recent advances in diabetic gastroparesis

1. “
”
CURRENT AND
EMERGING MEDICAL
THERAPIES FOR
GASTROPARESIS
Short Topic
Dr Shinde Viraj Ashok
Junior Resident – 3
Department of Pharmacology
Current and emerging medical therapies for gastroparesis
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Guided by
Dr Sonali Pimpalkhute
Associate Professor
Department of Pharmacology

2. OVERVIEW
Introduction
Correcting underlying conditions in diabetic gastroparesis
treatment
Current medical treatments
Upcoming promotilides for gastroparesis
Current and emerging medical therapies for gastroparesis
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3. INTRODUCTION
 Gastroparesis - Constellation of disorders of
varying aetiology & pathophysiology
 Gastroparesis –
 Defined by objective evidence of delayed gastric
emptying in absence of obstruction
 Symptoms commonly include early satiety, post-
prandial fullness, bloating, nausea, vomiting &
abdominal pain
Current and emerging medical therapies for gastroparesis
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4. INTRODUCTION CONT’D
 Mainstay of medical treatments includes
 Modifying lifestyle & diet
 Improving glucose control in diabetics
 Prokinetic, anti-emetic & analgesic drugs
 Non-medical modalities
 Acupuncture
 Hypnotherapy
 Gastric electric stimulation & surgical procedures -
Reserved for rare & severely refractory patients
Current and emerging medical therapies for gastroparesis
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5. CORRECTING UNDERLYING
CONDITIONS IN DIABETIC
GASTROPARESIS
Current and emerging medical therapies for gastroparesis
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6. TIGHTER GLUCOSE CONTROL IN
DIABETICS
 Chronically elevated blood glucose level in diabetes
results in damage to vagus nerve & blood vessels of
stomach
 In a Multicenter Safety, Feasibility & Potential
Efficacy of Continuous Glucose Monitoring & Insulin
Pump Therapy in Diabetic Gastroparesis (GLUMIT-
DG) study
 Preliminary results – Continuous glucose monitoring
(CGM) & combined with insulin pump
 Improves glycemic control
 Associated with improved symptoms & gastric
emptying
Current and emerging medical therapies for gastroparesis
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7. REVIEWING MEDICATIONS
 Various drugs
 Analgesic, Muscle relaxant, Antihistamines &
Neuropsychiatric medications like antidepressants -
may delay gastric emptying
 ↓ or withdrawn when possible
 Diabetes medications - mimic or modify incretins can
further slow gastric emptying
 Amylin & exenatide - inhibits gastric emptying &
should be avoided in gastroparesis
 Inhibitors of enzyme dipeptidyl peptidase 4 (DPP-4) -
do not delay gastric emptying nor reduce food intake
& should be considered as replacements
Current and emerging medical therapies for gastroparesis
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8. DIETARY CHANGES
 Small frequent meal, low-fat, low-residue & ↑ liquid
content meals are best tolerated in patients with
symptomatic gastroparesis
 Chewing food well, drinking non-carbonated liquids
with meals & avoiding lying down for 2 h after a
meal may assist with gastric emptying
Current and emerging medical therapies for gastroparesis
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9. DIETARY CHANGES CONT’D
 Ginger, peppermint & lavender, taken on their own,
appear helpful in ↓ discomfort & symptoms of
gastroparesis
 Ginger (1.2 g) - accelerate gastric emptying & enhance
antral contractions over placebo but does not alter
plasma levels of gut peptide GLP-1, motilin or ghrelin
 Peppermint tea
 For some symptoms of gastroparesis - abdominal pain,
bloating & gas
 Anti-spasmodic, anti-inflammatory, serotonergic & anti-
bacterial properties
Current and emerging medical therapies for gastroparesis
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10. CURRENT MEDICAL
TREATMENTS
 Medications used commonly for gastroparesis
include prokinetics, analgesics & anti-emetics.
