Use of pentagastrin to inhibit gastric acid secretion

Tag : benzene sulfonamide


Abstract
This invention pertains to the discovery that pentagastrin, whenadministered in conjunction with a proton pump inhibitor (PPI) issynergistic with the PPI and significantly increases the efficacyof the PPI in reducing/mitigating excess gastric acid secretion.
Description of the Invention
SUMMARY OF THE INVENTION

This invention provides a novel method of treating pathologicalconditions characterized by excess gastric acid secretion. Inparticular, this invention pertains to the discovery thatadministration of pentagastrin (an agent that is typically used toincrease acid secretion), in conjunction with a proton pumpinhibitor (PPI) will result in increased efficacy (e.g. prolongedeffect and/or greater effect at reduced dosage) than use of theproton pump inhibitor alone. The effect is also mediated by gastrinand gastrin or pentagastrin analogues or derivatives. In particularembodiments, the pentagastrin/PPI combination appears synergistic.

Thus, in one embodiment, this invention provides methods ofincreasing the efficacy of a gastric H.sup.+/K.sup.+-ATPase pumpinhibitor (PPI) in a mammal (e.g. a rodent, largomorph, bovine,canine, equine, non-human primate, human, etc.). The methodspreferably involve administering to the mammal pentagastrin,gastrin or analogues or derivatives thereof in conjunction with agastric proton pump inhibitor. Pentagastrin is used in particularlypreferred embodiments. The pentagastrin can be administered before,simultaneously with, or after the PPI, but in a most preferredembodiment, the pentagastrin administration precedes the PPIadministration. In addition to the use of exogenous gastrin orpentagastrin, the method can involve upregulating endogenousgastrin secretion using, for example, aromatic amino acids, or witha meal, etc. Essentially anything that stimulates G-cell activitywill increase the efficacy of a PPI.

Administration of the gastrin/pentagastrin/analogue and the PPI canbe by any route convenient for the application of these agents. Inpreferred embodiments, the gastrin/pentagastrin/analogue isadministered by injection (e.g. subcutaneous injection) and the PPIis administered orally or by injection (e.g. intravenousinjection). Particularly preferred pentagastrin/gastrin/analoguedosages range from about 0.1 mg/kg/hr to about 10 mg/kg/hr.

The mammal is preferably a mammal diagnosed with a pathologycharacterized by excess gastric acid secretion, e.g.,Zollinger/Ellison syndrome (ZES), gastroesophageal reflux disease(GERD), peptic ulcer disease, atrophic gastritis, esophagitis,stress induced hypersecretion, and/or idiopathic gastric acidhypersecretion. Preferred proton pump inhibitors used in thisinvention include, but are not limited to rabeprazole, omeprazole,lansoprazole, and pantoprazole, as well as cogeners or racemicmixtures of the same. The mammal may also suffer fromhypersensivity to normal acid secretion that may result ingastrointestinal inflammation and ulceration.

This invention also involves the discovery that administration ofpentagastrin gastrin or analogues thereof or other compounds thatact at the same receptor site (e.g. that are agonistic at thecholecystokinin (CCK) receptor (see, U.S. Pat. No. 5,319,073 for adescription of the CCK receptor) will increase urinary sodiumexcretion (e.g. gastrin, pentagastrin, cholecystokinin andderivatives or analogues thereof act as a diuretic). Thus, inanother embodiment, this invention provides methods of increasingurinary sodium excretion and free water excretion. These methodsinvolve administering to a mammal diagnosed with a pathologicalcondition characterized by excessive fluid retention, a dose ofpentagastrin or analogues thereof (or in certain embodiments,gastrin or analogues thereof) sufficient to increase urinary sodiumexcretion in the mammal. In preferred embodiments, the pathologicalcondition is high blood pressure, fluid retention associated withheart failure, fluid retention associated with acute or chronickidney failure, fluid retention associated with cirrhosis, calciumkidney stones, nephrogenic diabetes insipidus, renal tubularacidosis, treatment of Meniere's disease, constrictivepericarditis, and hepatorenal syndrome. The pentagastrin istypically administered in the dosage ranges indicated above.

