CA1309662C - GASTROPROTECTIVE COMPOSITION CONTAINING .beta.-ADRENERGIC AGONISTS - Google Patents
GASTROPROTECTIVE COMPOSITION CONTAINING .beta.-ADRENERGIC AGONISTSInfo
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Abstract
ABSTRACT OF DISCLOSURE
A pharmaceutical composition and process for administering non-steroidal anti-inflammatory drugs which are protected against injury to gastrointestinal tract by beta adrenergic agonists.
A pharmaceutical composition and process for administering non-steroidal anti-inflammatory drugs which are protected against injury to gastrointestinal tract by beta adrenergic agonists.
Description
This invention relates to non-steroidal anti-inflammatory drug (hereinafter referred to as NSAID) compositions containing protectants against gastrointestinal injury induced by such NSAIDs and to processes for administering such composition. More particularly it concerns compositions and processes of the aforesaid type that employ beta adrenergic agonists as the protectants. The compositions of this invention are useful in treating conditions and symptoms that are classically treated by the administration of NSAIDs e.g. headache pain, pain and inflammation associated with arthritis and other systemic diseases, elevated body temperatures etc. This invention also relates to a process for inhibiting gastric acid secretion and the treatment of peptic ulcers.
Acetylsalicylic acid (ASA) such as Aspirin (trademark) and other NSAIDs have long been the most popular drugs for the management of pain, inflammation and fever. However, one of the drawbacks in their use is the gastrointestinal injury and/or bleeding that sometimes accompanies their administration to individuals. This may become a particularly severe problem where large and sustained doses of NSAIDs must be given to control the symptoms, as for exampla, in the case of the management of arthritis.
It has now been found that NSAID induced gastrointestinal injury and particularly gastrointestinal mucosal injury can be significantly reduced when beta adrenergic agonists are admin-istered concurrently with a NSAID. The beta adrenergic agonists form a fairly well defined class of pharmaceutically effective compounds that are characterized by the fact that they act by stimulating beta adrenergic receptor sites. These receptor sites are of two types referred to as the beta 1 and beta 2 ,.1 ~
~ite~. Beta adrenergic agoni6ts may act on one or the other or on both type6 of ~ites. Any o~ these are e~fective in practicing the pre~ent invention.
It has also been found that gastric acid secretion can be inhibited, and peptic ulcers can be treated by the administration of a beta adrenergic agonist. Typical agonists of this type which can be used in accordance with the invention, include isoproterenol, metaproterenol, terbutaline, albuterol, fenoterol, bitolterol, isoetharine, colterol, or ritodrine or their pharmaceutically acceptable 6alts.
A number o~ beta adrenergic agonists are known in the prior art which are useful for the purpose~ o~ this invention. Of special interest are isoproterenol which i6 a mixed bata 1 and beta 2 agonist and terbutaline which i8 a beta 2 agonist. By way of illustrating other beta adrenergic agonists that may be employed herein, the following are given metaproterenol, albuterol, ritodrine. All of these ~ay be employed as such or as pharmaceutisally acceptable salts.
The NSAIDs al50 ~orm a well known class of druys that are anti-inflammatory analgesics. These have the common properky of inhibitiny the fo~mation of prostaglandins which have a protective affect on the gastrointestinal mucosa. See Goodman and Gilman "The Pharmacological Basi6 for Therapeutics" 7th Edition, p. 678. It is because of this inhibiting e~ect that the oral administrat$on o~ drugs o~ this class tend to result in gastrointestinal injury and/or bleeding, the problem that the present invention seeks to reduce or eliminate.
A number of NSAIDs are known in the prior art to which the present invention has application. The most aommonly known group are the salicylates o~ which ASA is the prime example. Another group of NSAIDs that have utility in con-nection with the instant invention are the proprionic acid 1 ~(3~66~
derivative~. Included in thi~ group, ~or example, arQ ibuprofen and naproxe~. A further group of NS~IDs employable herein are the fenama~e~ and compound~ closely related to them struc~
turally. ~hesa may be illustrated by such compound~ a mePenamlc acid, meclofenamake sodium, diclo~enac and its sodium salt. Also belonging to the class o~ NSAIDs with which the present invention iB concerned are the indolz derivatives (e.g.
indomethacin); pyrrolealkanoic acid derivatives (e.g. tolmetin);
pyrazalone derivatives (e.g. phenylbutazone); oxicams (e.g.
piroxicam); etc.
The quantitative relationship o~ the NSAID to beta adrenergic agonist contained in the present products may be expressed on the basis o~ th~ average daily dose of tha product i.e. milligrams/per Kg of body weight/per day. In this case the average do~e for the products will generally be from about lO
mg/Kg/day to about lO0 mg/~g/day o~ NSAID and from about 0.0003 mg/Kg/day to about 500 mg/Xg/day of one or a combination of beta adrenergic agonist~ with the preferred range being ~rom about 15 mg/~g/day to about 75 mg/Xg/day of NS~ID and from about 0.01 mg/Xg/day to about lO mg/KgJday o~ ~aid bata adrenergic agonists.
The unit dosage forms ~or the present product~ will be formulated for convenient oral admlnistration. Each such unit will generally contain from about 200 mg to about 600 mg o~
NSAID and fro~ about 0.7 mg to.about 70 mg of ons or a combination o~ adrenergic agonists. For therap~utic use th~
beta adrenergic agonist will normally be administered a~ a pharmaceutical composition comprislng as the essential active ingredient at least one of such agonist in its basia form or in the form o~ a non-toxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier. The pharmaceutical composition can be administered orally in~ranasally, parenterally, or by rectal suppository. A
wide variety o~ pharmaceutical forms may be employed. Thus, if a ~olid carrier is used, the preparation may b~ a tablet, placed 1 3 i(~ ~ !6 ~ ,~
. .
in a hard gelatin tabsule in powder or yranular form, or in a form o~ a trochs, caplet or capsule. I~ a liquid carrier i~
employed, the preparation may be in a form of a ~yrup, emulsion, soft gelat~n capsule, ~terile solution for in~ection, or an aqueous or non-aqueoua liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.
The dos2ge of the composition~ ~f this invention w~ll depend not only on such factors as the weight of the patient, but al30 in the degrea of gastric acid lnhibition desired and the potency of the particular compound being utilized. The dec~sion as to the particular dosage to be employed i~ within the discretion and the routine knowledga of the physician. In thQ Heidenhain Pouch ~og test described below, cimet~dina has an oral ED50 ~ approximately 3.3 moles/kg. Th~ usual human adult oral dose o~ cimetidine i9 3 00 mg, given four times a day~ The usual human adult starting oral dosag~
o~ the compound~ of this invention are readily dete~mined ~rom their oral ED50 in thi~ same test. Thu3, i~ the oral ~D50 i~ 0-33 moles/kg. the usual starting oral dosage would be approximately 30 mg. given four tlmes a day, ~tc. Si~llar calculat~ons may b~ made for intravenous dosages. These starting dosages (and the number of ti~e~ administered per day) may, o~ course, be varied by titration of ths dosage to tha particular circum~tances of the specific patient.
With th2 preferred co~pound~ o~ thi~ lnventlon, each oral dosage unit will contain the active ingredient in an amount o~ from about 0.5 mg.
to about 300 mg. and mostly pre~erably from about 190 mg. to about 100 mg. The active ingredient will preferably be administQred in egual dose~ from ona to ~our time~ a day.
1 ~.
Depending upon the do~age ~o~ employed the product~ o~ 'chi~
in~ention may also conta~n other ad~uvants that may be useful in formulating the particular dosage form or in its administration.
Thus, ~or example, when a~m~nistered a~ a tablet the products o~ this invention may al~o contain lubricant~ exclpiants, binding agen~s, di~lntegrating agents, flavoring agents, etc. In addition these products may also contaln other pharmaceutically active ingredient such ag deconge~tants~ analgesic ad~uvant~, antihis~amines, expectorants, antitussives, diuretics, other analgesics, other anti-lnflammatory agent~, other antipyretic~, other anti- rheumatics, antioxidants, vasodilators, ~moot~ muscle relax- ant~, skeletal muscle relaxants, bronchodilators, vitamin~, traca minerals, amino acids, biological peptide~ etc.
The product~ o~ thi~ ~nYsngion may takQ a variety o~ form~, A~ indicated above th~y ~ay ag~u~ the ~orm o~ tablat~ How-ever, tha NSAID and the bata adrenergic agonists may ba in powdered or granular ~orm containad in edible capsule~ such as qalatin cap ule~. The present products may al~o taks th2 form o~ suspension~ or ~olutions o~ the above ingredients in a sultable liquid medium or o~ powders packaged in 8U~ table pap~r envelope~. .
~ he mechanism by which the beta adrenergic agonists serve aæ
protectants again~t gastrointestinal injury when admlnistered as the solQ pharmaceuticaly active ingredient, or coadmin-istered with the NSAID is not clearly understood. one factor seems rairly certain and that 1~ that it is not necassarily ~imply related to the inhibition of gastric acid ~ecretion.
This is made evident by the observation that, for example, with 1 3Q~6~
certa~n level~ of isoproterenol, gastric in~ury protection has been noted notwithstanding the ~act that the pH o f the s omach content was essentially the same as the pH of the control stomach. Similarly, as reported by M.H. Steven et al ln the Abstract of Paper~; I'Gastroenterology" Vol. 88, No. 5 Part 2 at page 1600, although isoproterenol had a role in the regulation of gastric secretion stimulated by gastrin and acetylcholine, histamine-stimulated acid secretion was resistant to inhibition by isoproterenol. In passing, it mlght be noted that Steven et al were not measuring the effect of the coadministratlon of ASA with isoproterenol.
