Exendins and exendin agonist analogs to regulate gastrointestinal motility
United States Patent: 8,026,210
Issued: September 27, 2011
Inventors: Young; Andrew A.
(Rancho Santa Fe, CA), Gedulin; Bronislava (Del Mar, CA)
Pharmaceuticals, Inc. (San Diego, CA)
Appl. No.: 12/353,861
Filed: January 14, 2009
George Washington University's Healthcare MBA
Methods for reducing gastric motility and
delaying gastric emptying for therapeutic and diagnostic purposes are
disclosed which comprise administration of an effective amount of an
exendin or an exendin agonist. Methods for treating conditions associated
with elevated, inappropriate, or undesired post-prandial blood glucose
levels are disclosed which comprise administration of an effective amount
of an exendin or an exendin agonist alone or in conjunction with other
anti-gastric emptying agents.
Description of the
Exendin(9-39) is also reported to act as
an antagonist of the full length exendins, inhibiting stimulation of
pancreatic acinar cells by exendin 3 and exendin 4 (Raufman et al, J.
Biol. Chem., 266:2897-902 (1991); Raufman et al., J. Biol. Chem.,
266:21432-37 (1992)). Exendin(9-39) is said to inhibit the stimulation of
plasma insulin levels by exendin 4, and inhibits the somatostatin
release-stimulating and gastrin release-inhibiting activities of exendin-4
and GLP-1 (Kolligs et al, Diabetes, 44:16-19 (1995); Eissele et al., Life
Sciences, 55:629-34 (1994)).
Agents which serve to delay gastric emptying have found a place in
medicine as diagnostic aids in gastro-intestinal radiologic examinations.
For example, glucagon is a polypeptide hormone which is produced by the
alpha cells of the pancreatic islets of Langerhans. It is a hyperglycemic
agent which mobilizes glucose by activating hepatic glycogenolysis. It can
to a lesser extent stimulate the secretion of pancreatic insulin. Glucagon
is used in the treatment of insulin-induced hypoglycemia when
administration of glucose intravenously is not possible. However, as
glucagon reduces the motility of the gastrointestinal tract it is also
used as a diagnostic aid in gastrointestinal radiological examinations.
Glucagon has also been used in several studies to treat various painful
gastro-intestinal disorders associated with spasm. Daniel et al, Br. Med.
J., 3:720 (1974) reported quicker symptomatic relief of acute
diverticulitis in patients treated with glucagon compared with those who
had been treated with analgesics or antispasmodics. A review by Glauser et
al., J. Am. Coll. Emergency Physns, 8:228 (1979) described relief of acute
esophageal food obstruction following glucagon therapy. In another study
glucagon significantly relieved pain and tenderness in 21 patients with
biliary tract disease compared with 22 patients treated with placebo (Stower
et al, Br. J. Surg., 69:591-2 (1982)).
Methods for regulating gastrointestinal motility using amylin agonists are
described in International Application No. PCT/US94/10225, published Mar.
SUMMARY OF THE INVENTION
The present invention concerns the surprising discovery that exendins are
potent inhibitors of gastric emptying. Exendins and exendin agonists are
useful as inhibitors of gastric emptying for the treatment of, for
example, diabetes mellitus, obesity, the ingestion of toxins, or for
The present invention is directed to novel methods for reducing gastric
motility and slowing gastric emptying, comprising the administration of an
exendin, for example, exendin-3 (SEQ ID NO: 1), exendin-4 (SEQ ID NO: 2),
or other compounds which effectively bind to the receptor at which
exendins exert their action on gastric motility and gastric emptying.
These methods will be useful in the treatment of, for example, post-prandial
hyperglycemia, a complication associated with type 1 (insulin dependent)
and type 2 (non-insulin dependent) diabetes mellitus.