Kits are also provided for the practice of the methods of thisinvention. A preferred kit for the treatment of a pathologycharacterized by excess gastric acid secretion, said kit comprisesa container containing a proton pump inhibitor (PPI); and acontainer containing pentagastrin. Preferred proton pump inhibitorsinclude, but are not limited to rabeprazole, omeprazole,lansoprazole, and pantoprazole, as well as cogeners or racemicmixtures of the same. The pentagastrin and/or the PPI can beprovided in a pharmaceutically acceptable excipient or diluent. Thekits can additionally include materials describing the use ofpentagastrin, gastrin or analogues thereof in conjunction with aPPI to reduce gastric acid secretion and/or materials describingthe use of pentagastrin as a diuretic. Instructional materials canalso include recommended dosages and description(s) ofcounterindications, etc.

Also included are kits for increasing urinary sodium excretion in amammal. Preferred kits comprise a container containing apentagastrin, gastrin, or analogue thereof; and instructionalmaterials describing the use of said pentagastrin, gastrin, oranalogue thereof to increase urinary sodium excretion in a mammal.

DETAILED DESCRIPTION

A wide number of pathological conditions are characterized byoversecretion of gastric acid. Such conditions include, but are notlimited to Zollinger/Ellison syndrome (ZES), gastroesophagealreflux disease, peptic ulcer disease, duodenal ulcers, atrophicgastritis, esophagitis. In particular, conditions such as ZES andpeptic ulcers can have serious complications.

Peptic ulcers are one of the most prevalent diseases inindustrialized nations. Control of gastric acid secretion is themain therapy for peptic ulcers. Gastric acid secretion is, in turn,brought about by the interaction of three physiological stimulants,gastrin, acetylcholine and histamine with their respective parietalcell receptors. Prior to the discovery of histamineH.sub.2-receptor antagonists such as cimetidine and ranitidine,peptic ulcer treatment consisted of antacid therapy andanticholinergic drugs (e.g. dicyclomine HCl). With the advent ofH.sub.2-receptor antagonists, however, treatment withanticholinergic agents has been largely supplanted by histamineH.sub.2-receptor antagonist therapy. The development of this classof therapeutic entities presents one of the most important advancesin the field of medicinal chemistry.

Another major development in the treatment of peptic ulcers hasbeen realized with the introduction of H.sup.+/K.sup.+-ATPaseinhibitors e.g., omeprazole. The enzyme H.sup.+/K.sup.+-ATPase,which is also known as the proton pump, is located in the membraneof gastric parietal cells and is responsible for the transport ofprotons from blood to lumen, which, in turn, results in decreasingthe pH of stomach contents which leads to aggravation of pepticulcers.

This invention pertains to the discovery that administration ofpentagastrin (an agent that is typically used to increase acidsecretion) in conjunction with a proton pump inhibitor (PPI) willresult in increased efficacy (e.g. prolonged effect and/or greatereffect at reduced dosage) than use of the proton pump inhibitoralone. In particular embodiments, the pentagastrin/PPI combinationappears synergistic.

Thus, in one embodiment, this invention provides methods ofincreasing the efficacy of a gastric H.sup.+/K.sup.+-ATPase pumpinhibitor (PPI) in a mammal (e.g. a rodent, largomorph, bovine,canine, equine, non-human primate, human, etc.). The methodspreferably involve administering to the mammal pentagastrin inconjunction with the gastric proton pump inhibitor. Thepentagastrin can be administered before, simultaneously with, orafter the PPI, but in a most preferred embodiment, the pentagastrinadministration precedes the PPI administration.

It was also a discovery of this invention that essentially anyincrease in gastrin level in conjunction with a PPI will result inincreased efficacy of the PPI. Thus, instead of pentagastrinadministration, exogenous gastrin can be supplied. Alternativelyendogenous gastrin secretion can be upregulated using, for example,aromatic amino acids, or with a meal, etc. Thus, it is believedthat essentially anything that stimulates G-cell activity willincrease the efficacy of a PPI.