Determination of Gastric Antisecretory Activity in the Gastric ~istula Rat.
Male Long Evans rats weighing about 240-260 grams at the time of cannula implementation are used. The design and implementation of the ~tainless steel cannula into the anterior wall of the fore-stomach are carried out essentially as described by Pare et al. tLaboratory Animal Science, 27, 244 (1977). The ~iatula components ar~ designed and the operative procedure is carried out exactly as described in the above reference. Poæt operatively the animals are indiv~dually housed in solid bottom cages with sawdust and are allowed food and water ad libitum throughout the entire recovery period. Animals are not used for test purposes for at least 15 days a~ter the operative procedure.
The animals are fasted but allowed water ad llbitum for 20 hour~ before the testing procedure ~ 9 to begin. Immediately prior to collection, the cannula i8 opened and the stomach washed gently with 30-40 ml of warm ~aline or dlstilled water to remove any residual contents. The catheter is then ecrewed into the cannula in place o~ the plugging screw and the rat i6 placed in a clear plastic rectangular cage measuring 40 cm long, 15 cm wide and 13 cm high. The bottom o~ the cage has a slit ..
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approximately 1.5 cm wide and 25 cm long running down the center to accommodate the catheter which hangs through it. In this way the rat i8 not restricted and can move freely about the cage during collection periods. The remainder o~ the assay i carried out as described by Ridley et al. [Research Co~m. Chem.
Path. Pharm., 17, 365 (1977)].
Gastric secretions collected durinq the first hour a~ter washing the stomach are discarded as they may be contaminated.
For oral evaluation, the catheter is then removed from the cannula and replaced with the plugging screw. Water (2 ml/kg) i6 administered orally via gastric intubation and the animal is returned to the cage ~or 45 minutes. After thls time the plugging screw is removed and replaced with a catheter to which a small plastic vial has been attached to collect the gastric secretions. A two hour sample iOE collected (this represents the control secrPtion), the catheter removed and replaced with the plugging ~crew. The test drug is now administered orally in a volume of 2 ml/kg via gastric intubation. Forty five minutes later the plugging ~crew is again removed, replaced with the catheter attached to a small plastic vial and another 2 hour Eample is compared to those of the control sample in order to determine the effect~ of the test drug.
~ hen te~t compounds are to be evaluated parenterally, the animal i8 in~ected lp or 6C with the test compound vehicle in a volume of 2 ml/kg immediately after discarding the initial 60 minute collection. A two hour sample is collected ~control ~ecretion) and the animals are in~ected either ip or 6C with the test compound in a volume o~ 2 ml/kg. An additional two hour sampl2 i~ collected and its secret~ons are compared to those of th~
control period to datermine drug ePfect~.
The ~amples are centrifuged and pla ed in ~a gra~uated centrifuge tube for volume determination. Titratabl~ acLdity is measured by titrating a one ml sample to pR 7.0 with 0.2N NaO~, using an autoburet and an electrometric pH meter (radiometer). Titratable ac~d output i~ calculated ln microequivalent3 by multiplying the volume in milliliters by the acid concentration in mllllequivalents per liter.
Results are expressed a~ percent inhibition relative to control reading. Dose re~ponse curves are constructed and ED50 values are calculated by regression analyse~. At least three rat~ are used at each dosage level and a minimum of three dosage levels are utilized for determination of a do~a responaive curve.
Two o~ the ~tandard an~mal model~ for determin~ng gastric antisecretory activity o~ antagon~st are the Gastric Fistula ~at and the ~Pidenhain Pouch Dog. Comparative data between metaproterPnol, a known beta adrenergic agon$3t, and cimetidine, a known H2 receptor antagoni~t and e~ectivQ inhibitor of ga~tric secretlon, i8 ~hown in table3 I and II below:
1 3096~2 Table I
Gastric antisecretory actiY~ty ln the Gastric Fistula Rat ED50 values ~mg/kg) for oral treatment Metaproterenol Cimetidine Potence Ratio ~Cimetidine = 1 23.6 (15 - 42) * 12 (9.0 - lB) * 0.58 *(95% confidence limit) Determination of Gastric Antisecretory Activity in the Heidenhain Pouch Dog Prior to surgery, hematology and blood chemistry profiles are obtained and an assessment made a~ to the general health of selected female dog~. Dogs are vaccinated with Tissue Vax 5 (DHLP-Pitman-Moore) and housed in general animal guarters for an observation period of four weeks, 80 incipient diseases may become apparent. Dogs are fa~tPd with water ad libitium 24 hours prior to surgery.
Anesthesia i~ induced with ~odium pentothal (Abcott) 25-30 mg/kg iY. Subsequent anesthesia is maintained with methoxyflurane (Pitman-Moore~. A midline linea alba inci~ion fro~ xiphoid to umbilcu~
provides good exposure and ease o~ ~losureO The stomach is pulled up into the operative field, the greater curvature ~tretched out a~
multiple points and clamp~ placed along the 6elQrted line of in~i~ion.
The pouch i8 made from the corpu~ of the stomach 80 that true parietal cell ~uice is obtained. About 30% o~ the COrpU8 volume i8 resected.
The cannula is made of light-weight, biologically inert material such as nylon or Delrin with dimensions and attachments a~ter DeVito and Harkins [J. Appl. Phy~iol., 14, 138 (1959)]. Post operatively, dogs are medicated with antibiotics and an analgesic. They ar~ allowed 2-3 months for recovery. Experiments are carried out in the following way:
Dogs are fasted overnight (18 houræ3 with water ad libitum prior to each experiment. The dogs are placed in a sllng and a saphenous vein cannulated for drug administration. Histamine as the base (100 g/kg/hr) and chlorpheniram~ne maleate ~0.25 mg/kg/hr) are infused continuou~ly (in a volume of 6 ml/hr~ with a Harvard infusion pump.
A Ninety m~nute infusion is allowed for the dogs to reach a steady state of acid output. At thi3 time the drug or normal saline (control) is administered ¢oncomitantly with the secretagogue in a volume of 0.5 ml/kg over a 30 second period. When oral studies are to be carried out, the drug is administered via gastric gavage in a volume of 5 ml/kg. Infusion of the secretagogue is continued and 15 minute samples of the gastric ~uice are taken for 4.5 hours. Each sample is measured to the nearest 0.5 ml and titratable acidity i~ det~rmined by titrating a 1 ml sample to p~ 7.0 with 002N MaOH, using an autoburet and an electrometric pH meter (or radiometer~. Titratable acid output i8 calculated in microe~uivalents by multiplying the volume in milliliters by the acid concentration in a m~llequ~valents per liter.
Results are expressed a~ percent inhibition relative to control reading~. Dose response curves are constructed and ED~ values are calculated by re~ression analy~e~ From 3 to 5 dogs are used at each dose level and a minimum of three dosage levels are utilized for determination of a dose response curve.
.~i~ . - - ...............
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Table II
Gastric Antisecretory Activity in the Heidenhain Pouch Dog ED50 values (mg/kg for oral treatment) Metaproterenol Cimetidine PotQncy Ratio (Cimetidine - 1 0.05 0.71 14.2 The potency ratios ln the rat and canlne antisecretoxy model describe~ above are 0.58 and 14.2, respectively.
Cytoprotective ackivity was evaluated in five te3t models.
Metaproterenol was comparPd to cimetidine as a protectant. The term "cytoprotection" describes the phen~menon whereby some agents protect the gastric mucosa against injury induced by a variety o~ injurious stimuli. These assays are prlmarily used as secondary models to evaluate agents which have confirmed anti-gastric secretory activity and/or activity in primary (antisecretory) model In the present case, the beta adrenergic agonist metaproterenol was compared to the cytoprotective activity o~ cimetldineO The injuriou~ sti~uli in our present test were provided by ethyl alcohol, ASA and stress, hydrochloric acid, and indomethacin. The respective assays were carried out as described below:
Eth~l alcohol-The method employs 3.0 ml/kg ethyl alcohol (100%) a~ thenecrotizing agent and provides additional data besides ga~tric lesions.
`~ ~ 3 0 ~ !2 Adult male Long-Evans rats weighing 275 300 grams (~lue Spruce Farms, Alton, New York) are used. Animals are housed individually in stainless steel cages with wire-mesh bottom~. The housing battery is arranged into six groups of five each, individually numb2red. Food and water are removed 24 and 1 1/2 houxs, respectively, prior to exposure to ETOH. Animals receive the test compounds ~ither p.o., 6 . C , or ip.
(3 12 ml/kg) 60 minutes before administration o~ 100% ethanol (3.0 ml/kg/ by gavage). For some purposes, different water removal and drug pretreatment times may be used. Sixty minutes after ethanol administration the animals are sacrificed by administration of T 61 (Hoechst), 0.2 ml i.p.
An abdominal incision is made, and after clamping the esophagus ~ust above the esophageal sphincter with forceps, the stomach is carefully lifted ~rom the abdominal cavity. Two cuts are made, approximately 1/4 3~ below the pyloric valve and 1~4ll above the esophageal ~phincter, and the stomach remoYed rapidly without a~y loss o~ gastric contents. The size of the stomach including contents i8 noted as small ~ medium or large. Stomachs are cut open along the greater curvature and the content3 expressed into graduated centrifuge tubes. Gastric ~uice samples are centrifuged and total ~olume, and contentR of solid and mucus are estimated to the nearest 0.1 ml Na+
and K~ content o~ the gastric ~uice as well as pH are determined.
Under these conditions, ethanol produces prominent ~acroscopic lesions in the fundic stomach, but gross macroscopic changes are only ! `~- ` .. . ~ . .. .