In a first aspect, the invention features a method of beneficially
regulating gastrointestinal motility in a subject by administering to said
subject a therapeutically effective amount of an exendin or an exendin
agonist. By "exendin agonist" is meant a compound which mimics the effects
of exendins on gastric motility and gastric emptying, namely, a compound
which effectively binds to the receptor at which exendins exert their
action on gastric motility and gastric emptying, preferably an analog or
derivative of an exendin.
Exendin agonist compounds useful in present invention include those
compounds of the formula (I) (SEQ ID NO: 36)
-- see Original Patent. Also useful in the present invention are
pharmaceutically acceptable salts of the compounds of formula (I).
In one embodiment, the methods of the present invention are directed to
reducing gastric motility. In another embodiment, the invention is
directed to methods of delaying gastric emptying.
These methods may be used on a subject undergoing a gastrointestinal
diagnostic procedure, for example radiological examination or magnetic
resonance imaging. Alternatively, these methods may be used to reduce
gastric motility in a subject suffering from a gastrointestinal disorder,
for example, spasm (which may be associated with acute diverticulitis, a
disorder of the biliary tract or a disorder of the Sphincter of Oddi).
In another aspect, the invention is directed to a method of treating post-prandial
dumping syndrome in a subject by administering to the subject a
therapeutically effective amount of an exendin or exendin agonist.
In yet another aspect, the invention is directed to a method of treating
post-prandial hyperglycemia by administering to a subject a
therapeutically effective amount of an exendin or exendin agonist. In a
preferred embodiment, the post-prandial hyperglycemia is a consequence of
Type 2 diabetes mellitus. In other preferred embodiments, the post-prandial
hyperglycemia is a consequence of Type 1 diabetes mellitus or impaired
In another aspect, a therapeutically effective amount of an amylin agonist
is also administered to the subject. In a preferred aspect, the amylin
agonist is an amylin or an amylin agonist analog such as
.sup.25,28,29Pro-human-amylin. The use of amylin agonists to treat post-prandial
hyperglycemia, as well as to beneficially regulate gastrointestinal
motility, is described in PCT/US94/10225 published Mar. 16, 1995, which
has been incorporated by reference herein.
In yet another aspect, a therapeutically effective amount of an insulin or
insulin analog is also administered, separately or together with an
exendin or exendin agonist, to the subject.
In another aspect, the invention is directed to a method of treating
ingestion of a toxin by administering an amount of an exendin or an
exendin agonist effective to prevent or reduce passage of stomach contents
to the intestines and aspirating the stomach contents.
DETAILED DESCRIPTION OF THE INVENTION
Exendins and exendin agonists (including exendin analogs and exendin
derivatives) are useful in this invention in view of their pharmacological
properties. Activity as exendin agonists can be indicated by activity in
the assays described below. Effects of exendins or exendin agonists on
gastric motility and gastric emptying can be identified, evaluated, or
screened for, using the methods described in Examples 1-3 below, or other
art-known or equivalent methods for determining gastric motility. Negative
receptor assays or screens for exendin agonist compounds or candidate
exendin agonist compounds, such as a GLP-1 receptor preparation, an amylin
receptor assay/screen using an amylin receptor preparation as described in
U.S. Pat. No. 5,264,372, the contents of which are incorporated herein by
reference, one or more calcitonin receptor assays/screens using, for
example, T47D and MCF7 breast carcinoma cells, which contain calcium
receptors coupled to the stimulation of adenyl cyclase activity, and/or a
CGRP receptor assay/screen using, for example, SK-N-MC cells, can be used
to evaluate and/or confirm exendin agonist activity.
One such method for use in identifying or evaluating the ability of a
compound to slow gastric motility, comprises: (a) bringing together a test
sample and a test system, said test sample comprising one or more test
compounds, said test system comprising a system for evaluating gastric
motility, said system being characterized in that it exhibits, for
example, elevated plasma glucose in response to the introduction to said
system of glucose or a meal; and, (b) determining the presence or amount
of a rise in plasma glucose in said system. Positive and/or negative
controls may be used as well.
