disease typically characterized by facial pain or pressure, so when treating patients it_s very important to help them get better quickly." said Dr. Horatio Ariza, lead study author and Head of the Department of Infectious disease at Hospital Zonal General de Agudos "Mi Pueblo", Buenos Aires, Argentina. "This study clearly found that moxifloxacin is a fast and effective treatment offering rapid symptom relief to sinusitis patients."

ABS is caused by bacteria which multiply and invade the sinuses when the body's defenses weaken or sinus drainage is blocked by a viral infection like the common cold. Symptoms of ABS can be identical to those of a viral infection, although ABS is usually more severe and can last up to 30 days.

In the United Kingdom alone, six million restricted working days are estimated to be a result of acute sinusitis every year. In the United States, there are an estimated 20 million cases of ABS per year. The number of missed worked days due to sinusitis in the USA has reached 12.5 million while that of restricted activity days is 58.7 million.

"By getting ABS patients back on their feet quickly has positive effects not only for them but also for society in terms of the millions of lost days of productivity," added Dr. Ariza.

About The Study In this prospective open-label study, a total of 192 patients diagnosed with ABS were enrolled. Of these, 42 could be evaluated based on 48 forms of bacteria identified during screening. They received 400 mg of Avelox® once daily for 10 days. The screening process included using nasal endoscopy to obtain secretion samples to determine bacterial infection. The sampling procedure was repeated for three consecutive days after treatment started to determine bacterial eradication and persistence. The patients received Avelox treatment on the first day. By the second day, 83.3% of the types of bacteria were eradicated. On the third day, all types of bacteria were eliminated.

About Avelox In Europe , Avelox® IV (+ oral sequential therapy) is approved to treat Community Acquired Pneumonia (CAP), and Complicated Skin and Skin Structure Infections (cSSSI). Avelox® Oral is approved to treat Community Acquired Pneumonia (CAP) - except severe cases, Acute Bacterial Sinusitis (ABS) where adequately diagnosed, and Acute Exacerbations of Chronic Bronchitis (AECB).

For Avelox prescribing information and indicated organisms, log on to www.avelox.com or email global.avelox@bayer.com.

About Bayer HealthCare AG: Bayer HealthCare AG, a subsidiary of Bayer AG, is one of the world_s leading, innovative companies in the health care and Medical products industry. In 2004, the Bayer HealthCare subgroup generated sales amounting to some 8.5 billion Euro.

The company combines the global activities of the divisions Animal Health, Consumer Care, Diabetes Care, Diagnostics and Pharmaceuticals. Since January 1, 2006 the New Pharmaceutical Division consists of the former Biological Products and Pharmaceutical Division and now comprises three business units: Hematology/Cardiology; Oncology and Primary Care. Bayer HealthCare employed 35,300 people worldwide in 2004.

Bayer HealthCare's aim is to discover and manufacture innovative products that will improve human and animal health worldwide. The products enhance well-being and quality of life by diagnosing, preventing and treating disease.

Forward-Looking Statements This news release contains forward-looking statements based on current assumptions and forecasts made by Bayer Group management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in our public reports filed with the Frankfurt Stock Exchange and with the U.S. Securities and Exchange Commission (including our Form 20-F). The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

Name: Dr. Michael Diehl

Pharmaceuticals/Biological Products


Address: Bayer HealthCare AG
Building: Q 30
D-51368 Leverkusen


Telephone: + 49 (0) 214-30-58532

Telefax: + 49 (0) 214-30-71640

E-Mail: michael.diehl@bayerhealthcare.com



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

FDA Approves Remicade for Children with Crohn’s Disease

ROCKVILLE, Md., May 19, 2006-The Food and Drug Administration today approved Remicade (infliximab) to treat children with active Crohn's disease, a chronic, inflammatory condition of the bowel that can be severely debilitating. Remicade is a genetically engineered monoclonal antibody, which reduces inflammation (swelling/redness) by blocking the action of tumor necrosis factor-alpha (TNF-?), that was initially approved in 1998 to treat Crohn's disease in adults.


Dr. Steven Galson, director of the FDA's Center for Drug Evaluation and Research, noted that there have been no satisfactory treatments for children with Crohn's disease who have moderate to severe disease activity despite traditional or conventional therapies. Crohn's disease can cause diarrhea, cramping, abdominal pain, gastrointestinal bleeding, and in some cases creates abnormal connections (fistulas) leading from the intestine to the skin.

"Remicade is not a cure, but it provides a much-needed option for reducing the symptoms and inducing and maintaining disease remission in children who have no other safe and effective therapy," he said. "We believe that the potential benefits of this product outweigh the risks that are known and have been carefully evaluated."

The safety and effectiveness of Remicade in pediatric Crohn's disease were assessed in a randomized study in 112 children who were 6 to 17 years old with moderately to severely active Crohn's disease who had an inadequate response to conventional therapies. The proportion of these patients who achieved clinical response compared favorably with the proportion of adults in an earlier Remicade study in adult Crohn's disease, and the pediatric trial's results showed no New safety concerns not already expressed in the product's current label.

In general, the safety profile for Remicade in the pediatric trial was similar to the data that was presented at an FDA Arthritis Advisory Committee meeting in March 2003, and that dealt with the extent to which anti-TNF therapies may increase the risk of serious infections and malignancies, such as sepsis and pneumonia in certain patients.

These risks, which are described in a study in the May 17 issue of the Journal of the American Medical Association, are included in the current labels for all approved TNF-alpha blocking agents, including Remicade.

More recently, the FDA has received rare post-marketing reports of an aggressive and often fatal type of T-cell lymphoma (hepatosplenic T-cell lymphoma) in adolescent and young adult patients with the Crohn's disease. In most, but not all cases, these patients were treated with standard immunosuppressive therapies (azathioprine or 6-mercaptopurine) in combination with Remicade. The FDA is working with the manufacturer to address this risk by updating the Warnings sections of the Remicade label.

FDA continues to actively and carefully monitor the safety experience with Remicade and similar therapies in an effort to maximize their very real benefits yet limit, to the degree possible, the potential for very serious toxicities.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

AstraZeneca Launches Awareness Campaign to Support Proper Medication Dispensing

- Program Provides Important Reminders and Tips for Reducing Name Confusion Among TOPROL-XL(R) (metoprolol succinate) Extended-Release Tablets, Topamax(R), Tegretol(R) and Tegretol-XR(R) -

WILMINGTON, Del., May 19, 2006 /PRNewswire-FirstCall/ -- AstraZeneca has launched an educational campaign to promote and reinforce accurate prescribing and dispensing of TOPROL-XL. TOPROL-XL is indicated for the treatment of hypertension, the long-term treatment of angina pectoris, and the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. In heart failure, it was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis.


The campaign is prompted by reports of name confusion between TOPROL-XL, Topamax(R) (topiramate), a medication produced by Ortho-McNeil Neurologics Inc. To treat epilepsy and prevent migraines, and Tegretol(R)/Tegretol-XR(R) (carbamazepine), produced by Novartis Pharmaceuticals Corporation to treat complex partial seizures, generalized tonic-clonic seizures, and trigeminal neuralgia. TOPROL-XL is not the first prescription drug to ever encounter this name confusion, and it is important to note the Food and Drug Administration (FDA) does not question the established efficacy, safety profile, or tolerability of TOPROL-XL when used to treat its approved indications.

This program is directed to a broad audience including pharmacists and pharmacy technicians, physicians, physician assistants, nurse practitioners, nurses, and patients.

Steps that AstraZeneca is taking include changing the appearance of the package label for TOPROL-XL(R) (metoprolol succinate) to provide differentiation in a New font and colors; running monthly Journal ads raising awareness of the medication errors in key pharmacist, physician, and nursing journals; sending ongoing direct mail communications; developing "shelf- shouters" to remind physicians, pharmacists, pharmacy technicians, and prescribers of the potential for name confusion; and promoting legible handwriting on prescription forms, as well as updating both the TOPROL-XL brand professional and patient web sites with information about the medication errors and the importance of knowing one's medications.

Furthermore, the AstraZeneca sales force is visiting physicians and pharmacists to personally deliver this important message. The FDA's Division of Cardiovascular and Renal Products recommended these actions, among others implemented by the company, in response to reports of medication errors.

"Our priority at AstraZeneca is to ensure our products are administered appropriately and safely, and we are working together with the FDA to support this goal," said Tony Zook, the U.S. President and Chief Executive Officer of AstraZeneca.

This awareness campaign is in addition to the steps AstraZeneca already took in September 2005 to immediately alert health care professionals and consumers about these medication errors, including the distribution of "Dear Health Care Professional" and "Dear Pharmacist" letters and the creation of a 1-800 number for further information. The additional, forthcoming components of this program are aimed at further increasing awareness about proper medication dispensing, and are launching throughout the first half of 2006. AstraZeneca will evaluate the programs to ensure messages regarding medication errors are received and result in an increased awareness of the potential for medication errors with TOPROL-XL, in the hope that this knowledge will empower physicians and patients to double-check prescriptions to ensure they are accurate and correct.

Important Information About TOPROL-XL (R) (metoprolol succinate) Extended- Release Tablets

TOPROL-XL is a beta1-selective (cardioselective) adrenoceptor-blocking agent, for oral Administration, available as extended-release tablets. TOPROL- XL has been formulated to provide a controlled and predictable release of metoprolol for once-daily Administration.

