Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-10-26
2002-12-10
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S004100
Reexamination Certificate
active
06492339
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides methods to treat a subject with insulin resistance comprising administration of D-chiro-inositol and sulfonylurea, either as concurrent single agents or as a combined composition. The present invention also provides compositions comprising therapeutically effective amounts of D-chiro-inositol and sulfonylureas. The present invention also provides methods to treat a subject with insulin resistance comprising administration of D-chiro-inositol and sulfonylurea, either as concurrent single agents or as a combined composition. In particular, the methods of the present invention are useful in maintaining pancreatic beta cell function/viability and thus, delay diabetes progression. The methods and compositions of the present invention are particularly efficacious in treating insulin resistant subjects with a fasting blood glucose level of less than or equal to 180 mg/dL.
2. Related Art
Non-insulin dependent diabetes (NIDDM, or type 2 diabetes) is a worldwide health problem. According to the World Health Organization, an estimated 30 million people worldwide had diabetes in 1985. This number increased to 135 million people by 1995 and the WHO predicts a rise to 300 million people by 2025. The insidious nature of type 2 diabetes progression and medical complications that arise from hyperglycemia extract a heavy toll on the individual, healthcare resources, and society. As such, there is a continuing need for new therapeutic agents and therapeutic regimens that prevent diabetes, prevent or delay the progression of diabetes, or prevent or delay diabetic complications.
It is generally desirable to treat a subject with diabetes or at risk of developing diabetes in ways that reestablish or maintain the balance between insulin secretion and insulin sensitivity. It is highly desirable to employ methods that avoid administration of exogenous insulin. Therefore a regimen of diet and exercise is primarily used to attempt to establish more physiologic glycemic control. Sadly, however, pharmacological intervention becomes necessary. The current “second line” of therapies includes administration of pharmacological agents including sulfonylureas (e.g. GLUCOTROL®), biguanides (e.g. metformin), and PPAR gamma agonists (e.g. rosiglitazone) alone or in combination, which are used to increase endogenous insulin production, decrease hepatic glucose output, and increase periperial insulin sensitivity (Kobayashi,
Diabetes Obes. Metab.,
1(Suppl 1): S32-S40 (1999); Brown et al.,
J. Natl. Med. Assoc.,
91(7): 389-395 (1999)). Sulfonylureas are compounds that stimulate insulin secretion from beta cells in islet tissue of the pancreas and are currently the most frequently prescribed oral hypoglycemic drugs. Increased insulin secretion by sulfonylureas may lead to hypoglycemia (Imura,
N. Engl. J. Med.,
338: 908-909 (1998)). Unfortunately, prolonged use of sulfonylureas results in unfavorable side effects, particularly desensitization and/or apoptosis of the beta cells resulting in decreased insulin production. The effect is particularly manifest in subjects who have more severe insulin resistance in conjunction with less insulin (Kobayashi,
Diabetes Obes. Metab.,
1(Suppl 1): S32-S40 (1999); Kolterman et al.,
Diabetes Care,
7(Suppl 1): 81-89 (1984)). Biguanides are compounds that decrease hepatic glucose output, and thus aid in controlling hyperglycemia. PPAR gamma agonists are insulin-sensitizing compounds that increase the cell's ability to respond to smaller quantities of insulin. Eventually these therapies fail and exogenous insulin is required to maintain a balance of glucose metabolism.
Currently there is intensive investigation into beneficial combinations of therapies that maximize the benefit to the diabetic subject, while minimizing the side effects of the individual therapeutic agents. Generically, one could envision combinations of insulin sensitizer/sulfonylurea; insulin sensitizer/insulin; insulin sensitizer/biguanides; sulfonylurea/biguanide; biguanide/insulin and the like. The term “insulin sensitizer” is a generic phrase that describes any agent that enhances the cell's ability to respond to insulin. This phrase could encompass any agent that would potentate the insulin signal transduction cascade or any agent that would reduce a negative regulatory component of the insulin signal transduction cascade.
Potentially there are synergistic and/or beneficial combinations of insulin sensitizing drugs with other anti-diabetic agents, particularly anti-diabetic agents that increase the amount of insulin in a mammal. In one example, the thiazolidinedione class of drugs are agonists for the peroxisome proliferator activated receptor gamma (PPAR-&ggr;) and are “insulin sensitizers” because upregulation of PPAR-&ggr; activity positively upregulates the insulin signal transduction pathway, presumably because MAP kinase phosphorylates PPAR-&ggr; and influences its activity (Zhang et al.,
J. Biol. Chem.,
271(50): 31771-31774 (1996)). Other synergistic effects of the combination of TZD drugs with insulin have also been described, for example the demonstration TZD drugs enhanced the normal insulin response of glucokinase (GK) mRNA expression in animals (Hofmann et al,
Metabolism,
44(3): 384-389 (1995)).
Unfortunately, without undue experimentation, one cannot reasonably expect success with any particular drug combination simply because the drug is generically identified as an insulin sensitizer or an anti-diabetic drug. Such descriptions of combinatorial drug therapies comprising an insulin sensitizer drug and insulin or other anti-diabetic agent fail to enable one of ordinary skill in the art how to practice any particular drug combination. In fact, this generic description could lead to deleterious results for a patient in need of treatment. Insulin sensitizers represent different classes of drugs and drugs that are active against distinct biological targets and therefore must be viewed distinctly in terms of their use alone or in combination with other insulin sensitizer drugs or other anti-diabetic drugs. By analogy both a “roller coaster” and “bumper cars” could be described as “amusement park rides”, but they are clearly different and intended for different audiences.
One example of an insulin sensitizer used in combination with another anti-diabetic drug is described in U.S. Pat. No. 6,153,632 at col. 7, lines 4-17. A combination of DAIB-II, also known as V-411, with insulin resulted in the subject experiencing a hypoglycemic state that needed further intervention (i.e. sugar uptake) to prevent deleterious effects to the subject. Other examples of insulin sensitizer/anti-diabetic drugs are also known. Members of the TZD class of drugs, particularly pioglitazone, have also been used in combination with sulfonylurea or insulin. Unfortunately, this combination results in mild to moderate hypoglycemia at a rate of 1-2%. These examples raise safety concerns for the broad use of drug combinations in the diabetic population (Valsamakis et al.,
Exp. Opin. Pharmacother.,
1(7): 1413-1421 (2000)).
There is therefore, a need for new means to control progression of diabetes and prevent or delay the need for administration of exogenous insulin. This need and others are provided in the present invention that describes methods of treating subjects suffering from insulin resistance comprising administration of a therapeutically effective amount of D-chiro-inositol (DCI) and a therapeutically effective amount of a sulfonylurea.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a subject in need thereof comprising: (a) administration of a pharmaceutically effective amount of a D-chiro-inositol-like compound; and (b) administration of a pharmaceutically effective amount of a sulfonylurea, wherein the effective amounts of the D-chiro-inositol and the sulfonylurea are administered concurrently.
The combination of D-chiro-inositol and sulfonylurea surprisingly results in amelioration and/or el
Allan Geoffrey
Sleevi Mark
Insmed Incorporated
Lewis Patrick
Sterne Kessler Goldstein & Fox PLLC
Wilson James O.
LandOfFree
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