Methods for manipulating upper gastrointestinal transit, blood flow, and satiety, and for treating visceral hyperalgesia

• US 7,081,239 B2
• Filed: 03/26/2004
• Issued: 07/25/2006
• Est. Priority Date: 05/17/1995
• Status: Expired due to Fees

• Current Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Original Assignee: Cedars-Sinai Medical Center Burns and Allen Research Center
• Inventors: Lin, Henry C.
• Primary Examiner(s): Swartz, Rodney P
• Application Number:
  US10/810,020
• Publication Number:
  US 20040180834A1
• Time in Patent Office: 851 Days
• Field of Search: 424/9.1, 424/9.2, 424/116, 424/278.1, 424/439, 426/2, 426/71, 426/658, 426/800, 426/801, 435/4, 435/29
• US Class Current: 424/9.2
• CPC Class Codes: A23L 33/40 Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61B 5/0836 Measuring rate of CO2 production
• CPC Class Codes: A61B 5/412 Detecting or monitoring sepsis
• CPC Class Codes: A61B 5/415 the glands, e.g. tonsils, adenoids or thymus
• CPC Class Codes: A61B 5/418 lymph vessels, ducts or nodes
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/201 having one or two double bonds, e.g. oleic, linoleic acids
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/424 condensed with heterocyclic ring systems, e.g. clavulanic acid
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/7048 : having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 36/534 : Mentha (mint)
• CPC Class Codes: A61K 38/1796 : for hormones for neuromediators A61K38/1787
• CPC Class Codes: A61K 38/22 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/225 : Calcitonin gene related peptide
• CPC Class Codes: A61K 38/2271 : Neuropeptide Y
• CPC Class Codes: A61K 38/54 : Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0004 : Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61K 51/1206 : Administration of radioactive gases, aerosols or breath tests
• CPC Class Codes: A61K 9/0053 : Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0087 : Galenical forms not covered by A61K9/02 - A61K9/7023
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: G01N 2033/4977 : metabolic gass from microbes, cell cultures, plant tissues and the like
• CPC Class Codes: G01N 2333/70571 : for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 2800/06 : Gastro-intestinal diseases
• CPC Class Codes: G01N 33/497 : of gaseous biological material, e.g. breath
• CPC Class Codes: G01N 33/4977 : Metabolic gas from microbes, cell cultures or plant tissues
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere
• CPC Class Codes: Y10S 426/80 : Geriatric
• CPC Class Codes: Y10S 426/801 : Pediatric
• CPC Class Codes: Y10T 436/145555 : Hetero-N
• CPC Class Codes: Y10T 436/147777 : Plural nitrogen in the same ring [e.g., barbituates, creatinine, etc.]
• CPC Class Codes: Y10T 436/18 : Sulfur containing
• CPC Class Codes: Y10T 436/214 : Acyclic [e.g., methane, octane, isoparaffin, etc.]
• CPC Class Codes: Y10T 436/22 : Hydrogen, per se

Abstract

Disclosed is a method of manipulating the rate of upper gastrointestinal transit of a substance in a mammal. Also disclosed are methods of manipulating satiety and post-prandial visceral blood flow. A method of treating visceral pain or visceral hypersensitivity in a human subject is also described. A method for prolonging the residence time of an orally or enterally administered substance by promoting its dissolution, bioavailability and/or absorption in the small intestine is also described. These methods are related to a method of transmitting to and replicating at a second location in the central nervous system a serotonergic neural signal originating at a first location in the proximal or distal gut of a mammal and/or a method of transmitting to and replicating at a second location in the upper gastrointestinal tract a serotonergic neural signal originating at a first location in the proximal or distal gut.

