This invention pertains to the discovery that pentagastrin, when administered in conjunction with a proton pump inhibitor (PPI) is synergistic with the PPI and significantly increases the efficacy of 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 pathological conditions characterized by excess gastric acid secretion. In particular, this invention pertains to the discovery that administration of pentagastrin (an agent that is typically used to increase acid secretion), in conjunction with a proton pump inhibitor (PPI) will result in increased efficacy (e.g. prolonged effect and/or greater effect at reduced dosage) than use of the proton pump inhibitor alone. The effect is also mediated by gastrin and gastrin or pentagastrin analogues or derivatives. In particular embodiments, the pentagastrin/PPI combination appears synergistic.

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

Administration of the gastrin/pentagastrin/analogue and the PPI can be by any route convenient for the application of these agents. In preferred embodiments, the gastrin/pentagastrin/analogue is administered by injection (e.g. subcutaneous injection) and the PPI is administered orally or by injection (e.g. intravenous injection). Particularly preferred pentagastrin/gastrin/analogue dosages range from about 0.1 mg/kg/hr to about 10 mg/kg/hr.

The mammal is preferably a mammal diagnosed with a pathology characterized 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 acid hypersecretion. Preferred proton pump inhibitors used in this invention include, but are not limited to rabeprazole, omeprazole, lansoprazole, and pantoprazole, as well as cogeners or racemic mixtures of the same. The mammal may also suffer from hypersensivity to normal acid secretion that may result in gastrointestinal inflammation and ulceration.

This invention also involves the discovery that administration of pentagastrin gastrin or analogues thereof or other compounds that act at the same receptor site (e.g. that are agonistic at the cholecystokinin (CCK) receptor (see, U.S. Pat. No. 5,319,073 for a description of the CCK receptor) will increase urinary sodium excretion (e.g. gastrin, pentagastrin, cholecystokinin and derivatives or analogues thereof act as a diuretic). Thus, in another embodiment, this invention provides methods of increasing urinary sodium excretion and free water excretion. These methods involve administering to a mammal diagnosed with a pathological condition characterized by excessive fluid retention, a dose of pentagastrin or analogues thereof (or in certain embodiments, gastrin or analogues thereof) sufficient to increase urinary sodium excretion in the mammal. In preferred embodiments, the pathological condition is high blood pressure, fluid retention associated with heart failure, fluid retention associated with acute or chronic kidney failure, fluid retention associated with cirrhosis, calcium kidney stones, nephrogenic diabetes insipidus, renal tubular acidosis, treatment of Meniere's disease, constrictive pericarditis, and hepatorenal syndrome. The pentagastrin is typically administered in the dosage ranges indicated above.

Kits are also provided for the practice of the methods of this invention. A preferred kit for the treatment of a pathology characterized by excess gastric acid secretion, said kit comprises a container containing a proton pump inhibitor (PPI); and a container containing pentagastrin. Preferred proton pump inhibitors include, but are not limited to rabeprazole, omeprazole, lansoprazole, and pantoprazole, as well as cogeners or racemic mixtures of the same. The pentagastrin and/or the PPI can be provided in a pharmaceutically acceptable excipient or diluent. The kits can additionally include materials describing the use of pentagastrin, gastrin or analogues thereof in conjunction with a PPI to reduce gastric acid secretion and/or materials describing the use of pentagastrin as a diuretic. Instructional materials can also include recommended dosages and description(s) of counterindications, etc.

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

DETAILED DESCRIPTION

A wide number of pathological conditions are characterized by oversecretion of gastric acid. Such conditions include, but are not limited to Zollinger/Ellison syndrome (ZES), gastroesophageal reflux disease, peptic ulcer disease, duodenal ulcers, atrophic gastritis, esophagitis. In particular, conditions such as ZES and peptic ulcers can have serious complications.

Peptic ulcers are one of the most prevalent diseases in industrialized nations. Control of gastric acid secretion is the main 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 parietal cell receptors. Prior to the discovery of histamine H.sub.2-receptor antagonists such as cimetidine and ranitidine, peptic ulcer treatment consisted of antacid therapy and anticholinergic drugs (e.g. dicyclomine HCl). With the advent of H.sub.2-receptor antagonists, however, treatment with anticholinergic agents has been largely supplanted by histamine H.sub.2-receptor antagonist therapy. The development of this class of therapeutic entities presents one of the most important advances in the field of medicinal chemistry.

