AP646A - Use of fumagillol and derivatives thereof for preparing medicaments against intestinal infections. - Google Patents

Use of fumagillol and derivatives thereof for preparing medicaments against intestinal infections. Download PDF

Info

Publication number
AP646A
AP646A APAP/P/1997/001092A AP9701092A AP646A AP 646 A AP646 A AP 646A AP 9701092 A AP9701092 A AP 9701092A AP 646 A AP646 A AP 646A
Authority
AP
ARIPO
Prior art keywords
fumagillol
ester
use
preparation
drugs
Prior art date
Application number
APAP/P/1997/001092A
Other versions
AP9701092A0 (en
Inventor
Jean-Michel Molina
Francis Deriyubm
Original Assignee
Sanofi Sa
Assist Publ Hopitaux De Paris
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to FR9503549 priority Critical
Application filed by Sanofi Sa, Assist Publ Hopitaux De Paris filed Critical Sanofi Sa
Priority to PCT/FR1996/000448 priority patent/WO1996030010A2/en
Publication of AP9701092A0 publication Critical patent/AP9701092A0/en
Application granted granted Critical
Publication of AP646A publication Critical patent/AP646A/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/485The waterborne disease being caused by a protozoa
    • Y02A50/492The waterborne disease being caused by a protozoa of the phylum Microsporidia, i.e. Microsporidiosis

Abstract

The invention relates to the use of fumagillol and esters formed by fumagillol and saturated or unsaturated (c1-c12)alkylcarboxylic or (c1-c12)alkydicarboxylic acids, and their pharmaceutically acceptable salts, for the preparation of medicaments for comb

Description

AP 00646 ι

Use of fumagillol and derivatives thereof for preparing medicaments against intestinalinfections

The present invention relates to a novel use of fumagillol and its derivatives, 5 especially fumagillin.

Fumagillin is an antibiotic, first described in 1951 (The Merck Index 11thEdition, no. 4199), which is used especially for preventing or controlling parasiticdiseases in fish farming and beekeeping and which has also been used in man for thelocal treatment, in an eye lotion, of keratoconjunctivitis due to Encephalitozoon hellem 10 (J. Ophtal., 1993, 115, 293). However, it has been found to be inactive as a carcinolytic agent (Antibiotic Annual, 1958-1959, 541-546).

It has now been found that fumagillol and certain esters formed with thiscompound, when formulated in a drug, especially an oral drug, are capable of resolvingvery serious infectious conditions of the intestine due to microsporidia or 15 Cryptosporidia.

It has also been found, surprisingly, that fumagillol and the esters formed byfumagillol and saturated or unsaturated (C,-CI2)alkylcarboxylic or (C,-C12)alkyl-dicarboxylic acids are capable of inducing eradication of Enterocytozoon bieneusi inpatients affected by HIV. This discovery is surprising and decisive because there is 20 currently no known remedy for this type of infection, which constitutes 95% of theintestinal infections due to microsporidia which result in cachexia and death in patientssuffering from AIDS.

Thus, according to one of its features, the present invention relates to the use offumagillol or esters formed by fumagillol and saturated or unsaturated 25 (C,-C12)alkylcarboxylic or (C,-Cl2)alkyldicarboxylic acids, and their pharmaceuticallyacceptable salts, for the preparation of drugs for combating intestinal infections due tomicrosporidia and/or Cryptosporidia.

More particularly and advantageously, according to its preferred feature, thepresent invention relates to the use of fumagillol or esters formed by fumagillol and 30 saturated or unsaturated (C,-C12)alkylcarboxylic or (C,-C12)alkyldicarboxylic acids, andtheir pharmaceutically acceptable salts, for the preparation of drugs for combatingintestinal infections for which the parasite Enterocytozoon bieneusi is principallyresponsible. “Saturated or unsaturated (C,-Cl2)alkylcarboxylic or (CrC|2)alkyldicarboxylic 35 acids” are understood as meaning carboxylic or dicarboxylic acids of linear or branchedalkyls, it being possible for said alkyls to contain one or more double bonds. AP 00646 2

Examples of such acids are acetic, propionic, butyric, valeric, pivalic, malonic,succinic, acrylic, crotonic, isocrotonic, oleic, maleic, fumaric and 2,4,6,8-decatetraenedioic acids.