Current and emerging medical therapies for gastroparesis
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11. PROKINETICS
Dompamine D2-R antagonists
 Metoclopramide & domperidone - equally effective in
↓ symptoms of diabetic gastroparesis
Metoclopramide
 D2 receptor antagonist & 5-hydroxytryptamine
receptor 4 (5-HT4) agonist
 Prokinetic action & anti-emetic properties
 Provides prolonged symptomatic relief in
gastroparesis
 US-FDA - approved for gastroparesis
Current and emerging medical therapies for gastroparesis
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12. PROKINETICS CONT’D
Metoclopramide cont’d
 Overall adverse central nervous system (CNS)
effects of metoclopramide, e.g., somnolence, dystonia
& reduction in mental acuity, can be severe
 Tardive dyskinesia can be irreversible & disfiguring -
FDA black box warning in 2009
 Treatment beyond 3 months should be avoided in
most cases.
Current and emerging medical therapies for gastroparesis
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13. PROKINETICS CONT’D
Domperidone
 Anti-emetic & prokinetic effects
 Unlike metoclopramide, CNS reactions are uncommon
because of less penetration of blood–brain barrier
 Rationally suitable for use in gastroparetic patients such as
with Parkinson’s disease
 Treatment - doses of 80–120 mg per day for up to 3 months
is tried before considering as treatment failure
 US - FDA issued warning about cardiac safety - regarding
QT prolongation
 Intravenous dosage form - withdrawn due to cardiotoxicity
Current and emerging medical therapies for gastroparesis
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14. PROKINETICS CONT’D
Itopride
 Antiemetic & prokinetic properties
 Has D2 antidopaminergic & anti-ChE (ACh potentiating)
activity, but very low affinity for 5-HT4 receptor
 Very similar to domperidone & seems to be devoid of any
cardiac toxicity or CNS side effects
Levosulpiride
 Dopamine D2 receptor antagonist
 Reported to improve gastric emptying & symptoms (nausea,
vomiting & early satiety) in diabetic gastroparesis during 6
months of treatment
Current and emerging medical therapies for gastroparesis
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15. SEROTONERGIC 5-HT4
AGONISTS
Cisapride
 Mixed 5-HT4 agonist/5-HT3 antagonist
 ↑ acetylcholine release from enteric nervous
system & directly ↑ smooth muscle contractions –
↓ gastric emptying time
 Withdrawn in 2000 - side effect of causing long
QT syndrome
Mosapride
 Improves gastric emptying & symptoms of
gastroparesis & improves glycemic control
Current and emerging medical therapies for gastroparesis
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16. SEROTONERGIC 5-HT4
AGONISTS CONT’D
Prucalopride
 Dose selectivity for 5-HT4 receptors over cardiac
human ether-a-go-go-related gene (hERG) channel
& other receptors & has low adverse effects
 Accelerates gastric emptying in animal models
 Currently being studied for use in gastroparesis &
dyspepsia
Current and emerging medical therapies for gastroparesis
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17. MOTILIN RECEPTOR AGONISTS
Erythromycin
 Effect on gastroparesis - two pathways activating
motilin receptors on cholinergic neurons & muscle
 Most effective intravenous prokinetic agent in
acute setting - initial management of hospitalized
patients with diabetic gastroparesis
 Rapid development of tolerance is seen - By 4
weeks of oral treatment
 Drawbacks - Potential to induce abdominal cramps,
nausea & vomiting & to slow small intestinal transit
Current and emerging medical therapies for gastroparesis
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18. MOTILIN RECEPTOR AGONISTS
CONT’D
Clarithromycin & azithromycin
 Promotilides & ↑ antral contractions
 Effect on motilin receptor requires metabolism by
acid & this should be kept in mind while prescribing
to patients with dyspepsia , there by potentially
making drug less effective as a promotilide
 Fewer drug interactions than erythromycin, less
incidence of QTc interval prolongation, a longer
half-life & fewer untoward GI effects
Current and emerging medical therapies for gastroparesis
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19. MUSCARINIC RECEPTOR
AGONIST/CHOLINESTERASE
INHIBITORS
 Pyridostigmine - ↓ symptoms due to gastroparesis
