WO1992021350A1 - Combinaison de medicaments anti-inflammatoires non steroidiens et de prostaglandines et leur utilisation - Google Patents

Combinaison de medicaments anti-inflammatoires non steroidiens et de prostaglandines et leur utilisation Download PDF

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Publication number
WO1992021350A1
WO1992021350A1 PCT/US1992/004461 US9204461W WO9221350A1 WO 1992021350 A1 WO1992021350 A1 WO 1992021350A1 US 9204461 W US9204461 W US 9204461W WO 9221350 A1 WO9221350 A1 WO 9221350A1
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Prior art keywords
pge
nsaid
acid
meg
administered
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PCT/US1992/004461
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English (en)
Inventor
William J. Wechter
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Sepracor, Inc.
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Publication of WO1992021350A1 publication Critical patent/WO1992021350A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins

Definitions

  • Bone demineralizing states particularly osteoporosis and loosening of metal pros- theses set in bone and fractures which will not form a union, have also not been satisfactorily treated to date.
  • a large part of the problem is the long-term nature of these, often chronic, medical problems and the lack of understanding of bone physiology associated with the homeostatic control of bone mineralization/ de ineralizatio .
  • the present model of bone maintenance holds that there is constant bone loss and formation and, thus, the net bone mineral balance is dynamic.
  • Negative bone balance results from age, post-menopausal status in women, bacterially-induced inflammation at specific sites such as alveolar bone, mechanical usage or stress, etastatic disease, systemic mastocytosis and a host of other etiologies.
  • a positive bone balance needs to be achieved in the spine and long bones to counteract osteoporosis, alveolar bone to counteract periodontitis, the skeleton in age or steroid-induced osteoporosis, etc. Needless to say, many endogenous agents are involved in this homeostatic system.
  • An understanding of the influences and inter ⁇ action of cytokines, prostaglandins and a variety of hormones are, at the present time, poorly realized.
  • the bone maintenance treat ⁇ ments include administration of calcitonin, calcium supplements, vitamins, vitamin D metabolites, fluoride, anabolic steroids, parathyroid hormone, diphosphonates and progestogens.
  • the present invention is a method for the use of a combination of two classes of therapeutic agents that, until now, have not been indicated as such a combination for treating inflammatory diseases or promoting bone maintenance. This combination is administered in order to reduce or eliminate inflammatory diseases or bone demineralization and/or promote bone remineralization.
  • the present method and compositions are particularly useful for the treatment of osteoporosis, bone loss associated with periodontal disease, loosening of metal
  • the combinations of therapeutic agents of this invention are useful as prolonged anti-inflammatory compositions for the treatment of rheumatoid arthritis,
  • NSAID non-steroidal anti-inflammatory drug
  • ketoprofen 15 as ketoprofen, flurbiprofen, indoprofen, pirprofen, indomethacin, mefan ic acid, phenylbutazone, diclofenac, naproxen, piroxicam and tolmetin is administered sepa ⁇ rately or in combination with a prostaglandin of the E series (PGE., PG ⁇ _, misoprostol, 15-methyl E. and E. ,
  • the drugs are administered to an individual in whom inflammatory disease or bone loss is to be pre ⁇ vented, reduced or reversed.
  • the NSAID is administered at a dose that inhibits the cyclooxygenase that enzymat-
  • peripheral analgesia which avoids, most, if not all, of the complicating side effects associated with mono- drug NSAID therapy.
  • the dose of PGE should be sufficiently small so as to avoid substantially all of the adverse side effects associated with PGE therapy (e.g. diarrhea, abortifacient effects, etc.) .
  • the dose of NSAID can be limited to less than one-half the appropriate dose of the corresponding racemic drug. Both drugs can be administered orally or topically in the buccal cavity.
  • the NSAID may be administered by one of the above routes and the PGE may be administered via a transdermal delivery device.
