Diabetes : Dapagliflozin Clinical Trial Results Indicate Improvement In Key Glycemic Measures In Treatment-Naïve Type 2 Diabetes Patients

30 Mar 2009  

Findings published in Diabetes Care from a 12-week, Phase IIb dose-ranging study showed that dapagliflozin, a novel, selective, sodium glucose co-transporter2 (SGLT2) inhibitor, produced clinically meaningful reductions across all key glycemic measures studied [glycosylated hemoglobin level (HbA1c), fasting plasma glucose (FPG), and postprandial plasma glucose (PPG)] in treatment-naïve type 2 diabetes patients, compared to placebo. The study findings also showed that patients receiving dapagliflozin experienced greater reductions in body weight compared to patients on placebo. Adverse events across dapagliflozin and metformin doses were reported at a similar rate, which was somewhat higher than placebo.

Dapagliflozin is an investigational SGLT2 inhibitor currently in Phase III trials under joint development by Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) as a once-daily therapy for the treatment of type 2 diabetes. SGLT2 inhibitors act by inhibiting the reabsorption of glucose in the kidney, thereby reducing the return of filtered glucose to the circulation.

"These data suggest that dapagliflozin, the first SGLT2 to be studied in Phase III clinical trials, may reduce important glycemic measures and facilitate weight loss in patients with type 2 diabetes," said Elisabeth Svanberg, M.D., Ph.D., vice president, Development Lead, Bristol-Myers Squibb. "We look forward to further studies of dapagliflozin to fully understand its potential in the treatment of people with type 2 diabetes," said William Mezzanotte, M.D., M.P.H., vice president, Global Products, AstraZeneca.

About the Study

This Phase IIb study, presented at the 2008 American Diabetes Association annual meeting, was designed to assess the efficacy and safety of dapagliflozin across a wide range of doses. The data represent findings from a prospective, randomized, double-blind, placebo-controlled, parallel-group study of 389 individuals with type 2 diabetes (ages 18-79) who were treatment-naïve and whose HbA1c was greater than or equal to 7 percent and less than or equal to 10 percent. After a two-week lead-in phase that included diet, exercise and placebo, individuals were randomized to one of seven separate treatment arms: dapagliflozin 2.5 mg (n=59), 5 mg (n=58), 10 mg (n=47), 20 mg (n=59), 50 mg (n=56), metformin extended release 750 mg force-titrated at Week 2 to 1500 mg (n=56) or placebo (n=54), once daily for 12 weeks. Metformin was included as a positive control benchmark; no statistical comparison was made to the metformin arm.

The primary endpoint of the study compared mean HbA1c change from baseline for each dapagliflozin group versus placebo. The secondary endpoints included FPG change from baseline as compared to placebo, dose-dependent trends in glycemic efficacy, the proportion of individuals achieving the American Diabetes Association recommended HbA1c target of less than 7 percent and the change in 24-hour urinary glucose-to-creatinine ratio.

Study Results

After 12 weeks, individuals receiving dapagliflozin demonstrated a significant adjusted mean decrease in HbA1c from baseline of -0.71 percent for dapagliflozin 2.5 mg, -0.72 percent for dapagliflozin 5 mg, -0.85 percent for dapagliflozin 10 mg, -0.55 percent for dapagliflozin 20 mg and -0.90 percent for dapagliflozin 50 mg, compared to -0.18 percent for placebo (p-value at the 2.5, 5, 10 and 50 mg dose levels less than 0.001; p-value at the 20 mg dose level equal to 0.007). The adjusted mean decrease for metformin was -0.73 percent. No log-linear dose response relationship was demonstrated (P trend = 0.41).

Dapagliflozin also demonstrated a clinically meaningful adjusted mean decrease in FPG from baseline of -16 mg/dL for dapagliflozin 2.5 mg, -19 mg/dL for dapagliflozin 5 mg, -21 mg/dL for dapagliflozin 10 mg, -24 mg/dL for dapagliflozin 20 mg and -31 mg/dL for dapagliflozin 50 mg, compared to -6 mg/dL for placebo (p-value at the 2.5 mg dose level equal to 0.03; p-value at the 5 mg dose level equal to 0.005; p-value at the 10 mg dose level equal to 0.002; p-value at the 20 mg and 50 mg dose levels less than or equal to 0.001). The adjusted mean decrease for metformin was -18 mg/dL.

The percentage of individuals treated with dapagliflozin that achieved HbA1c of less than 7 percent after the 12 week treatment period was 46 percent for dapagliflozin 2.5 mg, 40 percent for dapagliflozin 5 mg, 52 percent for dapagliflozin 10 mg, 46 percent for dapagliflozin 20 mg and 59 percent for dapagliflozin 50 mg, compared to 32 percent for placebo and 54 percent for metformin. The 50 mg result was the only statistically significant result, with a p-value equal to 0.01.