The ester of fumagillol and 2,4,6,8-decatetraenedioic acid, fumagillin, is a5 particularly advantageous compound.

The esters of the present invention are easily prepared by reacting fumagillolwith the appropriate acid under the normal esterification conditions described in theliterature.

Fumagillol, either as such or esterified with a (C,-C|2)alkylcarboxylic or10 (C,-C,2)alkyldicarboxylic acid, can be administered in the form of the free acid or else in the form of one of its salts with a pharmaceutically acceptable base.

For their administration to patients suffering from an infection due tomicrosporidia or Cryptosporidia, fumagillol or the esters formed therewith are mixedwith pharmaceutical excipients commonly used for the preparation of pharmaceutical 15 formulations, preferably for oral administration.

Advantageously, the compounds of the present invention are formulated asactive principles in dosage units, for example tablets or gelatin capsules, containingfrom 1 to 200 mg of active principle, advantageously from 2 to 100 mg, moreadvantageously from 5 to 50 mg or preferably from 7.5 to 30 mg per dosage unit. 20 The pharmaceutical compositions for oral administration constitute a further subject of the present invention.

In the pharmaceutical compositions of the present invention for oraladministration, the active principle can be administered in the above-mentioned unitforms of administration, mixed with conventional pharmaceutical carriers, for the 25 treatment of the above-mentioned diseases. The appropriate unit forms of administrationinclude oral forms such as tablets, which may be scored, gelatin capsules, powders,granules and solutions or suspensions to be taken orally.

When a solid composition is prepared in the form of tablets, which is one of thepreferred forms, the main active ingredient is mixed with a pharmaceutical vehicle such 30 as gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or the like. Thetablets can be coated with sucrose or other appropriate substances or else they can betreated so as to have a prolonged or delayed activity and so as to release a predeterminedamount of active principle continuously. These delayed action or controlled releasetablets represent another very advantageous form. e* c v

C >*. r* c

C c A preparation in the form of gelatin capsules, which is another particularlyadvantageous form, is obtained by mixing the active ingredient with a diluent andpouring the resulting mixture into soft or hard gelatin capsules. A preparation in the form of a syrup or elixir can contain the active ingredient5 together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring and an appropriate color.

The water-dispersible granules or powders can contain the active ingredientmixed with dispersants or wetting agents or with suspending agents such aspolyvinylpyrrolidone, as well as with sweeteners or taste correctors. 10 The active principle can also be formulated as microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions according to the present invention, the activeprinciple can also be in the form of an inclusion complex in cyclodextrins, their ethersor their esters. 15 Pharmaceutical compositions for oral administration, containing from 1 to 200 mg, preferably from 2 to 100 mg, from 5 to 50 mg or from 7.5 to 30 mg, of fumagillol,an ester formed by fumagillol and one of the acids mentioned above, especiallyftimagillin, or one of their pharmaceutically acceptable salts as the active principle, in aform selected from tablets, delayed action tablets, controlled release tablets and gelatin 20 capsules, constitute a further subject of the present invention.

The compounds of the present invention can be administered with other drugs generally used during the development of AIDS, and can also be formulated inassociation with other antiparasitics or antibiotics or with drugs having an anti-HIVaction. 25 The therapeutic activity of the compounds of the present invention was demonstrated by administering different doses of the pharmaceutical composition ofExample 1 to four homosexual patients of the male sex presenting a high immunedeficiency with an average CD4 level of 66 (11-158). Three patients had recognizedAIDS and one patient had an ARC (Aids Related Complex). The average age was 40 30 years.

Prior to inclusion, all these patients had consecutive stool examinations whichwere positive for microsporidia. Two patients concomitantly presented an intestinalinfection with Cryptosporidia. The test for microsporidia in the urine remained negativein all the patients, these factors favoring the diagnosis of infection with Enterocytozoon 35 bieneusi.

AP o u 6 4 6 4

All the patients had a duodenal fibroscopy with biopsies. In three patients,microsporidia were identified on these biopsies in histology and in direct parasitology,as well as by electron microscopy. In the fourth case, only electron microscopyrevealed the presence of Enterocytozoon bieneusi. 5 The four patients received 20 mg of fumagillin three times a day, i.e. 60 mg/d, for 21 days.