  • the present compositions can be administered either singly or as a fixed combination where the amounts of the two components are, respectively, the accepted analgesic dose of the NSAID or its S-isomer and the minimal anti-ulcerogenic dose of the PGE.
  • the NSAIDs will be given at 10 to 100% of the total daily analgesic dose and the PGE at 10 to 100% of the total daily anti-ulcerogenic dose.
  • the ratio can be adjusted as needed to reduce observed side effects of either drug while maintaining anti-osteopenic and anti- inflammatory efficacy of the drug combination.
  • compositions and method of using them to prevent or treat inflammatory diseases or to prevent or treat bone resorptive states and to promote bone regrowth once bone resorption has occurred have many advantages over other formulations or methods of treating these conditions.
  • either drug class used alone may possess bone sparing activity in active disease.
  • the combination of these drugs acting via different biologic mechanisms are synergistic and capable of anti-inflammatory diseases activity or bone replacement beyond the effect of either an indi ⁇ vidual NSAID or PGE.
  • a dose even lower than 50% of the racemic dose is effective and useful. This can make topical or transdermal delivery of the NSAIDs practical (Cf. toothpaste or mouthwash for treatment of bone loss secondary to periodontitis) .
  • Arylpropionic Acid (APA) and other NSAIDs have often proven beneficial in the treatment of inflammatory diseases or bone demineralizing states, particularly alveolar bone loss secondary to periodontitis (see EP 0 137 668, The Upjohn Company (Wechter) , 17 July 1985; or Jeffcoat et al. , "Flurbiprofen for Treatment of Perio ⁇ dontal Disease in Beagles", J. Periodont. Res. 21, 624-633 (1986)). It is now apparent from recent studies that an NSAID alone will not be sufficient as an ef ⁇ fective therapy to ameliorate chronic inflammatory disease or in chronic osteoporosis secondary to meno ⁇ pause. While estrogen replacement therapy has been effective in slowing bone loss in this latter condition, it is not without significant side effects in many women.
  • the NSAIDs have also been used to treat rheumatoid arthritis and a variety of other inflammatory diseases.
  • such treatment is often accompanied by a number of side effects that limit the usefulness of the NSAID treatment. These effects are apparent in most body systems but are particularly evident in the gastro ⁇ intestinal, renal and hepatic systems.
  • the dosages of the NSAIDs in the combi ⁇ nation co-administration of the present invention are much less than in isolated NSAID therapy, the NSAIDs in the compositions of the present invention are fully effective in combating the indicated disease states and they do so without significant adverse side effects. This makes the NSAIDs of the present invention more useful for the treatment of chronic inflammatory diseases.
  • a particular combination of drugs is co-administered to reduce or eliminate inflammatory diseases or bone demineralization that accompanies such maladies as osteoporosis.
  • Combinations of any NSAID and any PGE acid or preferably lower alkyl ester can be used to practice this invention.
  • Preferred embodiments are selected from the following NSAIDs; the APA class (S(+) isomers being preferred over the racemic mixtures) flurbiprofen, ketoprofen, ibuprofen, naproxen, carprofen, pirprofen, fenoprofen, benoxyprofen, etc.
  • the salicylates including diflunisal, phenyl butazone, oxyphenbutazone and apazone; indomethacin, sulindac and their analogs; the fenamates including mefenamic acid, flurfenamic acid, meclofenamic acid and tolfenamic acid; tolmetin; oxicams, isoxicam, sudoxicam and peroxica ; as well as diclofenac, fenbufen, fenclofenac, ketorolac, etodolac and oxaprozin.
  • the preferred PGEs include misoprostol (particu ⁇ larly its active 11R, 16S isomer) , PGE. and PG and their lower alkyl esters, 15R-methyl PGE 1 and P E 2 and their lower alkyl esters, 16,16-dimethyl PGE ]L and E 2 , oxyprostol and their lower alkyl esters as well as other E type prostaglandins as they come into common use.
