Method and composition for the treatment of lipid and glucose metabolism disorders

Abstract

Disclosed are methods for modifying or regulating at least one of glucose or lipid metabolism disorders which comprises administering to a human or vertebrate subject a D1 dopamine agonist in conjunction with a dopamine D2 agonist where the conjoined administration is effective to improve at least one of the following lipid and glucose metabolic indices: body weight, body fat, plasma insulin, plasma glucose and plasma lipid, and plasma lipoprotein. In preferred embodiments, the administration of the D1 dopamine agonist and the D2 dopamine agonist is conducted at a predetermined time.

Description

[0001] This application claims priority under 35 U.S.C. .sctn.119 from provisional applications Ser. Nos. 60 / 017,377 and 60 / 019,336, the disclosures of which are incorporated herein in their entirety.[0002] This invention relates to novel, improved methods for modifying or regulating in a subject (vertebrate animal or human) of at least one of lipid and glucose metabolism.Obesity and Lipid Metabolism Disorders--Body Fat Loss[0003] In humans obesity can be defined as a body weight exceeding 20% of the desirable body weight for individuals of the same sex, height and frame (Salans, L. B., in Endocrinology & Metabolism, 2d Ed., McGraw-Hill, New York 1987, pp. 1203-1244; see also, R. H. Williams, Textbook of Endocrinology, 1974, pp. 904-916). In other animals (or also in humans) obesity can be determined by body weight patterns correlated with prolactin profiles given that members of a species that are young, lean and "healthy" (i.e., free of any disorders, not just metabolic disorders)...

AI Technical Summary

Benefits of technology

[0024] Another object of this invention is to provide methods for reducing at least one of insulin resistance (impaired glucose tolerance), hyperinsulinemia and hyperglycemia, and glycosylated hemoglobin (including A1C), and abating Type II diabetes.

[0033] The conjoined administration of a dopamine D.sub.1 agonist with one (or more) of the other agents identified above results in substantially augmented, and in fact often synergistic, effects in improvement of one or more metabolic indices related to glucose or lipid metabolism, and thus an improved modification or regulation of at least one of glucose and lipid metabolism.

[0075] The administration of the D.sub.1 agonist is also preferably timed, i.e. the D.sub.1 agonist is also administered at a predetermined time. Because the D.sub.1 agonist amplifies the effect of the conjoined agent, it is advantageous to administer the D.sub.1 agonist at or about the time of administration of the conjoined agent(s), such that the activity period of the D.sub.1 agonist in the bloodstream of the treated subject overlaps (in fact preferably overlaps as much as possible) with the activity period of the conjoined agent. For convenience of administration and in order to promote subject compliance, the D.sub.1 agonist can be administered at the same time as the conjoined agent(s).

[0078] At least one of body fat deposits, body weight, plasma or blood glucose, circulating insulin, plasma triglycerides (TG), plasma free fatty acids (FFA) and food consumption of the subject will be reduced as the result of the treatment. Disorders of lipid and glucose metabolism are thereby treated and subjects suffering from such pathologies as hyperphagia, obesity, insulin resistance (impaired glucose tolerance), hyperlipidemia, hyperinsulinemia, and hyperglycemia will exhibit improvement in corresponding metabolic indices.

[0079] While appropriately timed administration of certain D.sub.2 agonists (i.e., bromocriptine) alone will produce the effects described above to some degree, these effects are amplified (potentiated) by the conjoined administration of the D.sub.1 agonist agents described in the present invention. In other words, the synergistic effect of the conjoined administration of the D.sub.1 agonist and the conjoined agent (i.e., a D.sub.2 agonist, and / or .alpha..sub.1 antagonist, and / or serotonergic inhibitor and / or .alpha..sub.2 agonist) produces results that are superior to those experienced through administration of the same amount of a D.sub.2 agonist alone. It should be noted that the present invention permits but does not require each agent to be administered in an amount over the threshold amount (in the absence of a conjoined agent) to improve one or more metabolic indices precisely because of the augmented effect on these indices achieved by conjoined administration according to the present invention.

Problems solved by technology

Whereas controlled diet and exercise can produce modest results in the reduction of body fat deposits, prior to the cumulative work of the present inventors (including the prior co-pending patent applications and issued U.S. patents referred to below), no truly effective or practical treatment had been found for controlling obesity or other lipid metabolism disorders.

Moreover, use of the HMG-CoA enzyme inhibitor is sometimes accompanied by side effects such as liver toxicity, renal myoglobinuria, renal shutdown, and lenticular opacity.

The effectiveness of clofibrate also varies from subject to subject and its use is often accompanied by such side effects as nephrotic syndromes, myalgia, nausea and abdominal pain.

One third of all visits to physicians are occasioned by this disease and its complications, and diabetes and its complications are a leading cause of untimely death in the United States and in the Western world.

Diabetes adversely affects the way the body uses sugars and starches which, during digestion, are converted into glucose.

In noninsulin-dependent (NIDDM or Type II) diabetes the pancreas retains the ability to produce insulin and in fact may produce higher than normal amounts of insulin, but the amount of insulin is relatively insufficient, or less than fully effective, due to cellular resistance to insulin.

In either form of diabetes there are widespread abnormalities.

The cumulative effect of these diabetes-associated abnormalities is severe blood vessel and nerve damage.

Although these studies confirm the importance of a D.sub.2:D.sub.1 interaction in the activation of dopaminergic activities, the increased locomotor activity and decreased feeding response to D.sub.2:D.sub.1 agonists is acute and short lived, lasting for only a few hours.

The previous work by third parties with D.sub.1 and D.sub.2 dopamine agonists in combination has not demonstrated any effects on lipid and glucose metabolism, and has not produced long-term responses of dopaminergic activities.

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