Eradication of the parasite from the stool was observed in all the patients in thecontrol examinations after 15, 17 and 21 days of treatment. Microsporidia were stillabsent from the patients’ stool one month after cessation of the treatment. 10 Of the two patients who presented Cryptosporidia in their stool prior to inclusion, only one transitorily tested negative on his stool, Cryptosporidia reappearing one monthafter cessation of the treatment.

All the patients had a control duodenal fibroscopy to assess the disappearance ofthe parasites at tissue level. Also, in two cases, a negative result was observed in 15 histology, with the persistence of very rare microsporidia in direct parasitology 0(probably cadavers of microsporidia). The electron microscopy study confirmed the Ctotal disappearance of Enterocytozoon bieneusi in all four patients. *

Another group of patients was recruited for a tolerance/toxicology study. Dosesof 10, 20, 40 and 60 mg of fumagillin were administered to twenty-four patients (six per , 20 dose level). i

The treatment was tolerated well. In particular, no hepatic toxicity, cardiac toxicity (ECG) or renal toxicity (creatininemia) was observed. Even a very slightdecrease in the serum alkaline phosphatase level was noted, which could correspond to abeneficial effect of the treatment on cholangitis due to microsporidia. 25 The troublesome side effect observed was of the hematological type, namely thrombopenia which varied in degree but was never very severe (except in one casewhich caused the administration to be interrupted in the above group of four patients)and whose evolution was spontaneously regressive in 10 to 14 days after cessation ofthe treatment. This side effect, which is not immunological but due solely to a direct 30 toxicity towards the platelets, can be corrected by an appropriate choice of treatmentprotocol.

In conclusion, eradication of the parasite from the stool was observed for thefirst time in this opportunistic infection; this eradication persists for at least one monthafter cessation of the treatment and seems to be accompanied by eradication of the 35 parasite from the duodenal biopsies. This result has never been achieved with otherantiparasitics. AP 00646

The clinical benefit is difficult to evaluate in these patients in view of themultiple associated infections and the pursuance of symptomatic treatments. A verymarked clinical benefit was nevertheless obtained in the patients treated, who all gainedseveral kilograms and whose diarrhea stopped at the end of the treatment.

Consequently, spectacular parasitological results were obtained with fumagillinin Enterocytozoon bieneusi infections in the course of AIDS, with an excellent clinicalresult in some cases. EXAMPLE 1

Pharmaceutical composition in the form of gelatin capsules each containing 20 mg offumagillin acid 14 g of purified and pre-sieved fumagillin acid are gradually diluted to a volumeof 210 ml with the requisite amount of colloidal silica (AEROSIL®). The powderobtained is mixed thoroughly and the homogeneous powder prepared in this way isdivided up into no. 3 opaque hard gelatin capsules. This gives 700 gelatin capsules eachcontaining 20 mg of fumagillin acid. Γ" cr>

ΡΑΤΕΝΤΛ AGENT FOR THE

ANT

Claims (10)

  1. μ λ λ /* / r· ΑΚ υ υ ο ί ο CLAIMS Having now particularly described andascertained mv/our said invention and mw iut manner the same is to be pei lorinvdl/wc declare that what l/wc ci.ton is —
    1. Use of fumagillol or an ester formed by fumagillol and a saturated or unsaturated(C,-CI2)alkylcarboxylic or (C|-Ci2)alkyldicarboxylic acid, and their pharmaceutically 5 acceptable salts, for the preparation of drugs for combating intestinal infections due tomicrosporidia and/or Cryptosporidia.
  2. 2. Use according to claim 1 wherein said ester is fumagillin.
  3. 3. Use of fumagillol or an ester formed by fumagillol and a saturated or unsaturated(C,-Ci2)alkylcarboxylic or (C,-C12)alkyldicarboxylic acid, and their pharmaceutically 10 acceptable salts according to claim 1, for the preparation of drugs for combatingintestinal infections for which the parasite Enterocytozoon bieneusi is principallyresponsible.
  4. 4. Use according to claim 3 wherein said ester is fumagillin.
  5. 5. Use according to claim 1 or 2 for the preparation of drugs for oral 15 administration.
  6. 6. Use according to claim 3 or 4 for the preparation of drugs in the form of tablets,gelatin capsules or delayed action or controlled release tablets.
  7. 7. Pharmaceutical composition for oral administration, containing an ester formedby fumagillol and a saturated or unsaturated (C,-C,2)alkyldicarboxylic acid, or one of its 20 pharmaceutically acceptable salts, as the active principle.
  8. 8. Pharmaceutical composition according to claim 7 wherein said ester isfumagillin.
  9. 9. Pharmaceutical composition according to claim 7 or 8 containing from 1 to 200mg of active principle.
  10. 10. Pharmaceutical composition according to claim 9 containing from 7.5 to 30 mg of active principle. day .
    MODIFIED SHE
    APPLICANT C\ a c W“ C r c c i
APAP/P/1997/001092A 1995-03-27 1996-03-26 Use of fumagillol and derivatives thereof for preparing medicaments against intestinal infections. AP646A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FR9503549 1995-03-27
PCT/FR1996/000448 WO1996030010A2 (en) 1995-03-27 1996-03-26 Use of fumagillol and derivatives thereof for preparing medicaments against intestinal infections