Indications for TOPROL-XL include the treatment of hypertension, alone or in combination with other antihypertensives; the long-term treatment of angina pectoris; and the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis.

TOPROL-XL is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, and sick sinus syndrome (unless a permanent pacemaker is in place) and in patients who are hypersensitive to any component of this product.

Patients taking TOPROL-XL should avoid abrupt cessation of therapy. Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. The dosage should be reduced gradually over a one-to-two-week period, and the patient should be carefully monitored. For full Prescribing Information for TOPROL-XL including boxed WARNING, call 1-800-236-9933 or visit http://www.TOPROL-XL.com.

TOPROL-XL should be used with caution in patients who have bronchospastic disease, diabetes, thyrotoxicosis, peripheral vascular disease, who are undergoing major surgery, or who take calcium channel blockers of the verapamil and diltiazem type.

There is a risk of worsening cardiac failure during up-titration of the dose of TOPROL-XL(R) (metoprolol succinate). Patients need to consult their physicians if they experience signs or symptoms of worsening heart failure such as weight gain or increased shortness of breath.

Patients should be advised to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy has been determined.

In patients with hypertension and angina pectoris the most common adverse events reported with immediate-release metoprolol tartrate are tiredness (10%), dizziness (10%), depression (5%), diarrhea (5%), pruritus or rash (5%), shortness of breath (3%), diabetes, and bradycardia (3%).

In patients with heart failure, serious adverse events and adverse events leading to discontinuation of study medication in MERIT-HF at an incidence greater than or equal to 1% in the group receiving TOPROL-XL and greater than placebo by more than 0.5% were dizziness/vertigo (1.8% vs 1.0%), bradycardia (1.5% vs 0.4%), and accident and/or injury (1.4% vs 0.8%).

For more information, visit http://www.toprol-xl.com or contact AstraZeneca at 1-800-236-9933.

About AstraZeneca

AstraZeneca is a major international health care business engaged in the research, development, manufacture, and marketing of prescription pharmaceuticals and the supply of health care services. It is one of the world's leading pharmaceutical companies with health care sales of $23.95 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology, and infection products. In the United States, AstraZeneca is a $10.77 billion health care business with more than 12,000 employees. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

For more information about AstraZeneca, please visit: http://www.astrazeneca-us.com.

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Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Second-Hand Smoke Traces Detected in Babies' Urine

MINNEAPOLIS, May 12 — Nearly half the infants in a small study exposed to second-hand smoke from their parents' cigarettes showed signs of a potent carcinogen in their urine, according to investigators here.

"The take home message is, 'Don't smoke around your kids,'" said Stephen Hecht, Ph.D., of the University of Minnesota.


Dr. Hecht said the study, published in the May issue of Cancer Epidemiology, Biomarkers & Prevention, is the first to show that many infants living with at least one smoking parent have been exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, or NNK.


NNK is known to cause cancer in rats and is believed to play a significant role as a cause of lung cancer in smokers and in nonsmokers exposed to second-hand smoke.


Dr. Hecht and colleagues enrolled 144 mothers with babies ages three months to a year. Pairs were eligible if the mother was older than 18, not currently breast feeding, was herself a daily or occasional smoker, and if the infant recently had been exposed to tobacco smoke either in the home or in a car.


The researchers tested mainly for metabolites of NNK (compounds dubbed total NNAL) but also for nicotine, cotinine, and their respective glucuronides.


"NNAL is an accepted biomarker for uptake" of NNK, Dr. Hecht said. "You don't find NNAL in urine except in people who are exposed to tobacco smoke, whether they are adults, children, or infants."


All told, the study showed that:


Total NNAL was detectable in 67 of the 144 infants (46.5%), and the mean level of total NNAL in the 144 infants was 0.083 picomoles per milliliter.
134 infants (93.1%), had detectable cotinine and 141 (97.9%), had detectable nicotine.
The mean levels of total cotinine and total nicotine were 0.133 and 0.069 nanomoles per milliliter, respectively.

"The presence of NNAL in the urine of these infants can be explained only by their exposure to the tobacco-specific carcinogen NNK," the researchers concluded. The most likely vector was second-hand smoke, although some could also be absorbed from surfaces, such as rugs and furniture.


In fact, Dr. Hecht said, "the level of NNAL detected in the urine of these infants was higher than in most other field studies of environmental tobacco smoke in children and adults."


As might be expected, the more direct exposure the infant had to tobacco, the more likely he or she was to have NNK metabolites in the urine, the researchers found.


Among the 77 infants with no detectable total NNAL, the children were exposed to smoke from an average of 27 cigarettes a week, while among those with detectable NNAL, the average was 76. The difference was statistically significant at P<0.0001.


But that shouldn't be a consolation to light-smoking parents, Dr. Hecht said: "With more sensitive analytical equipment, the NNAL from urine of babies in lower-frequency cigarette smoking households would most likely be detectable."


The authors noted that a broad range of potentially effective interventions to decrease exposure exists. These include:


Efforts to encourage women to quit before or during pregnancy and to avoid postpartum relapse.
Encouraging smoking cessation among household members.
Establishing no-smoking policies for the home and car.

They pointed out that "evidence that nicotine is present in dust and surfaces of houses in which smoking takes places indicates that the complete elimination of smoking in homes is preferable to an emphasis on not smoking in the presence of children."


They added that "regulatory and economic policies (e.g., increasing the excise tax on cigarettes) are important approaches to decreasing the overall prevalence of smoking and therefore decreasing environmental tobacco smoke exposure of children."

Primary source: Cancer Epidemiology, Biomarkers & Prevention
Source reference:
Stephen S. Hecht et al. "4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol and its Glucuronides in the Urine of Infants Exposed to Environmental Tobacco Smoke." Cancer Epidemiol Biomarkers Prev 2006;15(5):988-92.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

APS: For Migraine and Cluster Headaches, Most Anything Is Worth a Try

SAN ANTONIO, May 15 — For patients with refractory intractable migraine, cluster headaches or occipital neuralgia, it may be worth trying anything.

Researchers reported a variety of old and New approaches at the American Pain Society meeting here, with some preliminary hints of promise.


For example, John Claude Krusz, M.D., Medical director of Anodyne Headache and Pain Care in Dallas, reported on a small study in which he injected subcutaneously Myobloc (botulinum toxin Type B) into the necks of patients suffering intractable migraine of cervical origin.


"Most people inject botulinum toxin into muscles," Dr. Krusz said. "I've been injecting it under the skin to see whether the molecules will penetrate through the skin and into the nerves causing these headaches."


He enrolled 40 patients into the study, treating 32 with Myobloc and eight with sham injections to determine whether there were differences in pain relief.


"These people want to get well so much that even the placebo patients said they felt better," Dr. Krusz said. "However, despite a large placebo effect—in some cases patients experienced a 50% relief in their symptoms with placebo—we still found significant improvement with the toxin." His study was supported by Elan Pharmaceuticals, the original developer of Myobloc.. Elan has since sold its interest to Solstice Pharmaceuticals.


A more than 66% drop in attacks and in the severity of those attacks with the active drug (P<.05 versus placebo) was maintained over a three-month period at which time further injections were required, Dr. Krusz said. He noted that in most trials involving botulinum toxin—either with Myobloc of with Type A (Botox)—for any disorder, the drugs are usually effective for about three months.


Bradley Carpentier, M.D., a private practice pain specialist in Salinas, Calif., reported on use of Myobloc on people who suffer from regular bouts of occipital neuralgia. "This is the type of headache that begins in the back of the skull and radiates to the front—almost always on one side," said Dr. Carpentier. "Patients describe the pain as similar to what they would feel if someone were sticking a knife into their eye."


In one of the three case studies he cited, a woman who had been treated with a variety of headache mediation, opiates, and even anti-seizure medication, still had no relief from occipital neuralgia.


In an attempt to relieve her pain, Dr. Carpentier injected Botox close to the occipital nerve. There was dramatic relief of pain from the almost constant headaches. The shots were repeated about two months later, this time with Myobloc and relief lasted longer.


"This use of botulinum toxin is off-label Administration," Dr. Carpentier noted. "It isn't approved for any headache use, but many doctors have been finding it helps patients. I've actually treated a total of six occipital neuralgia patients with botulinum toxins," he said. "The average pain relief lasts about three months. It indicates that botulinum toxin may have a role in neuropathic pain."


Another older drug being used in headache relief is Thalomid (thalidomide), the teratogenic drug that was off the market for decades but is making a comeback in the treatment of multiple myeloma.


Veerainder Goll, M.D., Medical director of Duke's Pain Evaluation and Treatment Services, treated three patients with Thalomid for tension and migraine headache. Women who were pregnant or lactating were excluded from the trial.


Dr. Goll described a 48-year-old woman, who had severe migraine headaches twice a month or more, who became headache-free through two months, and had mild headaches in the third month. She elected to remain on daily Thalomid therapy. Another 45-year-old woman also elected to stay on medication after her constant painful (10/10 on visual analog scales of headache intensity) daily headaches didn't recur through 12 weeks of therapy. A 32-year-old man with daily headaches also stayed on thalidomide when his headaches abated and were gone after 12 weeks of therapy.