  • the amount of each drug that is administered in the drug combination can be significantly less than the amount given when either drug is individually admin ⁇ istered in an attempt to achieve a specific therapeutic effect for that drug.
  • an NSAID e.g., peptic ulcerations, gastrointestinal bleeding, nephritis or renal toxicity
  • a prosta ⁇ glandin e.g. , fever, apnea, bradycardia, tachycardia or hypotension
  • the drug combination of the invention can be administered as isolated components or as a unitary entity containing both drugs. If administered sepa ⁇ rately, the individual components can be simultaneously administered or given at different times without sacri- ficing efficacy.
  • the mode of administration is a matter of choice, including parenteral, oral, topical or transdermal routes.
  • a prostaglandin PGE 1 , PGE 2 and the like
  • PGE 1 , PGE 2 and the like a prostaglandin
  • Such activators are ordinarily the product of the pathologic lesion (Cf. periodontitis, fracture, rheumatoid arthritis, etc.).
  • the second signal believed to be a hormone, factor or cytokine, is then inhibited by the NSAID resulting in amelioration of the inflammatory disease or promotion of a positive bone balance.
  • the problem in the case of inflammatory diseases and osteoporosis is that when there is no operating inflammatory lesion, the background level of PGE/s is critically depressed by the NSAIDs (which are also inhibitors of the cyclooxygenase enzyme requisite for prostaglandin synthesis) .
  • the plasma levels of PGE_ are in the range of 200-500 ng/mL.
  • an NSAID such as flurbiprofen
  • the circulating levels of PGE are reduced to about 50 ng/mL.
  • the therapeutic treatment of this invention therefore, consists of the chronic administration of a PG of the E series or an analog (Cf. 16,16 dimethyl-E. or E , 15R-methyl E or E_, PGE., or PGE themselves, misoprostol (Cytotec, Searle or preferably the active 11R, 16S diasterisomer) , and the like including simple esters such as in the case of misoprostol) .
  • the doses of PG are generally less than that required for gastric antisecretory activity (Cf. misoprostol less than 200 meg given 2 to 4 times per day in man) .
  • a subanti-inflammatory dose if admin ⁇ istered alone, of an APA (Cf. RS-flurbiprofen 10-50 mg bid, S-flurbiprofen 5-25 mg bid, RS-ketoprofen 5-25 mg qid, S-ketoprofen 2-10 mg qid, RS-ibuprofen 20-100 mg qid or S-ibuprofen 10-50 mg qid in man) .
  • APA Cf. RS-flurbiprofen 10-50 mg bid, S-flurbiprofen 5-25 mg bid, RS-ketoprofen 5-25 mg qid, S-ketoprofen 2-10 mg qid, RS-ibuprofen 20-100 mg qid or S-ibuprofen 10-50 mg qid in man
  • sustained release preparations are employed to maintain steady state blood levels of S-flurbiprofen or S-ketoprofen of about 1 mcg/mL ( ⁇ 75%) or S-ibuprofen 8 mcg/mL ( ⁇ 75%) .
  • the two drugs, PGE and APA can be administered as a fixed combination or independently.
  • the composition of the present invention includes at least one NSAID (achiral or racemic or S-isomer of an APA) and one PGE analog employed separately as tablets, topical formulation (toothpaste or mouthwash) or trans- dermal preparations that will be dosed separately.
  • NSAID achiral or racemic or S-isomer of an APA
  • PGE analog employed separately as tablets, topical formulation (toothpaste or mouthwash) or trans- dermal preparations that will be dosed separately.
  • a single oral tablet may be employed containing both drugs layered so that the NSAID is released first followed by the PGE in the innercore of the tablet.
  • the NSAIDs will be present at their analgesic dose (Cf. RS-flurbiprofen 50 mg for bid administration and the PGE at the minimal anti-ulcer dose of 200 meg) when both drugs are given conco it- antly.
  • the pH of the formulation should be main ⁇ tained at acid pH (5-6) .
