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Details for Patent: 6,558,708

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Details for Patent: 6,558,708

Title: Methods for manipulating upper gastrointestinal transit, blood flow, and satiety, and for treating visceral hyperalgesia
Abstract:Disclosed are 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.
Inventor(s): Lin; Henry C. (Manhattan Beach, CA)
Assignee: Cedars-Sinai Medical Center (Los Angeles, CA)
Filing Date:Apr 10, 2000
Application Number:09/546,119
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 enterochromaffln 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 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 the step of: administering a pharmaceutically acceptable composition comprising an active agent by an oral or enteral delivery route to the mammal, said active agent being selected from the group consisting of (A) serotonin, serotonin agonists, or serotonin re-uptake inhibitors; (B) peptide YY or peptide YY functional analogs; (C) calcitonin gene-related peptide or functional analogs thereof; (D) adrenergic agonists; (E) opioid agonists; (F) combinations of any of (A), (B), (C), (D), and/or (E); and (G) antagonists of receptors for any of (A), (B), (C), (D), and/or (E), 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 interneuron and/or the opioid interneuron are activated by the action of any of (A) through (F), 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 interneuron and/or the opioid interneuron is blocked by the action of (G), whereby the rate of upper gastrointestinal transit is accelerated.

2. The method of claim 1, wherein oral administration is by ingestion of coated or uncoated microspheres or particles, of a dispersible powder or granule formulation, of a suspension, emulsion, solution, syrup, elixir, or of a coated or uncoated tablet, troche, capsule, caplet, or lozenge.

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 interneuron linked in a myenteric 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 administering an active agent by an oral or enteral delivery route to a mammal, said active agent being selected from the group consisting of (A) active lipids; (B) serotonin, serotonin agonists, or serotonin re-uptake inhibitors; (C) peptide YY or peptide YY functional analogs; (D) clalcitonin gene-related peptide or functional analogs thereof; (E) adrenergic agonists; (F) opioid agonists; (G) combinations of any of (A), (B), (C), (D), (E) and/or (F); and (H) antagonists of receptors for any of (B), (C), (D), (E) and/or (F), 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 intemeuron and/or the opioid intemeuron are activated by the action of any of (A) through (G), 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 interneuron and/or the opioid interneuron is blocked by the action of (H), 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) through (G) on the primary sensory neuron.

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

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 interneuron linked in a myenteric plexus and/or submucous plexus to an opioid interneuron, 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: administering an active agent by an oral or enteral delivery route to a mammal, said active agent being selected from the group consisting of (A) active lipids (B) serotonin, serotonin agonists, or serotonin re-uptake inhibitors; (C) peptide YY or peptide YY functional analogs; (D) calcitonin gene-related peptide or functional analogs thereof; (E) adrenergic agonists; (F) opioid agonists; and (G) combinations of any of (A), (B), (C), (D), (E)and/or (F), said active agent 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 interneuron and/or the opioid interneuron are activated by the action of any of (A) through (G), 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 subject is activated by the action of any of (A) through (G) on the primary sensory neuron.

8. The method of claim 6, wherein the active agent is a member of (A) and a neuronal pathway from said ganglion to the hypothalamus of the subject is activated by the action of the active agent on the primary sensory neuron.

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 intemeuron linked in a myenteric plexus to an opioid interneuron, 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: administering a pharmaceutically acceptable composition comprising an active agent by an oral or enteral delivery route to the human subject, said active agent being selected from the group consisting of antagonists of (A) serotonin receptors; (B) peptide YY receptors; (D) calcitonin gene-related peptide or functional analogs thereof; (C) adrenoceptors; and (D) opioid receptors, said active agent 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 interneuron and/or the opioid interneuron is substantially reduced by the action of said active agent, whereby the sensation of esophageal, gastric, biliary, intestinal, colonic or rectal pain experienced by the human subject is reduced.

10. 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 interneuron linked in a myenteric plexus to an opioid intemeuron, said opioid interneuron 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: administering an active agent by an oral or enteral delivery route to a mammal, said active agent being selected from the group consisting of (A) active lipids; (B) serotonin, serotonin agonists, or serotonin re-uptake inhibitors; (C) peptide YY or peptide YY functional analogs; (D) calcitonin gene-related peptide or functional analogs thereof; (E) adrenergic agonists; (F) opioid agonists; (G) combinations of any of (A), (B), (C), (D), (E) and/or (F); and (H) antagonists of any of (B), (C), (D), (E) and/or (F), 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 any of (A) through (E), 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 interneuron is blocked by the action of (H), whereby the flow of blood to the gastrointestinal tract is decreased.

11. 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, comprising administering to a subject in need of the treatment at least one dose of an anti-atherogenic, anti-diarrheal, digestion, dissolution, absorption promoting and/or upper gastrointestinal transit slowing composition comprising a carrier and a dispersion consisting essentially of (A) serotonin, a serotonin agonist, or a serotonin re-uptake inhibitor; (B) peptide YY or a peptide YY functional analog; (C) calcitonin gene-related peptide or a functional analog thereof; (D) an adrenergic agonist; or (E) an opioid agonist, in the carrier, in a dose and in a form effective to prolong the residence time of an orally or enterally administered substance in the small intestine for a period of time effective to increase dissolution, bioavailability, and/or absorption of the substance therethrough.

12. 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 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 and/or submucous plexus to an opioid interneuron, 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: administering by an oral or enteral delivery route to the mammal a pharmaceutically acceptable composition comprising an active agent, said active agent being selected from the group consisting of (A) active lipids; (B) serotonin, serotonin agonists, or serotonin re-uptake inhibitors; (C) peptide YY, or peptide YY functional analogs; and (D) calcitonin gene-related peptide or functional analogs thereof, said composition being formulated to deliver said active agent to said first location in the proximal or distal gut, said active agent being delivered simultaneously with an adrenoceptor antagonist, said adrenoceptor antagonist also being delivered orally or enterally to said mammal, whereby a neural signal is transmitted via the prevertebral ganglion to the central nervous system and is replicated at said second location in the central nervous system as a serotonergic neural signal.

13. 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 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 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 and/or submucous plexus to an opioid interneuron, 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: administering by an oral or enteral delivery route to the mammal a pharmaceutically acceptable composition containing an active agent, said active agent being selected from the group consisting of (A) active lipids; (B) serotonin, serotonin agonists, or serotonin re-uptake inhibitors; (C) peptide YY, or peptide YY functional analogs; and (D) calcitonin gene-related peptide or functional analogs thereof, said composition being formulated to deliver said active agent to said first location in the proximal or distal gut, whereby a serotonergic neural signal is transmitted via the prevertebral ganglion and is replicated at said second location as a serotonergic neural signal.
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