Some clinicians consider the cluster headache phenomenon even more of a challenge than migraine. Joel Bernstein, M.D., chairman of Winston Laboratories in Vernon Hills, Ill., recruited 112 patients with headaches that often occur in clusters that last for weeks or months. Dr. Bernstein had these patients administer nasally the investigative drug, civamide that works by blocking pain receptors.


The drug is inhaled through the nose during the cluster attack period in an attempt to abort further headaches. The patients in the studies were randomly assigned to civamide or placebo, a saline nose spray. They had been suffering an average of 12 headaches a week, each lasting about an hour.


Those taking civamide had about a 30% greater decline in headache frequency than patients on placebo. However, there was a large placebo effect which Dr. Bernstein thought might have been due to the saline. He felt that phenomenon skewed results so that the difference in outcome registered a non-significant trend in favor of civamide (P=.08). Even so, the results have led Dr. Bernstein to plan Phase III clinical trials with the drug in these patients.


Dr. Krusz also is working to treat migraines by creating an intravenous infusion of the Ultram (tramadol) from tablets. The intravenous solution, he said, can be easily prepared by a compounding pharmacist.


He said that in 17 patients receiving the intravenous injections, three-fourths reported dramatic improvement. He said seven of those patients said the infusion instantly eliminated migraine pain.


In another study at his Dallas clinic, Dr. Krusz treated patients who suffered from early-morning migraine or menstrual migraine with dihydroergotamine nasal spray. These patients had well-defined aura—a sensation that an attack was imminent. In 50 of 57 cases, the spray aborted the migraine. Five attacks required two dosages of dihydroergotamine spray; two attacks required three doses.


"We conclude that the long half-life of dihydroergotamine used in a nasal spray formulation can very effectively preempt perimenstrual and early-morning migraines that affect a large proportion of people," said Virginia Scott, a researcher at Dr. Krusz' clinic.


"What we are seeing," said Dr. Carpentier, "is that doctors are taking the medications we have available and are learning to use them better and more effectively in different groups of patients, expanding the drugs' uses to improve the quality of the lives of our patients."

Primary source: American Pain Society 25th annual scientific meeting
Source reference:
Abstract 852: thalidomide in the Treatment of Chronic Tension and Migraine headache pain: A Case Study approach.
Abstract 824: IV TRAMADOL for Treatment of Refractory Headaches and Migraines

Abstract 841: Intradermal botulinum toxin, type B, for treating migraines of cervical origin.

Abstract 752: Dihydroergptamine Nasal Spray for Pre-Emption Of Menstrual/EarlyAM Migraines

Abstract 790: Botulinum toxins in the treatment of occipital neuralgia.



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Inhaled Corticosteroids in Childhood Do Not Stop Asthma

TUCSON, Ariz., May 10 — Inhaled corticosteroids do not alter the development of asthma in early childhood.

That's the conclusion of two randomized controlled trials — one in infants and one in preschoolers — reported in the May 11 issue of the New England Journal of Medicine.


In some children, the studies showed, the drugs controlled persistent or severe wheezing — thought to be a precursor to later asthma — but they "should not be used in the hope of altering the course of asthma in childhood," according to Diane Gold, M.D., and Anne Fuhlbrigge, M.D., both of Brigham and Women's Hospital in Boston.


Given that corticosteroid therapy is not free of risk, the use of the drugs in children under the age of two "should be highly selective," they wrote in an editorial accompanying the two studies. "There is no substitute for clinical judgment in deciding whether and for how long to use corticosteroids in very young children," they concluded.


The two studies — one conducted in the U.S. And one in Denmark — aimed to see whether using inhaled corticosteroids early in life would prevent the development of asthma later.


The American Prevention of Early Asthma in Kids (PEAK) study — led by Theresa Guilbert, M.D., of the University of Arizona College of Medicine here — randomized 285 preschoolers two or three years old to placebo or 44 micrograms of Flovent (fluticasone propionate) twice daily, followed by a one-year observation period without study medication.


The children were thought to be at high risk for developing asthma. They had symptoms such as frequent coughing, wheezing, or shortness of breath.


The primary outcome was the proportion of episode-free days during the observation year, although the researchers also monitored the effects of Flovent during the two treatment years. The study found:

• During the observation year, there were no significant differences between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function.
  
• On the other hand, during the treatment period, Flovent users were episode free 93.2% of the time, compared with 88.4% for those on placebo — a difference that was statistically significant at P=0.006.
  
• The treatment group also had a lower rate of exacerbations — 57.4 per 100 child-years versus 89.4 — which was significant at P<0.001.
  
• On average, the Flovent group grew 1.1 cm less than the placebo group at the end of the treatment period, but the difference had lessened to 0.7 cm at the end of the observation year.

"Although this study shows that inhaled corticosteroids do not prevent chronic asthma, it provides clear evidence that inhaled corticosteroids benefit even some of our youngest patients, said Elizabeth Nabel, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Md., which sponsored the study.


Drs. Gold and Fuhlbrigge concluded in the editorial that "the study offers strong evidence supporting the use of twice-daily inhaled corticosteroids for symptomatic control in a select subgroup of children who are at high risk for asthma with an established history of four or more wheezing episodes in the first two to three years of life, as well as additional risk factors for the persistence of wheezing. These factors include a family history of asthma, atopic dermatitis or allergy (particularly allergy to inhalants), and eosinophilia."


In the Danish study — led by Hans Bisgaard, M.D., of the Copenhagen University Hospital — researchers assigned 294 one-month-old infants (in a randomized, double-blind fashion) to two-week courses of either placebo or Pulmicort (budesonide) at 400 micrograms a day.


Treatment was initiated after a three-day episode of wheezing. The primary outcome was the number of symptom-free days during the three years of the study.


As in the American study, there was no significant difference between the study groups:

• The proportion of symptom-free days was 83% in the Pulmicort group and 82% in the placebo group.
  
• The frequency of episodes was 3.1 per child per year in the Pulmicort group versus 2.7 in the placebo group, but the 95% confidence interval crossed unity.

Unlike the U.S. Study, however, the use of the medication did not appear to improve symptoms: 24% of children in the Pulmicort group compared to have persistent wheezing, compared with 21% for placebo. Again the 95% confidence crossed unity.

Primary source: New England Journal of Medicine

Source reference:

Hans Bisgaard ET AL. "Intermittent Inhaled Corticosteroids in Infants with Episodic Wheezing." N Engl J Med 2006;354:1998-2005.

Additional source: New England Journal of Medicine

Source reference:
Theresa W. Guilbert et al. "Long-Term Inhaled Corticosteroids in Preschool Children at High Risk for Asthma." N Engl J Med 2006;354:1985-97.

Additional source: New England Journal of Medicine

Source reference:
Diane R. Gold and Anne L. Fuhlbrigge. "Inhaled Corticosteroids for Young Children with Wheezing." N Engl J Med 2006;354:2058-60.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Specific Immunotherapy Useful for Childhood Seasonal Allergic Asthma

News Author: Anthony J. Brown, MD
CME Author: Penny Murata, MD


March 10, 2006 — Specific immunotherapy appears to be a safe and effective treatment for children with seasonal allergic asthma sensitized to grass pollen, according to a report in the Journal of Allergy and Clinical Immunology for February.

"We currently have no curative therapy for asthma — specific immunotherapy has the potential for curing allergic asthma," lead author Dr. Graham Roberts told Reuters Health. "This study demonstrates that it is both efficacious and safe within a pediatric population."

Several reports have shown specific immunotherapy to safely reduce the symptoms of allergic rhinoconjunctivitis in children and adults, but its role as treatment for allergic asthma is less clear. Conflicting results have been obtained in adults and there are little data regarding specific immunotherapy for grass pollen–induced asthma in children.

In a randomized, placebo-controlled study, Dr. Roberts, from the Southampton University Hospital NHS Trust in the UK, and colleagues assessed the benefits of specific immunotherapy over two pollen seasons in 35 children with grass pollen–induced asthma. To be eligible for the study, the children had to require at least 200 micrograms of inhaled beclomethasone equivalent per day.

Alutard SQ grass pollen (Phleum pratense) was used for specific immunotherapy and was given in increasing doses, from 10 to 100,000 SQ-U, over eight visits, which took several weeks to complete. Each grass pollen injection was pretreated with topical anesthetic cream and loratadine. The children, who were between the ages of 3 and 16 years, were observed for 60 minutes after each injection.

Histamine was included in the placebo injections to mimic the skin reactions of the active treatment and maintain blinding, the report indicates.

The main outcome measure, the authors note, was the asthma symptom–medication score during the second pollen season. In addition, cutaneous, conjunctival, and bronchial reactivity to the allergen were determined as was the degree of airway inflammation.

Compared with placebo, specific immunotherapy lead to a significant reduction in the asthma symptom–medication score (P = 0.04), the authors state. Moreover, specific immunotherapy appeared to reduce all three types of allergen reactivity (P < 0.05 for all).

By contrast, sputum eosinophil and exhaled nitric oxide testing suggested no difference in airway inflammation between the groups. The authors note that this was despite the fact that patients in the specific immunotherapy group had reduced their steroid dose to half of that in control patients. Thus, specific immunotherapy may have had an antiinflammatory effect.

