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WO2002013759A2 - Method of treating the syndrome of type 2 diabetes in humans - Google Patents

Method of treating the syndrome of type 2 diabetes in humans Download PDF

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Publication number
WO2002013759A2
WO2002013759A2 PCT/US2001/022466 US0122466W WO0213759A2 WO 2002013759 A2 WO2002013759 A2 WO 2002013759A2 US 0122466 W US0122466 W US 0122466W WO 0213759 A2 WO0213759 A2 WO 0213759A2
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type
syndrome
diabetes
drug composition
impaired
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PCT/US2001/022466
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French (fr)
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WO2002013759A3 (en
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Anton H. Clemens
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Cpd Llc
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Priority to EP01953517A priority Critical patent/EP1365756A2/en
Priority to AU2001275959A priority patent/AU2001275959A1/en
Publication of WO2002013759A2 publication Critical patent/WO2002013759A2/en
Publication of WO2002013759A3 publication Critical patent/WO2002013759A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Type 2 Diabetes is a major cause of death in the industrialized world.
  • a wide variety of chemical and physical abnormalities are associated with Type 2 Diabetes, which are a consequence of, and associate with, imbalances in fuel metabolism and impaired hepatic fuel processing
  • the typical American and Western European diet, i.e. fuel intake, consists of 40-45% carbohydrates, 40% fat and 15-20% protein.
  • Type 2 Diabetes includes elevations in fasting blood glucose, gluconeogenesis and glucose production, in spite of significant increases in fasting insulin and C-peptide concentrations.
  • Hepatic gluconeogenesis is the formation of glucose, particularly by the liver, from non- carbohydrate sources like pyruvate, lactate, odd-chain fatty acids and amino acids, and glucose production (GP) is the formation of glucose from carbohydrate sources, e.g. glycogen.
  • GP glucose production
  • IR insulin resistance
  • dislipidemia typically associated with lipogenesis is dislipidemia, which is characterized by increases in levels of fasting free fatty acid (FFA), fasting triglycerides (TG) and total cholesterol concentrations, increases in levels of fasting LDL-cholesterol, decreases in levels of fasting HDL-cholesterol, an increased LDL HDL ratio, in addition, lipogenesis leads to increases in body weight and increases in systolic and diastolic blood pressure.
  • FFA fasting free fatty acid
  • TG fasting triglycerides
  • total cholesterol concentrations increases in levels of fasting LDL-cholesterol
  • fasting HDL-cholesterol decreases in levels of fasting HDL-cholesterol
  • LDL HDL ratio an increased LDL HDL ratio
  • Type 2 Diabetes represents a syndrome of various, in part sequential, disease states. Its pathophysiology slowly progresses through a long period of successive abnormalities: 1) Insulin Resistance (IR), which in association with excessive hepatic gluconeogenesis (GNG) and Glucose Production (GP), leads to 2) Impaired Fasting Glucose (LFG), which in turn leads to 3) Impaired Glucose Tolerance (IGT) and eventually to the clinical form of 4) Non Insulin Dependent Diabetes Mellitus (NTDDM).
  • IR Insulin Resistance
  • GNG hepatic gluconeogenesis
  • GP Glucose Production
  • ITT Impaired Glucose Tolerance
  • NTDDM Non Insulin Dependent Diabetes Mellitus
  • Type 2 Diabetes syndrome Compared to Type 1 Diabetes (juvenile diabetes), the Type 2 Diabetes syndrome, particularly its NTDDM form, is characterized by relatively inadequate endogenous insulin concentrations. However, insulin concentrations in Type 2 diabetics may, in fact, be higher than in the normal population.
  • Non-diabetics experience a biphasic insulin response, i.e. an acute phase and a proportional phase.
  • the acute phase also referred to as first phase insulin release
  • the proportional phase is characterized by a more sustained insulin release governed by the level of blood glucose and follows the acute phase.
  • Type 2 diabetics experience an absence of the acute phase insulin release. Type 2 diabetics suffer from impaired first phase ⁇ -cell insulin secretion.
  • Type 2 diabetics as well as IGT, overweight and obese subjects are characterized by an impaired ⁇ -cell function (islet dysfunction) with relatively intact second, proportional phase insulin release capacity, but defective acute, first phase insulin release (Pfeifer, M.A., Craigr, J.B., Porte D., Jr.; Am J Med, 70:579-88). They are also characterized by impaired hepatic carbohydrate oxidation and storage (Felber, J.-P., Meyer, H.U., Curchod, B., Maeder, E., Pahud, P., and Jequier, E.; Metabolism, 30,2; 184- 189; and Diabetologia, 20: 39-44).
  • Metformin hydrochloride a non-sulfonylurea type antihyperglycemic agent, improves glucose tolerance in Type 2 diabetic subjects, primarily by decreasing hepatic gluconeogenesis and glucose production (Edelman, S.N.: Clinical Diabetes, 1998: 16,1: 37-40).
  • metformin does not restore first phase insulin secretion.
