Classifications

• • 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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