Specific immunotherapy appeared to be well tolerated with no serious side effects observed and no treatment withdrawals due to adverse events, the investigators point out.

Dr. Roberts emphasized that appropriate patient selection is critical for specific immunotherapy to work.

"Good candidates have summer asthma and often hay fever. They should have a positive skin prick test to the grass pollen allergy and positive serum specific IgE to it," he said. Importantly, the children should have no significant asthma symptoms from other allergens or unstable asthma during the winter when treatment tapering occurs.

The New findings extend those of a recent study in which immunotherapy reduced the symptoms of rhinoconjunctivitis in children and helped prevent progression from hay fever to asthma, the authors note.

J Allergy Clin Immunol. 2006;117:263-268

Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
Describe the efficacy of specific immunotherapy in the treatment of children with grass pollen–induced asthma.
Identify adverse effects of specific immunotherapy in the treatment of children with grass pollen-induced asthma.
Clinical Context
Immunotherapy has been reported to be effective in the treatment of adults with allergic asthma. In the August 12, 1999, issue of The New England Journal of Medicine, Durham and colleagues found that in adults with allergic rhinitis, specific immunotherapy leads to decreased need for corticosteroid therapy. However, in the July 1993 issue of the Journal of Allergy Clinical Immunology, Reid and colleagues presented concerns about the adverse effects of specific immunotherapy in patients with asthma. A study of children with seasonal allergies, reported by Moller and colleagues in the February 2002 Journal of Allergy Clinical Immunology, found that immunotherapy decreases rhinoconjunctivitis symptoms and the development of asthma.

The current study is a randomized, double-blind, placebo-controlled trial to evaluate (1) the efficacy of grass pollen–specific immunotherapy using measures of asthma symptoms; cutaneous, conjunctival, and bronchial allergen reactivity; lung function; and airway inflammation (exhaled nitric oxide, sputum eosinophilia) and (2) the safety of specific immunotherapy in children with asthma induced by grass pollen (P. Pratense) for 2 grass pollen seasons.

Study Highlights
39 children aged 3 to 16 years with the following criteria were enrolled: grass pollen–induced asthma requiring at least 200 μg of inhaled beclomethasone daily; positive skin prick, specific IgE, and conjunctival provocation test results. After 4 patients withdrew or were excluded, data for 35 subjects were analyzed during 2 grass pollen seasons.
Exclusion criteria included previous grass pollen immunotherapy, perennial asthma requiring inhaled corticosteroids, perennial allergic rhinitis, or sensitization to household pet.
18 children were randomized to receive specific immunotherapy with P. pratense pollen preparation for 8 visits for standard updosing and approximately 6-week intervals for maintenance injections; 17 children received histamine-containing placebo. All received pretreatment with loratidine and topical anesthetic cream.
The groups were similar in sex, mean age, weight, height, severity of summer asthma symptoms, and median daily inhaled beclomethasone dose during previous summer. There appeared to be differences in ethnicity, severity of summer rhinoconjunctivitis symptoms, atopic dermatitis, and symptoms on exposure to tree pollen, house dust mites, and animal hair and dander (P values were not reported).
Subjects completed symptom-medication diary during 2 grass pollen seasons: asthma symptoms of wheezing, coughing, shortness of breath, tight chest, and breathing problems while exercising were rated on scale of 0 (no symptoms) to 3 (severe symptoms). Rescue medications (with assigned scores) were allowed for hay fever and asthma symptoms.
Primary outcome data for 1783 (86%) of possible 2065 days during second pollen season showed significant reduction in asthma symptom–medication score for specific immunotherapy group vs placebo group (median, 0.5 vs 1.0; P = .04). There was no significant difference in corticosteroid or inhaled bronchodilator use between the 2 groups.
Skin prick, conjunctival provocation, and bronchial provocation tests with increasing concentrations of P. pratense allergen at baseline and after pollen season showed significant increase in allergen required to cause reaction in the specific immunotherapy vs placebo group.
Lung function measured by portable spirometers twice daily in 13 specific immunotherapy subjects and 16 placebo subjects showed normal baseline function and forced expiratory volume in 1 second was less than 85% of predicted value for one third of second season for both groups.
Exhaled nitric oxide measured every 4 weeks during second season in 9 specific immunotherapy subjects and 14 placebo subjects during second season showed no difference in highest value for both groups.
Induced sputum samples from 6 specific immunotherapy subjects and 10 placebo subjects during peak of second season showed no difference in number of eosinophils per gram of sputum.
Of 54 adverse events, 34 were reported by 13 (72%) of specific immunotherapy subjects and 20 were reported by 7 (41%) of placebo subjects. Of 24 local adverse effects (including pruritis, pain, or swelling), 13 occurred in specific immunotherapy group and 11 in placebo group. Of 30 systemic events (mostly eczema, urticaria, or rhinoconjunctivitis), 21 occurred in specific immunotherapy group and 9 in placebo group. Of 7 mild pulmonary events, 4 occurred in specific immunotherapy group and 3 in placebo group; 2 occurred more than 1-hour postinjection. No subjects withdrew due to adverse events.
2 (57%) of 35 subjects withdrew prior to second season: 1 due to needle phobia and 1 due to family reasons.
Pearls for Practice
In children with grass pollen–induced asthma, specific immunotherapy improves the asthma symptom–medication score and allergen sensitivity in the skin, eyes, and lungs; specific immunotherapy shows no effect on lung function or allergic airway inflammation.
In children with grass pollen–induced asthma treated with specific immunotherapy, adverse events included local, systemic, and pulmonary effects, none of which required discontinuation of treatment.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Perimenopause May Trigger First-Time Depression

The transition to menopause may stir hormones and bring on depression in women with no history of the mood disorder, according to two studies.

In an evaluation over eight years of 231 premenopausal women, ages 35 to 47, with no history of depression, high depression scores (16 or more) were almost four times more likely to occur during a woman's menopausal transition compared with her premenopausal status (odds ratio, 4.29; 95% CI, 2.39-7.72, P<0.001), researchers reported in the April issue of the Archives of General Psychiatry.

Furthermore, depression scores, assessed by the Center for Epidemiological Studies of Depression Scale (CES-D), were significantly linked to changes in hormonal status, according to Ellen Freeman, Ph.D., of the University of Pennsylvania here and colleagues.


Within individual women, the change in menopausal status brought about destabilizing hormonal effects, including increased levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), decreased levels of inhibin B, and greater variability of estradiol, FSH levels, and LH.

The hormone-depression results held even after adjusting for other risk factors, such as smoking, body mass index, premenstrual syndrome, hot flashes, poor sleep, Health status, employment, and marital status, the researchers reported.

On average, the women were 4.58 times more likely to have higher FSH levels (P=.001), three times likelier to have higher LH levels (P=.002), and 63% more likely to have lower inhibin B levels (P=.001) at the time of high CES-D scores compared with the time before the high scores, Dr. Freeman said.


The researchers also found that a Clinical diagnosis of depressive disorder was 2.5 times more likely to occur during a woman's menopausal transition compared with her premenopausal status (OR, 2.50, 95% CI, 1.25-5.02, P=0.01). Diagnoses were assessed by the Primary Care Evaluation of Mental Disorders (PRIME-MD).


The hormone measures were also significantly associated with a Clinical diagnosis of depressive disorder, Dr. Freeman said. For example, on average, women with Clinical depressive disorder were 9.33 times more likely to have higher FSH levels (P=.001) and 4.47 times more likely to have higher LH levels (P=.002) than before the diagnosis of depressive disorder, the researchers said.

"Transition to menopause and its changing hormonal milieu are strongly associated with both new onset of high depressive symptoms and new onset of diagnosed depressive Disorders in women with no history of depression," Dr. Freeman said. The results also indicated that other Health and demographic factors, such as hot flashes, PMS, and smoking status, are also part of the multifactorial Nature of depressive symptoms.

"Further follow-up Study is needed to determine the extent to which the reports of depressed mood are limited to the perimenopausal period and to determine whether the identified risk factors are associated with more persistent depression," she concluded.

In the same issue of the Archives of General Psychiatry, a six-year Study of 460 women, ages 36 to 45, with no history of depression, also found that early transition to menopause may increase the risk of first-time depression.

Compared with 134 women who remained premenopausal, 326 women who entered menopausal transition earlier were twice as likely (adjusted OR 1.9 [95% CI 0.9-4.0]) to develop significant depressive symptoms, according to Lee Cohen, M.D., of Massachusetts General Hospital and colleagues of the Harvard Study of Moods and Cycle. This relationship, the researchers said, held even after adjustment for age at Study enrollment and history of negative life events.

The increased risk for depression, was somewhat greater among women with self-reported vasomotor symptoms, they said, adding that the relationship between hot flashes and depression is not fully understood and may result From a number of factors such as sleep disruption. On the other hand, Dr. Cohen said, the relationship may be caused by changes in the reproductive hormone milieu to which a woman may be sensitive.

The Study included women living in seven Boston-area communities. New onset of depression was based on structured Clinical interviews, CES-D scores, and self-administered questionnaires. The women were interviewed every six months through the initial three years of follow-up and then at substantially greater intervals, the later larger intervals being a limitation of the Study, the researchers said.