  • the ability of a particular formulation to have the desired effect i.e., reduce inflammation, reduce bone loss, promote bone remineral- ization) can be assessed using standard techniques.
  • the adjuvant arthritis model is used since it mimics rheumatoid arthritis.
  • arthritis is induced in Sprague-Dawley rats by injecting them with Freund's complete adjuvant or a material that can substitute for this adjuvant in inducing arthritis.
  • the progression of arthritis or its long-term amelioration can be followed by measuring the amount of a. acid glycoprotein, whose blood titer is elevated in arthritic conditions, the amount of a - macroglobulin plasma albumin, whose blood titer is depressed in arthritic conditions, or the size or functionality of a specified joint susceptible to arthritic changes.
  • the dosages are * either 0.1, 0.3 or 1 mg/kg.
  • the misoprostol dosages are either 1, 10, 30 or 100 mcg/kg.
  • ketoprofen is added to that of misoprostol for a panel of patients exhibit ⁇ ing chronic rheumatoid arthritis.
  • This study is for an extended term and includes patients to whom subthreshold doses of the NSAID and PG are administered, compared to doses for each therapeutic agent when administered alone.
  • This study follows a double blind protocol and uses x-ray analysis (periodic CAT scanning) of the arthritically affected joints to evaluate the effects of the administration of the combination of therapeutic agents of this invention.
  • a technique for assessing the reduction in bone loss or the promotion of bone remineralization for experimental animals is quantitative histomorphometry adapted from Jee et al. , Bone _9, 381-389 (1988) or Li et al. Bone 10, 35-44 (1989) .
  • Ovariectomy (OVX)-induced osteopenia is primarily due to an estrogen/ progesterone deficiency which stimulates a marked increase in bone remodeling. This leads to an imbalance of bone resorption over bone formation. The negative bone balance results in an osteopenic skeleton.
  • This characterization of osteo- penic changes in OVX rats serves as the basis for the design of the example infra which uses the OVX rat as an animal model for postmenopausal bone loss.
  • Femoral bone mineral content is determined using single photon absorptometry (Norland Corporation, Fort Atkinson, WI) .
  • Three femoral sites (proximal, middle and distal) are scanned transversely. The proximal site is at the point just distal to the lesser trochanter, the middle site is at the midpoint of total femoral length, and the distal site is at the point most proximal to the femoral condyle.
  • Bone mineral content (BMC in gm/cm) and bone width (BW in cm) are obtained, and bone mineral density (BMC/BW m gm/cm 2) calculated.
  • proximal tibia, tibial shaft and metatarsals are dehydrated in graded concentrations of ethanol and defatted in acetone, then embedded in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY) .
  • Frontal sections of proximal tibia and cross sections of tibial shaft and metatarsals at 230 um thickness are cut using a low-speed metallurgical saw, then ground to 100 um using a precision lapping machine (Maruto Co. , Tokyo, Japan) and then microradiographed on Kodak spectroscopic plates (649-0 Eastman Kodak, Rochester, NY) at 12 kv, 25 mA for 7 minutes. Thereafter, sections are mounted on plastic slides using cyanoacrylate ester glue (Per a- bound 910, Adhesive, NJ) and further ground to a thick- ness of 20 um and coverslipped for morphometric measure ⁇ ments.
  • cyanoacrylate ester glue Per a- bound 910,
  • Microradiographs and 20 um sections are viewed qualitatively and/or quantitatively. Static and kinetic parameters are measured on 20 um sections of proximal tibia or tibial shaft for trabecular or cortical bone histomorphometry, respectively, using a digitizing image analyzing system coupled to an epifluorescent micro ⁇ scope.