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

This invention pertains to the discovery that administration of pentagastrin (an agent that is typically used to increase acid secretion) in conjunction with a proton pump inhibitor (PPI) will result in increased efficacy (e.g. prolonged effect and/or greater effect at reduced dosage) than use of the proton pump inhibitor alone. In particular embodiments, the pentagastrin/PPI combination appears synergistic.

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

It was also a discovery of this invention that essentially any increase in gastrin level in conjunction with a PPI will result in increased efficacy of the PPI. Thus, instead of pentagastrin administration, exogenous gastrin can be supplied. Alternatively endogenous gastrin secretion can be upregulated using, for example, aromatic amino acids, or with a meal, etc. Thus, it is believed that essentially anything that stimulates G-cell activity will increase the efficacy of a PPI.

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

Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are compounds that are selectively inhibit activity of the gastric acid pump, H.sup.+/K.sup.+-adenosine triphosphatase (ATPase). Preferred PPIs include substituted pyridyl methylsulfinyl benzimidazoles. These compounds accumulate in the acid space of the parietal cell and convert to active sulfonamide by an acid-catalyzed reaction. Consequent covalent inhibition of H.sup.+/K.sup.+-ATPase blocks the final step of acid secretion. Other preferred PPIs include various substituted 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 thiadiazole compounds that are effective as proton pumps inhibitors. European Patent Nos. 322133 and 404322 disclose quinazoline derivatives, European Patent No. 259174 describes quinoline derivatives, and WO 91/13337 and U.S. Pat. No. 5,750,531 offer pyrimidine derivatives, as proton pump inhibitors.

Suitable proton pump inhibitors are also disclosed, for example in EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and WO90/06925, WO91/19711, WO91/19712, WO94/27988 and WO95/01977.

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

The proton pump inhibitors used in the dosage forms of the invention 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 the Mg.sup.2+ salts. Further where applicable, the compounds can be used in racemic form or in the form of a substantially pure enantiomer thereof, or salts of the racemates or the single enantiomers.

In addition this invention contemplates the use of a single proton pump inhibitor, or in certain embodiments, combinations of two or more 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 Patent Applications 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 a gastrin carboxyl terminal tetrapeptide, the active portion found in essentially all natural gastrins. Pentagastrin is a colorless crystalline solid soluble in dimethylformamide and dimethylsulfoxide; it is almost insoluble in water, ethanol, ether, benzene, chloroform, and ethyl acetate. Pentagastrin contains the C-terminal tetrapeptide responsible for the actions of the natural gastrins and, therefore, acts as a physiologic gastric acid secretagogue. The recommended dose of 6 .mu.g/kg subcutaneously (in applications where increased gastric acid secretion is desired) produces a peak acid output which is reproducible when used in the same individual. Pentagastrin stimulates gastric acid secretion approximately ten minutes after subcutaneous injection, with peak responses occurring in most cases twenty to thirty minutes after administration. Pentagastrin is typically used as a diagnostic agent for evaluation of gastric acid secretory function. In one preferred formulation, pentagastrin is formulated with sodium chloride and water for injection. The pH is typically adjusted with ammonium hydroxide and or hydrochloric acid. In one commercially available formulation, each ml of injection contains 0.25 mg (250 mcg) pentagastrin along with 8.8 mg sodium chloride and water for injection, USP.

The methods of this invention are not limited to the use of pentagastrin. To the contrary, it was a discovery of this invention that in addition to pentagastrin, exogenous gastrin can be supplied or endogenous gastrin secretion can be upregulated using, for example, aromatic amino acids, or with a meal, etc. Thus, it is believed that essentially anything that stimulates G-cell activity will increase the efficacy of a PPI.

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

In addition, it is noted that gastrins are structurally related to the CCK's are structurally-related neuropeptides which exist in gastrointestinal 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 or analogues or derivatives thereof that stimulate endogenous gastrin secretion or that generally stimulate G-cell activity will be useful 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 peptide synthesis methodologies (see, e.g. Barany and Merrifield Solid-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 or analogue etc.) can be administered simultaneously. However, in a preferred embodiment, the pentagastrin or analogue thereof is administered first followed by the PPI. In certain embodiments, the pentagastrin or analogue thereof can be administered after the PPI.

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

In certain embodiments, it is desirable to administer one or more antibiotics in conjunction with the PPI and pentagastrin. Thus, for example, the treatment of ulcers associated with Helicobacter sp infection (e.g. Helicobacter pylori), the antibiotic will mitigate/eliminate the bacterial component of the pathology.