Exendins and exendin agonist compounds such as exendin analogs and exendin
derivatives, described herein may be prepared through peptide purification
as described in, for example, Eng et al, J. Biol. Chem., 265:20259-62
(1990); and Eng et al, J. Biol. Chem., 267:7402-05 (1992), hereby
incorporated by reference herein. Alternatively, exendins and exendin
agonist peptides may be prepared by methods known to those skilled in the
art, for example, as described in Raufman et al, J. Biol. Chem.,
267:21432-37 (1992), hereby incorporated by reference herein, using
standard solid-phase peptide synthesis techniques and preferably an
automated or semiautomated peptide synthesizer. Typically, an .alpha.-N-carbamoyl
protected amino acid and an amino acid attached to the growing peptide
chain on a resin are coupled at room temperature in an inert solvent such
as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the
presence of coupling agents such as dicyclohexylcarbodiimide and
1-hydroxybenzotriazole in the presence of a base such as
diisopropylethylamine. The .alpha.-N-carbamoyl protecting group is removed
from the resulting peptide-resin using a reagent such as trifluoroacetic
acid or piperidine, and the coupling reaction repeated with the next
desired N-protected amino acid to be added to the peptide chain. Suitable
N-protecting groups are well known in the art, with t-butyloxycarbonyl (tboc)
and fluorenylmethoxycarbonyl (Fmoc) being preferred herein.
The solvents, amino acid derivatives and 4-methylbenzhydryl-amine resin
used in the peptide synthesizer may be purchased from Applied Biosystems
Inc. (Foster City, Calif.). The side-chain protected amino acids, such as
Boc-Arg(Mts), Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl),
Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z), Fmoc-Lys(Boc),
Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt), Fmoc-Asn(Trt), and
Fmoc-Gln(Trt) may be purchased from Applied Biosystems, Inc. Boc-His(BOM)
may be purchased from Applied Biosystems, Inc. or Bachem Inc. (Torrance,
Calif.). Anisole, methylsulfide, phenol, ethanedithiol, and thioanisole
may be obtained from Aldrich Chemical Company (Milwaukee, Wis.). Air
Products and Chemicals (Allentown, Pa.) supplies HF. Ethyl ether, acetic
acid and methanol may be purchased from Fisher Scientific (Pittsburgh,
Solid phase peptide synthesis may be carried out with an automatic peptide
synthesizer (Model 430A, Applied Biosystems Inc., Foster City, Calif.)
using the NMP/HOBt (Option 1) system and tBoc or Fmoc chemistry (see,
Applied Biosystems User's Manual for the ABI 430A Peptide Synthesizer,
Version 1.3B Jul. 1, 1988, section 6, pp. 49-70, Applied Biosystems, Inc.,
Foster City, Calif.) with capping. Boc-peptide-resins may be cleaved with
HF (-5.degree. C. to 0.degree. C., 1 hour). The peptide may be extracted
from the resin with alternating water and acetic acid, and the filtrates
lyophilized. The Fmoc-peptide resins may be cleaved according to standard
methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc.,
1990, pp. 6-12). Peptides may be also assembled using an Advanced Chem
Tech Synthesizer (Model MPS 350, Louisville, Ky.). Peptides may be
purified by RP-HPLC (preparative and analytical) using a Waters Delta Prep
3000 system. A C4, C8 or C18 preparative column (10.mu., 2.2.times.25 cm;
Vydac, Hesperia, Calif.) may be used to isolate peptides, and purity may
be determined using a C4, C8 or C18 analytical column (5.mu.,
0.46.times.25 cm; Vydac). Solvents (A=0.1% TFA/water and B=0.1% TFA/CH.sub.3CN)
may be delivered to the analytical column at a flow rate of 1.0 ml/min and
to the preparative column at 15 ml/min. Amino acid analyses may be
performed on the Waters Pico Tag system and processed using the Maxima
program. The peptides may be hydrolyzed by vapor-phase acid hydrolysis
(115.degree. C., 20-24 h). Hydrolysates may be derivatized and analyzed by
standard methods (Cohen, S. A., Meys, M., and Tarrin, T. L. (1989), The
Pico Tag Method: A Manual of Advanced Techniques for Amino Acid Analysis,
pp. 11-52, Millipore Corporation, Milford, Mass.). Fast atom bombardment
analysis may be carried out by M-Scan, Incorporated (West Chester, Pa.).