  • Major side effects of using metformin include potential lactic acidosis and negative impact on liver and kidney function resulting from the requisite massive therapeutic doses. Therefore, metformin is contraindicated for patients with hepatic or renal insufficiency, which is aggravated by the fact that a typical daily dose ranges between 1,500 and 2,500 mg.
  • a new method for treating the G ⁇ G and GP symptoms of Type 2 Diabetes it is desirable to provide a new method for treating the G ⁇ G and GP symptoms of Type 2 Diabetes.
  • a method is desired wherein Type 2 Diabetes in a human can be treated by restoring first phase insulin release.
  • a new method for decreasing the elevated fasting glucose levels in patients suffering from Type 2 Diabetes is also desired. n other words, a new treatment is desirable that lowers the high glucose levels resulting from rises in GNG and GP, and impaired insulin secretion in patients afflicted with Type 2 Diabetes.
  • the present invention addresses these needs by providing methods for treating a human suffering from the Syndrome of Type 2 Diabetes.
  • the present invention provides a method of treating a human suffering from the Syndrome of Type 2 Diabetes comprising administering, by a pharmaceutically effective mode, a drug composition comprising opiates having ⁇ agonist activity.
  • the invention provides a method of treating a human suffering from the syndrome of Type 2 Diabetes comprising, administering, by a pharmaceutically effective mode, a drug composition comprising opiates having ⁇ agonist activity and opiates having K antagonist activity.
  • the present invention also provides a method for treating the Syndrome of Type 2 Diabetes which includes various progressive disease states from TR, GNG, GP, TFG and IGT to the clinical form of Type 2 Diabetes, as well as lipogenesis excess and dislipidemia.
  • the invention also provides a method for treating elevated fasting glucose levels in individuals, which results from increased gluconeogenesis, increased glucose production, and/or impaired insulin secretion, both associated with Type 2 Diabetes.
  • the invention also provides a method to restore the physiologic acute, first phase ⁇ -cell insulin secretion.
  • Administering, by a pharmaceutically effective mode, drug compositions comprising opiates having ⁇ agonist activity treats elevated fasting glucose levels and helps to restore first phase insulin release in humans suffering from Type 2 Diabetes.
  • the invention also provides an improved first pass insulinization of the liver, resulting in a restoration of enzyme functions involved in hepatic carbohydrate oxidation and storage.
  • Figure 1 is a graph showing the daily blood glucose profile of a 71-year subject afflicted with Type 2 Diabetes after four different treatments. The four different treatments are described in the detailed description.
  • the blood glucose (BG) of the subject was measured in mg/dL over several time intervals measured in hours (h).
  • opioid As used herein, the terms “opioids,” “opioid agonists,” “opiate agonists,” “opiates having agonist activity” and “agonists” are meant to refer to substances, natural or synthetic, that bind to centrally and/or peripherally located opioid receptors to produce an agonist action.
  • opiates having ⁇ agonist activity As used herein, the terms “opiates having ⁇ agonist activity,” “opioids having ⁇ agonist activity” and “ ⁇ agonists” are meant to refer to substances, natural or synthetic, that bind to the ⁇ receptor to produce an agonist action.
  • opioid antagonists opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.
  • opioid antagonists opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.
  • opioid antagonists opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.
  • opioid antagonists opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.
  • opioid antagonists opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.
  • opioid antagonists opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.
  • “Pharmaceutically effective modes” are meant to include, but not be limited to the application of a drug composition as a solution in an innocuous pharmaceutically acceptable solvent, as an emulsion, as a suspension, as a dispersion in suitable carriers, as a patch or in the form of pills or capsules with solid carriers, and other such methods well- known in the art.
  • the formulations of this invention may include pharmaceutically acceptable excipients such as stabilizers, anti-oxidants, binders, coloring agents, emulsifiers, and other such excipients well-known in the art.
  • the drugs and drug compositions comprising the agonists and antagonists described above and below, may be administered in any pharmaceutically effective mode.
  • non-addictive morphine based analgesics typically requiring a combination of agonistic and antagonistic actions at various opiate receptor sites, i.e. ⁇ , ⁇ and receptors
  • antagonists have evolved as by-products, and some of these narcotic antagonists, or anti-opioids, have been shown to have potential in the treatment of a variety of disease conditions.
  • U.S. Patent 4,619,936 discloses pharmaceutical compositions containing (5 ⁇ ,6 )7,8-didehydro-4,5-epoxy-17-(2-propanyl)-morphinano-3,6-diol for the purpose of appetite reduction.
  • U.S. Patent 5,727,570 discloses a method of treatment of humans suffering hyperlipidimia from by administering a drug composition selected from a group consisting of opiate antagonists and drugs which substantially equally reduce the amount of catecholamines bound to catecholamine binding sites.
  • U.S. Patent 5,878,750 discloses a method of treating humans suffering from the Coronary Heart Disease Syndrome by administering a drug composition selected from the group of opiate antagonists or anti-opioids and drugs which substantially equally reduce the amounts of catecholamines bound to all catecholamine binding sites.