Over 12 weeks, the incidence of adverse events was 59 percent for dapagliflozin 2.5 mg, 60 percent for dapagliflozin 5 mg, 68 percent for dapagliflozin 10 mg, 68 percent for dapagliflozin 20 mg and 63 percent for dapagliflozin 50 mg; the incidence of events was 54 percent for placebo and 68 percent for metformin. The percentages of the most commonly reported (greater than or equal to 10 percent in any group) adverse events for dapagliflozin 2.5 mg, 5 mg, 10 mg, 20 mg, and 50 mg doses and placebo and metformin, respectively, were: urinary tract infection [5, 9, 11, 7, 7, 6, 7], nausea [5, 7, 6, 3, 5, 6, 11], headache [7, 5, 4, 5, 2, 11, 4], and diarrhea [2, 2, 2, 7, 2, 7, 13].

The rate of reported hypoglycemic events was 7 percent for dapagliflozin 2.5 mg, 10 percent for dapagliflozin 5 mg, 6 percent for dapagliflozin 10 mg, 7 percent for dapagliflozin 20 mg and 7 percent for dapagliflozin 50 mg; the incidence of reported hypoglycemic events was 4 percent for placebo and 9 percent for metformin. There was no occurrence of confirmed hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less than or equal to 50 mg/dL).

Effects of Dapagliflozin on Weight Loss

The Phase IIb study also evaluated the potential impact of dapagliflozin-induced glucosuria on weight loss in people with type 2 diabetes, compared to placebo. These findings included data measuring changes in total body weight and body mass index over the 12-week study period.

Overall, greater percent decreases in total body weight occurred in the dapagliflozin treatment groups: -2.7 percent for dapagliflozin 2.5 mg, -2.5 percent for dapagliflozin 5 mg, -2.7 percent for dapagliflozin 10 mg, -3.4 percent for dapagliflozin 20 mg and -3.4 percent for dapagliflozin 50 mg compared to -1.2 percent for placebo and -1.7 percent for metformin.

About Type 2 Diabetes

Diabetes (diabetes mellitus) is a chronic disease in which the body does not produce or properly use insulin. Insulin is a hormone that is needed to convert sugar, starches (carbohydrates) and other nutrients into glucose, which is used as energy needed for daily life. The cause of diabetes continues to be investigated, and both genetic and environmental factors such as obesity and lack of exercise appear to play a role. Diabetes is associated with long-term complications that affect almost every part of the body. The disease may lead to blindness, heart and blood vessel disease, stroke, kidney failure, amputations, and nerve damage.

There are two primary underlying causes associated with type 2 diabetes: the body does not produce enough insulin (insulin deficiency), and the cells ignore the insulin (insulin resistance). Symptoms of type 2 diabetes develop gradually, and their onset is not as sudden as in type 1 diabetes. Symptoms may include fatigue, frequent urination, increased thirst and hunger, weight loss, blurred vision, and slow healing of wounds or sores. Some people, however, have no symptoms.

The kidneys play a key role in the overall regulation of blood glucose levels in the body. Normally, in healthy individuals, the kidneys filter a large volume of glucose and actively reabsorb virtually all of it. In patients with type 2 diabetes that have hyperglycemia, a greater amount of glucose is filtered and reabsorbed by the kidneys despite the fact that this perpetuates the hyperglycemia.

Over time, the factors that contribute to sustained hyperglycemia lead to glucotoxicity, which worsens insulin resistance and contributes to dysfunction in the beta cells of the pancreas. In this way, hyperglycemia appears to perpetuate a vicious cycle of deleterious effects that exacerbate type 2 diabetes.

Type 2 diabetes is most often associated with older age, obesity, family history of diabetes, previous history of gestational diabetes, physical inactivity and certain ethnicities. People with type 2 diabetes often are characterized with: insulin resistance, abdominal obesity, a sedentary lifestyle, having low HDL-C ("good") cholesterol levels and high triglyceride levels and hypertension.

About SGLT2 Inhibitors

The kidney continuously filters glucose through the glomerulus; however, nearly all of this glucose is reabsorbed in a separate part of the kidney called the proximal tubule. A protein called SGLT2 is responsible for the majority of glucose reabsorption and helps the body retain glucose for it's energy requirements. Inhibiting the activity of SGLT2 helps limit the amount of glucose that is reabsorbed and retained in the body, thereby leading to the excretion of glucose in the urine.

Bristol-Myers Squibb and AstraZeneca Partnership

Bristol-Myers Squibb and AstraZeneca entered into collaboration in January 2007 to enable the companies to research, develop and commercialize two investigational drugs for type 2 diabetes - saxagliptin and dapagliflozin. The Bristol-Myers Squibb/AstraZeneca Diabetes collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of type 2 diabetes.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information visit http://www.bms.com.