  • T.Ar total tissue area
  • Tb.Ar trabecular area
  • Tb.Pm perimeter
  • sL.Pm single labeled perimeter
  • dL.Pm double labeled perimeter
  • Percent cortical bone, percent labeled periosteal and endosteal surfaces, periosteal and endosteal mineral apposition and formation rates are calculated according to the measurements. Statistical differences between control and treat ⁇ ment groups are tested by the Kruskal-Wallis test. The data are further analyzed as a function of dose (dose dependent response) and as a function of time (time dependent response) by linear regression. The following example is representative of the above-described technique for assessing the reduction in bone loss.
  • Rats in Groups 2-5 were injected subcutaneously with freshly thawed mixtures of the appropriate drug(s) and vehicle (50% ethanol/water) beginning at day 1. The volume of injection solution was 0.5 mL/kg body weight. All rats, including the controls, received bone fluoro- chromes by subcutaneous injection (10 mg/kg) on day 1 (tetracycline) and 7 (calcein) .
  • ketoprofen and PGE_ combination treatment significantly inhibited trabecular bone loss secondary to ovariectomy.
  • ketoprofen or PGE_ as an individual treatment, exhibits some inhibition of bone loss
  • the combination of ketoprofen and GE 2 exhibits a previously unexpected significant inhibition of bone loss.
  • Visual comparisons of the proximal regions of the tibiae in each of the 5 treatment groups also provided evidence that the ketoprofen-PGE_ combination markedly inhibits the loss of bone that accompanies ovariectomy.
  • Another technique for assessing the reduction in bone loss or the promotion of bone remineralization as well as the inflammation of surrounding tissue that accompanies such bone loss is the treatment of chronic destructive periodontal disease with the combination of therapeutic agents of this invention. This technique is adapted from Jeffcoat et al. , J. Period. Res. 21, 624-633 (1986) .
  • the experimental design employs a 6-month pretreatment period, a 12-month treatment period, and a 6-month post-treatment period.
  • a 6-month pretreatment period radiographs are taken every 3 months and a baseline, or pretreatment rate of bone loss is calculated.
  • measure ⁇ ments of baseline, bone-seeking radiopharmaceutical uptake (BSRU) and gingival inflammation are performed.
  • the beagles are separated into two groups of dogs such that the mean rate of bone loss for the two groups is similar.
  • This experimental design allows each tooth surface to serve as its own control so that rates of bone loss, BSRU, and gingival inflammation found in the treatment period and post-treatment period can be compared to the pretreatment period.
  • Radiographs Standardized radiographs of the premolar teeth are taken using modified Rinn radiographic holders. These radiographs are utilized to measure the amount and rate of alveolar bone loss.
  • Measurement of the alevolar bone height is per- formed by projecting each radiograph so that an approxi ⁇ mately 10-fold increase in the size of the image is obtained to facilitate the reading process.
  • the dis ⁇ tance from alveolar crest to root apex is expressed as a percent of the tooth root length (cemento-enamel junction to root apex) . All measurements are made with the assistance of a digitizer and microcomputer.
  • bone seeking radiophar a- ceutical uptake in the alveolar bone surrounding the second and third premolar teeth is measured.
  • Each dog receives 1.5 mCi/kg technetium 99m-tin-diphosphonate (99mTc-Sn-MDP) intravenously.
  • uptake is measured in the alveolar bone surrounding the teeth using a miniaturized semiconductor probe radiation detector. Measurements of radiopharmaceutical uptake are taken at the alveolar crest.
  • Uptake measurements are also taken from the nuchal crest (the bony prominence dividing the dorsal and posterior skull surfaces) before and after uptake in each quadrant is measured.
  • the mean counts per minute of each aleveolar bone area are divided by the mean counts per minute of the nuchal crest to normalize the alveolar bone uptake data with respect to physical decay and biological clearance of the radiopharmaceutical. Repeated measurements using this methodology have been found to vary by less than 3%.
  • Bone Loss The rate of bone loss from one study period to the next is calculated for each tooth surface using the following formula:
  • the rate of bone loss is calculated in each of the two groups of teeth studied.
  • the analysis of variance is used to test for statistically significant differ ⁇ ences in the rate of bone loss over the course of the pretreatment, treatment and post-treatment period in each group.