Mass calibration may be performed using cesium iodide or cesium
iodide/glycerol. Plasma desorption ionization analysis using time of
flight detection may be carried out on an Applied Biosystems Bio-Ion 20
Peptide compounds useful in the invention may also be prepared using
recombinant DNA techniques, using methods now known in the art. See, e.g.,
Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2d Ed., Cold
Spring Harbor (1989). Alternatively, such compounds may be prepared by
homogeneous phase peptide synthesis methods.
The use of exendin analogs or derivatives is included within the methods
of the present invention. Exendin analogs or derivatives are functional
variants having similar amino acid sequence and retaining, to some extent,
at least the gastric motility- and gastric emptying-related activities of
the related exendin. By "functional variant" is meant an analog or
derivative which has an activity that can be substituted for one or more
activities of a particular exendin. Preferred functional variants retain
all of the activities of a particular exendin, however, the functional
variant may have an activity that, when measured quantitatively, is
stronger or weaker, as measured in exendin functional assays, for example,
such as those disclosed herein. Preferred functional variants have
activities that are within about 1% to about 10,000% of the activity of
the related exendin, more preferably between about 10% to about 1000%, and
more preferably within about 50% to about 500%. Derivatives have at least
about 15% sequence similarity, preferably about 70%, more preferably about
90%, and even more preferably about 95% sequence similarity to the related
exendin. "Sequence similarity" refers to "homology" observed between amino
acid sequences in two different polypeptides, irrespective of polypeptide
The ability of the analog or derivative to retain some activity can be
measured using techniques described herein.
Derivatives include modification occurring during or after translation,
for example, by phosphorylation, glycosylation, crosslinking, acylation,
proteolytic cleavage, linkage to an antibody molecule, membrane molecule
or other ligand (Ferguson et al, Annu. Rev. Biochem., 57:285-320 (1988)).
Specific types of analogs include amino acid alterations such as
deletions, substitutions, additions, and amino acid modifications. A
"deletion" refers to the absence of one or more amino acid residue(s) in
the related polypeptide. An "addition" refers to the presence of one or
more amino acid residue(s) in the related polypeptide. Additions and
deletions to a polypeptide may be at the amino terminus, the carboxy
terminus, and/or internal. Amino acid "modification" refers to the
alteration of a naturally occurring amino acid to produce a non-naturally
occurring amino acid. A "substitution" refers to the replacement of one or
more amino acid residue(s) by another amino acid residue(s) in the
polypeptide. Analogs can contain different combinations of alterations
including more than one alteration and different types of alterations.
Preferred analogs have one or more amino acid alteration(s) which do not
significantly affect exendin agonist activity. In regions of the exendin
not necessary for exendin agonist activity, amino acids may be deleted,
added or substituted with less risk of affecting activity. In regions
required for exendin agonist activity, amino acid alterations are less
preferred as there is a greater risk of affecting exendin activity. Such
alterations should be conservative alterations For example, one or more
amino acid residues within the sequence can be substituted by another
amino acid of a similar polarity which acts as a functional variant.
Conserved regions tend to be more important for protein activity than
non-conserved regions. Known procedures may be used to determine the
conserved and non-conserved regions important of receptor activity using
in vitro mutagenesis techniques or deletion analyses and measuring
receptor activity as described by the present disclosure.