1 ~9~b2 var~ rarely observed in the forestomach. An occasional control animal shows some degrae of redness or hyperemia and/or s~ell petechiae in the forestomach. Lesions characteristic of ~undic damage are not usually observPdO For these reasons, the forestomach (along with nongastric tissue) is removed and not examined. In addition, absence of the forestomach facilitat~s the photocopy and gross examlnation o~ the remaining stomach.
The remalning fundic-pyloric stomach remnant is rinsed in water and placed flat in a standard position. The tissue is photographed with a Polaroid camera with a close-up lens. Scoring of lesions is done from this permanent record. Each photograph includes a reference scale in mm. Individual ulcers are measured by total lesion area (mm2) and these scores are added together to determine total ulcer area for a stomach. Small well defined but quite visible ~pot (petechiae) are often present; a conglomerate area estimate i8 made for these and added to the total. Some variability in ulcer scoring between persons may occur because even optimal quality photographs will show minor shadows, shades, overexposed ~pots and irregularly shaped ulcers.
Standard photographs are about 2 X actual siza. An estimate Qf real ulcer area (mm23 is obtained after dividing the area score by ~our. For each treatment group, the ~ean area i8 calculated. From this, the percent inhibition of le~ion formation, I ls calculated as:
I = Lesion Score (controls~ - Lesion Score~.(treated3 X 100 Lesion Score (Controls) The mean ulcer score ~or a control group will be used to calculate "I" but normally ~ndividual lesion ~coreR ar~ used in drug treatment groups. In some cases, the observed treatment ~core iæ greater than the mean control valve, in which case that ~core i~ taken as the mean control valve (exacerbation o~ lesion formation is not considered). In rare instances, the da~a from an animal will be discarded if, e.g., ~eces are ~ound in the stomach~
In dose-response studies, the ED50 (dose at which 50%
inhibition of lesion formation occur6) is determined by probit analysis.
ASA + Stress . . .
Male Lvng Evans rats (approximately 275-300 g~s) are housed 6 per cage and acclimated at least three days while maintained on an ad libitum schedule of food and water~ Prior to starting an experiment, rats are deprived o~ food for twenty-four hours and water for one hour. Thlrty mlnute~ be~ore 6ubjecting animals to cold restraint stress, each rat i~ dosed by gastric intubation (6 ml/kg) with ASA (80 mg/Xg) homogenized with methy-cellulos~ (0.1%) in water.
TeYt agents are admini~tered 60 or 30 min prior to the ASA
mixture either orally or parenterally. Each control o~ drug treated group normally con~ists of 5 rata. The multi-stress method entails placing the dosed rat in a ventilated plastic tub2 closed at one end -- lg --1 30966~
with a rubber ~topper. The open end ~8 then closed with a 6econd stopper and $he tube is place in an environmental cha~ber maintained at 4-5C for two hour~. The tube contains ~everal 3~8" holes for breathing purposes and iB about ten inches long and two inches wide.
At the end of ~he two-hour cold-restraint period, each animal is sacrificed with an injection of T-61 euthanasia solution (Hoechst).
An abdominal incision is mada and the stomach removed by cutting just above the esophageal ephincter and just below the pyloric valve.
The ~tomach is opened along the greater curvature and the stomach contents di6carded. Under the conditions described, ASA plus cold reskraint stress produce6 spotty and narrow dark bands of linear macroscopic lesions which are usually found in the corpus ~undic stomach. There~ore, forestomach and other accessory ti sue which show no macroscopic leslon damage are trimmed. The remaining fundic portion is rlnsed wlth water and placed flat in a standard poæition for photographing. The stomach along with a millimeter reference scale i5 photographed at 2X actual size with a Polaroid camera.
Scoring of leslon~ i8 done from thi~ permanent r~cord.
The lesion ~core i8 determlned by measuring and adding together the total millimeter lengths of all visible erosions. Small spots (petechia) are scored as 1.0 mm each and added to the aggregate. An estimate of real lesion length i~ obtained by dividing the aggregate score by two. For each treatment gxoup, a mean lesion score is determined. From this, the percent inhibltion of lesion ~ormation, I, is calculated as:
.~
1 30~6~
I = Le~ion Scor~ ~controls~ - Les~on Score (t_eated) X 100 ~esion Score Control~
The mean lesion ~core for a control group will be used to calculat~ "I" but indivldual lesion score~ will usually ba used in drug treatment groups. Observed treatment ~cores tha~ exceed th~
mean control value are taken a~ the mean control value without considering ~xacerbation o~ le~ion ~ormatlon.
In doso response studie~, thQ ED50 (dose at which 50%
inhibition o~ lesion formation occurs) i~ determlned by probit analy~is.
HCl:
The present method to produce ga~tr~c lesions in rats employs 3.0 ml/kg 0.75N HCl as the necrotlzing agent and provide additional data besides gastric le~ions.
Adult male Long~Evan~ rats weighing 275-3~0 gram3 ~Blue Spruce Farms, AltQn~ Ne~ York) are u~ed. An~mals are housad individually in 6tainless ~teel cages with wir~ mesh boktom~. Th~ hou~ing battery is arranged into 5iX group o~ ~iv~ each, indlvidually numbered. Food and water are removQd 24 and 1 1~2 hours, respectiv21y, prior to HCl. Animal~ receive th~ test compounds either p.o., ~.c., or i.p.
(3-12 ml/kg) 60 minute~ befor~ administration of 0.75N HCl (3.0 ml/kg, by gavage). For some purposes, di~fer~nt water removal and :
: ''' `
1 30`~6`~
-.
drug pretreatment times may ba used. Sixty ~inutes after ~Cl th~
animal~ are sacrificed by admini~tration o~ T-61 (Hoechst), 0.2 ml, i .p.
An abdominal incision i~ made, and after clamplng the esophagu~
~ust above the esophageal sphincter with tweezer~, the stomach is carefully lifted ~rom the abdomina~ cavity. Tw~ cut8 are made, approximately 1/4 " below the pyloric valve and 1/4 ~i above the esophageal sphincter, and the stomach rapidly removed without any 1088 0~ gastric contents. The size o~ the stomach including content~
is noted as small, medium or large. Stomachs are cut open along the greater curvature and the content~ expressed into graduated centrifuge tube~. Gastric ~uic~ samples are centrl~uged and total volume, and contents o~ olid~ and mucus are e~timated to the neare~t 0.1 ml. Na~ and K~ contents o~ the gastric jUiCQ as well as pH
are determined.
Under these condition~, 0.75N HCl produce~ prominent macroscopic lesions in the fundic sto~ach, but gros~ macroscopic changes are only very rarely observed in the ~orestomach. An occas~onal control animal ~how~ 80mQ degra~ o~ radnes~ or hyperemia and/or ~mall petechiae ln the iorestomach, but never lesion~ charactsristlc o~
fundlc damage. Fox these reasons, the fore~tomach (along with nongastric ti~sue) i~ removed and not examinad. In addition, absenc2 o~ the fore~to~ach ~acilitates the. photography and examination of the remaining stomach. W~t wsight of th~ whola stomach i9 determined be~ore removal of the ~ore~tomach.
096`62 ~ h~ rema~ning fundic-pyl~ric ~tomach remnant 1~ rinsed in water and placed ~lat ln a ~tandard po8ition~ ~h~ tissue i8 photographed with a Polarold camera with a c~o~e-up lens. Scoring of lesions i~
done from this permanent record. Each photograph includ8~ a referencs scale in m~. Individual ulcer~ are measured by total lesion length in mm and these scores ar~ added tog~ther to determine total ulcer length for a stomachc Small well d~ined but quite visiblc ~pot~ (petechiae) are often present: a conglomerate length estima~e i~ made for these and added to the total. Some variability ulcer scoring between persons may occur because even optimal qual~ty photographs will show minor shadows, shades, overexposed spots and irregularly shaped ulcers.
Standard photograph~ are about 2 x actual size. An estimate of real ulcer length (mm~ i~ obtained after div~ding th2 length score by two. For each treatment group, the mean length 1~ calculated. From this, the percen~ inhibition of lesion formation, I, i~ calculated as:
I = Lesion score (controls) - Lesion Score (treated~ X 100 Lesion Score (controls~
The ~ean ulcer score for a control group will be used to calculate 'II" but normally lndividual lQsion scores ara u6ed in drug treatment group~. In ~ome casas, th~ obs~rved treat~ent ~cor~ 13 1 3~ ~!6 ~,~
greater than the mean control value (~xacerbation o~ lesion ~ormation 1~ not considared). In rare lnstance~, tha data ~rom an animal will be discarded i~, s.g., fece~ are ~ound in the ~tomach.
In dose-response studie~, thQ ED50 (dose at which 50~
inhibition o~ lesion ~ormation occurs) iQ determined by probit analysis.
IndomethaCin Male Long Evan~ rat~ (approx~mately 275-300 ~s~ ar~ housed 6 per cage and acclli~ate~ a~ lea~t thre~ dayg ln ~ c~trolled environment whilo maintained on an ad libitum schedule o~ food and water. Prior to the exper~ment, rats are deprived o~ food Por twenty-four hours and water ~or 1 1/2 hour. On thQ day of t~e exper~menk, rat-~ are randomly placed individually into a Rtainles~ steel cage with a wire mesh botto~. Control or drug treated groups consist o~ 5 rats earh.