that may be secondary to an underlying
autoimmune disease
Current and emerging medical therapies for gastroparesis
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20. ANTIEMETICS
Prochlorperazine
 D2 antagonist - one of most commonly used medicines for
treatment of nausea in patients with gastroparesis
 Major side effects are sedation, extrapyramidal side effects
Granisetron transdermal form - effective for refractory nausea
& vomiting in gastroparesis
Aprepitant
 Substance P antagonist & works by blocking neurokinin 1 (NK1)
receptor
 Effective for refractory nausea in severe gastroparesis & is
currently under investigation
Current and emerging medical therapies for gastroparesis
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21. PAIN MANAGEMENT
 Anti-convulsant/anti-epileptic drugs have much
less adverse effect on GI motility & could be very
valuable options for treating pain associated with
gastroparesis
 Of alternative medical treatments, acupuncture &
acupressure (shiatsu) treatment may lead to
symptomatic improvement in patients with
gastroparesis
Current and emerging medical therapies for gastroparesis
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22. GASTRIC ACID SUPPRESSION
 Stomach acid suppression plays important role for
overall symptom management in gastroparesis
 Careful choice of acid-suppressing drugs can
optimize gastroparesis symptom management
 Nizatidine - Histamine H2 receptor antagonist -
demonstrated to hasten stomach emptying in
patients with Parkinson’s disease
Current and emerging medical therapies for gastroparesis
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23. GASTRIC ACID SUPPRESSION
CONT’D
 Misoprostol synthetic prostaglandin E1 analogue
 Particularly at higher doses - Profound effect on
intestinal post-prandial motility & results in
accelerated transit time, particularly expediting
orocecal transit
Current and emerging medical therapies for gastroparesis
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24. TARGETING ACCOMMODATION
 Impaired accommodation - may contribute to
symptoms of post-prandial fullness & early satiety
 Clonidine acts - alpha 2 sympathetic receptor agonist
& also blocks other sympathetic receptors
 Evidence for acutely improving symptoms in patients
with dyspeptic symptoms & diabetic gastroparesis -
might be due to changes in accommodation
 Recent study indicates that clonidine causes
hyperglycemia & also interacts with glibenclamide to ↓
hypoglycemic activity in rats
 Role in improving gastric emptying remains
controversial
Current and emerging medical therapies for gastroparesis
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25. TARGETING ACCOMMODATION
CONT’D
 Other medications implicated in gastric
accommodation include acotiamide (Z-338, YM
443) - muscarinic M1/M2 receptor antagonist &
possibly an M5-like receptor approved in Japan
that enhances acetylcholine release & appears to
enhance gastric accommodation
 Associated with improved dyspeptic symptoms
Current and emerging medical therapies for gastroparesis
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26. TARGETING ACCOMMODATION
CONT’D
Buspirone -5HT1A agonist
 Positive effect on gastroparesis symptomatic relief,
even without evidence showing of gastric emptying in
healthy volunteers
 In addition to ↓ in transient lower esophageal
sphincter relaxation, which is major mechanism
underlying gastroesophageal reflux disorder, this
symptomatic relief might be due to fundic relaxation
& ↑ gastric accommodation
Sumatriptan - 5-HT1D/1B agonist,
 Relaxes fundus & effective in functional dyspepsia
Both buspirone & sumatriptan have potential
disadvantage of slowing gastric emptying
Current and emerging medical therapies for gastroparesis
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27. TARGETING PYLORIC
FUNCTION
 Conceptually, gastric retention could be due to
impaired relaxation of pyloric sphincter, which might
be caused by a lack of normal inhibitory innervation
through nitric-oxide-producing intrinsic neurons
 Nitric oxide exerts its effect through cyclic GMP as
a mediator & sildenafil which protects second
messenger from breakdown should mimic effects of
nitric oxide release & relieve gastric retention
 Sildenafil did not improve emptying in pilot study of