Modifications to a specific polypeptide may be deliberate, as through
site-directed mutagenesis and amino acid substitution during solid-phase
synthesis, or may be accidental such as through mutations in hosts or
systems which produce the polypeptide.
Compounds particularly useful according to the present invention are
exendin agonist compounds of the formula (I) (SEQ ID NO: 36)
-- see Original Patent.
The compounds referenced above form salts with various inorganic and
organic acids and bases. Such salts include salts prepared with organic
and inorganic acids, for example, HCl, HBr, H.sub.2SO.sub.4,
H.sub.3PO.sub.4, trifluoroacetic acid, acetic acid, formic acid,
methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and
camphorsulfonic acid. Salts prepared with bases include ammonium salts,
alkali metal salts, e.g. sodium and potassium salts, and alkali earth
salts, e.g. calcium and magnesium salts. Acetate, hydrochloride, and
trifluoroacetate salts are preferred. The salts may be formed by
conventional means, as by reacting the free acid or base forms of the
product with one or more equivalents of the appropriate base or acid in a
solvent or medium in which the salt is insoluble, or in a solvent such as
water which is then removed in vacuo or by freeze-drying or by exchanging
the ions of an existing salt for another ion on a suitable ion exchange
The compounds described above are useful in view of their pharmacological
properties. In particular, the compounds of the invention possess activity
as agents to regulate gastric motility and to slow gastric emptying, as
evidenced by the ability to inhibit gastric emptying levels in mammals.
As described in Example 1, gastric emptying was measured in normal Sprague
Dawley rats using the retention of an acaloric methylcellulose gel
containing Phenol Red delivered by gavage. Dye content in stomachs removed
after sacrifice 20 minutes later was determined spectroscopically, and was
compared to that in rats sacrificed immediately after gavage to assess
emptying. The exendins, exendin-3 and exendin-4, dose-dependently
inhibited gastric emptying. The ED.sub.50 of the response to exendin-3 and
exendin-4 was 0.1 and 0.08 .mu.g, respectively, demonstrating that the
exendins were about 170-290 times more potent than GLP-1(7-36)NH.sub.2 in
inhibiting gastric emptying.
As described in Example 2, the effects of exendin-4 and the exendin-4
analogs, exendin-4 acid and .sup.14Leu,.sup.25Phe exendin-4 (SEQ ID NO:
37), on inhibition of gastric emptying were examined. Exendin-4 and the
exendin-4 analogs dose dependently inhibiting gastric emptying.
The ED.sub.50 of exendin-4 was 0.27 .mu.g. The ED.sub.50 of exendin-4 acid
and .sup.14Leu,.sup.25Phe exendin-4 were 0.12 .mu.g and 0.29 .mu.g,
respectively, indicating that the potency of the analogs was comparable to
that of exendin-4.
As described in Example 3, the effects of exendin-4 and the cloned GLP-1
receptor antagonist, exendin(9-39) on gastric emptying were examined.
After 20 minutes, the animals treated with exendin-4 showed potent
inhibition of gastric emptying, which was not reversed by exendin(9-39).
This occurred regardless of whether the exendin(9-39) was administered sc
or iv. Exendin(9-39) alone had no effect on gastric emptying.
As noted above, exendin(9-39) is a potent antagonist of GLP-1 which binds
at the cloned GLP-1 receptor (Fehmann et al, Peptides, 15(3):453-6 (1994);
Thorens et al, Diabetes, 42(11):1678-82 (1993)). Surprisingly, however,
exendin(9-39) did not block the effect of exendin-4 on gastric emptying
(see FIGS. 4 and 5 (see Original Patent)). These results indicate that the
effects of exendins and exendin agonists on gastric emptying are not due
binding of the exendins at the cloned GLP-1 receptor, but instead that the
gastric emptying effects of exendins and exendin agonists are due to their
action on a separate receptor.