Grouped rats receive a test drug or vehicle admlnistered orally 30 or 60 minutes prior to ths lesionlng agent. Gastric le~io~s are induced by administratlon o~ indo~ethacln ~olution (30 mg~kg3 by gavage ~3. a~
ml/kg). The indom~thacln i8 prepared ~y di~olving 100 mg powdar ln 1.0 ml of lN Na~C03 and heating un~11 d~Q301ved. Water i8 added to giv~ a ~inal lndo~ethacin concentration o~ 10 mg/ml in O.lN
NaHC03. Four hsurs a~ter indo~thacln ths rat~ are ~acri~ic~d by in~erting T-61 euthanasia ~olution (HoPchst)O ~o determ~nQ duration or mechanlsm o~ act~on, different ti~e~ or routes o~ compound -- 19 _ 1 ~ 6 6 ~
administration are used, The ~tomach~ are removed, opened along khe curvatur~, r~nsed with water and ~pread out ~lat ~n a standard position for examination and photographing.
Under the conditions described, indomethacin normally produces prominent macroscopic lesion~ in the ~undic glandular secr~ting portion of ths ~tomach.
Nonlesioned forestomach and other accessory tiS9UQB are trimmed of~ to improve standard placement. The remaining ~undic tis~u~ along with a millimeter reference scale i~ photograph~d at 2X actual size with a Polaroid camera with a close-up lens. Scoring o~ le~ion~ i~
donQ ~rom thls permanent record.
For ea h animal the severity o~ gastric le~on~ i3 defined a~ the 8um 0~ the maximu~ continuou~ lengths of tha lesions (in mm). Barely visible spot~ tpetechia) are ~cored as 1.O mm each an~ added to the total length. Real lesion length ~mm) i8 obtained aftar dividing th~
total length score by two.
The mean lesion score i5 calculated ~or each treatment group.
From this, the percent inhibition o~ lesion ~ormation, I, i~
calculated:
,~
3 ~ 6 6 ~
I = Lesion score (cont,r,ols) - Lesion score (treated~ X 100 Lesion Score (controls) The mean lesion ~core for a control group will be usPd to calculate "I" but individual lesion ~cores will usually be used in drug treatment groups. Observed treatment scores that exceed the mean control value are taken as the mean control value without considering exacarbation of lesion formation~
In dose response studies, the ED50 (dose at which 50%
inhibition of lesion formation occurs) is determined by probit analysis.
The results of the gastroprotective studies in the rat models with respect to ED50 values (mg/kg) for the various irritants, by oral treatment, are ~ummarized in Table III.
Table III
Irritant Metap,r,oterenol Cimetidine Potency Ratio tCi~etidine = 1) ETOH 0.19 (0.03-0.47)* 223 (191-256) 1174 ASA ~ Stress 11.3 (7.29-16.2) 4.5 (2.0-7.1) 0.4 HCl 8.9 (4.4-17.8) 225 (176-284) 25.3 Indomethacin 2.0 (1.0-3~7) 5.5 (3.9-7.3) 2.8 * (95~ confidenae limit) In three out of four tests, metaproterenol was more effective than cimetidine (potency ratio range 2.75-1174~.
, ` 1 309662 In vlew o~ the above test results, using metaproterenol which is a typical beta adrenergic agoni~t used commonly for testing such materials, beta adrenerglc agonist~ are indicated as good gastro-protectant and antisecretory agents useful in the treatment of gastro-intestinal disorders such a~ gastroesopha~eal reflux disease (GERD), dyspepsia, undue gastrlc acid secretion, gastritis and peptic ulcer.
The following Exa~ples are given to further illustrate the present invention. It is to be understood, however, that this invention is not limited thereto.
EXAMPLES
1 2 3 _ 4 ASA 325 mg 325 mg 325 mg325 mg metaproterenol3.33 mg - - _ i60pro~Qrenol - 10 mg - -albuterol - - 2.67 ~g terbutaline - - - 1.67 mg ~ o test the effectiveness of the beta adrener~ic agonists in protecting the 6tomach against NSAID induced ~ucosal in~ury each ~eta adrenerglc agonist is admini~tered to dogs si~ultaneously and orally with, for example, aspirin in capsules. A ~tandard dose of 975 mg of ASA is admin-istered with varying doses of the beta adrenergic agonist in a capsule and the stomach lining of the dogs were examined endoscopically and rated for the degree of ln~ury.
..,~
All test Pormulations are prepared on the day of the tests.
The capsules are placed in the back of the dog's throatO A
catheter with attached funnel is positioned in the doy's stomach and 50ml of deionized water is administered.
Healthy ad~llt beagle dogs of either sex are ~elected for testing. Dogs are housed individually ln stainless steel cages with grid floore to allow excreta to pass through. Room temperature in the holding rooms and test laboratories is maintained between 65-F and 85F and relative humidity of between 30% and 80%, Room light~ remain on from 6:00 AM to 4:00 PM.
Each dog 18 tralned to stand in a ~tanchion with ~ling support and to accept a bit tied in its mouth. A gastroscope is then passed through the bit into the dog' stomach. This training requires ken days to two weeks in most dogs.
To determine whethar a dog i8 suitable for test purposes, its stomach i8 examlned for a norDal mucosa, and its yastric responsivaness to ASA is evaluated (as under Test Procedure). An acceptable gastric irritation ~core in the antrum must be 5 or greater, 2 hours after dosage.
Food i6 withheld from test dogs ~or 24 hrs. before the test and during the te~t and water is allowed ad lib. The dogs are moved into a holding area away from the kennel. Fasted dogs of either ~ex are examined gastroscop~cally to ensure that their ~tomachs have normal healthy mucosal linings. The dogs are dosed orally with test formulations, which are flushed into their stomachs with 50 ml. of deionized water. They are then re-examined two hour~ later for ga~tric petechiae and signs o~
bleeding according to the following scale:
0 = uniform, pale to dark pink mucosa 1 = darker pink or blotchy mucosa 1 30~`662
Acetylsalicylic acid (ASA) such as Aspirin (trademark) and other NSAIDs have long been the most popular drugs for the management of pain, inflammation and fever. However, one of the drawbacks in their use is the gastrointestinal injury and/or bleeding that sometimes accompanies their administration to individuals. This may become a particularly severe problem where large and sustained doses of NSAIDs must be given to control the symptoms, as for exampla, in the case of the management of arthritis.
It has now been found that NSAID induced gastrointestinal injury and particularly gastrointestinal mucosal injury can be significantly reduced when beta adrenergic agonists are admin-istered concurrently with a NSAID. The beta adrenergic agonists form a fairly well defined class of pharmaceutically effective compounds that are characterized by the fact that they act by stimulating beta adrenergic receptor sites. These receptor sites are of two types referred to as the beta 1 and beta 2 ,.1 ~
~ite~. Beta adrenergic agoni6ts may act on one or the other or on both type6 of ~ites. Any o~ these are e~fective in practicing the pre~ent invention.
It has also been found that gastric acid secretion can be inhibited, and peptic ulcers can be treated by the administration of a beta adrenergic agonist. Typical agonists of this type which can be used in accordance with the invention, include isoproterenol, metaproterenol, terbutaline, albuterol, fenoterol, bitolterol, isoetharine, colterol, or ritodrine or their pharmaceutically acceptable 6alts.
A number o~ beta adrenergic agonists are known in the prior art which are useful for the purpose~ o~ this invention. Of special interest are isoproterenol which i6 a mixed bata 1 and beta 2 agonist and terbutaline which i8 a beta 2 agonist. By way of illustrating other beta adrenergic agonists that may be employed herein, the following are given metaproterenol, albuterol, ritodrine. All of these ~ay be employed as such or as pharmaceutisally acceptable salts.
The NSAIDs al50 ~orm a well known class of druys that are anti-inflammatory analgesics. These have the common properky of inhibitiny the fo~mation of prostaglandins which have a protective affect on the gastrointestinal mucosa. See Goodman and Gilman "The Pharmacological Basi6 for Therapeutics" 7th Edition, p. 678. It is because of this inhibiting e~ect that the oral administrat$on o~ drugs o~ this class tend to result in gastrointestinal injury and/or bleeding, the problem that the present invention seeks to reduce or eliminate.
A number of NSAIDs are known in the prior art to which the present invention has application. The most aommonly known group are the salicylates o~ which ASA is the prime example. Another group of NSAIDs that have utility in con-nection with the instant invention are the proprionic acid 1 ~(3~66~
derivative~. Included in thi~ group, ~or example, arQ ibuprofen and naproxe~. A further group of NS~IDs employable herein are the fenama~e~ and compound~ closely related to them struc~
turally. ~hesa may be illustrated by such compound~ a mePenamlc acid, meclofenamake sodium, diclo~enac and its sodium salt. Also belonging to the class o~ NSAIDs with which the present invention iB concerned are the indolz derivatives (e.g.
indomethacin); pyrrolealkanoic acid derivatives (e.g. tolmetin);
pyrazalone derivatives (e.g. phenylbutazone); oxicams (e.g.
piroxicam); etc.
The quantitative relationship o~ the NSAID to beta adrenergic agonist contained in the present products may be expressed on the basis o~ th~ average daily dose of tha product i.e. milligrams/per Kg of body weight/per day. In this case the average do~e for the products will generally be from about lO
mg/Kg/day to about lO0 mg/~g/day o~ NSAID and from about 0.0003 mg/Kg/day to about 500 mg/Xg/day of one or a combination of beta adrenergic agonist~ with the preferred range being ~rom about 15 mg/~g/day to about 75 mg/Xg/day of NS~ID and from about 0.01 mg/Xg/day to about lO mg/KgJday o~ ~aid bata adrenergic agonists.