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of US$ 31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. For more information about AstraZeneca, please visit: http://www.astrazeneca.com.

Source
AstraZeneca

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Article URL: http://www.medicalnewstoday.com/articles/144154.php

New cochlear implant improves the quality of sound while doing less damage to the ear

A new cochlear implant developed in the Biosystems Interface Laboratory at the Georgia Institute of Technology improves the quality of sound several times more than the conventional cochlear implants.

The new device called the thin film array uses a thinner wire on which are paired 12 electrodes. The thinner wire does less damage to the ear and could preserve residual hearing more than standard cochlear implants, while the higher number of electrodes improves the quality of sound. Dr. Kenneth Iverson, one of the researchers who worked on the device, said: “For the patient, it would be like the difference between hearing a Bach concerto played by a music box versus a quartet.”
Researchers presented their findings about the new device at the 11^th International Conference on Cochlear Implants and Other Auditory Implantable Technology in Stockholm, Sweden June 30 – July 3/2010


Source:
healthyfeeds.com

Glutathione :Short discription

Glutathione

Description
Glutathione is produced in the human liver and plays a key role in intermediary metabolism, immune response and health, though many of its mechanisms and much of its behavior await further medical understanding. It is also known as gamma-Glutamylcysteineglycine and GHS. It is a small protein composed of three amino acids, cysteine, glutamic acid and glyceine. Glutatione is found in two forms, a monomerthat is a single molecule of the protein, and a dimmer that is two of the single molecules joined together. The monomer is sometimes called reduced glutathione, while the dimmer is also called oxidized glutathione. The monomer is the active form of glutathione. Oxidized glutathione is broken down to the single molecule by an enzyme called glutathione reductase.
Glutathione, in purified extracted form, is a white powder that is soluble in water and in alcohol. It is found naturally in many fruits, vegetables, and meats. However, absorption rates of glutathione from food sources in the human gastrointestinal tract are low.
 
General use
Glutathione was first isolated in yeast in 1929. Its metabolism in the body was described in 1984, and its role in cancer treatment dates from 1984.
Glutathione is a major antioxidant highly active in human lungs and many other organ systems and tissues. It has many reported uses. It has a critical role in protecting cells from oxidative stress and maintaining the immune system. Higher blood levels of glutathione have been associated with better health in elderly people, but the exact association between glutathione and the aging process has not been determined.
Among the uses that have been reported for glutathione are:
•    treatment of poisoning, particularly heavy metal poisons
•    treatment of idiopathic pulmonary firbosis
•    increasing the effectiveness and reducing the toxicity of cis-platinum, a chemo drug used to treat breast cancer
•    treating Parkinson's disease
•    lowering blood pressure in patients with diabetes
•    increasing male sperm counts in humans and animals
•    treatment of liver cancer
•    treatment of sickle cell anemia
Claims made about glutathione have included that it will increase energy, improve concentration, slow aging, and protect the skin.
The importance of glutathione is generally recognized, although its specific functions and appropriate clinical use remain under study. Similarly, because ingested glutathione has little or no effect on intracellular glutathione levels, there are questions regarding the optimal method for raising the intracellular levels.
In addition to ongoing studies of the role of glutathione in cancer and cancer therapy, there are currently clinical trials of glutathione in Amyotrophic lateral sclerosis (ALS). The U. S. National Cancer Institute has included glutathione in a study to determine whether nutritional factors could inhibit development of some types of cancer.
European researchers, with support from the Cystic Fibrosis Foundation, are examining the potential uses of inhaled glutathione in cystic fibrosis. Some physicians also use inhaled glutathione in treating airway restriction and asthma. Other studies are investigating whether administration of alpha-lipoic acid, a material that can elevate intracellular glutathione, may be beneficial in restoring the immune system in AIDS patients.
 
Preparations
Although glutathione is marketed as a nutritional supplement, it does not appear that glutathione supplements actually increase the levels of glutathione inside cells. In human studies, oral doses of glutathione had little effect in raising blood levels. Further, glutathione is so widely distributed in common foods that supplements are not normally required. Supplements of vitamin C are more effective at increasing intracellular glutathione than taking oral glutathione supplements. Oral supplements of whey protein and of alpha-lipoic acid appear to help restore intracellular levels of glutathione.
Glutathione is available as capsules of 50, 100, and 250 milligrams. It is also included in many multivitamin and multi-nutrient formulations.
 
Precautions
At this time, the only established precautions are sensitivity to any of the inactive ingredients in the preparations of glutathione or the products used to stimulate glutathione levels. This is a discussion of glutathione, not C and whey. There is some new literature that suggests supplementing it may be helpful to some cancer patients, but detrimental to others.
 
Side effects
There are no established side effects to glutathione or to the substances used to elevate glutathione levels.
 