That exendins can act via mechanisms other than those attributable to the
cloned GLP-1 receptor is further evidenced by the reported absence of
effect of exendin-4 on inhibition of pentagastrin-induced gastric acid
secretion, despite the inhibitory effect of GLP-1 on such secretion.
Gedulin et al, Diabetologia, 40(Suppl. 1):A300 (Abstract 1181) (1997).
Additionally, as described in WO 98/30231 and U.S. Pat. No. 6,956,026,
peripherally injected exendin inhibited food intake in mice, an action not
observed with GLP-1.
Compositions useful in the invention may conveniently be provided in the
form of formulations suitable for parenteral (including intravenous,
intramuscular and subcutaneous) or nasal or oral administration. In some
cases, it will be convenient to provide an exendin or exendin agonist and
another anti-emptying agent, such as glucagon, or amylin, or an amylin
agonist, in a single composition or solution for administration together.
In other cases, it may be more advantageous to administer another
anti-emptying agent separately from said exendin or exendin agonist. A
suitable administration format may best be determined by a medical
practitioner for each patient individually. Suitable pharmaceutically
acceptable carriers and their formulation are described in standard
formulation treatises, e.g., Remington's Pharmaceutical Sciences by E. W.
Martin. See also Wang, Y. J. and Hanson, M. A. "Parenteral Formulations of
Proteins and Peptides: Stability and Stabilizers," Journal of Parental
Science and Technology, Technical Report No. 10, Supp. 42:2 S (1988).
Compounds useful in the invention can be provided as parenteral
compositions for injection or infusion. They can, for example, be
suspended in an inert oil, suitably a vegetable oil such as sesame,
peanut, olive oil, or other acceptable carrier. Preferably, they are
suspended in an aqueous carrier, for example, in an isotonic buffer
solution at a pH of about 5.6 to 7.4. These compositions may be sterilized
by conventional sterilization techniques, or may be sterile filtered. The
compositions may contain pharmaceutically acceptable auxiliary substances
as required to approximate physiological conditions, such as pH buffering
agents. Useful buffers include for example, sodium acetate/acetic acid
buffers. A form of repository or "depot" slow release preparation may be
used so that therapeutically effective amounts of the preparation are
delivered into the bloodstream over many hours or days following
transdermal injection or delivery.
The desired isotonicity may be accomplished using sodium chloride or other
pharmaceutically acceptable agents such as dextrose, boric acid, sodium
tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or
other inorganic or organic solutes. Sodium chloride is preferred
particularly for buffers containing sodium ions.
The claimed compositions can also be formulated as pharmaceutically
acceptable salts (e.g., acid addition salts) and/or complexes thereof.
Pharmaceutically acceptable salts are non-toxic salts at the concentration
at which they are administered. The preparation of such salts can
facilitate the pharmacological use by altering the physical-chemical
characteristics of the composition without preventing the composition from
exerting its physiological effect. Examples of useful alterations in
physical properties include lowering the melting point to facilitate
transmucosal administration and increasing the solubility to facilitate
the administration of higher concentrations of the drug.
Pharmaceutically acceptable salts include acid addition salts such as
those containing sulfate, hydrochloride, phosphate, sulfamate, acetate,
citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
Pharmaceutically acceptable salts can be obtained from acids such as
hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic
acid, citric acid, lactic acid, tartaric acid, malonic acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid, cyclohexylsulfamic acid, and quinic acid. Such salts may be prepared
by, for example, reacting the free acid or base forms of the product with
one or more equivalents of the appropriate base or acid in a solvent or
medium in which the salt is insoluble, or in a solvent such as water which
is then removed in vacuo or by freeze-drying or by exchanging the ions of
an existing salt for another ion on a suitable ion exchange resin.