The unit dosage forms ~or the present product~ will be formulated for convenient oral admlnistration. Each such unit will generally contain from about 200 mg to about 600 mg o~
NSAID and fro~ about 0.7 mg to.about 70 mg of ons or a combination o~ adrenergic agonists. For therap~utic use th~
beta adrenergic agonist will normally be administered a~ a pharmaceutical composition comprislng as the essential active ingredient at least one of such agonist in its basia form or in the form o~ a non-toxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier. The pharmaceutical composition can be administered orally in~ranasally, parenterally, or by rectal suppository. A
wide variety o~ pharmaceutical forms may be employed. Thus, if a ~olid carrier is used, the preparation may b~ a tablet, placed 1 3 i(~ ~ !6 ~ ,~
. .
in a hard gelatin tabsule in powder or yranular form, or in a form o~ a trochs, caplet or capsule. I~ a liquid carrier i~
employed, the preparation may be in a form of a ~yrup, emulsion, soft gelat~n capsule, ~terile solution for in~ection, or an aqueous or non-aqueoua liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.
The dos2ge of the composition~ ~f this invention w~ll depend not only on such factors as the weight of the patient, but al30 in the degrea of gastric acid lnhibition desired and the potency of the particular compound being utilized. The dec~sion as to the particular dosage to be employed i~ within the discretion and the routine knowledga of the physician. In thQ Heidenhain Pouch ~og test described below, cimet~dina has an oral ED50 ~ approximately 3.3 moles/kg. Th~ usual human adult oral dose o~ cimetidine i9 3 00 mg, given four times a day~ The usual human adult starting oral dosag~
o~ the compound~ of this invention are readily dete~mined ~rom their oral ED50 in thi~ same test. Thu3, i~ the oral ~D50 i~ 0-33 moles/kg. the usual starting oral dosage would be approximately 30 mg. given four tlmes a day, ~tc. Si~llar calculat~ons may b~ made for intravenous dosages. These starting dosages (and the number of ti~e~ administered per day) may, o~ course, be varied by titration of ths dosage to tha particular circum~tances of the specific patient.
With th2 preferred co~pound~ o~ thi~ lnventlon, each oral dosage unit will contain the active ingredient in an amount o~ from about 0.5 mg.
to about 300 mg. and mostly pre~erably from about 190 mg. to about 100 mg. The active ingredient will preferably be administQred in egual dose~ from ona to ~our time~ a day.
1 ~.
Depending upon the do~age ~o~ employed the product~ o~ 'chi~
in~ention may also conta~n other ad~uvants that may be useful in formulating the particular dosage form or in its administration.
Thus, ~or example, when a~m~nistered a~ a tablet the products o~ this invention may al~o contain lubricant~ exclpiants, binding agen~s, di~lntegrating agents, flavoring agents, etc. In addition these products may also contaln other pharmaceutically active ingredient such ag deconge~tants~ analgesic ad~uvant~, antihis~amines, expectorants, antitussives, diuretics, other analgesics, other anti-lnflammatory agent~, other antipyretic~, other anti- rheumatics, antioxidants, vasodilators, ~moot~ muscle relax- ant~, skeletal muscle relaxants, bronchodilators, vitamin~, traca minerals, amino acids, biological peptide~ etc.
The product~ o~ thi~ ~nYsngion may takQ a variety o~ form~, A~ indicated above th~y ~ay ag~u~ the ~orm o~ tablat~ How-ever, tha NSAID and the bata adrenergic agonists may ba in powdered or granular ~orm containad in edible capsule~ such as qalatin cap ule~. The present products may al~o taks th2 form o~ suspension~ or ~olutions o~ the above ingredients in a sultable liquid medium or o~ powders packaged in 8U~ table pap~r envelope~. .
~ he mechanism by which the beta adrenergic agonists serve aæ
protectants again~t gastrointestinal injury when admlnistered as the solQ pharmaceuticaly active ingredient, or coadmin-istered with the NSAID is not clearly understood. one factor seems rairly certain and that 1~ that it is not necassarily ~imply related to the inhibition of gastric acid ~ecretion.
This is made evident by the observation that, for example, with 1 3Q~6~
certa~n level~ of isoproterenol, gastric in~ury protection has been noted notwithstanding the ~act that the pH o f the s omach content was essentially the same as the pH of the control stomach. Similarly, as reported by M.H. Steven et al ln the Abstract of Paper~; I'Gastroenterology" Vol. 88, No. 5 Part 2 at page 1600, although isoproterenol had a role in the regulation of gastric secretion stimulated by gastrin and acetylcholine, histamine-stimulated acid secretion was resistant to inhibition by isoproterenol. In passing, it mlght be noted that Steven et al were not measuring the effect of the coadministratlon of ASA with isoproterenol.
Determination of Gastric Antisecretory Activity in the Gastric ~istula Rat.
Male Long Evans rats weighing about 240-260 grams at the time of cannula implementation are used. The design and implementation of the ~tainless steel cannula into the anterior wall of the fore-stomach are carried out essentially as described by Pare et al. tLaboratory Animal Science, 27, 244 (1977). The ~iatula components ar~ designed and the operative procedure is carried out exactly as described in the above reference. Poæt operatively the animals are indiv~dually housed in solid bottom cages with sawdust and are allowed food and water ad libitum throughout the entire recovery period. Animals are not used for test purposes for at least 15 days a~ter the operative procedure.
The animals are fasted but allowed water ad llbitum for 20 hour~ before the testing procedure ~ 9 to begin. Immediately prior to collection, the cannula i8 opened and the stomach washed gently with 30-40 ml of warm ~aline or dlstilled water to remove any residual contents. The catheter is then ecrewed into the cannula in place o~ the plugging screw and the rat i6 placed in a clear plastic rectangular cage measuring 40 cm long, 15 cm wide and 13 cm high. The bottom o~ the cage has a slit ..
-1 30966~
approximately 1.5 cm wide and 25 cm long running down the center to accommodate the catheter which hangs through it. In this way the rat i8 not restricted and can move freely about the cage during collection periods. The remainder o~ the assay i carried out as described by Ridley et al. [Research Co~m. Chem.
Path. Pharm., 17, 365 (1977)].
Gastric secretions collected durinq the first hour a~ter washing the stomach are discarded as they may be contaminated.
For oral evaluation, the catheter is then removed from the cannula and replaced with the plugging screw. Water (2 ml/kg) i6 administered orally via gastric intubation and the animal is returned to the cage ~or 45 minutes. After thls time the plugging screw is removed and replaced with a catheter to which a small plastic vial has been attached to collect the gastric secretions. A two hour sample iOE collected (this represents the control secrPtion), the catheter removed and replaced with the plugging ~crew. The test drug is now administered orally in a volume of 2 ml/kg via gastric intubation. Forty five minutes later the plugging ~crew is again removed, replaced with the catheter attached to a small plastic vial and another 2 hour Eample is compared to those of the control sample in order to determine the effect~ of the test drug.
~ hen te~t compounds are to be evaluated parenterally, the animal i8 in~ected lp or 6C with the test compound vehicle in a volume of 2 ml/kg immediately after discarding the initial 60 minute collection. A two hour sample is collected ~control ~ecretion) and the animals are in~ected either ip or 6C with the test compound in a volume o~ 2 ml/kg. An additional two hour sampl2 i~ collected and its secret~ons are compared to those of th~
control period to datermine drug ePfect~.
The ~amples are centrifuged and pla ed in ~a gra~uated centrifuge tube for volume determination. Titratabl~ acLdity is measured by titrating a one ml sample to pR 7.0 with 0.2N NaO~, using an autoburet and an electrometric pH meter (radiometer). Titratable ac~d output i~ calculated ln microequivalent3 by multiplying the volume in milliliters by the acid concentration in mllllequivalents per liter.
Results are expressed a~ percent inhibition relative to control reading. Dose re~ponse curves are constructed and ED50 values are calculated by regression analyse~. At least three rat~ are used at each dosage level and a minimum of three dosage levels are utilized for determination of a do~a responaive curve.
Two o~ the ~tandard an~mal model~ for determin~ng gastric antisecretory activity o~ antagon~st are the Gastric Fistula ~at and the ~Pidenhain Pouch Dog. Comparative data between metaproterPnol, a known beta adrenergic agon$3t, and cimetidine, a known H2 receptor antagoni~t and e~ectivQ inhibitor of ga~tric secretlon, i8 ~hown in table3 I and II below:
1 3096~2 Table I
Gastric antisecretory actiY~ty ln the Gastric Fistula Rat ED50 values ~mg/kg) for oral treatment Metaproterenol Cimetidine Potence Ratio ~Cimetidine = 1 23.6 (15 - 42) * 12 (9.0 - lB) * 0.58 *(95% confidence limit) Determination of Gastric Antisecretory Activity in the Heidenhain Pouch Dog Prior to surgery, hematology and blood chemistry profiles are obtained and an assessment made a~ to the general health of selected female dog~. Dogs are vaccinated with Tissue Vax 5 (DHLP-Pitman-Moore) and housed in general animal guarters for an observation period of four weeks, 80 incipient diseases may become apparent. Dogs are fa~tPd with water ad libitium 24 hours prior to surgery.
Anesthesia i~ induced with ~odium pentothal (Abcott) 25-30 mg/kg iY. Subsequent anesthesia is maintained with methoxyflurane (Pitman-Moore~. A midline linea alba inci~ion fro~ xiphoid to umbilcu~
provides good exposure and ease o~ ~losureO The stomach is pulled up into the operative field, the greater curvature ~tretched out a~
multiple points and clamp~ placed along the 6elQrted line of in~i~ion.
The pouch i8 made from the corpu~ of the stomach 80 that true parietal cell ~uice is obtained. About 30% o~ the COrpU8 volume i8 resected.
The cannula is made of light-weight, biologically inert material such as nylon or Delrin with dimensions and attachments a~ter DeVito and Harkins [J. Appl. Phy~iol., 14, 138 (1959)]. Post operatively, dogs are medicated with antibiotics and an analgesic. They ar~ allowed 2-3 months for recovery. Experiments are carried out in the following way:
Dogs are fasted overnight (18 houræ3 with water ad libitum prior to each experiment. The dogs are placed in a sllng and a saphenous vein cannulated for drug administration. Histamine as the base (100 g/kg/hr) and chlorpheniram~ne maleate ~0.25 mg/kg/hr) are infused continuou~ly (in a volume of 6 ml/hr~ with a Harvard infusion pump.