Claims

1. A method of manipulating the rate of upper gastrointestinal transit of a substance in a mammal having an intrinsic cholinergic afferent neural pathway projecting from a peptide YY-sensitive primary sensory neuron in the intestinal wall to a prevertebral celiac ganglion and having an adrenergic efferent neural pathway projecting from said ganglion to one or more enterochromaffin cells in the intestinal mucosa and/or to a serotonergic interneuron linked in a myenteric plexus and/or submucous plexus to an opioid interneuron, said opioid intemeuron also being linked by an intestino-fugal opioid pathway projecting to said ganglion, with one or more neural connections to the central nervous system and back to the gut projecting from the ganglion, said method comprising:

providing a pharmaceutically acceptable composition, comprising an active agent selected from the group consisting of

(A) peptide YY, and

(B) antagonists of receptors for (A); and

administering the pharmaceutically acceptable composition to the mammal,

said active agent being delivered in an amount and under conditions such that the cholinergic intestino-fugal pathway, at least one prevertebral ganglionic pathway, the adrenergic efferent neural pathway, the serotonergic intemeuron and/or the opioid interneuron are activated by the action of (A), whereby the rate of upper gastrointestinal transit is slowed, or such that activation of the cholinergic intestino-fugal pathway, at least one prevertebral ganglionic pathway, the adrenergic efferent neural pathway, the serotonergic intemeuron and/or the opioid intemeuron is blocked by the action of (B), whereby the rate of upper gastrointestinal transit is accelerated.

2. The method of claim 1, wherein administering the pharmaceutically acceptable composition to the mammal further comprises administering the pharmaceutically acceptable composition by a delivery route selected from the group consisting of oral, intravenous, intraperitoneal, and nasal.

3. A method of manipulating satiety in a mammalian subject having a cholinergic afferent neural pathway projecting from a peptide YY-sensitive primary sensory neuron in the intestinal wall to a prevertebral celiac ganglion and having an adrenergic efferent neural pathway projecting from said ganglion to one or more enterochromaffin cells in the intestinal mucosa and/or to a serotonergic intemeuron linked in amyenteric plexus to an opioid intemeuron, said opioid interneuron also being linked by an intestino-fugal opioid pathway projecting to said ganglion, with one or more neural connections to the central nervous system and back to the gut projecting from the ganglion, said method comprising:

providing a pharmaceutically acceptable composition, comprising an active agent selected from the group consisting of

(A) peptide YY, and

(B) antagonists of receptors for (A); and

administering the pharmaceutically acceptable composition to the mammal,

said active agent being delivered in an amount and under conditions such that the cholinergic intestino-fugal pathway, one or more prevertebral ganglionic pathways, adrenergic efferent neural pathway, the serotonergic interneuron and/or the opioid intemeuron are activated by the action of (A), whereby a state of satiety is induced, or such that activation of the cholinergic intestino-fugal pathway, prevertebral ganglionic pathways, ganglion to central nervous system pathways, central nervous system pathways, adrenergic efferent neural pathway, the serotonergic intemeuron and/or the opioid interneuron is blocked by the action of (B), whereby satiety is suppressed.

4. The method of claim 3, wherein a neuronal pathway projecting from said ganglion to the hypothalamus of the subject is activated by the action of any of(A) on the primary sensory neuron.

5. The method of claim 3, wherein administering the pharmaceutically acceptable composition to the mammal further comprises administering the pharmaceutically acceptable composition by a delivery route selected from the group consisting of oral, intravenous, intraperitoneal, and nasal.

6. A method of inducing satiety in a mammal having an intrinsic cholinergic afferent neural pathway projecting from a peptide YY-sensitive primary sensory neuron in the intestinal wall to a prevertebral celiac ganglion and having a adrenergic efferent neural pathway projecting from said ganglion to one or more enterochromaffin cells in the intestinal mucosa and/or to a serotonergic intemeuron linked in a myenteric plexus and/or submucous plexus to an opioid intemeuron, said opioid intemeuron also being linked by anintestino-fugal opioid pathway projecting to said ganglion, with one or more neural connections to the central nervous system and back to the gut projecting from the ganglion, said method comprising:

providing a pharmaceutically acceptable composition, comprising peptide YY; and

administering the pharmaceutically acceptable composition to the mammal,

said peptide YY being delivered in an amount and under conditions such that the cholinergic intestino-fugal pathway, prevertebral ganglionic pathways, ganglion to central nervous system pathways, adrenergic efferent neural pathway, the serotonergic intemeuron and/or the opioid interneuron are activated by the action of said peptide YY, whereby a state of satiety is induced in the mammal.