Training & certification
Glutathione has been classified as an orphan drug for treatment of AIDS. For this purpose, medical licensure is required. Glutathione has been given intravenously for amelioration of the side effects of cisplatin therapy. Specific training is required to order, prepare, start, and monitor intravenous therapy. No specific training is required to use glutathione or the compounds which have been reported to raise glutathione levels for other purposes.

BOOKS
Pressman, A. H. Glutathione: the Ultimate Antioxidant. New York: St. Martin's Press, 1997.
Rozzorno J. E., J. T. Murray, eds. Textbook of Natural Medicine, 2nd ed. Edinborough, Scotland: Churchill Livingston, 1999.
PERIODICALS
Carlo, M. D. Jr, and R. F. Loeser. "Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels." Arthritis Rheum (December 2003): 3419–30.
Hamilton D., and G. Batist. "Glutathione analogues in cancer treatment." Curr Oncol Rep (March 2004): 116–22.
Wessner, B., E. M. Strasser, A. Spittler, and E. Roth. "Effect of single and combined supply of glutamine, glycine, N-acetylcysteine, and R, S-alpha-lipoic acid on glutathione content of myelomonocytic cells." Clin Nutr (December 2003): 515–22.
Witschi A., S. Reddy, B. Stofer, and B. H. Lauterburg. "The systemic availability of oral glutathione." Eur J Clin Pharmacol
Wu, G., Y. Z. Fang, S. Yang, J. R. Lupton, and N. D. Turner. "Glutathione metabolism and its implications for health." J Nutr (March 2004): 489–92.
Zenger, F., S. Russmann, E. Junker, C. Wuthrich, M. H. Bui, and B. H. Lauterburg. "Decreased glutathione in patients with anorexia nervosa. Risk factor for toxic liver injury?" Eur J Clin Nutr. (February 2004): 238–43.
ORGANIZATIONS
ALS Therapy Development Foundation. 215 First Street, Cambridge Mass. 02142.
Cystic Fibrosis Foundation. 6931 Arlington Road, Bethesda MD 20814.
NCCAM Clearinghouse. P.O. Box 7923 Gaithersburg, MD 20898.
Samuel Uretsky, Pharm.D
 

Resorbable Heart Device Effective in Kids

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: July 20, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner 

A novel partially biodegradable device appears to close small to moderate congenital atrial septal defects (ASD) in children as well as the standard permanent device does, according to a small cohort study.

The biodegradable BioSTAR device implanted in 10 eligible patients successfully closed 90% of small to moderate size holes within 24 hours, compared with 100% of repairs among 10 matched controls with the most commonly-used nonbiodegradable implant, reported Lee Benson, MD, of the Hospital for Sick Children in Toronto, and colleagues.

At six months, closure rates were 100% for both devices, the researchers reported in the July issue of Catheterization and Cardiovascular Interventions.
Only one child had a residual hole with the new device, a shunt of less than 2 mm (0.078 in), in an area of prolapsed anterior arm, which the authors termed of "no hemodynamic significance."

This suggested that there had been sufficient overgrowth of the novel device, which leaves behind only the metal supporting arms after the collagen discs dissolve within six months, they said.
While Benson's group suggested the device be considered for repairing small-to-moderate ASDs, they noted that this size of hole is relatively uncommon and the learning curve is steep.
However, a biodegradable closure that leaves behind minimal metal may solve the problem of transseptal access in treating the heart rhythm disorders that show up often decades later in children with ASDs, they suggested.
Traditional devices with substantial amounts of metal have been linked to late complications including erosion, apparently from chronic friction with the cardiac chamber walls, Benson's group said.
The study included a consecutive series of 10 children treated with the BioSTAR biodegradable device by a single operator (in Canada, where the device has regulatory approval) for atrial septal defect occlusions of 16 mm (0.62 in) in diameter or smaller.
The 10 controls were matched for defect size, imaging modality, and body weight from a cohort of 54 children treated for ASD closure using the nonbiodegradable Amplatzer Septal Occluder.
Device implantation was ultimately successful in all cases, although one biodegradable device had to be retrieved and replaced with a larger size version during the procedure due to instability.
No vascular complications were seen in either group, which has been a concern in adult patent foramen ovale closure. Nor were there any thrombotic or bleeding complications reported.
Hospital stay and recovery times were similar between groups as well.
However, the biodegradable device resulted in substantially longer procedural times at a median of 52 versus 39.5 minutes (P<0.05). It didn't prolong fluoroscopy time, though, compared with the standard device (median 6.7 versus 6.1 min, P=NS).

 

Primary source: Catheterization and Cardiovascular Interventions
Source reference:
Morgan G, et al "A biodegradable device (BioSTARTM) for atrial septal defect closure in children" Catheter Cardiovasc Interv 2010; DOI: 10.1002/ccd.22517.