A Ninety m~nute infusion is allowed for the dogs to reach a steady state of acid output. At thi3 time the drug or normal saline (control) is administered ¢oncomitantly with the secretagogue in a volume of 0.5 ml/kg over a 30 second period. When oral studies are to be carried out, the drug is administered via gastric gavage in a volume of 5 ml/kg. Infusion of the secretagogue is continued and 15 minute samples of the gastric ~uice are taken for 4.5 hours. Each sample is measured to the nearest 0.5 ml and titratable acidity i~ det~rmined by titrating a 1 ml sample to p~ 7.0 with 002N MaOH, using an autoburet and an electrometric pH meter (or radiometer~. Titratable acid output i8 calculated in microe~uivalents by multiplying the volume in milliliters by the acid concentration in a m~llequ~valents per liter.
Results are expressed a~ percent inhibition relative to control reading~. Dose response curves are constructed and ED~ values are calculated by re~ression analy~e~ From 3 to 5 dogs are used at each dose level and a minimum of three dosage levels are utilized for determination of a dose response curve.
.~i~ . - - ...............
-`` 1 30~6~
Table II
Gastric Antisecretory Activity in the Heidenhain Pouch Dog ED50 values (mg/kg for oral treatment) Metaproterenol Cimetidine PotQncy Ratio (Cimetidine - 1 0.05 0.71 14.2 The potency ratios ln the rat and canlne antisecretoxy model describe~ above are 0.58 and 14.2, respectively.
Cytoprotective ackivity was evaluated in five te3t models.
Metaproterenol was comparPd to cimetidine as a protectant. The term "cytoprotection" describes the phen~menon whereby some agents protect the gastric mucosa against injury induced by a variety o~ injurious stimuli. These assays are prlmarily used as secondary models to evaluate agents which have confirmed anti-gastric secretory activity and/or activity in primary (antisecretory) model In the present case, the beta adrenergic agonist metaproterenol was compared to the cytoprotective activity o~ cimetldineO The injuriou~ sti~uli in our present test were provided by ethyl alcohol, ASA and stress, hydrochloric acid, and indomethacin. The respective assays were carried out as described below:
Eth~l alcohol-The method employs 3.0 ml/kg ethyl alcohol (100%) a~ thenecrotizing agent and provides additional data besides ga~tric lesions.
`~ ~ 3 0 ~ !2 Adult male Long-Evans rats weighing 275 300 grams (~lue Spruce Farms, Alton, New York) are used. Animals are housed individually in stainless steel cages with wire-mesh bottom~. The housing battery is arranged into six groups of five each, individually numb2red. Food and water are removed 24 and 1 1/2 houxs, respectively, prior to exposure to ETOH. Animals receive the test compounds ~ither p.o., 6 . C , or ip.
(3 12 ml/kg) 60 minutes before administration o~ 100% ethanol (3.0 ml/kg/ by gavage). For some purposes, different water removal and drug pretreatment times may be used. Sixty minutes after ethanol administration the animals are sacrificed by administration of T 61 (Hoechst), 0.2 ml i.p.
An abdominal incision is made, and after clamping the esophagus ~ust above the esophageal sphincter with forceps, the stomach is carefully lifted ~rom the abdominal cavity. Two cuts are made, approximately 1/4 3~ below the pyloric valve and 1~4ll above the esophageal ~phincter, and the stomach remoYed rapidly without a~y loss o~ gastric contents. The size of the stomach including contents i8 noted as small ~ medium or large. Stomachs are cut open along the greater curvature and the content3 expressed into graduated centrifuge tubes. Gastric ~uice samples are centrifuged and total ~olume, and contentR of solid and mucus are estimated to the nearest 0.1 ml Na+
and K~ content o~ the gastric ~uice as well as pH are determined.
Under these conditions, ethanol produces prominent ~acroscopic lesions in the fundic stomach, but gross macroscopic changes are only ! `~- ` .. . ~ . .. .
1 ~9~b2 var~ rarely observed in the forestomach. An occasional control animal shows some degrae of redness or hyperemia and/or s~ell petechiae in the forestomach. Lesions characteristic of ~undic damage are not usually observPdO For these reasons, the forestomach (along with nongastric tissue) is removed and not examined. In addition, absence of the forestomach facilitat~s the photocopy and gross examlnation o~ the remaining stomach.
The remalning fundic-pyloric stomach remnant is rinsed in water and placed flat in a standard position. The tissue is photographed with a Polaroid camera with a close-up lens. Scoring of lesions is done from this permanent record. Each photograph includes a reference scale in mm. Individual ulcers are measured by total lesion area (mm2) and these scores are added together to determine total ulcer area for a stomach. Small well defined but quite visible ~pot (petechiae) are often present; a conglomerate area estimate i8 made for these and added to the total. Some variability in ulcer scoring between persons may occur because even optimal quality photographs will show minor shadows, shades, overexposed ~pots and irregularly shaped ulcers.
Standard photographs are about 2 X actual siza. An estimate Qf real ulcer area (mm23 is obtained after dividing the area score by ~our. For each treatment group, the ~ean area i8 calculated. From this, the percent inhibition of le~ion formation, I ls calculated as:
I = Lesion Score (controls~ - Lesion Score~.(treated3 X 100 Lesion Score (Controls) The mean ulcer score ~or a control group will be used to calculate "I" but normally ~ndividual lesion ~coreR ar~ used in drug treatment groups. In some cases, the observed treatment ~core iæ greater than the mean control valve, in which case that ~core i~ taken as the mean control valve (exacerbation o~ lesion formation is not considered). In rare instances, the da~a from an animal will be discarded if, e.g., ~eces are ~ound in the stomach~
In dose-response studies, the ED50 (dose at which 50%
inhibition of lesion formation occur6) is determined by probit analysis.
ASA + Stress . . .
Male Lvng Evans rats (approximately 275-300 g~s) are housed 6 per cage and acclimated at least three days while maintained on an ad libitum schedule of food and water~ Prior to starting an experiment, rats are deprived o~ food for twenty-four hours and water for one hour. Thlrty mlnute~ be~ore 6ubjecting animals to cold restraint stress, each rat i~ dosed by gastric intubation (6 ml/kg) with ASA (80 mg/Xg) homogenized with methy-cellulos~ (0.1%) in water.
TeYt agents are admini~tered 60 or 30 min prior to the ASA
mixture either orally or parenterally. Each control o~ drug treated group normally con~ists of 5 rata. The multi-stress method entails placing the dosed rat in a ventilated plastic tub2 closed at one end -- lg --1 30966~
with a rubber ~topper. The open end ~8 then closed with a 6econd stopper and $he tube is place in an environmental cha~ber maintained at 4-5C for two hour~. The tube contains ~everal 3~8" holes for breathing purposes and iB about ten inches long and two inches wide.
At the end of ~he two-hour cold-restraint period, each animal is sacrificed with an injection of T-61 euthanasia solution (Hoechst).
An abdominal incision is mada and the stomach removed by cutting just above the esophageal ephincter and just below the pyloric valve.
The ~tomach is opened along the greater curvature and the stomach contents di6carded. Under the conditions described, ASA plus cold reskraint stress produce6 spotty and narrow dark bands of linear macroscopic lesions which are usually found in the corpus ~undic stomach. There~ore, forestomach and other accessory ti sue which show no macroscopic leslon damage are trimmed. The remaining fundic portion is rlnsed wlth water and placed flat in a standard poæition for photographing. The stomach along with a millimeter reference scale i5 photographed at 2X actual size with a Polaroid camera.
Scoring of leslon~ i8 done from thi~ permanent r~cord.
The lesion ~core i8 determlned by measuring and adding together the total millimeter lengths of all visible erosions. Small spots (petechia) are scored as 1.0 mm each and added to the aggregate. An estimate of real lesion length i~ obtained by dividing the aggregate score by two. For each treatment gxoup, a mean lesion score is determined. From this, the percent inhibltion of lesion ~ormation, I, is calculated as:
.~
1 30~6~
I = Le~ion Scor~ ~controls~ - Les~on Score (t_eated) X 100 ~esion Score Control~
The mean lesion ~core for a control group will be used to calculat~ "I" but indivldual lesion score~ will usually ba used in drug treatment groups. Observed treatment ~cores tha~ exceed th~
mean control value are taken a~ the mean control value without considering ~xacerbation o~ le~ion ~ormatlon.
In doso response studie~, thQ ED50 (dose at which 50%
inhibition o~ lesion formation occurs) i~ determlned by probit analy~is.
HCl:
The present method to produce ga~tr~c lesions in rats employs 3.0 ml/kg 0.75N HCl as the necrotlzing agent and provide additional data besides gastric le~ions.
Adult male Long~Evan~ rats weighing 275-3~0 gram3 ~Blue Spruce Farms, AltQn~ Ne~ York) are u~ed. An~mals are housad individually in 6tainless ~teel cages with wir~ mesh boktom~. Th~ hou~ing battery is arranged into 5iX group o~ ~iv~ each, indlvidually numbered. Food and water are removQd 24 and 1 1~2 hours, respectiv21y, prior to HCl. Animal~ receive th~ test compounds either p.o., ~.c., or i.p.