However, they added, when they limited analysis to the first three years of follow-up, they still observed that 7.2% of the women who made the perimenopausal transition developed new onset of depression, compared with 2.9% of those who remained premenopausal (OR 2.7. 95% CI, 1.0-6.9, P= .04).

A spectrum of symptoms and syndromes -- severe vasomotor symptoms, loss of bone density, sexual dysfunction, decline in cognitive function -- has been extensively described during the menopausal transition, the authors wrote. "Thus, the comorbidity of these problems with perimenopause-associated depression could affect many aging women, leading to a compounded burden of illness," they concluded.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Bladder Cancer

Disclosures

Cheryl Lee, MD


Introduction
Various aspects of bladder cancer management were discussed at the 2005 American Urological Association (AUA) meeting in San Antonio, Texas, and a great deal of innovative bench, translational, and clinical bladder cancer research was presented. Five courses discussed contemporary management of early-stage and late-stage bladder malignancies, as well as specific clinical challenges, demonstrating the AUA's commitment to bladder cancer education. Several preclinical studies provided evidence to support the future study of targeted biologic therapies in patients. Overall, the meeting showcased a large number of high-quality studies. In view of space limitations, remarks are confined to a selected number of clinical studies relevant to the practice or interest of most clinicians.

Cystoscopy: White Light vs Fluorescence
The gold standard for bladder cancer detection has been cystoscopy guided by white light. For nearly 10 years, however, European centers have used fluorescence to improve cystoscopic detection of bladder tumors. 5-aminolevulinic acid, instilled intravesically approximately 1 hour before cystoscopy, induces macroscopic fluorescence of tumor tissue in the bladder. Currently, this technique is only available for research purposes in the United States, but an increasing number of recent reports from Europe have suggested that standard white light cystoscopy may miss bladder tumors and that fluorescent cystoscopy can increase the detection of small papillary tumors and carcinoma in situ (CIS), as well as decrease the number of residual tumors at the time of restaging transurethral resection of bladder tumor.[1]

Two studies at this year's meeting demonstrated the effectiveness of this technology. Schmidbauer and colleagues[2] described the efficacy of flexible fluorescent cystoscopy. In 92 evaluable patients, they examined 389 lesions. Fluorescent flexible cystoscopy had a 21% higher detection rate of CIS (82%) than standard flexible (61%) or standard rigid (67%) cystoscopy. Fluorescent flexible cystoscopy identified Ta and T1 tumors (92% and 93%, respectively) at a higher rate than standard flexible cystoscopy (86% and 87%, respectively) and at a rate similar to standard rigid cystoscopy (91% and 91%, respectively). Rigid fluorescent cystoscopy outperformed all other modalities, with detection rates of 92%, 97%, and 95% for CIS, Ta tumors, and T1 tumors, respectively. These results suggest that flexible fluorescent cystoscopy is feasible for use in office surveillance of bladder tumors.

Use of this cystoscopic strategy can also reduce recurrence and progression in patients with superficial and non–muscle invasive disease. In a prospective randomized study, Sachs and colleagues[3] compared patients with Ta and T1 tumors surveyed with white light (n = 51) and fluorescent (n = 51) cystoscopy, with a median follow-up of nearly 3.5 years. Compared with patients surveyed with white light, those surveyed with fluorescence had a longer time to first recurrence (12 vs 5 months), a lower number of tumor recurrences (61 vs 82), a lower number of residual tumors at the restaging transurethral resection (16% vs 41%), lower recurrence rates at 12, 36, and 60 months, and a lower rate of progression (8% vs 18%). It will be imperative to make this technology available to urologists in North America.

Are Cystoscopy and Urine Cytology Enough?
During the past decade, a number of urinary marker assays have become available. The benefits of each of these various markers have not always been clear, and each has been associated with its own limitation, having to do with cost, difficulty of interpretation of results, inadequate sensitivity or specificity, or unsuitability for use in the office setting. Recently, the NMP22 assay was reported to increase the detection of bladder tumors.[4] This point-of-care proteomic test measures the nuclear matrix protein NMP22 in voided urine. A portion of the data from this study was reported at the AUA by Katz and Messing.[5] Study participants included 1331 patients at increased risk for bladder cancers who were screened with cystoscopy, cytology, and the NMP22 assay. Bladder cancer was diagnosed in 79 patients. The NMP22 assay detected 55% of these cancers, whereas urine cytology detected only 17%; cystoscopy alone detected 89%. Combined cystoscopy and NMP22 detected 94% of tumors, with the NMP22 assay discovering 4 significant cancers not identified by cystoscopy. The study showed that the NMP22 assay combined with cystoscopy could increase the detection of bladder tumors with information available at the time of the cystoscopic surveillance. In view of this report, it is likely that the use of this assay will increase significantly in screening high-risk patients for bladder cancer. Its ease of use in the office setting and its lower cost make it an attractive alternative to urine cytology in this population.

Improvements in Bladder Cancer Staging
Tumor understaging has hampered the management of bladder cancer. Limitations in transurethral resection, examination while the patient is under anesthesia, bone scans, and especially abdominal and pelvic imaging have resulted in inaccurate staging for many patients. In a group of 422 patients from the University of Michigan, understaging was demonstrated in 43% of patients with superficial and non–muscle invasive cancers and 59% to 60% of patients with muscle invasive disease.[6] Within this cohort, 32% had evidence of lymphovascular invasion (LVI). Those patients with LVI had a much higher rate of understaging (87%) than those without LVI (46%). In multivariable analysis, LVI was the only independent predictor of understaging; patients with LVI had nearly 8 times the risk of understaging than those without LVI (P < .001).

Hydronephrosis on abdominal imaging is another important staging tool, since it often signifies more advanced stage disease when detected. Bartsch and colleagues[7] retrospectively reviewed a population of 788 patients with primary transitional cell carcinoma of the bladder who underwent radical cystectomy without neoadjuvant or adjuvant chemotherapy or radiation therapy. Of these, 108 patients had unilateral hydronephrosis and 25 patients had bilateral hydronephrosis. The presence of hydronephrosis was associated with a higher rate of nodal metastases and extravesical tumors (35% and 62%, respectively) when compared with those without hydronephrosis (15% and 32%, respectively). Moreover, hydronephrosis was an independent predictor of diminished recurrence-free survival in multivariate analysis (P = .0015). Five-year recurrence-free survival for patients with and without hydronephrosis was 42% and 69%, respectively.

Predictors of understaging or advanced stage may allow clinicians to recommend early cystectomy in some patients and even neoadjuvant chemotherapy in others. Using readily available clinical tools, such as the presence of LVI or hydronephrosis on preoperative imaging, may help to refine our treatment decisions and avoid delay in definitive therapy.

Intravesical Therapy: A Potential Application for Docetaxel
Intravesical BCG vaccine revolutionized the treatment of CIS and greatly enhanced conservative options for high-grade Ta and non–muscle invasive tumors. However, we still continue to struggle with the development of second-line therapies for patients who have a poor or limited response to this agent. Although mitomycin C, interferon alfa plus BCG, and gemcitabine are all possible treatment options, none offers a success rate better than 35%. The taxane family may be an alternative second-line therapy in the future. Docetaxel is a microtubule depolymerization inhibitor that has demonstrated safety and efficacy when administered intravenously to patients with metastatic bladder cancer.

The safety of its intravesical use has now been reported by McKiernan and coworkers[8] in a phase 1 study. Eighteen patients with superficial and non–muscle invasive bladder cancer in whom prior intravesical therapy had failed were included in this trial. Patients received 6 weekly intravesical instillations of docetaxel at increasing dose levels and then had their disease restaged with cystoscopy with biopsy, cytology, and computed tomography. The maximum tolerated dose of 75 mg in 100 mL of normal saline was associated with few side effects and no evidence of systemic absorption. The most common side effect was grade 1-2 dysuria. At a median follow-up of 12.5 months, a 60% preliminary response rate was seen. This study lays the groundwork for a phase 2 trial that will investigate the true efficacy of this agent as a second-line intravesical treatment.

Laparoscopic Radical Cystectomy
Laparoscopic and robotic surgery have been used more and more to treat pelvic and retroperitoneal malignancies.[9] Clear benefits in decreased perioperative pain, diminished perioperative use of pain medication, decreased intraoperative blood loss, and quicker return to work have been demonstrated for laparoscopic nephrectomy and adrenalectomy. Many investigators expect that some of these benefits will be translated to patients with pelvic malignancies. The popularity of robotic prostatectomy has grown tremendously in the past few years, with particular benefit of decreased blood loss. Clear benefit of other perioperative variables is less clear, particularly when compared with the results from open series by experienced surgeons. A number of laparoscopists have applied the concept of minimally invasive surgery to radical cystectomy.

Rozet and colleagues[10] reported their experience with laparoscopic-assisted radical cystectomy in 72 cases. The median operating time was 280 minutes, with a median blood loss of 590 mL and a 5% transfusion rate. All margins were negative. Fifty patients had pT2 disease, whereas 9 had pT3 and 1 had a pT4 tumor. Diversion is this series was performed using an open approach. Deger and associates[11] presented their experience with complete intracorporeal laparoscopic cystectomy and urinary diversion. Of 37 patients who underwent laparoscopic cystectomy, 12 patients opted for a rectosigmoid pouch as the urinary diversion. In these 12 individuals, all aspects of the procedure were intracorporeal. The mobilized specimens were removed in an endoscopy bag via the rectum or vagina. The median operating time was 485 minutes. One patient required a blood transfusion. Two patients required additional operation. At a median follow-up of 33 months, all patients were continent at day and night. Two patients have died of metastatic disease.