Thus, in various embodiments, this invention contemplatesadministration of a PPI or combination of PPIs in conjunction withpentagastrin, and/or gastrin, and/or pentagastrin analogues, and/orgastrin analogues to increase the efficacy of the PPI(s).

Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are compounds that are selectivelyinhibit activity of the gastric acid pump,H.sup.+/K.sup.+-adenosine triphosphatase (ATPase). Preferred PPIsinclude substituted pyridyl methylsulfinyl benzimidazoles. Thesecompounds accumulate in the acid space of the parietal cell andconvert to active sulfonamide by an acid-catalyzed reaction.Consequent covalent inhibition of H.sup.+/K.sup.+-ATPase blocks thefinal step of acid secretion. Other preferred PPIs include varioussubstituted benzimidazoles. Commercially available PPIs include,but are not limited to, omeprazole, lansoprazole, and pantoprazole.

Numerous proton pump inhibitors are known to those of skill. Thus,for example, U.S. Pat. No. 6,093,738 describes novel thiadiazolecompounds that are effective as proton pumps inhibitors. EuropeanPatent Nos. 322133 and 404322 disclose quinazoline derivatives,European Patent No. 259174 describes quinoline derivatives, and WO91/13337 and U.S. Pat. No. 5,750,531 offer pyrimidine derivatives,as proton pump inhibitors.

Suitable proton pump inhibitors are also disclosed, for example inEP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 andWO90/06925, WO91/19711, WO91/19712, WO94/27988 and WO95/01977.

Particularly preferred PPIs include, but are not limited toomeprazole, lansoprazole, and pantoprazole and derivatives oranalogues thereof. One such derivative is s-omeprazole(Nexium.TM.).

The proton pump inhibitors used in the dosage forms of theinvention can be used in neutral form or in the form of a salt(e.g., an alkaline salt), such as for instance the Mg.sup.2+,Ca.sup.2+, Na.sup.+, K.sup.+, or Li.sup.+ salts, preferably theMg.sup.2+ salts. Further where applicable, the compounds can beused in racemic form or in the form of a substantially pureenantiomer thereof, or salts of the racemates or the singleenantiomers.

In addition this invention contemplates the use of a single protonpump inhibitor, or in certain embodiments, combinations of two ormore proton pump inhibitors.

Proton pump inhibitors are commercially available. In addition,synthesis protocols are well known to those of skill in the art(see, e.g., European Patent Nos. 322133, 404322, 259174,EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, PCT PatentApplications WO 91/13337, WO90/06925, WO91/19711, WO91/19712,WO94/27988 and WO95/01977, U.S. Pat. No. 5,750,531, etc.)

Pentagastrin

Pentagastrin(N-t-butyloxycarbonyl-Beta-alanyl-L-tryptophyl-L-methionyl-L-aspartyl-L-p-henyl-alanyl amide, SEQ ID NO:1) is a pentapeptide containing agastrin carboxyl terminal tetrapeptide, the active portion found inessentially all natural gastrins. Pentagastrin is a colorlesscrystalline solid soluble in dimethylformamide anddimethylsulfoxide; it is almost insoluble in water, ethanol, ether,benzene, chloroform, and ethyl acetate. Pentagastrin contains theC-terminal tetrapeptide responsible for the actions of the naturalgastrins and, therefore, acts as a physiologic gastric acidsecretagogue. The recommended dose of 6 .mu.g/kg subcutaneously (inapplications where increased gastric acid secretion is desired)produces a peak acid output which is reproducible when used in thesame individual. Pentagastrin stimulates gastric acid secretionapproximately ten minutes after subcutaneous injection, with peakresponses occurring in most cases twenty to thirty minutes afteradministration. Pentagastrin is typically used as a diagnosticagent for evaluation of gastric acid secretory function. In onepreferred formulation, pentagastrin is formulated with sodiumchloride and water for injection. The pH is typically adjusted withammonium hydroxide and or hydrochloric acid. In one commerciallyavailable formulation, each ml of injection contains 0.25 mg (250mcg) pentagastrin along with 8.8 mg sodium chloride and water forinjection, USP.