Publications (2)

Publication Number Publication Date
AP9701092A0 AP9701092A0 (en) 1997-10-31
AP646A true AP646A (en) 1998-04-27

Family

ID=9477436

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1997/001092A AP646A (en) 1995-03-27 1996-03-26 Use of fumagillol and derivatives thereof for preparing medicaments against intestinal infections.

Country Status (23)

Country Link
US (1) US5900431A (en)
EP (1) EP0817626B1 (en)
JP (1) JP3260378B2 (en)
CN (1) CN1072485C (en)
AP (1) AP646A (en)
AT (1) AT172641T (en)
AU (1) AU706161B2 (en)
CA (1) CA2216623C (en)
CZ (1) CZ286821B6 (en)
DE (2) DE69600879T2 (en)
DK (1) DK0817626T3 (en)
EA (1) EA000150B1 (en)
ES (1) ES2128846T3 (en)
HU (1) HU224028B1 (en)
IS (1) IS2048B (en)
MX (1) MX9707150A (en)
NO (1) NO315968B1 (en)
NZ (1) NZ304906A (en)
OA (1) OA10515A (en)
PL (1) PL183378B1 (en)
SK (1) SK283883B6 (en)
TR (1) TR199701048T1 (en)
WO (1) WO1996030010A2 (en)