It is noted that U.S. Pat. No. 5,629,305 teaches that a proton pump inhibitor (e.g. omeprazole or lansoprazole) which increases intragastric pH, can increase the bioavailability of various antibiotics, in particular the therapeutic amount of an acid degradable antibacterial compound such as a penicillin or a macrolide. A wide variety of antibiotics are suitable for use with the methods of this invention. Such antibiotics include, but are not 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 analogues thereof, and/or PPI(s) used in the methods of this invention, (e.g. the therapeutic catalytic antagonists) are preferably administered by intravenous, parenteral, or oral means. The active molecules (e.g., PPI or pentagastrin) are typically combined with a pharmaceutically acceptable carrier (excipient) to form a pharmacological composition. Pharmaceutically acceptable carriers can contain a physiologically acceptable compound that acts, for example, to stabilize the composition or to increase or decrease the absorption of the agent. Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, compositions that reduce the clearance or hydrolysis of the anti-mitotic agents, or excipients or other stabilizers and/or buffers.

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

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

It is noted that, in certain embodiments, the PPI and the gastrin/pentagastrin/analogue can be provided combined with different excipients but in a single unit dosage form. Thus, for example, a tablet can comprise two lamina, one lamina containing the pentagastrin and a first excipient and the second lamina containing the PPI and a second excipient. If necessary the lamina can 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 container gelatin capsules, etc.).

Thus, the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. For example, unit dosage forms suitable for oral administration include powder, tablets, pills, capsules and lozenges. Certain therapeutic molecules of this invention may be only marginally soluble in aqueous solutions. In a preferred embodiment, these compositions are typically solubilized, emulsified or suspended in an acceptable excipient.

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

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

Dosages for typical therapeutics, particularly for PPIs, are well known to those of skill in the art. Moreover, such dosages are typically advisorial in nature and may be adjusted depending on the particular therapeutic context, patient tolerance, etc. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient.

In preferred embodiments, the pentagastrin and PPI will be administered in an amount sufficient to effect a measurable decrease in gastric acid secretion, more preferably in an amount sufficient to effect a significant decrease in gastric acid secretion (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 about 0.05 to about 0.05 to about 25 .mu.g/kg/hr, preferably from about 0.1 .mu.g/kg/hr to about 15 .mu.g/kg/hr and most preferably from about 0.5 .mu.g/kg/hr to about 10 .mu.g/kg/hr, while the PPI dosage, in preferred embodiments, will be consistent with current clinical practice.

Similarly, where the pentagastrin and PPI are administered in combination with an antibiotic, the antibiotic is typically administered in a manner and concentration consisting with clinical practice.

Uses of PPI and Pentagastrin Combinations

The proton pump inhibitors are, as already mentioned, useful for inhibiting gastric acid secretion in mammals and man. In a more general sense, they may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they may be useful in the treatment of Helicobacter infections and diseases related to these. Other conditions well suited for treatment according to the methods of this invention include, but are not limited to Zollinger-Ellison syndrome (ZES), Werner's syndrome, and systemic mastocytosis.

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

Therapeutic Kits

In another embodiment, this invention provides therapeutic kits for practice of the methods of this invention. Such kits preferably include a container containing one or more proton pump inhibitor(s) and a container containing pentagastrin and/or a pentagastrin/gastrin analogue or derivative. Both the pentagastrin and the PPI(s) can be in one container or they can be in separate containers. In certain embodiments, the "pentagastrin/gastrin/analogue" and/or the PPIs are provided in a dry form, while in other embodiments, the "pentagastrin/gastrin/analogue" and/or PPIs are suspended, or dissolved in an excipient/buffer.

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

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

In addition, the kits can include instructional materials containing directions teaching the use of a pentagastrin, a gastrin, or a derivative or analogure thereof in combination with one or more PPIs to enhance the efficacy of the PPI. While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited 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 provide such instructional materials.
 

Claim 1 of 20 Claims

1. A method of increasing the efficacy of a gastric H.sup.+/K.sup.+-ATPase pump inhibitor (PPI) in a human in need of a PPI treatment, said method comprising: injecting into said human an effective amount of one or more agents selected from the group consisting of a pentagastrin and a gastrin, in conjunction with an amount of said gastric proton pump inhibitor effective to reduce gastric acid secretion, whereby the efficiency of said gastric proton pump inhibitor is increased.

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