  • Drugs which are useful in the methods of the present invention include centrally or peripherally acting opioid compositions, e.g. opiates having ⁇ agonist activity.
  • effective drug compositions include ⁇ agonists in combination with selective K antagonists.
  • Drug compositions including pure non-selective antagonists with pronounced K antagonist characteristics can also be utilized in these methods.
  • Drug compositions comprising mixed ⁇ - agonist/ K - antagonists can also be employed in the methods. Examples of different agonists and antagonists are listed below, and are not meant to limit the scope of drug compositions which can be administered to treat Type 2 Diabetes.
  • ⁇ and K agonists such as ⁇ agonists producing euphoria and K agonists producing the opposite, namely disphoria.
  • ⁇ antagonists can antagonize euphoria and enhance the effect of the K agonist, while the K antagonist can produce or enhance euphoria.
  • Examples of this phenomenon also include the opposing effects of ⁇ and K opiates in motivational processes (Herz A.: NTDA Res Monogr 90:17-26), or in opioid reward mechanisms (Herz A.: Can J Physiol Pharmacol 76,3:252-8), and other ⁇ -opposing actions of the -opioid receptor (Pan Z.Z.: Trends Pharmacol Sci; 19,3: 94-8).
  • Opioids having selective or predominant K-antagonist activity include, but are not limited to, nor-binaltorphine, (Portoghese, P. S., Lipkowski, A.W., Takemori, A.E.; Life Sciences 40: 1287-92); guanidylated naltrindole (GNTI), (Jones R.M., Hjorth, A.S., Schwartz, T.W., and Portoghese, P.S.; Journal of Medicinal Chemistry 41,25: 4911-4), (-)- (lR,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomo han (MR 2266) (Merz, H., Langbein, A., Stockhaus, K., Walther, G., & Wick, H.; Advances in biochemical psychopharmacology, Nol 8: 91-107), a triethylenedioxy derivative of B- nal
  • Opioids having selective or predominant ⁇ agonist activity include, but are not limited to, dihydromorphine, morphine, hydromorphone, methadone, fentanyl, sufentanyl, buprenorphine, demorphine, codeine, ethylmorphine, etonitazene, hydrocodone, levorphanol, norcodeine, normorphine and oxycodone.
  • Most opioids pass the Blood Brain Barrier (BBB) and are, therefore both, centrally and peripherally active, i.e. they can act upon C ⁇ S sites as well as peripheral sites, such as the gut and hormone producing glands, including the endocrine pancreas and the adrenal medulla.
  • BBB Blood Brain Barrier
  • peripherally acting opioid agonists are typically not addictive and generally not 'scheduled' as narcotics.
  • Buprenorphine is a mixed agonist-antagonist with high affinity at the ⁇ opiate receptor with partial agonist activity, and at the K receptor with antagonist activity. Because of its K receptor antagonist activity and low partial ⁇ activity it will produce minimal and perhaps clinically insignificant physical dependence, and has been used as an effective analgesic for the treatment of moderate to severe pain and of opioid dependence. (Lewis J.W.: Drug and Alcohol Dependence; 14:363-372). Elevations in cortisol and glucose, caused by surgical stress, have been observed to decline following the administration of buprenorphine to treat analgesia during and following total hip replacement (McQuay HJ. et. al. : Br J Anaesth; 52:1013-19).
  • Loperamide is a synthetic opioid used for the treatment of diarrhea, which is more effective and safer than other opioid drugs in the treatment of diarrhea of various causes (Ruppin H: Acta Physiol Scand; 127,3:275-9)
  • Loperamide is a 'non-scheduled' opioid with ⁇ agonist activity as opposed to most other opioid agonists which are listed as 'controlled substances'.
  • Loperamide is reported to raise blood glucose concentrations at dose levels required for the acute treatment of diarrhea (Caldara R. et. al. : Eur J Clin Pharmacol; 21,3:185-8), and has been used in the "Loperamide test": a simple and highly specific screening test for hypercortisolism in children and adolescents" (Buzi F. et. al. : Acta Paediatr; 86, 11 : 1177-80).
  • Diabetes and dislipidemia was monitored on four different occasions. For each occasion, the glucose profile of the subject was monitored for one day after a different treatment had been administered. Sufficient time intervals were allowed between treatments to eliminate any carry-over effect from earlier treatment methods.
  • BG blood glucose
  • Figure 1 and the supporting data demonstrate that post prandial peaks in glucose concentration are reduced with the administration of 850 mg of metformin, i.e. by selectively reducing GNG and GP (- ⁇ -).
  • metformin i.e. by selectively reducing GNG and GP (- ⁇ -).
  • a ⁇ -agonist such as loperamide
  • ⁇ agonist results in very significant increases in first phase insulin secretion, as can be derived from the pronounced decreases of blood glucose concentrations throughout the intake of meals, and from the reduced duration and excursion of the post-prandial glucose peaks, compared to placebo or metformin treatment.