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69600879T2 (en) * 1995-03-27 1999-06-02 Sanofi Sa Use of fumagillol and its derivatives for the manufacture of medicines against intestinal infections
EP0799616A1 (en) * 1996-04-01 1997-10-08 Takeda Chemical Industries, Ltd. Oral composition comprising a fumagillol derivative
WO2000050084A1 (en) * 1999-02-26 2000-08-31 Sanofi-Synthelabo Stable formulation containing fumagillin
JP3265394B1 (en) 2001-03-14 2002-03-11 泰三 矢野 Acrylic resin gloves
DE10341887A1 (en) * 2003-09-09 2005-03-31 Leopold Kostal Gmbh & Co. Kg Electrical switch module
FR2886855B1 (en) * 2005-06-08 2009-07-17 Agronomique Inst Nat Rech Use of fumagillin and its derivatives to increase the bioavailability of the macrocyclic lactones
JP5557746B2 (en) * 2007-11-28 2014-07-23 メルサナ セラピューティックス,インク. Biocompatible biodegradable fumagillin analog complex
US8865746B2 (en) * 2008-07-18 2014-10-21 Zafgen, Inc. Methods of treating an overweight or obese subject
WO2010065877A2 (en) 2008-12-04 2010-06-10 Zafgen Corporation Methods of treating an overweight or obese subject
US8642650B2 (en) 2008-12-04 2014-02-04 Zafgen, Inc. Methods of treating an overweight or obese subject
CN102639494B (en) 2009-10-09 2016-11-09 扎夫根公司 Sulfone compounds and their preparation and use
MX343135B (en) 2010-01-08 2016-10-25 Zafgen Corp * Fumagillol type compounds and methods of making and using same.
WO2011085198A1 (en) 2010-01-08 2011-07-14 Zafgen Corporation Metap-2 inhibitor for use in treating benign prostatic hypertrophy (bph)
US20130266578A1 (en) 2010-04-07 2013-10-10 Thomas E. Hughes Methods of treating an overweight subject
KR20130043207A (en) 2010-07-22 2013-04-29 자프겐 인크. Tricyclic compounds and methods of making and using same
WO2012064838A1 (en) 2010-11-09 2012-05-18 Zafgen Corporation Crystalline solids of a metap-2 inhibitor and methods of making and using same
EP2646016B1 (en) 2010-11-29 2017-05-17 Zafgen, Inc. Treatment if obesity using non-daily administration of 6-0-(4-dimethylaminoethoxy)cinnamoyl fumagillol
US9321740B2 (en) 2011-01-26 2016-04-26 Zafgen, Inc. Tetrazole compounds and methods of making and using same
CN103534244B (en) 2011-03-08 2016-10-12 扎夫根股份有限公司 Oxa-spiro [2.5] octane derivative, and the like
CA2835261C (en) 2011-05-06 2019-06-04 Zafgen, Inc. Partially saturated tricyclic compounds and methods of making and using same
WO2012154678A1 (en) 2011-05-06 2012-11-15 Zafgen Corporation Tricyclic sulfonamide compounds and methods of making and using same
MX343688B (en) 2011-05-06 2016-11-16 Zafgen Inc Tricyclic pyrazole sulfonamide compounds and methods of making and using same.
WO2013055385A2 (en) 2011-10-03 2013-04-18 Zafgen Corporation Methods of treating age related disorders
KR20140112565A (en) 2012-01-18 2014-09-23 자프겐 인크. Tricyclic sulfonamide compounds and methods of making and using same
MX2014008705A (en) 2012-01-18 2015-02-05 Zafgen Inc Tricyclic sulfone compounds and methods of making and using same.
KR20150016303A (en) 2012-05-07 2015-02-11 자프겐 인크. Polymorphic salt of the oxalate salf of 6-o-(4-dimethylaminoethoxy) cinnamoyl fumagillol and methods of making and using same
CN104363905A (en) 2012-05-08 2015-02-18 扎夫根股份有限公司 Treating hypothalamic obesity with metap2 inhibitors
KR20150016534A (en) 2012-05-09 2015-02-12 자프겐 인크. Fumagillol type compounds and methods of making and using same
MX2015005732A (en) 2012-11-05 2015-12-16 Zafgen Inc Tricyclic compounds and methods of making and using same.
BR112015010196A2 (en) 2012-11-05 2017-07-11 Zafgen Inc methods of treating liver disease
MX2015005733A (en) 2012-11-05 2016-02-10 Zafgen Inc Tricyclic compounds for use in the treatment and/or control of obesity.
AU2014236528A1 (en) 2013-03-14 2015-09-24 Zafgen, Inc. Methods of treating renal disease and other disorders
AR105671A1 (en) 2015-08-11 2017-10-25 Zafgen Inc Heterocyclic compounds of fumagillol and its methods of making and using
CN106432255A (en) 2015-08-11 2017-02-22 扎夫根公司 Fumigillol spiro-compound, preparation and use method thereof
CN106591389A (en) * 2015-10-15 2017-04-26 中国科学院微生物研究所 Method for producing fumagillin by aspergillus fumigatus
CN105622593B (en) * 2016-02-25 2018-06-26 中国农业科学院蜜蜂研究所 Extraction Methods fumagillin

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994019946A1 (en) * 1993-03-01 1994-09-15 Emory University Treatment of microsporidial and acanthamoeba keratoconjunctivitis with topical fumagillin

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2791530A (en) * 1953-08-31 1957-05-07 Abbott Lab Stabilized fumagillin compositions
JPH0629278B2 (en) * 1985-06-26 1994-04-20 藤沢薬品工業株式会社 Oxa spirooctane compound
US5135920A (en) * 1988-11-16 1992-08-04 Takeda Chemical Industries, Ltd. Angiostatic agents
JPH06504262A (en) * 1990-07-27 1994-05-19
DE69600879T2 (en) * 1995-03-27 1999-06-02 Sanofi Sa Use of fumagillol and its derivatives for the manufacture of medicines against intestinal infections
EP0799616A1 (en) * 1996-04-01 1997-10-08 Takeda Chemical Industries, Ltd. Oral composition comprising a fumagillol derivative
CA2210600A1 (en) * 1996-07-17 1998-01-17 Takashi Houkan Inhibitor of tumor metastasis or recurrence
WO1998005293A2 (en) * 1996-08-02 1998-02-12 The Children's Medical Center Corporation Method of regulating the female reproductive system through angiogenesis inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994019946A1 (en) * 1993-03-01 1994-09-15 Emory University Treatment of microsporidial and acanthamoeba keratoconjunctivitis with topical fumagillin