The methods of this invention are not limited to the use ofpentagastrin. To the contrary, it was a discovery of this inventionthat in addition to pentagastrin, exogenous gastrin can be suppliedor endogenous gastrin secretion can be upregulated using, forexample, aromatic amino acids, or with a meal, etc. Thus, it isbelieved that essentially anything that stimulates G-cell activitywill increase the efficacy of a PPI.

Thus, in addition to gastrin and pentagastrin, this inventioncontemplates the use of gastrin or pentagastrin analogues orderivatives. Such analogues or derivatives are well known to thoseof skill in the art. Such variants include, but are not limited tothe 34-, 17-, and 14-amino acid species of gastrin, and othertruncation variants comprising the active C-terminal tetrapeptide(TrpMetAspPhe-NH.sub.2, SEQ ID NO:2) which is reported in theliterature to have full pharmacological activity (see Tracey andGregory (1964) Nature (London), 204: 935). Also included arevariants of gastrin and/or truncated gastrins where native aminoacids are replaces with conservative substitutions. Also includeare various analogues of these molecules, including, but notlimited to the N-protected derivative Boc-TrpMetAspPhe-NH.sub.2(SEQ ID NO:3).

In addition, it is noted that gastrins are structurally related tothe CCK's are structurally-related neuropeptides which exist ingastrointestinal tissue and in the CNS (see Mutt V.,Gastrointestinal Hormones, Glass G. B. J., ed., Raven Press, N.Y.,p 169 and Nisson G., ibid, 127). Thus it is believed that CCKs oranalogues or derivatives thereof that stimulate endogenous gastrinsecretion or that generally stimulate G-cell activity will beuseful in the methods of this invention.

Gastrins, pentagastrins, or analaogues are commercially available.In addition synthetic protocols are well known. Thus, for example,pentagastrin can be chemically synthesized using well known peptidesynthesis methodologies (see, e.g. Barany and MerrifieldSolid-Phase Peptide Synthesis; pp. 3-284 in The Peptides: Analysis,Synthesis, Biology. Vol. 2: Special Methods in Peptide Synthesis,Part A.; Merrifield et al. (1963) J. Am. Chem. Soc., 85: 2149-2156;and Stewart et al. (1984) Solid Phase Peptide Synthesis, 2nd ed.Pierce Chem. Co., Rockford, Ill.).

Combining PPI and Pentagastrin and, Optionally, Antibiotics

The proton pump inhibitor (PPI) and the pentagastrin (or gastrin oranalogue etc.) can be administered simultaneously. However, in apreferred embodiment, the pentagastrin or analogue thereof isadministered first followed by the PPI. In certain embodiments, thepentagastrin or analogue thereof can be administered after the PPI.

The methods of this invention are not limited to the use of asingle pentagastrin/analogue or to the use of a single PPI. Incertain embodiments, combinations of two or more PPIs and/or two ormore pentagastrin/analogues are contemplated.

In certain embodiments, it is desirable to administer one or moreantibiotics in conjunction with the PPI and pentagastrin. Thus, forexample, the treatment of ulcers associated with Helicobacter spinfection (e.g. Helicobacter pylori), the antibiotic willmitigate/eliminate the bacterial component of the pathology.

It is noted that U.S. Pat. No. 5,629,305 teaches that a proton pumpinhibitor (e.g. omeprazole or lansoprazole) which increasesintragastric pH, can increase the bioavailability of variousantibiotics, in particular the therapeutic amount of an aciddegradable antibacterial compound such as a penicillin or amacrolide. A wide variety of antibiotics are suitable for use withthe methods of this invention. Such antibiotics include, but arenot limited to penicillin based antibiotics, tetracyclines,macrolides, cephalosporins, fluoroguinolones, and the like.