  • Type 2 Diabetes, IGT, Overweight and Obesity are associated with impaired first phase insulin release.
  • all these afflictions except late stage Type 2 Diabetes, retain second, proportional phase insulin secretory capacity.
  • the restoration of hepatic carbohydrate oxidation and storage which in Type 1 Diabetics requires appropriately controlled exogenous insulin infusions, can be accomplished in subjects afflicted with Type 2 Diabetes syndrome and dislipidemia by the administration of drug compositions comprising a ⁇ -agonist.
  • the administration of a peripherally acting ⁇ -agonist is preferred over the administration of a centrally acting ⁇ -agonists, because the latter are classified as scheduled drugs.
  • any of the ⁇ -agonists can be enhanced, or supplemented by selective K-antagonists, non-selective antagonists having K antagonist activity, or by mixed ⁇ -agonist/ ⁇ -antagonists. It is also a subject of this invention to use a mixed ⁇ -agonist/ ⁇ -antagonists as a single molecular entity.
  • Drug compositions useable in the present invention may be single substances or may also be a combination of opioids.
  • the effective dose of loperamide is less than 0.5 mg per day, or smaller by more than an order of magnitude than the typical dose required for the treatment of diarrhea.
  • the effective dose for other ⁇ -agonists, or single- or multi-molecular mixed ⁇ -agonist/ ⁇ - antagonist compositions may vary depending upon factors such as receptor binding, the absorption rate, bio-availability, excretion rate and the rate of metabolism of the drug.
  • the preferred method of administration is in a time release format, administered before dinner, or before the onset of the early rise in GNG and GP.

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Abstract

A method of treating a human suffering from the Syndrome of Type 2 Diabetes. The method includes administering, by a pharmaceutically effective mode, a drug composition including opiates having mu agonist activity.

Description

I
METHOD OF TREATING THE SYNDROME OF TYPE 2 DIABETES IN HUMANS
BACKGROUND OF THE INVENTION Type 2 Diabetes is a major cause of death in the industrialized world. A wide variety of chemical and physical abnormalities are associated with Type 2 Diabetes, which are a consequence of, and associate with, imbalances in fuel metabolism and impaired hepatic fuel processing The typical American and Western European diet, i.e. fuel intake, consists of 40-45% carbohydrates, 40% fat and 15-20% protein. Type 2 Diabetes includes elevations in fasting blood glucose, gluconeogenesis and glucose production, in spite of significant increases in fasting insulin and C-peptide concentrations. Hepatic gluconeogenesis is the formation of glucose, particularly by the liver, from non- carbohydrate sources like pyruvate, lactate, odd-chain fatty acids and amino acids, and glucose production (GP) is the formation of glucose from carbohydrate sources, e.g. glycogen. The underlying insulin resistance (IR) associated with Type 2 Diabetes also contributes to increases in lipogenesis. Typically associated with lipogenesis is dislipidemia, which is characterized by increases in levels of fasting free fatty acid (FFA), fasting triglycerides (TG) and total cholesterol concentrations, increases in levels of fasting LDL-cholesterol, decreases in levels of fasting HDL-cholesterol, an increased LDL HDL ratio, in addition, lipogenesis leads to increases in body weight and increases in systolic and diastolic blood pressure.
Type 2 Diabetes represents a syndrome of various, in part sequential, disease states. Its pathophysiology slowly progresses through a long period of successive abnormalities: 1) Insulin Resistance (IR), which in association with excessive hepatic gluconeogenesis (GNG) and Glucose Production (GP), leads to 2) Impaired Fasting Glucose (LFG), which in turn leads to 3) Impaired Glucose Tolerance (IGT) and eventually to the clinical form of 4) Non Insulin Dependent Diabetes Mellitus (NTDDM). IR is characterized as a state in which a normal amount of insulin produces a subnormal biological response in carbohydrate metabolism. IR tends to remain active throughout the entire pathophysiology of this syndrome. In order to normalize blood glucose levels, affected subjects require (and endogenously produce) above-normal levels of insulin to compensate for their insulin resistance.
Compared to Type 1 Diabetes (juvenile diabetes), the Type 2 Diabetes syndrome, particularly its NTDDM form, is characterized by relatively inadequate endogenous insulin concentrations. However, insulin concentrations in Type 2 diabetics may, in fact, be higher than in the normal population.
Non-diabetics experience a biphasic insulin response, i.e. an acute phase and a proportional phase. The acute phase, also referred to as first phase insulin release, is prompted by a rise in blood glucose; the proportional phase is characterized by a more sustained insulin release governed by the level of blood glucose and follows the acute phase. Contrastly, Type 2 diabetics experience an absence of the acute phase insulin release. Type 2 diabetics suffer from impaired first phase β-cell insulin secretion.
Persons afflicted with Type 2 Diabetes also experience a rise in GNG and GP during the early morning before waking. Compounded with the somewhat impaired insulin secretion, the rise in GNG and GP results in elevated fasting glucose levels. Many different treatments have been sought to try to address the impaired insulin secretion and increased glucose levels.