(3-12 ml/kg) 60 minute~ befor~ administration of 0.75N HCl (3.0 ml/kg, by gavage). For some purposes, di~fer~nt water removal and :
: ''' `
1 30`~6`~
-.
drug pretreatment times may ba used. Sixty ~inutes after ~Cl th~
animal~ are sacrificed by admini~tration o~ T-61 (Hoechst), 0.2 ml, i .p.
An abdominal incision i~ made, and after clamplng the esophagu~
~ust above the esophageal sphincter with tweezer~, the stomach is carefully lifted ~rom the abdomina~ cavity. Tw~ cut8 are made, approximately 1/4 " below the pyloric valve and 1/4 ~i above the esophageal sphincter, and the stomach rapidly removed without any 1088 0~ gastric contents. The size o~ the stomach including content~
is noted as small, medium or large. Stomachs are cut open along the greater curvature and the content~ expressed into graduated centrifuge tube~. Gastric ~uic~ samples are centrl~uged and total volume, and contents o~ olid~ and mucus are e~timated to the neare~t 0.1 ml. Na~ and K~ contents o~ the gastric jUiCQ as well as pH
are determined.
Under these condition~, 0.75N HCl produce~ prominent macroscopic lesions in the fundic sto~ach, but gros~ macroscopic changes are only very rarely observed in the ~orestomach. An occas~onal control animal ~how~ 80mQ degra~ o~ radnes~ or hyperemia and/or ~mall petechiae ln the iorestomach, but never lesion~ charactsristlc o~
fundlc damage. Fox these reasons, the fore~tomach (along with nongastric ti~sue) i~ removed and not examinad. In addition, absenc2 o~ the fore~to~ach ~acilitates the. photography and examination of the remaining stomach. W~t wsight of th~ whola stomach i9 determined be~ore removal of the ~ore~tomach.
096`62 ~ h~ rema~ning fundic-pyl~ric ~tomach remnant 1~ rinsed in water and placed ~lat ln a ~tandard po8ition~ ~h~ tissue i8 photographed with a Polarold camera with a c~o~e-up lens. Scoring of lesions i~
done from this permanent record. Each photograph includ8~ a referencs scale in m~. Individual ulcer~ are measured by total lesion length in mm and these scores ar~ added tog~ther to determine total ulcer length for a stomachc Small well d~ined but quite visiblc ~pot~ (petechiae) are often present: a conglomerate length estima~e i~ made for these and added to the total. Some variability ulcer scoring between persons may occur because even optimal qual~ty photographs will show minor shadows, shades, overexposed spots and irregularly shaped ulcers.
Standard photograph~ are about 2 x actual size. An estimate of real ulcer length (mm~ i~ obtained after div~ding th2 length score by two. For each treatment group, the mean length 1~ calculated. From this, the percen~ inhibition of lesion formation, I, i~ calculated as:
I = Lesion score (controls) - Lesion Score (treated~ X 100 Lesion Score (controls~
The ~ean ulcer score for a control group will be used to calculate 'II" but normally lndividual lQsion scores ara u6ed in drug treatment group~. In ~ome casas, th~ obs~rved treat~ent ~cor~ 13 1 3~ ~!6 ~,~
greater than the mean control value (~xacerbation o~ lesion ~ormation 1~ not considared). In rare lnstance~, tha data ~rom an animal will be discarded i~, s.g., fece~ are ~ound in the ~tomach.
In dose-response studie~, thQ ED50 (dose at which 50~
inhibition o~ lesion ~ormation occurs) iQ determined by probit analysis.
IndomethaCin Male Long Evan~ rat~ (approx~mately 275-300 ~s~ ar~ housed 6 per cage and acclli~ate~ a~ lea~t thre~ dayg ln ~ c~trolled environment whilo maintained on an ad libitum schedule o~ food and water. Prior to the exper~ment, rats are deprived o~ food Por twenty-four hours and water ~or 1 1/2 hour. On thQ day of t~e exper~menk, rat-~ are randomly placed individually into a Rtainles~ steel cage with a wire mesh botto~. Control or drug treated groups consist o~ 5 rats earh.
Grouped rats receive a test drug or vehicle admlnistered orally 30 or 60 minutes prior to ths lesionlng agent. Gastric le~io~s are induced by administratlon o~ indo~ethacln ~olution (30 mg~kg3 by gavage ~3. a~
ml/kg). The indom~thacln i8 prepared ~y di~olving 100 mg powdar ln 1.0 ml of lN Na~C03 and heating un~11 d~Q301ved. Water i8 added to giv~ a ~inal lndo~ethacin concentration o~ 10 mg/ml in O.lN
NaHC03. Four hsurs a~ter indo~thacln ths rat~ are ~acri~ic~d by in~erting T-61 euthanasia ~olution (HoPchst)O ~o determ~nQ duration or mechanlsm o~ act~on, different ti~e~ or routes o~ compound -- 19 _ 1 ~ 6 6 ~
administration are used, The ~tomach~ are removed, opened along khe curvatur~, r~nsed with water and ~pread out ~lat ~n a standard position for examination and photographing.
Under the conditions described, indomethacin normally produces prominent macroscopic lesion~ in the ~undic glandular secr~ting portion of ths ~tomach.
Nonlesioned forestomach and other accessory tiS9UQB are trimmed of~ to improve standard placement. The remaining ~undic tis~u~ along with a millimeter reference scale i~ photograph~d at 2X actual size with a Polaroid camera with a close-up lens. Scoring o~ le~ion~ i~
donQ ~rom thls permanent record.
For ea h animal the severity o~ gastric le~on~ i3 defined a~ the 8um 0~ the maximu~ continuou~ lengths of tha lesions (in mm). Barely visible spot~ tpetechia) are ~cored as 1.O mm each an~ added to the total length. Real lesion length ~mm) i8 obtained aftar dividing th~
total length score by two.
The mean lesion score i5 calculated ~or each treatment group.
From this, the percent inhibition o~ lesion ~ormation, I, i~
calculated:
,~
3 ~ 6 6 ~
I = Lesion score (cont,r,ols) - Lesion score (treated~ X 100 Lesion Score (controls) The mean lesion ~core for a control group will be usPd to calculate "I" but individual lesion ~cores will usually be used in drug treatment groups. Observed treatment scores that exceed the mean control value are taken as the mean control value without considering exacarbation of lesion formation~
In dose response studies, the ED50 (dose at which 50%
inhibition of lesion formation occurs) is determined by probit analysis.
The results of the gastroprotective studies in the rat models with respect to ED50 values (mg/kg) for the various irritants, by oral treatment, are ~ummarized in Table III.
Table III
Irritant Metap,r,oterenol Cimetidine Potency Ratio tCi~etidine = 1) ETOH 0.19 (0.03-0.47)* 223 (191-256) 1174 ASA ~ Stress 11.3 (7.29-16.2) 4.5 (2.0-7.1) 0.4 HCl 8.9 (4.4-17.8) 225 (176-284) 25.3 Indomethacin 2.0 (1.0-3~7) 5.5 (3.9-7.3) 2.8 * (95~ confidenae limit) In three out of four tests, metaproterenol was more effective than cimetidine (potency ratio range 2.75-1174~.
, ` 1 309662 In vlew o~ the above test results, using metaproterenol which is a typical beta adrenergic agoni~t used commonly for testing such materials, beta adrenerglc agonist~ are indicated as good gastro-protectant and antisecretory agents useful in the treatment of gastro-intestinal disorders such a~ gastroesopha~eal reflux disease (GERD), dyspepsia, undue gastrlc acid secretion, gastritis and peptic ulcer.
The following Exa~ples are given to further illustrate the present invention. It is to be understood, however, that this invention is not limited thereto.
EXAMPLES
1 2 3 _ 4 ASA 325 mg 325 mg 325 mg325 mg metaproterenol3.33 mg - - _ i60pro~Qrenol - 10 mg - -albuterol - - 2.67 ~g terbutaline - - - 1.67 mg ~ o test the effectiveness of the beta adrener~ic agonists in protecting the 6tomach against NSAID induced ~ucosal in~ury each ~eta adrenerglc agonist is admini~tered to dogs si~ultaneously and orally with, for example, aspirin in capsules. A ~tandard dose of 975 mg of ASA is admin-istered with varying doses of the beta adrenergic agonist in a capsule and the stomach lining of the dogs were examined endoscopically and rated for the degree of ln~ury.
..,~
All test Pormulations are prepared on the day of the tests.
The capsules are placed in the back of the dog's throatO A
catheter with attached funnel is positioned in the doy's stomach and 50ml of deionized water is administered.
Healthy ad~llt beagle dogs of either sex are ~elected for testing. Dogs are housed individually ln stainless steel cages with grid floore to allow excreta to pass through. Room temperature in the holding rooms and test laboratories is maintained between 65-F and 85F and relative humidity of between 30% and 80%, Room light~ remain on from 6:00 AM to 4:00 PM.
Each dog 18 tralned to stand in a ~tanchion with ~ling support and to accept a bit tied in its mouth. A gastroscope is then passed through the bit into the dog' stomach. This training requires ken days to two weeks in most dogs.
To determine whethar a dog i8 suitable for test purposes, its stomach i8 examlned for a norDal mucosa, and its yastric responsivaness to ASA is evaluated (as under Test Procedure). An acceptable gastric irritation ~core in the antrum must be 5 or greater, 2 hours after dosage.
Food i6 withheld from test dogs ~or 24 hrs. before the test and during the te~t and water is allowed ad lib. The dogs are moved into a holding area away from the kennel. Fasted dogs of either ~ex are examined gastroscop~cally to ensure that their ~tomachs have normal healthy mucosal linings. The dogs are dosed orally with test formulations, which are flushed into their stomachs with 50 ml. of deionized water. They are then re-examined two hour~ later for ga~tric petechiae and signs o~
bleeding according to the following scale:
0 = uniform, pale to dark pink mucosa 1 = darker pink or blotchy mucosa 1 30~`662
2 ~ peteahia6 and/or light red 6treaks
3 - ~w small le~ion~
4 = many or connected ~mall lasions ~striati~ns)
5 = ~ew large lesion~
6 = ~any large lesion~
7 = masslve hemorrhagic dama~e Severity of bleeding for each treatment and at each time is calculated as the mean gastric irritation 6core.