  • each tooth surface serves as its own ' control.
  • the preceding analysis can demonstrate whether or not a treatment regimen has a significant positive or negative effect on the rate of bone loss compared to the pretreatment period.
  • the concept of change in rate from the pretreatment value is used. This concept is of particular importance if the rate of bone loss is increasing or decreasing in the control group. Therefore, the data are further analyzed to determine the difference between the pretreatment rate of bone loss and the rate at each time period studied.
  • Rates are calculated for: a) the overall pretreatment period, b) for the treatment period from the start of treatment to each study interval in the treatment period, and c) from the start of the post-treatment period to each point in the post-treatment period.
  • Rate Change Rate (time x)
  • An unpaired t-test is used to determine if the change in rate of bone loss from the pretreatment period is significantly different in placebo versus flurbiprofen- treated group.
  • Bone Seeking Radiopharmaceutical Uptake The difference between the pretreatment BSRU and the BSRU measurement at 3,6, or 9 months of the treatment periods is calcu ⁇ lated. An unpaired t-test is used to determine if a significant difference exists between the placebo and the flurbiprofen-treated groups.
  • Gingival Inflammation The mean gingival index for each group is calculated for descriptive purposes. The Mann Whitney U test is used to test for significant differ ⁇ ences between the placebo and the flurbiprofen-treated groups.

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Abstract

Combinaison d'un médicament anti-inflammatoire non stéroïdien et d'une prostaglandine de série E, que l'on administre à des individus pour traiter les maladies inflammatoires, ou pour réduire ou prévenir la déminéralisation osseuse chronique, ou pour stimuler la reminéralisation osseuse. Ce médicament combiné est utilisé pour traiter l'arthrite rhumatoïde ou d'autres maladies inflammatoires, ou pour traiter l'ostéoporose, la dégénérescence osseuse liée à la parodontolyse, ou pour stimuler le ressoudage des os après fracture. Les quantités de médicament anti-inflammatoire non stéroïdien et de prostaglandine administrées sont inférieures aux quantités administrées généralement en cas d'utilisation individuelle de chaque médicament pour obtenir l'effet désiré. Cette particularité permet de réduire au minimum les effets secondaires indésirables associés à ces médicaments.
PCT/US1992/004461 1991-05-29 1992-05-29 Combinaison de medicaments anti-inflammatoires non steroidiens et de prostaglandines et leur utilisation WO1992021350A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0682521A1 (fr) * 1993-02-12 1995-11-22 McKEE, Rex N. Procede de traitement au misoprostol de muqueuses et de tissus epitheliaux presentant des lesions
EP0970694A2 (fr) * 1998-05-22 2000-01-12 Pfizer Products Inc. Utilisation du carprofène et ses dérivés pour la prévention ou le traitement de la dégénération articulaire
EP1020182A2 (fr) * 1999-01-18 2000-07-19 SHERMAN, Bernard Charles Comprimé pharmaceutique à deux couches contenant un anti-inflammatoire non steroidique et misoprostol
WO2000051585A2 (fr) * 1999-03-05 2000-09-08 The Procter & Gamble Company Augmentation du volume osseux par utilisation d'agonistes selectifs d'ep1 n'existant pas naturellement
GB2368793A (en) * 2000-06-12 2002-05-15 Jack Colover Treatment of multiple sclerosis
US7241746B2 (en) 2003-08-06 2007-07-10 Regena Therapeutics, Lc Method and composition for treating periodontal disease