patients with diabetic gastroparesis, possibly because
of its concurrent relaxatory action on fundus
Current and emerging medical therapies for gastroparesis
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28. TARGETING PYLORIC
FUNCTION CONT’D
 Botulinum toxin A injected into pyloric area during
endoscopy initially reported symptomatic
improvement & acceleration of gastric emptying
 Two controlled trials did not demonstrate
superiority over placebo
Current and emerging medical therapies for gastroparesis
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29. ANTIBIOTICS FOR TREATMENT
OF BACTERIAL OVERGROWTH
 Gastric stasis can lead to bacterial overgrowth in
stomach & intestine
 Patients with small intestinal bacterial overgrowth
also present with symptoms similar to those of
gastroparesis & various antibiotics used for
bacterial overgrowth may also improve gastric
motility
 Rifaximin has gained more recent attention since it
is poorly absorbed & therefore works primarily in
intestine with fewer potential side effects
Current and emerging medical therapies for gastroparesis
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30. UPCOMING PROMOTILIDES
FOR GASTROPARESIS
Current and emerging medical therapies for gastroparesis
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31. SEROTONERGIC RECEPTOR
AGENTS
 TD-5108 is a potent, highly selective & high-
efficacy 5-HT4 agonist
 Can significantly accelerate intestinal and colonic
transit after single dosing & recent phase 2
blinded, placebo randomized control trial involving
both diabetic & idiopathic gastroparesis patients
demonstrated accelerated gastric emptying
Current and emerging medical therapies for gastroparesis
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32. SEROTONERGIC RECEPTOR
AGENTS
CONT’D
 Prucalopride - undergoing phase 3 clinical trial in
diabetic gastroparesis
 Alosetron - Being considered for treatment of
gastroparesis
 Naronapride - investigational 5-HT4 receptor
agonist that was designed to have similar activity
as cisapride without QT prolongation
Current and emerging medical therapies for gastroparesis
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33. SEROTONERGIC RECEPTOR
AGENTS
CONT’D
 In addition, naronapride is not metabolized by
CYP450
 ↑ spontaneous bowel movements in a phase 2
randomized, placebo-controlled study of patients
with chronic idiopathic constipation
 Study demonstrated that it can accelerate overall
colonic transit & tends to accelerate gastric &
ascending colon emptying & loosen stool
consistency
Current and emerging medical therapies for gastroparesis
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34. SEROTONERGIC RECEPTOR
AGENTS CONT’D
 Renzapride - Gastroprokinetic agent & anti-emetic
 Despite initial encouraging results, however, phase
III trial in the USA in 2008 did not show
sufficient efficacy over placebo to justify further
development
 TD-2749 - selective 5-HT4 agonists - currently
being studied for use in gastroparesis
Current and emerging medical therapies for gastroparesis
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35. MOTILIN RECEPTOR AGONISTS
 Several erythromycin derivatives are being studied
as promotilides without antibiotic activity
 EM574 has emerging evidence to improve delayed
gastric emptying in dogs, but evidence in humans is
still lacking
 Various other coded molecules in pipeline are
ABT81229, KC11458, GM611 , GSK962040
Current and emerging medical therapies for gastroparesis
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36. OTHER CCK-A ANTAGONIST
 Loxiglumide ↑ gastric & colonic motilities & reduces
visceral perception
 Appears effective for constipation & studies in
healthy volunteers showed acceleration of both
liquid & solid gastric emptying
Current and emerging medical therapies for gastroparesis
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37. GHRELIN AND GHRELIN
RECEPTOR AGONISTS
 Pharmacological doses of ghrelin accelerate gastric
emptying & improve symptoms but contraction of
proximal stomach may conceivably aggravate post-
prandial symptoms
 TZP-101 - small studies to ↓ overall post-meal
symptom intensity & post-prandial fullness &
improve symptoms in six patients with severe
gastroparesis
 Other coded compounds undergoing trials are TZP