Also Published As

Publication number Publication date
IS4557A (en) 1997-09-11
DE69600879T2 (en) 1999-06-02
WO1996030010A2 (en) 1996-10-03
SK130797A3 (en) 1998-03-04
EP0817626B1 (en) 1998-10-28
NZ304906A (en) 1999-06-29
IS2048B (en) 2005-09-15
JP3260378B2 (en) 2002-02-25
TR199701048T1 (en) 1998-01-21
CZ304997A3 (en) 1997-12-17
NO315968B1 (en) 2003-11-24
KR19980703271A (en) 1998-10-15
HU9801220A3 (en) 2001-10-29
DK0817626T3 (en) 1999-07-12
DK817626T3 (en)
CZ286821B6 (en) 2000-07-12
EA000150B1 (en) 1998-10-29
AU706161B2 (en) 1999-06-10
NO974466L (en) 1997-09-26
CN1072485C (en) 2001-10-10
JPH11506421A (en) 1999-06-08
DE69600879D1 (en) 1998-12-03
CA2216623C (en) 2005-05-31
AP9701092A0 (en) 1997-10-31
AT172641T (en) 1998-11-15
WO1996030010A3 (en) 1996-11-28
OA10515A (en) 2002-04-24
EP0817626A2 (en) 1998-01-14
AU5278696A (en) 1996-10-16
NO974466D0 (en) 1997-09-26
EA199700267A1 (en) 1998-04-30
CA2216623A1 (en) 1996-10-03
US5900431A (en) 1999-05-04
HU9801220A2 (en) 1999-09-28
PL322470A1 (en) 1998-02-02
PL183378B1 (en) 2002-06-28
ES2128846T3 (en) 1999-05-16
SK283883B6 (en) 2004-04-06
HU224028B1 (en) 2005-05-30
MX9707150A (en) 1998-07-31
CN1179715A (en) 1998-04-22

Similar Documents

Publication Publication Date Title
EP0236684B1 (en) Galanthamine or analogues thereof for treating alzheimer's disease
AU745281B2 (en) Utilization of alkyl hydrogen fumerates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis
DE69634613T2 (en) New stabilized pharmaceutical formulations containing an acid sensitive benzimidazole, and methods for their preparation
EP0397831B1 (en) Treatment of obesity
US20090018193A1 (en) Essential fatty acids in the prevention of cardiovascular events
USRE34656E (en) Use of tetracycline to enhance bone protein synthesis and/or treatment of bone deficiency
US5698225A (en) Pharmaceutical composition
RU2136281C1 (en) Oral liquid pharmaceutical composition containing complex of paroxitine and amberlite irp-88 and method of treatment using this composition
AU2003227516B2 (en) A combination of an NMDA-antagonist and acetylcholine esterase inhibitors for the treatment of alzheimer's disease
US6562835B1 (en) Method for the treatment of urinary incontinence
EP0174006B1 (en) Antidiarrheal compositions and use thereof
JP2614164B2 (en) And compositions for tumor therapy for antitumor effect potentiator
CA1302270C (en) Carcinostatic agent
CA2238553C (en) Cholesterol-lowering composition
US5190748A (en) Absorption enhancement of antibiotics
US4888347A (en) Use of specific N-methyl-D-aspartate receptor antagonists in the prevention and treatment of neurodegeneration
CN1076196C (en) Pharmaceutical composition
EP0748220A1 (en) Methods and compositions for treating androgen-dependent diseases using optically pure r-(-)-casodex
US20030149010A1 (en) Combination of an aldosterone receptor antagonist and an HMG CoA reductase inhibitor
CY1112861T1 (en) Use acetate production (-) (3-trialomethylofainoxy) (4-halophenyl) ACID for the treatment of yperourikaimias
US5219865A (en) Pharmaceutical combination for the prophylaxis and therapy of malaria
US20070105954A1 (en) Formulation containing a carboxylic acid or an ester thereof
JP3963976B2 (en) Chlamydial infection therapeutic agent
HU226689B1 (en) Use of dialkylfumarates for producing pharmaceutical compositions for the treatment autoimmune diseases
DE19543271A1 (en) Oral pharmaceutical preparation