These reports demonstrate the feasibility of laparoscopic cystectomy and rectosigmoid diversion. Although we will ultimately need reports about direct benefits to the patients and long-term oncologic efficacy, the experience is intriguing. The challenge will be to justify the use of an expensive technology if patient outcomes and quality of life are not better than (not just as good as) standard open cystectomy. Moreover, hospital outcomes will ultimately need to provide some cost advantage to justify widespread use. It is likely that specific patient demographics will need to be defined to achieve the most benefit from the technology.

Prediction of Bladder Cancer Outcome
Nomograms have become increasingly used in clinical practice, mostly in patients with prostate cancer,[12] although a host of nomograms exist for other malignancies. These statistical models essentially use large datasets that contain multiple clinical parameters to predict individual patient outcome. Bochner and the International Bladder Cancer Nomogram Consortium[13] presented a nomogram to predict survival following radical cystectomy using an international dataset of nearly 5500 bladder cancer patients from 12 centers of excellence around the world. Death after cystectomy was observed in 38% of patients. The nomogram included predictors of survival, such as pathologic stage, nodal status, histologic cell type, grade, age at cystectomy, and preoperative radiation therapy. Perioperative chemotherapy and intravesical therapy were not predictors of survival.

A second nomogram to predict tumor recurrence 2, 5, and 8 years after radical cystectomy was presented by Karakiewicz and colleagues.[14] This nomogram was based on data from a cohort of 672 patients, of which 29% experienced tumor relapse after cystectomy. Three parameters identified patients at high risk of relapse: adjuvant radiotherapy, adjuvant chemotherapy, and neoadjuvant chemotherapy. These variables, along with pathologic stage and presence of LVI, were included within the nomogram. As these nomograms continue to be refined, they will no doubt provide useful tools for clinical decision making. Still, prospective validation of these findings will ultimately be required.

Prediction of tumor recurrence and survival can improve our selection of patients for particular therapies and potentially alter patterns of posttreatment surveillance and encourage the use of adjuvant therapies. Prediction of progression is also an important consideration, particularly in the patients with non–muscle invasive disease that are at high risk of progression to muscle invasion. It is not always clear when to apply cystectomy in this group, because many patients strongly desire bladder preservation. A nomogram for progression has not been developed at this time but will be beneficial in the future. In the meanwhile, predictors of survival in patients with cT1 tumors may be of interest in directing early cystectomy.

Our own group has demonstrated the predictive impact of LVI in 63 patients with clinical stage T1 disease.[15] In this population, LVI was present in 21% of patients. The presence of LVI was associated with a higher rate of extravesical disease and tumor understaging (77% and 84%, respectively) when compared with patients with no evidence of LVI (17% and 30%, respectively). In multivariate survival analyses of cT1 patients, the presence of LVI was associated with a 16-fold increase in death from bladder cancer (P = .001) and a nearly 5-fold increase in death from any cause (P = .004). The presence of LVI in the T1 cancer population should be used to encourage early cystectomy. With increased interest in the development of predictive molecular and clinical models, the 2006 AUA will likely offer additional methods of outcome predictors.

References

1. Jichlinski P, Leisinger HJ. Fluorescence cystoscopy in the management of bladder cancer: a help for the urologist! Urol Int. 2005;74:97-101.
   
2. Schmidbauer J, Loidl W, Marberger M. Flexible hexyl-aminolevulinate fluorescence cystoscopy in detecting high risk bladder cancer. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 855.
   
3. Sachs MD, Daniltchenko DI, Riedl CR, et al. Fluorescence detection with 5-aminolevulinic acid (ALA) reduces the risk of tumor recurrence and progression in patients with superficial bladder cancer: 5 year results of a prospective randomized trial. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 912.
   
4. Grossman HB, Messing E, Soloway M, et al. Detection of bladder cancer using a point-of-care proteomic assay. JAMA. 2005;293:810-816.
   
5. Katz G, Messing E. Diagnosis of bladder cancer using a point of care proteomic assay: a multicenter study. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 846.
   
6. Lee, CT, Dunn RL, Zhang Y, et al. Why bladder cancer surveillance may not be effective for high risk patients allowed to progress to muscle invasion. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 1376.
   
7. Bartsch GC Jr, Hautmann RE, Braun C, et al. Hydronephrosis at cystectomy – impact on prognosis in bladder cancer patients. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 1377.
   
8. McKiernan JM, Murphy AM, Goetzl M, et al. Phase I trial intravesical docetaxel (Taxotere) for recurrent superficial bladder cancer. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 916.
   
9. Matin SF. Laparoscopic approaches to urologic malignancies. Curr Treat Options Oncol. 2003;4:373-383.
   
10. Rozet F, Cathelineau X, Arroyo C, et al. Laparoscopic assisted radical cystectomy: experience after 72 cases. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 1117.
    
11. Deger S, Peters R, Roigas J, et al. Laparoscopic radical cystectomy with continent urinary diversion (rectosigmoid pouch) performed completely intracorporeally: an intermediate functional and oncological analysis. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 278.
    
12. Ross PL, Gerigk C, Gonen M, et al. Comparisons of nomograms and urologists' predictions in prostate cancer. Semin Urol Oncol. 2002;20:82-88.
    
13. International Bladder Cancer Nomogram Consortium and Bochner BH. Development of an international bladder cancer specific nomogram predicting survival following radical cystectomy. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 1112.
    
14. Karakiewicz PI, Shariat SF, Rogers CG, et al. A prognostic tool to identify patients at high risk of relapse at 2, 5, and 8 years after cystectomy for transitional cell carcinoma (TCC) of the urinary bladder: nomogram development and internal validation. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 1116.
    
15. Lee, CT, Montie JE, Zhang Y, et al. Lymphovascular invasion is an independent predictor of survival in cT1 bladder cancer. Program and abstracts of the American Urological Association Annual Meeting; May 21-26, 2005; San Antonio, Texas. Abstract 911
    
    
    Saludos Cordiales
    Dr. José Manuel Ferrer Guerra
    

FDA Approves Smoking-Cessation Drug

ROCKVILLE, Md., May 11 — The FDA today approved the smoking-cessation drug Chantix (varenicline tartrate), which targets nicotine receptors in the brain.

The approval followed a priority review that the FDA said was necessary because of the drug's "significant potential benefit to public health."

The drug, which was developed by Pfizer, effectively occupies nicotine receptors in the brain and produces effects similar to nicotine, while blocking nicotine itself from the receptors. This one-two approach is designed to prevent withdrawal symptoms while it blocking the nicotine high from cigarettes for smokers who relapse.

In a press release, Scott Gottlieb, M.D., the FDA's deputy commissioner for medical and scientific Affairs, said the Chantix approval underlines the FDA's commitment to "helping facilitate the development of products to help people quit smoking and improve their overall quality of life."

The fast FDA approval followed a somewhat chilly reception given to phase III trial results reported last November at the American Heart Association meeting in Dallas.

Serena Tonstad, M.D., Ph.D., of the University of Oslo reported then that smokers taking Chantix were more likely to be smoke-free at 12 weeks than patients taking Zyban (bupropion) or placebo. But by one year, only one in five patients treated with Chantix were still smoke free, which led a number of researchers to raise questions about the drug's staying power.

Chantix works by partially blocking the alpha4-beta2 nicotinic receptor in the brain, which Dr. Tonstad said is the main nicotine receptor. Within 10 to 19 seconds of a single puff from a cigarette, nicotine attaches to this receptor. The receptor, in turn, triggers large increases in dopamine, which rewards the smoker with a pleasurable sensation.

Chantix attaches to the receptor and by occupying the receptor it prevents nicotine from attaching, which can break the cycle of addiction by blocking the reward reinforcement associated with large increases in dopamine, Dr. Tonstad said in November. She said the drug was well tolerated with the major side-effect of nausea, but it was mild and did not cause any patient to stop taking the drug.

At the AHA Dr. Tonstad reported results from two of the six clinical trials that were considered in the FDA approval. Those two studies enrolled roughly 2,000 patients, and used the same design. Patients were randomized to Chantix (1 mg/bid.), Zyban (150 mg/bid.) or placebo.

Timothy Gardner, M.D., of Wilmington, Del., who was chairman of the AHA program committee, said at the time that the absolute numbers reported by Dr. Tonstad were "a little disappointing." He noted, for example, that the one-year cessation rate was 22.1% for the Chantix group versus 16.4% in the Zyban group and 10% in the placebo arm. He said those rates were "underwhelming" given the fact that the patients were "motivated to quit since they entered a smoking cessation study." Moreover, he pointed out that the smokers enrolled in the study were not "really heavy smokers since they smoked only about a pack a day."

The FDA said the approved course of Chantix treatment is 12 weeks. Patients who successfully quit smoking during Chantix treatment may continue with an additional 12 weeks of Chantix treatment to further increase the likelihood of long-term smoking cessation.