-102, RM -131
Current and emerging medical therapies for gastroparesis
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38. GUANYL CYCLASE AGONIST
 Linaclotide - peptide agonist of guanylate cyclase
2C - ↑ smooth muscle contraction and promotes
bowel movement
 Target receptor is less expressed in stomach,
some have used this off-label for gastroparesis
 IW-9179 - GC-C agonist - for potential treatment
of functional dyspepsia and gastroparesis
Current and emerging medical therapies for gastroparesis
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39. OTHER PROMOTILITY
MEDIATORS
 Calcitonin gene-related peptide, or CGRP - potent
smooth muscle relaxant shown to slow gastric
emptying in healthy rodents
 CGRP & transient receptor potential vanilloid
subtype 1 (TRPV1) antagonists - potential in
treatment of gastroparesis
 Recent study TRPV1 blockade elicited marked, but
reversible & generally plasma concentration
dependent hyperthermia
Current and emerging medical therapies for gastroparesis
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40. OTHER PROMOTILITY
MEDIATORS CONT’D
Lubiprostone
 selective type 2 chloride channel (ClC-2) activator
- induces intestinal secretion & has been shown to
relieve constipation in clinical trials
 Some of its action may be mediated through
prostaglandin E2 effects, raising possibility that
this could also enhance gastric emptying
 Accelerated small bowel & colonic transit & fasting
↑ gastric volume but retarded gastric emptying
 ↓ fullness 30 min after fully satiating meal
Current and emerging medical therapies for gastroparesis
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41. CONCLUSION
Current available medications are limited symptomatic
control is aimed at improving gastric emptying , alleviating
nausea and vomiting, and treating abdominal pain . Many
drugs are in pipeline for treating gastroparesis.
Various newer mechanism under study are
1. Serotonergic agents – prucalopride
2. Motilin receptor agonists – EM574
3. CCK – A Antagonist- loxiglumide
4. Ghrelin receptor antagonists – TZP101
5. Guanyl cyclase agonist – Linactolide
6. Calcitonin gene related peptides antagonists
Current and emerging medical therapies for gastroparesis
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42. REFERENCES
 Current and Emerging Medical Therapies for
Gastroparesis ,Xiaofeng Zhao, PhDHiroshi
Mashimo, Drugs 2015
 “ The pharmacological basis of therapeutics”
Goodman and Gilman( 12th edition )
 Basic and clinical pharmacology – Bertram Katzung
(12th edition)
Current and emerging medical therapies for gastroparesis
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43. Current and emerging medical therapies for gastroparesis
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44. REMOVE ???
 A number of herbal preparations have emerged as
dietary supplements for treatment of functional
bowel and gastroparesis symptoms
 STW5 (Iberogast, Steigerwald Arzneimittelwerk
GmbH) is a herbal preparation of nine herbs
(clown’s mustard, German chamomile, angelica,
caraway, milk thistle, lemon balm, peppermint,
celandine & licorice)
 Initial studies of Iberogast - show promise in
treatment of dyspeptic symptoms & for
gastroparesis, although gastric emptying was not
enhanced
Current and emerging medical therapies for gastroparesis
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45. CHOLECYSTOKININ (CCK)
ANTAGONISTS
 Cholecystokinin (CCK) natural hormone in body that
influences gastric motor, gall bladder & pancreatic
enzyme function
Current and emerging medical therapies for gastroparesis
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46. TZP-102 - oral counterpart of TZP-101
 Did not accelerate gastric emptying
 Initially ↓ composite symptom score of nausea, inability to
finish meals, upper abdominal pain & bloating
 Phase 2b trial with diabetic gastroparesis - no significant
symptomatic benefit over placebo
RM-131 - pentapeptide synthetic ghrelin receptor agonist
 In animal models has nearly 100-fold greater potency than
native ghrelin and a longer plasma half-life.
 Two studies - accelerated gastric emptying & ↓ subjective
vomiting severity but not other GI symptoms
Current and emerging medical therapies for gastroparesis
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