Friday, September 02, 2005

FDA Issues Nationwide Alert for “Liqiang 4” Due to Potential Health Risk

The U.S. Food and Drug Administration (FDA) is warning consumers not to take Liqiang 4 Dietary Supplement Capsules because they contain glyburide ??“ a drug that could have serious, life-threatening consequences in some people.

Glyburide is a drug used to lower blood sugar, and is safe and effective when used as labeled in FDA-approved medications. People who have low blood sugar or those with diabetes can receive dangerously high amounts of glyburide by consuming Liqiang 4. Consumers should immediately stop using these products and seek medical attention, especially if they are currently being treated with diabetes drugs or if they have symptoms of fatigue, excessive hunger, profuse sweating, or numbness of the extremities. Consumers who have this product should dispose of it immediately.

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Sep 02, 05 • Diabetes News

GlaxoSmithKline Signs Consent Decree with FDA; Agrees to Correct Manufacturing Deficiencies

The U.S. Food and Drug Administration (FDA) today announced that GlaxoSmithKline, Inc. (GSK), (through its U.S. subsidiaries SB Pharmco Puerto Rico, Inc., GlaxoSmithKline Puerto Rico Inc., and SmithKline Beecham Corporation), has signed a consent decree with FDA to correct manufacturing deficiencies at its Cidra, Puerto Rico facility.

FDA is concerned that GSK’s violation of manufacturing standards may have resulted in the production of drug products that could potentially pose risks to consumers.

The Decree requires GSK to post a penal bond of $650,000,000 contingent upon GSK’s either successfully reconditioning drugs seized in March 2005 or destroying them and paying costs to the government.

“The consent decree shows that FDA is serious about enforcing the manufacturing standards essential for safe and effective prescription drugs,” said John Taylor, FDA Associate Commissioner for Regulatory Affairs. “It should also reassure the American people that we are doing everything we can to preserve the integrity of the American drug supply.”

FDA’s last inspection found Paxil CR tablets, approved to treat depression and panic disorder, could split apart. This deficiency could cause patients to receive a portion of the tablets that lacks any active ingredient, or alternatively a portion that contains an active ingredient and does not have the intended controlled-release effect. Additionally, FDA found that some Avandamet tablets, used to treat Type II diabetes, did not have an accurate dose of rosiglitazone, an active ingredient in this product.

The FDA urges patients who use these two drugs to continue taking their medication and to talk with their health care provider about possible alternative products until the manufacturing issues have been resolved.

Under the terms of this decree the company has agreed to take measures to ensure that its Cidra facility and the two drugs, Paxil CR and Avandamet, fully comply with current Good Manufacturing Practice ( cGMP) requirements and to ensure that ongoing shipments have the quality attributes they are required to possess. The decree also requires that all corrections and the firm’s compliance with cGMP requirements be certified by a third-party expert. Additionally, FDA will continue to monitor these activities through its inspections.

The Decree was presented yesterday for consideration by the United States District Court for the Eastern District of North Carolina. The Decree will take effect after it has been signed and entered by the Court. 

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Sep 02, 05 • Diabetes News

Thursday, September 01, 2005

The Story of Insulin

Insulin Synthesis

The insulin-making cells of the body are called beta cells, and they are found in the pancreas gland. These cells clump together to form the “islets of Langerhans”, named for the German medical student who described them.

The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane.

Once the preproinsulin reaches the endoplasmic reticulum, a protease cleaves off the signal peptide to create proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide.

Within the endoplasmic reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin. In the Golgi apparatus, insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the beta cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.
Insulin Structure

In 1958, Frederick Sanger was awarded his first Nobel Prize for determining the sequence of the amino acids that make up insulin. This marked the first time that a protein had had the order of its amino acids (the primary sequence) determined.

Insulin is composed of two chains of amino acids named chain A (21 amino acids) and chain B (30 amino acids) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together.

In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can be used to replace deficient human insulin levels in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria (recombinant insulin).

Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers. Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action. In the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor. In this way, a range of preparations of insulin is made, varying from short acting to long acting.
Insulin secretion

Rising levels of glucose inside the pancreatic beta cells trigger the release of insulin:

Sep 01, 05 • Diabetes mellitus

History of Diabetes

Physicians have observed the effects of diabetes for thousands of years. For much of this time, little was known about this fatal disease that caused wasting away of the body, extreme thirst, and frequent urination. It wasn’t until 1922 that the first patient was successfully treated with insulin.

One of the effects of diabetes is the presence of glucose in the urine (glucosuria). Ancient Hindu writings, many thousands of years old, document how black ants and flies were attracted to the urine of diabetics. The Indian physician Sushruta in 400 B.C. described the sweet taste of urine from affected individuals, and for many centuries to come, the sweet taste of urine was key to diagnosis.

Around 250 B.C., the name ???diabetes??? was first used. It is a Greek word that means ???to syphon???, reflecting how diabetes seemed to rapidly drain fluid from the affected individual. The Greek physician Aretaeus noted that as affected individuals wasted away, they passed increasing amounts of urine as if there was ???liquefaction of flesh and bones into urine???. The complete term ???diabetes mellitus??? was coined in 1674 by Thomas Willis, personal physician to King Charles II. Mellitus is Latin for honey, which is how Willis described the urine of diabetics (???as if imbued with honey and sugar???).