In addition to the endoscopic observatlon of the gastric mucosa of each dog a qualitative deæcript$on of gastric ~luid is recorded and a pH measurement i8 made of the ga~tr~c fluid. All of thess are don~ 2 hours after administration o~ the test product.
A ~ase line t~ established by measuring the various para-meters after the administration of 975 mg of ASA by itself.
The resting stomach ha~ an irritation score of O and a pH of 5 to 5.5. ASA alone produced injury which scored at approximately 5.5 a~ter 2 hours and the gastric pH at this time i8 about 3.1. After 4 hour~ these values were 3.7 for the irritation factor and the pH was 4.8. Thi~ indicate~ that a certain a~ount of healing takQs place between the 2nd and 4th hour after administration.
. ~ ,, , 1 3nq6~
The re~ults o~ the various tests are summarized in Table IV below.
able I
Test Composition 2 Hr. Score In~ury _ pK
ASA (975 ~) 5.6 3.1 ASA ~975 ~g) + isoproterenol (7.5 mg) 3.8 3.5 ASA (975 mg) + isoproterenol (15 mg) 2.7 3.8 ~SA (975 mg) + isoproterenol (30 mg) 1.3 5.0 ASA (975 mg) + terbutaline (1.25 mg) 4.0 2.9 ASA (975 mg) + terbutaline ~5.0 mg) 1.4 4.0 ASA (975 mg) + terbutaline ~10.0 mg) 1.2 4.~
ASA (975 mg) + albuterol (8 mg) 1.0 5.4 ASA (975 mg~ + metaproterenol (20 mg) 0.75 5.7 An examinat$on of these data shows that the beta adrenergic agonists provide significant protection against ASA induced ~ucosal in~ury particularly at thQ 2 hour leval after admin-istration. This protection, moreovsr, does not appear to be particularly x~lated to the p~ of the gastric contents.
In addition to the endoscopic observatlon of the gastric mucosa of each dog a qualitative deæcript$on of gastric ~luid is recorded and a pH measurement i8 made of the ga~tr~c fluid. All of thess are don~ 2 hours after administration o~ the test product.
A ~ase line t~ established by measuring the various para-meters after the administration of 975 mg of ASA by itself.
The resting stomach ha~ an irritation score of O and a pH of 5 to 5.5. ASA alone produced injury which scored at approximately 5.5 a~ter 2 hours and the gastric pH at this time i8 about 3.1. After 4 hour~ these values were 3.7 for the irritation factor and the pH was 4.8. Thi~ indicate~ that a certain a~ount of healing takQs place between the 2nd and 4th hour after administration.
. ~ ,, , 1 3nq6~
The re~ults o~ the various tests are summarized in Table IV below.
able I
Test Composition 2 Hr. Score In~ury _ pK
ASA (975 ~) 5.6 3.1 ASA ~975 ~g) + isoproterenol (7.5 mg) 3.8 3.5 ASA (975 mg) + isoproterenol (15 mg) 2.7 3.8 ~SA (975 mg) + isoproterenol (30 mg) 1.3 5.0 ASA (975 mg) + terbutaline (1.25 mg) 4.0 2.9 ASA (975 mg) + terbutaline ~5.0 mg) 1.4 4.0 ASA (975 mg) + terbutaline ~10.0 mg) 1.2 4.~
ASA (975 mg) + albuterol (8 mg) 1.0 5.4 ASA (975 mg~ + metaproterenol (20 mg) 0.75 5.7 An examinat$on of these data shows that the beta adrenergic agonists provide significant protection against ASA induced ~ucosal in~ury particularly at thQ 2 hour leval after admin-istration. This protection, moreovsr, does not appear to be particularly x~lated to the p~ of the gastric contents.
Claims (28)
1. A pharmaceutical composition having reduced potential for NSAID induced gastrointestinal injury comprising a therapeutically effective amount of NSAID and a protective quantity of a beta adrenergic agonist component.
2. A composition according to claim 1 in which said beta adrenergic agonist component is isoproterenol.
3. A composition according to claim 1 wherein said beta adrenergic agonist component is terbutaline.
4. A composition according to claim 1 wherein said beta adrenergic agonist is albuterol.
5. A composition according to claim 1 wherein said beta adrenergic agonist is metaproterenol.
6. A composition according to any one of claims 1, 2, 3, 4 or 5 in which said NSAID is ASA.
7. A composition according to any one of claims 1, 2, 3, 4 or 5 wherein said NSAID is ibuprofen.
8. A composition according to any one of claims 1, 2, 3, 4 or 5 having a daily average dose of from about 10 mg/Kg/day to about 100 mg/Kg/day of said NSAID and from 0.0003 mg/Kg/day to about 500 mg/Kg/day of said beta adrenergic agonist component.
9. A composition according to any one of claims 1, 2, 3, 4 or 5 in the form of unit dosage form containing from about 200 mg to about 600 mg of said NSAID and from abut 0.7 mg to about 70 mg of said beta adrenergic agonist component.
10. A composition according to any one of claims 1, 2, 3, 4 or 5 in which said NSAID is ASA, the daily average dose of said ASA being from about 10 mg/Kg/day to about 100 mg/Kg/day and of said beta adrenergic agonist being from about 0.0003 mg/Kg/day to ahout 500 mg/Kg/day.
11. A composition according to any one of claims 1, 2, 3, 4 or 5 in the form of a unit dosage form containing from about 200 mg to about 600 mg of ASA and from about 0.70 mg to about 70 mg of said beta adrenergic agonist component.
12. A composition according to any one of claims 1, 2, 3, 4 or 5 in which said NSAID is ibuprofen, the daily average dose of said ibuprofen being from about 10 mg/Kg/day to about 100 mg/Kg/day and of said beta adrenergic agonist being from about 0.0003 mg/Kg/day to about 500 mg/Kg/day.
13. A composition according to any one of claims 1, 2, 3, 4 or 5 in the form of unit dosage form containing from about 30 mg to about 300 mg of ibuprofen being from about 0.7 mg to about 70 mg of said beta adrenergic agonist component.
14. A composition according to any one of claims 1, 2, 3, 4 or 5 having a daily average dose of from about 15 mg/Kg/day to about 75 mg/Kg/day of said NSAID and from about 0.01 mg/Kg/day to about 10 mg/Kg/day of said beta adrenergic agonist component.
15. The use of a protective amount of a beta adrenergic agonist component for reducing potential for NSAID induced gastrointestinal injury, when administering a therapeutically effective amount of an NSAID to a subject.
16. A use in accordance with claim 15 wherein the beta adrenergic agonist component is isoproterenol. 17.
A use in accordance with claim 15 wherein the beta adrenergic agonist is terbutaline.
18. A use in accordance with claim 15 wherein the beta adrenergic agonist component is albuterol.
19. A use in accordance with claim 15 wherein the beta adrenergic agonist component is metaproteranol.
20. A use in accordance with any one of claims 15, 16, 17, 18, and 19 wherein said NSAID is chosen from the group consisting of ASA and ibuprofen.
21. The use of a protective amount of a beta adrenergic agonist component for the preparation of a medicament comprising a therapeutically effective amount of an NSAID, whereby the potential for NSAID induced gastrointestinal injury in said subject is reduced.
22. A use according to claim 21 wherein the average daily dose of said NSAID given to said subject is from about 10 mg/Kg/day to about 100 mg/Kg/day and the daily average dose of said beta adrenergic agonist component is from about 0.0003 mg/Kg/day to about 500 mg/Kg/day.
23. A use according to claim 21 wherein said NSAID and said beta adrenergic agonist component are administered as a unit dosage form containing from about 200 mg to about 600 mg of NSAID and from about 0.7 mg to about 70 mg of said beta adrenergic agonist component.
24. A use according to claim 21 wherein said NSAID is ASA, the daily average dose of said ASA being from about 10 mg/Kg/day to about 100 mg/Kg/day and said beta adrenergic agonist being from about 0.0003 mg/Kg/day to about 500 mg/Kg/day.
25. A use according to claim 21 wherein the composition is employed in the form of a unit dosage form containing from about 200 mg to about 600 mg of asa and from about 0.7 mg to about 70 mg of said beta adrenergic agonist component.
26. The use of a beta adrenergic agonist in an amount effective to provide cytoprotection and/or an anti-secretory result, in the treatment of gastrointestinal disorders.
27. A use as set out in claim 26 wherein the beta adrenergic agonist is isoproterenol, metaproterenol, terbutaline, albuterol, fenoterol, bitolterol, isoetharine, coletrol, ritodrine, or their pharmaceutically acceptable salts.
28. A use in accordance with either one of claims 26 or 27 wherein the gastrointestinal disorder is one or more of GERD, undue gastric acid secretion, dyspepsia, gastritis and peptic ulcer.
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CA000559431A CA1309662C (en) | 1987-02-06 | 1988-02-22 | GASTROPROTECTIVE COMPOSITION CONTAINING .beta.-ADRENERGIC AGONISTS |
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US07/011,792 US4965065A (en) | 1986-04-29 | 1987-02-06 | Gastroprotective process and compositions |
CA000559431A CA1309662C (en) | 1987-02-06 | 1988-02-22 | GASTROPROTECTIVE COMPOSITION CONTAINING .beta.-ADRENERGIC AGONISTS |
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1988
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