Restoration of the first phase insulin release in clinical research by the Artificial Beta Cell (Clemens, A.H.; US Patent 4,055,175) in Type 1 diabetics has been used to return a Type 1 diabetic patient's hepatic capacity to oxidize and store carbohydrates to normal. (Foss, M.C., Nlachokoska, N., Cunningham, L.Ν. and Aoki, T.T.; Diabetes, 31:46-52). Type 2 diabetics as well as IGT, overweight and obese subjects are characterized by an impaired β-cell function (islet dysfunction) with relatively intact second, proportional phase insulin release capacity, but defective acute, first phase insulin release (Pfeifer, M.A., Halter, J.B., Porte D., Jr.; Am J Med, 70:579-88). They are also characterized by impaired hepatic carbohydrate oxidation and storage (Felber, J.-P., Meyer, H.U., Curchod, B., Maeder, E., Pahud, P., and Jequier, E.; Metabolism, 30,2; 184- 189; and Diabetologia, 20: 39-44). Metformin hydrochloride, a non-sulfonylurea type antihyperglycemic agent, improves glucose tolerance in Type 2 diabetic subjects, primarily by decreasing hepatic gluconeogenesis and glucose production (Edelman, S.N.: Clinical Diabetes, 1998: 16,1: 37-40). However, metformin does not restore first phase insulin secretion. Major side effects of using metformin include potential lactic acidosis and negative impact on liver and kidney function resulting from the requisite massive therapeutic doses. Therefore, metformin is contraindicated for patients with hepatic or renal insufficiency, which is aggravated by the fact that a typical daily dose ranges between 1,500 and 2,500 mg.
As a result, it is desirable to provide a new method for treating the GΝG and GP symptoms of Type 2 Diabetes. In addition, a method is desired wherein Type 2 Diabetes in a human can be treated by restoring first phase insulin release. A new method for decreasing the elevated fasting glucose levels in patients suffering from Type 2 Diabetes is also desired. n other words, a new treatment is desirable that lowers the high glucose levels resulting from rises in GNG and GP, and impaired insulin secretion in patients afflicted with Type 2 Diabetes.
SUMMARY OF THE INVENTION
The present invention addresses these needs by providing methods for treating a human suffering from the Syndrome of Type 2 Diabetes. The present invention provides a method of treating a human suffering from the Syndrome of Type 2 Diabetes comprising administering, by a pharmaceutically effective mode, a drug composition comprising opiates having μ agonist activity. In another aspect, the invention provides a method of treating a human suffering from the syndrome of Type 2 Diabetes comprising, administering, by a pharmaceutically effective mode, a drug composition comprising opiates having μ agonist activity and opiates having K antagonist activity.
The present invention also provides a method for treating the Syndrome of Type 2 Diabetes which includes various progressive disease states from TR, GNG, GP, TFG and IGT to the clinical form of Type 2 Diabetes, as well as lipogenesis excess and dislipidemia. The invention also provides a method for treating elevated fasting glucose levels in individuals, which results from increased gluconeogenesis, increased glucose production, and/or impaired insulin secretion, both associated with Type 2 Diabetes. The invention also provides a method to restore the physiologic acute, first phase β-cell insulin secretion. Administering, by a pharmaceutically effective mode, drug compositions comprising opiates having μ agonist activity, treats elevated fasting glucose levels and helps to restore first phase insulin release in humans suffering from Type 2 Diabetes.
The invention also provides an improved first pass insulinization of the liver, resulting in a restoration of enzyme functions involved in hepatic carbohydrate oxidation and storage. Other features and advantages of the invention will become apparent to those skilled in the art upon review of the following detailed description and claims.
Before embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of the composition and concentration of components set forth in the following description. The invention is capable of other embodiments and of being practiced or being carried out in various ways. Also, it is understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The patents, references and articles cited herein are fully incorporated by reference.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is a graph showing the daily blood glucose profile of a 71-year subject afflicted with Type 2 Diabetes after four different treatments. The four different treatments are described in the detailed description. The blood glucose (BG) of the subject was measured in mg/dL over several time intervals measured in hours (h).
DETAILED DESCRIPTION
As used herein, the terms "opioids," "opioid agonists," "opiate agonists," "opiates having agonist activity" and "agonists" are meant to refer to substances, natural or synthetic, that bind to centrally and/or peripherally located opioid receptors to produce an agonist action.
As used herein, the terms "opiates having μ agonist activity," "opioids having μ agonist activity" and "μ agonists" are meant to refer to substances, natural or synthetic, that bind to the μ receptor to produce an agonist action.
As used herein, the terms "opioid antagonists," "opiate antagonists," "anti- opioids," "opiates having antagonist activity" and "antagonists" are meant to refer to opioid-like substances that bind to opioid receptors, but produce little or no agonist activity. As used herein, the terms "opiates having K antagonist activity," "opioids having K antagonist activity" and "K antagonists" are meant to refer to opioid-like substances that bind to the K receptor, but produce little or no agonist activity.