Up until the mid-1800s, the treatments offered for diabetes varied tremendously. Various ???fad??? diets were prescribed, and the use of opium was suggested, as were bleeding and other therapies. The most successful treatments were starvation diets in which calorie intake was severely restricted. Naturally, this was intolerable for the patient and at best extended life expectancy for a few years.

A breakthrough in the puzzle of diabetes came in 1889. German physicians Joseph von Mering and Oskar Minkowski surgically removed the pancreas from dogs. The dogs immediately developed diabetes. Now that a link was established between the pancreas gland and diabetes, research focused on isolating the pancreatic extract that could treat diabetes.

When Dr. Frederick Banting took up the challenge of isolating a pancreatic extract, he was met with much skepticism. Many great physiologists had tried and failed to isolate an internal secretion from the pancreas. But Banting, a surgeon, persisted and in May 1921, he began work in the laboratory of Professor John Macloed in Toronto, Canada. Charles Best, a medical student at the time, worked as his assistant.

To concentrate what we now know as insulin, Banting tied the pancreatic ducts of dogs. The pancreatic cells that released digestive enzymes (and could also destroy insulin) degenerated, but the cells that secreted insulin were spared. Over several weeks the pancreas degenerated into a residue from which insulin could be extracted. In July 1921, a dog that had had its pancreas surgically removed was injected with an extract collected from a duct-tied dog. In the two hours that followed the injection, the blood sugar level of the dog fell, and its condition improved. Another de-pancreatized (diabetic-like) dog was kept alive for eight days by regular injections until supplies of the extract, at that time called “isletin”, were exhausted.

Further experiments on dogs showed that extracts from the pancreas caused a drop in blood sugar, caused glucose in the urine to disappear, and produced a marked improvement in clinical condition. So long as the extract was being given, the dogs were kept alive. The supply of the extract was improved: the pancreas of different animals were used until that of the cow was settled upon. This extract kept a de-pancreatized dog alive for 70 days. Dr. J. Collip, a biochemist, was drafted to continue improving the purity of the pancreas extract, and later, Best carried on this work.

A young boy, Leonard Thompson, was the first patient to receive insulin treatment. On January 11, 1922, aged 14 and weighing only 64 pounds, he was extremely ill. The first injections of insulin only produced a slight lowering of blood sugar level. The extract still was not pure enough, and abscesses developed at the injection site. Collip continued to refine the extract. Several weeks later, Leonard was treated again and showed a remarkable recovery. His blood sugar levels fell, he gained weight and lived for another 13 years. He died from pneumonia at the age of 27.

During the spring of 1922, Best increased the production of insulin to enable the treatment of diabetic patients coming to the Toronto clinic. Over the next 60 years, insulin was further refined and purified, and long-acting and intermediate types were developed to provide more flexibility. A revolution came with the production of recombinant human DNA insulin in 1978. Instead of collecting insulin from animals, new human insulin could be synthesized.

In 1923, Banting and Macloed were awarded the Nobel Prize for the discovery of insulin. Banting split his prize with Best, and Macloed split his prize with Collip. In his Nobel Lecture, Banting concluded the following about their discovery:

???Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of life.???

Sep 01, 05 • Diabetes mellitus

Diabetes Classification

Diabetes is classified by underlying cause. The categories are: type 1 diabetes??”an autoimmune disease in which the body’s own immune system attacks the pancreas, rendering it unable to produce insulin; type 2 diabetes??”in which a resistance to the effects of insulin or a defect in insulin secretion may be seen; gestational diabetes; and ???other types???. Table 1 compares the presentation (phenotype) of type 1 and type 2 diabetes.

Type 2 diabetes commonly occurs in adults who are obese. There are many underlying factors that contribute to the high blood glucose levels in these individuals. An important factor is the body’s resistance to insulin in the body, essentially ignoring its insulin secretions. A second factor is the falling production of insulin by the beta cells of the pancreas. Therefore, an individual with type 2 diabetes may have a combination of deficient secretion and deficient action of insulin.

In contrast to type 2, type 1 diabetes most commonly occurs in children and is a result of the body’s immune system attacking and destroying the beta cells. The trigger for this autoimmune attack is not clear, but the result is the end of insulin production. 

Sep 01, 05 • Diabetes mellitus

Introduction to Diabetes

Diabetes mellitus is characterized by abnormally high levels of sugar (glucose) in the blood.

When the amount of glucose in the blood increases, e.g., after a meal, it triggers the release of the hormone insulin from the pancreas. Insulin stimulates muscle and fat cells to remove glucose from the blood and stimulates the liver to metabolize glucose, causing the blood sugar level to decrease to normal levels.

In people with diabetes, blood sugar levels remain high. This may be because insulin is not being produced at all, is not made at sufficient levels, or is not as effective as it should be. The most common forms of diabetes are type 1 diabetes (5%), which is an autoimmune disorder, and type 2 diabetes (95%), which is associated with obesity. Gestational diabetes is a form of diabetes that occurs in pregnancy, and other forms of diabetes are very rare and are caused by a single gene mutation.

For many years, scientists have been searching for clues in our genetic makeup that may explain why some people are more likely to get diabetes than others are. “The Genetic Landscape of Diabetes” introduces some of the genes that have been suggested to play a role in the development of diabetes

Sep 01, 05 • Diabetes mellitus
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