Carriers or excipients can also be used to facilitate administration of
the compound. Examples of carriers and excipients include calcium
carbonate, calcium phosphate, various sugars such as lactose, glucose, or
sucrose, or types of starch, cellulose derivatives, gelatin, vegetable
oils, polyethylene glycols and physiologically compatible solvents. The
compositions or pharmaceutical composition can be administered by
different routes including intravenously, intraperitoneal, subcutaneous,
and intramuscular, orally, topically, or transmucosally.
If desired, solutions of the above compositions may be thickened with a
thickening agent such as methyl cellulose. They may be prepared in
emulsified form, either water in oil or oil in water. Any of a wide
variety of pharmaceutically acceptable emulsifying agents may be employed
including, for example, acacia powder, a non-ionic surfactant (such as a
Tween), or an ionic surfactant (such as alkali polyether alcohol sulfates
or sulfonates, e.g., a Triton).
Compositions useful in the invention are prepared by mixing the
ingredients following generally accepted procedures. For example, the
selected components may be simply mixed in a blender or other standard
device to produce a concentrated mixture which may then be adjusted to the
final concentration and viscosity by the addition of water or thickening
agent and possibly a buffer to control pH or an additional solute to
For use by the physician, the compositions will be provided in dosage unit
form containing an amount of an exendin or exendin agonist, for example,
exendin-3, exendin-4, with or without another anti-emptying agent.
Therapeutically effective amounts of an exendin or exendin agonist for use
in the control of gastric emptying and in conditions in which gastric
emptying is beneficially slowed or regulated are those that decrease post-prandial
blood glucose levels, preferably to no more than about 8 or 9 mM or such
that blood glucose levels are reduced as desired. In diabetic or glucose
intolerant individuals, plasma glucose levels are higher than in normal
individuals. In such individuals, beneficial reduction or "smoothing" of
post-prandial blood glucose levels, may be obtained. As will be recognized
by those in the field, an effective amount of therapeutic agent will vary
with many factors including the age and weight of the patient, the
patient's physical condition, the blood sugar level or level of inhibition
of gastric emptying to be obtained, and other factors.
Such pharmaceutical compositions are useful in causing gastric
hypomotility in a subject and may be used as well in other disorders where
gastric motility is beneficially reduced.
The effective daily anti-emptying dose of the compounds will typically be
in the range of 0.001 or 0.003 to about 5 mg/day, preferably about 0.001
or 0.05 to 2 mg/day and more preferably about 0.001 or 0.01 to 1 mg/day,
for a 70 kg patient, administered in a single or divided doses. The exact
dose to be administered is determined by the attending clinician and is
dependent upon where the particular compound lies within the above quoted
range, as well as upon the age, weight and condition of the individual.
Administration should begin at the first sign of symptoms or shortly after
diagnosis of diabetes mellitus. Administration may be by injection,
preferably subcutaneous or intramuscular. Orally active compounds may be
taken orally, however dosages should be increased 5-10 fold.
Generally, in treating or preventing elevated, inappropriate, or undesired
post-prandial blood glucose levels, the compounds of this invention may be
administered to patients in need of such treatment in a dosage ranges
similar to those given above, however, the compounds are administered more
frequently, for example, one, two, or three times a day.
The optimal formulation and mode of administration of compounds of the
present application to a patient depend on factors known in the art such
as the particular disease or disorder, the desired effect, and the type of
patient. While the compounds will typically be used to treat human
patients, they may also be used to treat similar or identical diseases in
other vertebrates such as other primates, farm animals such as swine,
cattle and poultry, and sports animals and pets such as horses, dogs and
Claim 1 of 21 Claims
1. A method for treating post-prandial dumping
syndrome, ingestion of a toxin, or a gastrointestinal spasm in a patient in
need thereof comprising administering to the patient a therapeutically
effective amount of an exendin-4 peptide comprising the amino acid sequence
of SEQ ID NO:2 to treat the patient for post-prandial dumping syndrome,
ingestion of a toxin, or the gastrointestinal spasm.
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