"Pharmaceutically effective modes" are meant to include, but not be limited to the application of a drug composition as a solution in an innocuous pharmaceutically acceptable solvent, as an emulsion, as a suspension, as a dispersion in suitable carriers, as a patch or in the form of pills or capsules with solid carriers, and other such methods well- known in the art. The formulations of this invention may include pharmaceutically acceptable excipients such as stabilizers, anti-oxidants, binders, coloring agents, emulsifiers, and other such excipients well-known in the art. The drugs and drug compositions comprising the agonists and antagonists described above and below, may be administered in any pharmaceutically effective mode.
During the investigations into, and development of, non-addictive morphine based analgesics, typically requiring a combination of agonistic and antagonistic actions at various opiate receptor sites, i.e.μ, δ and receptors, a variety of so-called antagonists have evolved as by-products, and some of these narcotic antagonists, or anti-opioids, have been shown to have potential in the treatment of a variety of disease conditions.
U.S. Patent 4,619,936 discloses pharmaceutical compositions containing (5α,6 )7,8-didehydro-4,5-epoxy-17-(2-propanyl)-morphinano-3,6-diol for the purpose of appetite reduction.
U.S. Patent 5,727,570 discloses a method of treatment of humans suffering hyperlipidimia from by administering a drug composition selected from a group consisting of opiate antagonists and drugs which substantially equally reduce the amount of catecholamines bound to catecholamine binding sites.
U.S. Patent 5,878,750 discloses a method of treating humans suffering from the Coronary Heart Disease Syndrome by administering a drug composition selected from the group of opiate antagonists or anti-opioids and drugs which substantially equally reduce the amounts of catecholamines bound to all catecholamine binding sites. Drugs which are useful in the methods of the present invention, i.e. methods for treating human suffering from the Syndrome of Type 2 Diabetes, include centrally or peripherally acting opioid compositions, e.g. opiates having μ agonist activity. In addition, effective drug compositions include μ agonists in combination with selective K antagonists. Drug compositions including pure non-selective antagonists with pronounced K antagonist characteristics can also be utilized in these methods. Drug compositions comprising mixed μ - agonist/ K - antagonists can also be employed in the methods. Examples of different agonists and antagonists are listed below, and are not meant to limit the scope of drug compositions which can be administered to treat Type 2 Diabetes.
Bi-directional effects of opioids are known to exist, in particular between μ and K agonists, such as μ agonists producing euphoria and K agonists producing the opposite, namely disphoria. Conversely, μ antagonists can antagonize euphoria and enhance the effect of the K agonist, while the K antagonist can produce or enhance euphoria. Examples of this phenomenon also include the opposing effects of μ and K opiates in motivational processes (Herz A.: NTDA Res Monogr 90:17-26), or in opioid reward mechanisms (Herz A.: Can J Physiol Pharmacol 76,3:252-8), and other μ -opposing actions of the -opioid receptor (Pan Z.Z.: Trends Pharmacol Sci; 19,3: 94-8).
Opioids having selective or predominant K-antagonist activity include, but are not limited to, nor-binaltorphine, (Portoghese, P. S., Lipkowski, A.W., Takemori, A.E.; Life Sciences 40: 1287-92); guanidylated naltrindole (GNTI), (Jones R.M., Hjorth, A.S., Schwartz, T.W., and Portoghese, P.S.; Journal of Medicinal Chemistry 41,25: 4911-4), (-)- (lR,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomo han (MR 2266) (Merz, H., Langbein, A., Stockhaus, K., Walther, G., & Wick, H.; Advances in biochemical psychopharmacology, Nol 8: 91-107), a triethylenedioxy derivative of B- naltrexamine (TEΝA), (Portoghese, P.S., Takemori, A.E.; Life Sciences 36: 801-5) and buprenorphine.
Opioids having selective or predominant μ agonist activity include, but are not limited to, dihydromorphine, morphine, hydromorphone, methadone, fentanyl, sufentanyl, buprenorphine, demorphine, codeine, ethylmorphine, etonitazene, hydrocodone, levorphanol, norcodeine, normorphine and oxycodone. Most opioids pass the Blood Brain Barrier (BBB) and are, therefore both, centrally and peripherally active, i.e. they can act upon CΝS sites as well as peripheral sites, such as the gut and hormone producing glands, including the endocrine pancreas and the adrenal medulla. Some opioids, e.g. loperamide, do not pass the BBB and are, therefore, only peripherally active with little or no CΝS effect. Since drug addiction generally requires a central effect, peripherally acting opioid agonists are typically not addictive and generally not 'scheduled' as narcotics.