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US4397865A (en) * 1982-10-12 1983-08-09 The Upjohn Company Method for preventing renal papillary necrosis with prostaglandins
EP0297842A2 (fr) * 1987-06-29 1989-01-04 Elizabeth May Wood Utilisations d'un acide 2-phénoxyphényl acétique comme agent immunosuppresseur
US5015481A (en) * 1990-05-03 1991-05-14 G. D. Searle & Co. Stabilized pharmaceutical admixture composition

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US4397865A (en) * 1982-10-12 1983-08-09 The Upjohn Company Method for preventing renal papillary necrosis with prostaglandins
EP0297842A2 (fr) * 1987-06-29 1989-01-04 Elizabeth May Wood Utilisations d'un acide 2-phénoxyphényl acétique comme agent immunosuppresseur
US5015481A (en) * 1990-05-03 1991-05-14 G. D. Searle & Co. Stabilized pharmaceutical admixture composition

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Title
CHEMICAL ABSTRACTS, vol. 110, no. 21, 22 May 1989, Columbus, Ohio, US; abstract no. 185574, BJARNASSON, INGVAR ET AL.: 'Misoprostol reduces indomethacin-induced changes im human small intstin permeability' page 40 ;column 2 ; *
CHEMICAL ABSTRACTS, vol. 111, no. 9, 28 August 1989, Columbus, Ohio, US; abstract no. 70549, LANZA, FRANK ET AL.: 'A double-blind placebo-controlled comparison of the efficacy and safety of 50, 100, and 200 microg. of misoprostol QID in the prevention of ibuprofen induced gastric and duodenal mucosal lesions and sympoms' page 41 ;column 1 ; *
CHEMICAL ABSTRACTS, vol. 112, no. 7, 12 February 1990, Columbus, Ohio, US; abstract no. 49377, PATRICE, T ET AL.: 'Endothelial cell growth regulation by PGE1 analog misoprostol and indomethacin' page 4937 ;column 1 ; *
PROSTAGLANDINS vol. 37, no. 2, February 1989, pages 229 - 235; RAISZL. G. & WOODIEL F. N.: 'Effect of alterations in the cyclopentane ring on bone resorpive activity of prostaglandin' *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0682521A1 (fr) * 1993-02-12 1995-11-22 McKEE, Rex N. Procede de traitement au misoprostol de muqueuses et de tissus epitheliaux presentant des lesions
EP0682521A4 (fr) * 1993-02-12 1997-07-30 Rex N Mckee Procede de traitement au misoprostol de muqueuses et de tissus epitheliaux presentant des lesions.
EP0970694A2 (fr) * 1998-05-22 2000-01-12 Pfizer Products Inc. Utilisation du carprofène et ses dérivés pour la prévention ou le traitement de la dégénération articulaire
EP0970694A3 (fr) * 1998-05-22 2000-01-26 Pfizer Products Inc. Utilisation du carprofène et ses dérivés pour la prévention ou le traitement de la dégénération articulaire
US6506785B2 (en) 1998-05-22 2003-01-14 Pfizer, Inc. Treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in mammals using carprofen and derivatives
EP1020182A2 (fr) * 1999-01-18 2000-07-19 SHERMAN, Bernard Charles Comprimé pharmaceutique à deux couches contenant un anti-inflammatoire non steroidique et misoprostol
EP1020182A3 (fr) * 1999-01-18 2000-12-20 SHERMAN, Bernard Charles Comprimé pharmaceutique à deux couches contenant un anti-inflammatoire non steroidique et misoprostol
WO2000051585A2 (fr) * 1999-03-05 2000-09-08 The Procter & Gamble Company Augmentation du volume osseux par utilisation d'agonistes selectifs d'ep1 n'existant pas naturellement
WO2000051585A3 (fr) * 1999-03-05 2001-01-25 Procter & Gamble Augmentation du volume osseux par utilisation d'agonistes selectifs d'ep1 n'existant pas naturellement
GB2368793A (en) * 2000-06-12 2002-05-15 Jack Colover Treatment of multiple sclerosis
US7241746B2 (en) 2003-08-06 2007-07-10 Regena Therapeutics, Lc Method and composition for treating periodontal disease
US7691862B2 (en) 2003-08-06 2010-04-06 Regena Therapeutics Lc Method and composition for treating periodontal disease

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