Pharmaceutical Formulations and Administration Thereof

The gastrin and/or pentagastrin or derivatives or analoguesthereof, and/or PPI(s) used in the methods of this invention, (e.g.the therapeutic catalytic antagonists) are preferably administeredby intravenous, parenteral, or oral means. The active molecules(e.g., PPI or pentagastrin) are typically combined with apharmaceutically acceptable carrier (excipient) to form apharmacological composition. Pharmaceutically acceptable carrierscan contain a physiologically acceptable compound that acts, forexample, to stabilize the composition or to increase or decreasethe absorption of the agent. Physiologically acceptable compoundscan include, for example, carbohydrates, such as glucose, sucrose,or dextrans, antioxidants, such as ascorbic acid or glutathione,chelating agents, low molecular weight proteins, compositions thatreduce the clearance or hydrolysis of the anti-mitotic agents, orexcipients or other stabilizers and/or buffers.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives which areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include,for example, phenol and ascorbic acid. One skilled in the art wouldappreciate that the choice of a pharmaceutically acceptablecarrier, including a physiologically acceptable compound depends,for example, on the route of administration of the PPI/pentagastrinand on the particular physio-chemical characteristics of the agent.

In various embodiments the gastrin/pentagastrin/analogue and/or thePPI can be provided in a substantially dry and/or pure form to becombined with a diluent/excipient at the time of use or one or bothagents can be provided already combined with an appropriateexcipient (e.g. in a unit dosage form). In certain embodiments, thegastrin/pentagastrin/analogure or the PPI is provided in a dry(e.g. lyophilized/dehydrated) form, while the other component issuspended in a fluid excipient. Addition of the dry component tothe excipient results in the admixture of thegastrin/pentagastrin/analogure and the PPI. In other embodiments,both the pentagastrin and the PPI are provided combined in acompatible excipient.

It is noted that, in certain embodiments, the PPI and thegastrin/pentagastrin/analogue can be provided combined withdifferent excipients but in a single unit dosage form. Thus, forexample, a tablet can comprise two lamina, one lamina containingthe pentagastrin and a first excipient and the second laminacontaining the PPI and a second excipient. If necessary the laminacan be separated by an inert/neutral layer. Other"multi-excipient" systems can be similarly formulated(e.g. as time release particles in a capsule, dual containergelatin capsules, etc.).

Thus, the pharmaceutical compositions can be administered in avariety of unit dosage forms depending upon the method ofadministration. For example, unit dosage forms suitable for oraladministration include powder, tablets, pills, capsules andlozenges. Certain therapeutic molecules of this invention may beonly marginally soluble in aqueous solutions. In a preferredembodiment, these compositions are typically solubilized,emulsified or suspended in an acceptable excipient.

It is noted that pharmaceutically acceptable formulations forpentagastrin and PPIs are well known to those of skill in the art.Thus, the PPI and the pentagastrin can be administered in theformulation(s) and by the means typically used for these drugs. Inparticularly preferred embodiments, the pentagastrin isadministered by subcutaneous injection.

The concentration of therapeutic agent in these formulations canvary widely, and will be selected primarily based on fluid volumes,viscosities, body weight and the like in accordance with theparticular mode of administration selected and the patient's needs.Actual methods for preparing administrable compositions will beknown or apparent to those skilled in the art and are described inmore detail in such publications as Remington's PharmaceuticalScience, 15th ed., Mack Publishing Company, Easton, Pa. (1980).

Dosages for typical therapeutics, particularly for PPIs, are wellknown to those of skill in the art. Moreover, such dosages aretypically advisorial in nature and may be adjusted depending on theparticular therapeutic context, patient tolerance, etc. Single ormultiple administrations of the compositions may be administereddepending on the dosage and frequency as required and tolerated bythe patient.

In preferred embodiments, the pentagastrin and PPI will beadministered in an amount sufficient to effect a measurabledecrease in gastric acid secretion, more preferably in an amountsufficient to effect a significant decrease in gastric acidsecretion (e.g., a statistically significant decrease at the 90%,more preferably at the 95%, and most preferably at the 98% or 99%confidence level). The pentagastrin dosage will range from about0.05 to about 0.05 to about 25 .mu.g/kg/hr, preferably from about0.1 .mu.g/kg/hr to about 15 .mu.g/kg/hr and most preferably fromabout 0.5 .mu.g/kg/hr to about 10 .mu.g/kg/hr, while the PPIdosage, in preferred embodiments, will be consistent with currentclinical practice.