Buprenorphine is a mixed agonist-antagonist with high affinity at the μ opiate receptor with partial agonist activity, and at the K receptor with antagonist activity. Because of its K receptor antagonist activity and low partial μ activity it will produce minimal and perhaps clinically insignificant physical dependence, and has been used as an effective analgesic for the treatment of moderate to severe pain and of opioid dependence. (Lewis J.W.: Drug and Alcohol Dependence; 14:363-372). Elevations in cortisol and glucose, caused by surgical stress, have been observed to decline following the administration of buprenorphine to treat analgesia during and following total hip replacement (McQuay HJ. et. al. : Br J Anaesth; 52:1013-19).
Loperamide is a synthetic opioid used for the treatment of diarrhea, which is more effective and safer than other opioid drugs in the treatment of diarrhea of various causes (Ruppin H: Acta Physiol Scand; 127,3:275-9) Loperamide is a 'non-scheduled' opioid with μ agonist activity as opposed to most other opioid agonists which are listed as 'controlled substances'. Loperamide is reported to raise blood glucose concentrations at dose levels required for the acute treatment of diarrhea (Caldara R. et. al. : Eur J Clin Pharmacol; 21,3:185-8), and has been used in the "Loperamide test": a simple and highly specific screening test for hypercortisolism in children and adolescents" (Buzi F. et. al. : Acta Paediatr; 86, 11 : 1177-80).
Example: The examples are being described for purely illustrative purposes, and are in no way meant to limit the scope of the invention.
The daily blood glucose profile of a 71 year old subject with early stage Type 2
Diabetes and dislipidemia was monitored on four different occasions. For each occasion, the glucose profile of the subject was monitored for one day after a different treatment had been administered. Sufficient time intervals were allowed between treatments to eliminate any carry-over effect from earlier treatment methods.
The four different treatments are described below. The blood glucose (BG) of the man was measured in mg/dL at the time intervals listed below. This data compiled below has been graphed in Figure 1.
Treatment 1
O - no drug treatment.
Breakfast: 08:40 - 09:00; lunch: 12:25 - 12:50; dinner: 18:40 - 19:00 time [h] 08:10 10:00 12:20 14:00 18:30 20:00
BG [mg/dL] 132 156 104 150 98 117
Treatment 2
■ - 850 mg metformin administered orally at 08:10.
Breakfast: 08:40 - 09:00; lunch: 12:20 - 12:40; dinner: 19:10 - 19:30 time [h] 08:10 09:45 12:30 14:00 19:00 20:55
BG [mg/dL] 122 146 106 129 90 112 Treatment 3
▲ - 850 mg metformin administered orally at 08:20, plus 0.5 mg loperamide, a μ-agonist, administered orally at dinner the preceding day.
Breakfast: 08:40 - 09:00; lunch: 11:55 - 12:15; dinner: 18:25 - 18:45 time [h] 08:20 09:50 10:30 12:05 13:00 18:15 20:20 BG [mg/dL] 118 131 126 107 125 85 115
5
Treatment 4
T - 0.1 mg loperamide, a μ-agonist, administered orally at 20:00 the preceding day.
Breakfast: 08:20 - 08:40; lunch: 13:00 - 13:20; dinner: 20:00 - 20:20 time [h] 07:55 08:40 09:20 09:50 10:20 13:00 13:25 14:05 15:15 17:50 18:30 19:35 20:20
BG 107 105 115 99 105 100 97 111 102 93 87 113 88
[mg/dL]
10
Figure 1 and the supporting data demonstrate that post prandial peaks in glucose concentration are reduced with the administration of 850 mg of metformin, i.e. by selectively reducing GNG and GP (-■ -). In addition, supplementing administration of metformin with the administration of a μ-agonist, such as loperamide, not only reduces the
15 post prandial glucose peaks, but also lowers the fasting glucose concentration as well (-A- ). The most significant reduction of a post prandial glucose peak occurs after breakfast. The data also demonstrate the ability of μ -agonists, in suitable dose ranges, to effectively reduce GNG and GP. Of particular significance is the data produced with the administration of the μ-agonist alone (-T-). It demonstrates a highly significant reduction
20 in fasting, pre- and post prandial blood glucose values by effectively reducing GNG and GP. The administration of the μ agonist also results in very significant increases in first phase insulin secretion, as can be derived from the pronounced decreases of blood glucose concentrations throughout the intake of meals, and from the reduced duration and excursion of the post-prandial glucose peaks, compared to placebo or metformin treatment.
25 Type 2 Diabetes, IGT, Overweight and Obesity are associated with impaired first phase insulin release. In contrast to Type 1 Diabetes, all these afflictions, except late stage Type 2 Diabetes, retain second, proportional phase insulin secretory capacity. The restoration of hepatic carbohydrate oxidation and storage, which in Type 1 Diabetics requires appropriately controlled exogenous insulin infusions, can be accomplished in subjects afflicted with Type 2 Diabetes syndrome and dislipidemia by the administration of drug compositions comprising a μ-agonist. The administration of a peripherally acting μ-agonist is preferred over the administration of a centrally acting μ-agonists, because the latter are classified as scheduled drugs.