Related articles:

AHA: Investigational Smoking-Cessation Drug May Offer Short-Term Help


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Journal Scan - Sleep Medicine

Andrew N. Wilner, MD, FAAN, FACP


From
Sleep Medicine
October 28, 2005 (Volume 7, Number 2)

A Preliminary Study of Sleep-Disordered Breathing in Major Depressive Disorder

Deldin PJ, Phillips LK, Thomas RJ
Sleep Med. 2005;Oct 28; [Epub ahead of print]

The incidence of sleep-disordered breathing was evaluated with a home monitoring device in patients with major depressive disorder compared with controls.

Study Design
The investigators studied 19 people (15 women, 4 men; mean age, 34; body mass index, 26) with major depression and 15 controls (10 women, 5 men, mean age 34, body mass index 24). At baseline, patients with depression had statistically higher scores on the Beck Depression Inventory (BDI) (P < .01) and the Spielberger Trait Anxiety Inventory (STAI-T) (P < .01) than controls. Patients with major depression also had significantly higher scores on the Pittsburgh Sleep Quality Index (PSQI) (P = 0.001) and lower sleep efficiency (P = .010) than controls. However, scores on the Epworth Sleepiness Scale (ESS) did not significantly differ between the 2 groups. A home polysomnography system (Stardust) recorded body position, oximetry, heart rate, respiratory rate and effort, and nasal airflow. Airflow was measured with a nasal cannula pressure transducer rather than a thermistor.

Results
Respiratory parameters that differed significantly between people with major depressive disorder and controls included major flow limitation events (P = .02), the percentage of major flow limitation events accompanied by a desaturation of at least 3% (P = .01), and average oxygen saturation (P = .02). In addition, 5 of 19 (26%) of the depressed patients had greater than 5 major flow limitation events/hour. Antidepressant medication or sedative hypnotics did not appear to be responsible for these differences.

Conclusion
Compared with controls, patients with major depressive disorder have symptoms of sleep-disordered breathing, increased PSQI scores, lower sleep efficiency, an increased number of major flow limitations, major flow limitations with oxygen saturation, and decreased oxygen saturation.

Commentary
Patients with obstructive sleep-disordered breathing may have symptoms of depression that respond to treatment of their breathing disorder. Conversely, patients with depression may have sleep-disordered breathing. This pilot home study reveals significant differences in reported and measured sleep variables between patients with major depression and controls. These findings suggest that patients with major depressive disorder should be screened for symptoms of obstructive sleep-disordered breathing and studied with polysomnography when indicated. If significant breathing limitations are discovered, these should be treated along with the depression. The hypothesis that treatment of minor breathing disorder symptoms may improve depressive symptoms in patients with major depressive disorder should be tested. Future studies should include a larger number of patients and matched controls. Although the use of a nasal cannula pressure transducer is innovative, standard polysomnographic techniques would allow a more direct comparison of the magnitude of sleep-disordered breathing in patients with major depressive disorder to other populations.

January 2006 (Volume 7, Number 1)

An Efficacy, Safety, and Dose-Response Study of Ramelteon in Patients With Chronic Primary Insomnia

Erman M, Seiden D, Zammit G, Sainati S, Zhang J
Sleep Med. 2006;7:17-24

The study authors report the results of a double-blind, randomized, placebo-controlled study of ramelteon, a novel agent for chronic primary insomnia.

Study Design
One hundred seven patients (64% women, 36% men; mean age, 37.7) with chronic insomnia for at least 3 months enrolled in this double-blind, randomized, placebo-controlled, crossover study of 4 doses of ramelteon (4 mg, 8 mg, 16 mg, and 32 mg). Each patient participated in each of the 5 study arms, which lasted 2 days, and were separated by a 5- to 12-day washout period. Polysomnography was performed after each dose of medication (or placebo).

Results
One hundred three patients completed the study. Latency to persistent sleep (LPS) as measured by polysomnography was 37.7 minutes with placebo. Compared with placebo, all doses of ramelteon resulted in statistically significant reductions in LPS: LPS was 24 minutes with ramelteon 4 mg, 24.3 minutes with ramelteon 8 mg, 24 minutes with ramelteon 16 mg, and 22.9 minutes with ramelteon 32 mg (P < .001 for all doses). In addition, subjective sleep latency was 57 minutes with placebo compared with 43.9 minutes with ramelteon 16 mg (P = .040). Total sleep time as measured by polysomnography was 400.2 minutes with placebo. Total sleep time was longer with all ramelteon doses compared with placebo: 411 minutes with ramelteon 4 mg (P ≤ .050), 412.9 minutes with ramelteon 8 mg (P ≤ .010), 411.2 minutes with ramelteon 16 mg (P ≤ .050), and 418.2 minutes with ramelteon 32 mg (P ≤ .001). Ramelteon did not improve wake after sleep onset or subjective sleep quality. Next-day performance was not adversely affected by ramelteon, as measured by word list memory and digit symbol substitution tests. The most common adverse events were headache, somnolence, and sore throat.

Conclusion
Ramelteon significantly reduces LPS and increases total sleep time as measured by polysomnography without adverse next-day effects.

Commentary
A variety of drugs are used for the treatment of insomnia, including GABAA benzodiazepine receptor sedative hypnotics (eszopiclone, zaleplon, and zolpidem), benzodiazepines, sedating antidepressants, antipsychotics, and over-the-counter antihistamines. Ramelteon is a novel pharmacologic agent that acts as a highly selective agonist on MT1/MT2 receptors in the suprachiasmatic nucleus. MT1 receptors may mediate the suppressive effect of melatonin and MT2 receptors affect phase shifting. Thus, it appears that the primary target of ramelteon is the body's chronoregulation of sleep rather than providing sedation as a fortuitous side effect of other actions. Results from this study show that ramelteon significantly improved objectively measured sleep latency and total sleep time without residual next-day effects, thereby suggesting that ramelteon will be an important pharmacologic agent for many patients with sleep-onset insomnia.

Abstract

From
Epilepsia
January 2006 (Volume 47, Number 1)

Effect of Levetiracetam on Nocturnal Sleep and Daytime Vigilance in Healthy Volunteers

Cicolin A, Magliola U, Giordano A, Terreni A, Bucca C, Mutani R
Epilepsia. 2006;47:82-85

In this article, statistically significant increases in total sleep time, sleep efficiency, and stages II and IV of nonrapid eye movement (NREM) sleep were observed with levetiracetam compared with placebo in 14 healthy volunteers after 3 weeks of treatment.

Study Design
Fourteen healthy adult volunteers (7 men, 7 women; mean age, 28.9 years) participated in a double-blind, placebo-controlled, crossover study of levetiracetam (≤ 2000 mg/day) or placebo for 3 weeks separated by a 4-week washout period. The Epworth Sleepiness Scale was performed at baseline. Polysomnography was performed 1 week after a steady-state dose of levetiracetam (2000 mg/day) was reached. Subsequently, subjects completed the Epworth Sleepiness Scale and Multiple Sleep Latency Test.

Results
Statistically significant reductions were observed after treatment with levetiracetam in total sleep time (P = .01), REM (P = .004), wake after sleep onset (P = .004), and the number of stage shifts (P = .001). Sleep efficiency (P = .004) and time spent in NREM stages II (P = .001) and IV (P = .001) significantly increased. There were no significant differences in Epworth Sleepiness Scale scores, the mean sleep time per night based on sleep logs, REM latency, or Multiple Sleep Latency Test scores. Mean levetiracetam serum concentrations were 14.9 ± 4.7 mcg/mL.

Conclusion
Levetiracetam has beneficial effects on sleep without resulting in excessive daytime somnolence in healthy volunteers.

Commentary
Sleep disruption and excessive daytime sleepiness commonly occur in people with epilepsy. Nocturnal seizures may disrupt sleep and may not be remembered by the patient. Antiepileptic drugs often have a sedating effect and may contribute to daytime somnolence. Less commonly, antiepileptic drugs may have alerting properties and result in insomnia, as may be seen with felbamate (Felbatol, MedPointe, Somerset, New Jersey) and lamotrigine (Lamictal, GlaxoSmithKline, Research Triangle Park, North Carolina). Consequently, it is reassuring that levetiracetam (Keppra, UCBPharma, Brussels, Belgium), another "new" antiepileptic drug, appears to consolidate sleep. A lack of effect on the Epworth Sleepiness Scale suggests that daytime somnolence is not increased. Because sleep deprivation may exacerbate seizures, sleep disruption should be minimized in people with epilepsy. Replication of these results in people with epilepsy would lead to the recommendation that levetiracetam should be considered in people with epilepsy who have sleep difficulties due to their antiepileptic drugs.

Abstract

From
Sleep and Biological Rhythms
June 2005 (Volume 3, Number 2)

Dreaming and Schizophrenia: A Common Neurobiological Background?

Gottesmann C
Sleep Biol Rhythms. 2005;3:64-74

This article probes the physiologic similarities between the rapid eye movement (REM) dream state and schizophrenia.

Study Design
In a wide-ranging discussion, the study author compares the physiology of the REM dream state with the pathophysiology of schizophrenia.