Similarly, where the pentagastrin and PPI are administered incombination with an antibiotic, the antibiotic is typicallyadministered in a manner and concentration consisting with clinicalpractice.

Uses of PPI and Pentagastrin Combinations

The proton pump inhibitors are, as already mentioned, useful forinhibiting gastric acid secretion in mammals and man. In a moregeneral sense, they may be used for prevention and treatment ofgastric-acid related diseases in mammals and man, including e.g.reflux esophagitis, gastritis, duodenitis, gastric ulcer andduodenal ulcer. Furthermore, they may be used for treatment ofother gastrointestinal disorders where gastric acid inhibitoryeffect is desirable, e.g. in patients on NSAID therapy, in patientswith Non Ulcer Dyspepsia, in patients with symptomaticgastro-esophageal reflux disease, and in patients with gastrinomas.They may also be used in patients in intensive care situations, inpatients with acute upper gastrointestinal bleeding, pre- andpostoperatively to prevent aspiration of gastric acid and toprevent and treat stress ulceration. Further, they may be useful inthe treatment of Helicobacter infections and diseases related tothese. Other conditions well suited for treatment according to themethods of this invention include, but are not limited toZollinger-Ellison syndrome (ZES), Werner's syndrome, and systemicmastocytosis.

The methods and formulations of this invention are suitable for usein essentially any mammal and this invention embraces veterinary aswell as human medical applications. Thus, the methods of thisinvention are applicable to humans and non-human mammals (e.g. arodent, largomorph, bovine, canine, equine, non-human primate,etc.).

Therapeutic Kits

In another embodiment, this invention provides therapeutic kits forpractice of the methods of this invention. Such kits preferablyinclude a container containing one or more proton pump inhibitor(s)and a container containing pentagastrin and/or apentagastrin/gastrin analogue or derivative. Both the pentagastrinand the PPI(s) can be in one container or they can be in separatecontainers. In certain embodiments, the"pentagastrin/gastrin/analogue" and/or the PPIs areprovided in a dry form, while in other embodiments, the"pentagastrin/gastrin/analogue" and/or PPIs aresuspended, or dissolved in an excipient/buffer.

In certain embodiments, the kits optionally include one or moreantibiotics, e.g. an antibiotic selected from the group consistingof penicillin based antibiotics, tetracyclines, macrolides,cephalosporins, and fluoroguinolones.

The kit can comprise packaging that retains and presents themedicants at separate respective consecutive locations identifiedby visibly discernible indicia and the times at which the medicantsare to be taken by the patient. In various embodiments, the timescan include each day of the week and specified times within eachday presented in the form of a chart located on one face of thepackage wherein the days of the week are presented and the timeswithin each day the medicants are to be taken are presented insystematic fashion.

In addition, the kits can include instructional materialscontaining directions teaching the use of a pentagastrin, agastrin, or a derivative or analogure thereof in combination withone or more PPIs to enhance the efficacy of the PPI. While theinstructional materials typically comprise written or printedmaterials they are not limited to such. Any medium capable ofstoring such instructions and communicating them to an end user iscontemplated by this invention. Such media include, but are notlimited to electronic storage media (e.g., magnetic discs, tapes,cartridges, chips), optical media (e.g., CD ROM), and the like.Such media may include addresses to internet sites that providesuch instructional materials.

Claim 1 of 20 Claims
1. A method of increasing the efficacy of a gastricH.sup.+/K.sup.+-ATPase pump inhibitor (PPI) in a human in need of aPPI treatment, said method comprising: injecting into said human aneffective amount of one or more agents selected from the groupconsisting of a pentagastrin and a gastrin, in conjunction with anamount of said gastric proton pump inhibitor effective to reducegastric acid secretion, whereby the efficiency of said gastricproton pump inhibitor is increased.
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