The application of any of the μ-agonists, according to this invention, can be enhanced, or supplemented by selective K-antagonists, non-selective antagonists having K antagonist activity, or by mixed μ-agonist/κ-antagonists. It is also a subject of this invention to use a mixed μ-agonist/κ-antagonists as a single molecular entity.
Drug compositions useable in the present invention may be single substances or may also be a combination of opioids.
The effective dose of loperamide is less than 0.5 mg per day, or smaller by more than an order of magnitude than the typical dose required for the treatment of diarrhea. The effective dose for other μ-agonists, or single- or multi-molecular mixed μ-agonist/κ- antagonist compositions may vary depending upon factors such as receptor binding, the absorption rate, bio-availability, excretion rate and the rate of metabolism of the drug. The preferred method of administration is in a time release format, administered before dinner, or before the onset of the early rise in GNG and GP.

Claims

CLAIMS:I claim:
1. A method of treating a human suffering from the Syndrome of Type 2 Diabetes comprising administering, by a pharmaceutically effective mode, a drug composition comprising one or more opiates having μ agonist activity.
2. The method of claim 1, wherein the drug composition includes at least one of the following: i) dihydromorphine; ii) morphine; iii) hydromorphone; iv) methadone; v) fentanyl; vi) sufentanyl; vii) buprenorphine; viii) demorphine; ix) codeine; x) ethylmoφhine; xi) etonitazene; xii) hydrocodone; xiii) levorphanol; xiv) norcodeine; xv) normorphine; and xvi) oxycodone.
3. The method of claim 1, wherein the drug composition comprises a centrally acting μ agonist.
4. The method of claim 1, wherein the drug composition comprises a peripherally acting μ agonist.
5. The method of claim 4, wherein the drug composition is loperamide.
6. The method of claim 1, wherein the Syndrome of Type 2 Diabetes includes Impaired Fasting Glucose (TFG).
7. The method of claim 1, wherein the Syndrome of Type 2 Diabetes includes Impaired Glucose Tolerance (IGT).
8. The method of claim 1, wherein the Syndrome of Type 2 Diabetes includes impaired hepatic fuel processing.
9. The method of claim 8, wherein the impaired hepatic fuel processing includes control of carbohydrate oxidation and storage.
10. The method of claim 1, wherein in the Syndrome of Type 2 Diabetes includes excessive endogenous gluconeogenesis (GNG).
11. The method of claim 1 , wherein the Syndrome of Type 2 Diabetes includes excessive endogenous glucose production (GP).
12. The method of claim 1, wherein the Syndrome of Type 2 Diabetes includes lipogenesis excess and dislipidemia.
13. The method of claim 1, wherein the Syndrome of Type 2 Diabetes includes impaired first phase β-cell insulin secretion.
14. A method of treating a human suffering from the Syndrome of Type 2
Diabetes comprising administering, by a pharmaceutically effective mode, a drug composition comprising one or more opiates having μ agonist activity and one or more opiates having K antagonist activity.
15. The method of claim 14, wherein the drug composition comprises a single molecular entity.
16. The method of claim 15, wherein the drug composition is buprenorphine.
17. The method of claim 14, wherein the drug composition comprises a combination of molecular entities.
18. The method of claim 14, wherein the drug composition includes at least one of the following: i) dihydromorphine; ii) morphine; iii) hydromorphone; iv) methadone; v) fentanyl; vi) sufentanyl; vii) buprenorphine; viii) demorphine; ix) codeine; x) ethylmorphine; xi) etonitazene; xii) hydrocodone; xiiϊ) levorphanol; xiv) norcodeine; xv) normorphine; and xvi) oxycodone.
19. The method of claim 14, wherein the drug composition comprises a centrally acting μ agonist.
20. The method of claim 14, wherein the drug composition comprises a peripherally acting μ agonist.
21. The method of claim 20, wherein the drug composition is loperamide.
22. The method of claim 14, wherein the drug composition includes at least one of the following: i) nor-binaltorphine; ii) (-)-(lR,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomorphan (MR 2266); iii) a triethylenedioxy derivative of B-naltrexamine (TENA); and iv) guanidylated naltrindole (GNTI).
23. The method of claim 14, wherein the Syndrome of Type 2 Diabetes includes Impaired Fasting Glucose (TFG).
24. The method of claim 14, wherein the Syndrome of Type 2 Diabetes includes Impaired Glucose Tolerance (IGT).
25. The method of claim 14, wherein the Syndrome of Type 2 Diabetes includes impaired fuel processing.
26. The method of claim 25, wherein the impaired hepatic fuel processing includes control of carbohydrate oxidation and storage.
27. The method of claim 14, wherein in the Syndrome of Type 2 Diabetes includes excessive gluconeogenesis (GNG).
28. The method of claim 14, wherein the Syndrome of Type 2 Diabetes includes excessive endogenous glucose production (GP).
29. The method of claim 14, wherein the Syndrome of Type 2 Diabetes includes lipogenesis excess and dislipidemia.
30. The method of claim 14, wherein the Syndrome of Type 2 Diabetes includes impaired first phase β-cell insulin secretion.
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