7. The method of claim 6, wherein a neuronal pathway from said ganglion to the hypothalamus of the mammal is activated by the action of said peptide YY on the primary sensory neuron.

8. The method of claim 6, wherein administering the pharmaceutically acceptable composition to the mammal further comprises administering the pharmaceutically acceptable composition by a delivery route selected from the group consisting of oral, intravenous, intraperitoneal, and nasal.

9. A method of treating visceral pain or visceral hypersensitivity in a human subject having a cholinergic afferent neural pathway projecting from a peptide YY-sensitive primary sensory neuron in the intestinal wall to a prevertebral celiac ganglion and having a adrenergic efferent neural pathway projecting from said ganglion to one or more enterochromaffin cells in the intestinal mucosa and/or to a serotonergic interneuron linked in a myenteric plexus to an opioid intemeuron, said opioid intemeuron also being linked by an intestino-fugal opioid pathway projecting to said ganglion, with one or more neural connections to the central nervous system and back to the gut projecting from the ganglion, said method comprising:

providing a pharmaceutically acceptable composition, comprising peptide YY; and

administering the pharmaceutically acceptable composition to the mammal,

said peptide YY being delivered in an amount and under conditions such that activation of a cholinergic intestino-fugal pathway, one or more prevertebral ganglionic pathways, a gangalion to central nervous system pathway, the adrenergic efferent neural pathway, the serotonergic intemeuron and/or the opioid intemeuron is substantially reduced by the action of said peptide YY, whereby the sensation of esophageal, gastric, biliary, intestinal, colonic or rectal pain experienced by the human subject is reduced.

10. The method of claim 9, wherein administering the pharmaceutically acceptable composition to the mammal further comprises administering the pharmaceutically acceptable composition by a delivery route selected from the group consisting of oral, intravenous, intraperitoneal, and nasal.

11. A method of manipulating post-prandial visceral blood flow to the gastrointestinal tract of a mammal having a cholinergic afferent neural pathway projecting from a peptide YY-sensitive primary sensory neuron in the intestinal wall to a prevertebral celiac ganglion and having an adrenergic efferent neural pathway projecting from said ganglion to one or more enterochromaffin cells in the intestinal mucosa and/or to a serotonergic intemeuron linked in a myenteric plexus to an opioid intemeuron, said opioid intemeuron also being linked by an intestino-fugal opioid pathway projecting to said ganglion, with additional neural connections to the central nervous system and back to the gut projecting from the ganglion, comprising:

providing a pharmaceutically acceptable composition, comprising an active agent selected from the group consisting of

(A) peptide YY, and

(B) antagonists of receptors for (A); and

administering the pharmaceutically acceptable composition to the mammal,

said active agent being delivered in an amount and under conditions such that the cholinergic intestino-fugal pathway, prevertebral ganglionic pathways, gangalion to central nervous system pathways, central nervous system pathways, adrenergic efferent neural pathway, the serotonergic interneuron and/or the opioid intemeuron are activated by the action of (A), whereby the flow of blood to the gastrointestinal tract is increased, or such that activation of the cholinergic intestino-fugal pathway, prevertebral ganglionic pathways, gangalion to central nervous system pathways, the adrenergic efferent neural pathway, the serotonergic intemeuron and/or the opioid intemeuron is blocked by the action of (B), whereby the flow of blood to the gastrointestinal tract is decreased.

12. The method of claim 11, wherein administering the pharmaceutically acceptable composition to the mammal further comprises administering the pharmaceutically acceptable composition by a delivery route selected from the group consisting of oral, intravenous, intraperitoneal, and nasal.