Results
The study author observes that 40-Hz electroencephalographic (EEG) activity, which occurs during REM sleep, is uncoupled over the cortical areas. This uncoupling may parallel a "problem of connectivity" that occurs with schizophrenia. Decreased blood flow occurs in the dorsolateral prefrontal cortex during REM sleep and in schizophrenia. Hallucinations that occur in schizophrenia may be due to a decrease in sensory constraints, which also occur during REM sleep. The study author speculates that the failure of inhibitory cortical neurotransmitters could allow the individual to remember "useless memories" created during REM dreams, perhaps leading to schizophrenia. Dopamine levels are decreased during REM sleep compared with waking, which could correlate with the negative symptoms of schizophrenia, which may also be due to reduced levels of dopamine.

Conclusion
Dreams, with their disjointed, at times illogical, and time-distorted imagery, harbor similarities with the psychotic mentation of schizophrenia. In addition, a decrease in the neurotransmitter dopamine appears to play an important role in REM sleep as well as in the negative symptoms of schizophrenic psychosis. The study author postulates that REM sleep could become an experimental model for schizophrenia.

Commentary
Although dreams have fascinated humankind for millennia, the study of dreams is fraught with technically challenging methodologic problems. Dreams that occur during REM sleep represent a normal physiologic phenomenon, but at least superficial similarities exist with the abnormal state of schizophrenia. The study author articulates some commonalities underlying the physiology of dreams and the pathology of schizophrenia. However, it is premature to establish REM sleep as a neurobiological model for schizophrenia. Continued research may lead to an increased understanding of the creation of dreams and perhaps provide insights leading to novel treatments for schizophrenia.

From
Journal of Neurology, Neurosurgery & Psychiatry
January 2006 (Volume 77, Number 1)

Effects of Sleep Deprivation on Cortical Excitability in Patients Affected by Juvenile Myoclonic Epilepsy: A Combined Transcranial Magnetic Stimulation and EEG Study

Manganotti P, Bongiovanni LG, Fuggetta G, Zanette G, Fiaschi A
J Neurol Neurosurg Psychiatry. 2006;77:56-60

The study authors measured the effects of sleep deprivation with magnetic stimulation and electroencephalography (EEG) in 10 patients with juvenile myoclonic epilepsy (JME) and in 10 controls.

Study Design
Ten patients with JME (8 women, 2 men; ages 16-33) were compared with 10 controls (5 women, 5 men; ages 18-30). Eight of the patients were treated with phenobarbital and valproate, whereas the other two did not receive treatment. Subjects were studied with EEG and magnetic stimulation presleep and postsleep deprivation. Patients were sleep-deprived in the hospital from midnight until morning. Stimulation was over the presumed hand area of the motor cortex and recorded from the contralateral thenar eminence. Epileptic activity was quantified on the basis of 30 minutes of EEG recording before and after sleep deprivation.

Results
At baseline, JME patients had significantly decreased short-latency intracortical inhibition (SICI) values compared with controls (P < .001). This effect was larger in the 2 untreated patients than those on antiepileptic drugs. Sleep deprivation further decreased SICI values in patients with JME, but not in controls (P < .001). At baseline, short-latency intracortical facilitation (SICF) did not differ between patients and controls. However, sleep deprivation significantly increased SICF in patients with JME, but not in controls (P < .005). Motor threshold (MT) was significantly reduced by sleep deprivation in patients with JME, but not in controls (P < .001).

Conclusion
Several variables measured by magnetic stimulation were significantly affected by sleep deprivation in patients with JME: SICI decreased; SICF increased; and MT decreased.

Commentary
Every textbook on epilepsy mentions sleep deprivation as a "trigger" for seizures, yet little is known about the pathophysiology of this phenomenon. This study reveals that sleep deprivation can significantly modify the results of several variables (SICI, SICF, and MT) elicited by magnetic stimulation that represent primary motor cortex excitability. Of interest, patients treated with antiepileptic drugs had less prominent changes in SICI. If these results are routinely reproducible, this paradigm could prove extremely valuable in pursuing our understanding of the pathophysiology of epileptic activity and in providing a platform for the evaluation of new antiepileptic drugs. (Drugs that have the greatest effects on magnetic excitability parameters would merit further study.)

This study suffers from several basic technical limitations. The small population includes adults and children who may well differ in cortical excitability. The subjects were not sex-matched and were poorly age-matched. In addition, 8 patients were treated with antiepileptic drugs, whereas 2 were not. In such a small study, these variables should be eliminated. Future studies should endeavor to provide age- and sex-matched controls, control for treatment, and focus on adults or children. Further, although the text clearly states that SICI decreased, the table and figure reveal an apparent increase and are difficult to interpret. The EEG results were also not clearly reported relative to sleep deprivation.

Abstract

Supported by an independent educational grant from Takeda.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Type 2 Diabetes Invading Teenage Years

SEATTLE, May 1 — Thirty-nine thousand U.S. Adolescents are estimated to have type 2 diabetes, and more than 2.5 million may have impaired fasting glucose levels, according to statistical estimates extrapolated from a national survey.

In addition to the alarming prevalence of type 2 diabetes among teenagers, impaired fasting glucose levels in this many young people suggests an even larger number arriving at the threshold of diabetes, according to a study in the May issue of the Archives of Pediatrics and Adolescent Medicine.

It should be noted, however, that these estimates from National Health and Nutrition Examination Surveys (NHANES) for 1999-2002 were derived from a weighted statistical analysis of a total of 18 patients and that some of the 95% confidence intervals were broad.

In a sample of 4,370 adolescents, ages 12 to 19, (equal to a weighted sample of 26,649,401 subjects), 18 individuals reported having diabetes.

Analysis with population-based sample weights found this number (18) equivalent to 134,071 adolescents or 0.5% of all young people in this age group (95% confidence interval, 0.24%-0.76%) having diabetes, said Glen Duncan, Ph.D., of the University of Washington here.

In this self-reported group of 18 diabetic teenagers, 10 individuals were categorized as having type 1 diabetes (used insulin) and eight as having type 2 diabetes (no insulin). Population-based sample weights found these proportions equivalent to 39,005 adolescents with type 2 diabetes. This estimate is consistent with estimates reported elsewhere, Dr. Duncan said.

In a sub-sample of 1,496 teenagers (equal to a weighted sample of almost 25,000 adolescents) without self-reported diabetes who had fasted for at least eight hours, 178 adolescents had impaired fasting glucose levels, defined as a level greater than or equal to 5.6 mmol/L (100 mg/dL).

According to population-based sample weights analysis, this was equal to approximately 2, 769,736 with impaired fasting glucose levels, or roughly 11% (95% CI 8%-14%) of all people in this age group, Dr. Duncan said. The higher prevalence in this study compared with previous reports, he wrote, resulted from the lower contemporary cut-off value for normal levels compared with the older 6.1 mmol/L (110 mg/dL).

Impaired fasting glucose levels were more common in boys (14.8% of all boys in the population vs. 7.3% of all girls).

Although BMI did not differ significantly between adolescents with normal or impaired fasting glucose levels when expressed on an absolute basis (P>.05), there was a statistically significant association when BMI was expressed as a percentile for age and sex. Analysis showed that more than 23.9% of those with impaired fasting glucose levels were overweight (P<.001), defined as ≥ 95th percentile for weight compared with 16.8% who had normal fasting glucose.

Among the study's limitations noted by Dr. Duncan was the fact that the population prevalence was based on only 18 self-reported cases. Nevertheless, he said, the population estimates in this age group "appear quite reasonable" as shown by a previous report that estimated 0.25% of people younger than 20 years have diagnosed diabetes.

Similarly, he said, the classification into a specific type of diabetes was based on self-reported use or non-use of insulin, which "is not optimal."

Finally, the classification and prevalence estimates for impaired fasting glucose levels were determined by only one measurement.

Despite these limitations, Dr. Duncan concluded that these findings have important implications for public health because of the high rate of conversion from impaired fasting glucose levels to type 2 diabetes in adults and the increased risk of cardiovascular disease in individuals with type 2 diabetes.

In an accompanying editorial, Arlan Rosenbloom, M.D., of the Children's Medical Services Center in Gainesville, Fla., pointed to a problem with the case definitions based on insulin use, inasmuch as 50% of pediatric endocrinologists treat type 2 patients with insulin. For example, he said, only one of the eight participants not taking insulin reported taking an oral hypoglycemic agent. Therefore, Dr. Rosenbloom said, the diagnosis of type 2 diabetes is not clear in the other seven.

Further concerns about the definitions were magnified when these small numbers of purported subjects were stratified, for example, for ethnicity, resulting in wide confidence intervals for the estimates.

However, he said, particularly relevant to the clinician is the high frequency of impaired glucose levels in youth. In addition, according to other studies even individuals with normal glucose levels in the upper range of 5.1 to 5.5 mmoL (91 to 99 mg/dL) were at greater risk of developing type 2 diabetes. Whether weight loss will prevent or slow progression in this age group is also unknown, although studies in adults suggest a benefit.

Concerned about the potential for cardiovascular disease, type 2 diabetes, and dyslipidemia in children or adolescents who are overweight or have other risk factors, Dr. Rosenbloom urged lipid testing, regular glucose level retesting, tracking of cardiovascular risk factors, and overall greater vigilance.

"It is hoped," he wrote, "that the recognition of the public health time bomb reflected in the report by Duncan will lead to a pervasive societal effort to prevent obesity, a daunting task of such magnitude that enormous community and governmental commitment will be required."


Saludos Cordiales
Dr. José Manuel Ferrer Guerra