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WO1996009063A1 - Utilisation de composes peptidiques de muramyle - Google Patents

Utilisation de composes peptidiques de muramyle Download PDF

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Publication number
WO1996009063A1
WO1996009063A1 PCT/GB1995/002237 GB9502237W WO9609063A1 WO 1996009063 A1 WO1996009063 A1 WO 1996009063A1 GB 9502237 W GB9502237 W GB 9502237W WO 9609063 A1 WO9609063 A1 WO 9609063A1
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WO
WIPO (PCT)
Prior art keywords
acetyl
alanyl
glucosaminyl
acetylmuramyl
gmdp
Prior art date
Application number
PCT/GB1995/002237
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English (en)
Inventor
Roger Aston
Iouri Maitchouk
Tatyana Mikhailovna Andronova
Original Assignee
Peptech(Uk) Limited
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
Application filed by Peptech(Uk) Limited filed Critical Peptech(Uk) Limited
Priority to KR1019970701823A priority Critical patent/KR970706015A/ko
Priority to EP95932084A priority patent/EP0782454A1/fr
Priority to AU35274/95A priority patent/AU3527495A/en
Priority to SK366-97A priority patent/SK36697A3/sk
Priority to JP8510688A priority patent/JPH10506387A/ja
Priority to CZ97861A priority patent/CZ86197A3/cs
Publication of WO1996009063A1 publication Critical patent/WO1996009063A1/fr
Priority to BG101325A priority patent/BG101325A/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention relates to the treatment of ophthalmic conditions and in particular to the treatment or prevention of corneal scarring which may be associated with bacterial or viral ophthalmic infections.
  • the eye is a relatively complex organ and is susceptible to many types of viral and bacterial infection and also to non-infectious conditions. Examples include conjunctivitis which is an infection of the conjunctiva and may be caused by bacteria, viruses, other microorganisms such as Chlamydia or by allergy. Disorders of the cornea include keratitis which may be caused by bacteria such as staphylococcus, streptococcus , pseudomonas or enterobacteria or by viruses such as Herpes simplex. Systemic viral illness such as measles, mumps and chicken pox can also cause keratitis but it can also result simply from dryness of the eyes. Certain eye conditions particularly keratitis, other corneal conditions and damage or infections of the eyelids can result in scarring of the cornea which can impair vision and restrict the movement of the eyelids.
  • prototype muramyl dipeptide (now frequently referred to as "prototype muramyl dipeptide” or “prototype MDP”) to protect mice against bacterial infection (Klebsiella pneumonia) has been described (Chedid et al , Proc . Na tl . Acad. Sci . USA, 74 2089 (1977) ) .
  • analogues of prototype muramyl dipeptide were synthesised, some of which have been proposed as treatments for the restoration of immune function or the non-specific stimulation of the immune system.
  • These analogues, and prototype MDP itself, are muramyl peptide compounds.
  • MDPs are effective for use as immunoadjuvants for the potentiation of antigenicity of recombinant or component vaccines.
  • MTP-PE was found to be particularly useful as an adjuvant with a Herpes simplex virus subunit vaccine.
  • muramyl peptide compounds may be of particular use in the treatment of ophthalmic conditions and indeed there is some suggestion in the prior art that the use of muramyl dipeptide analogues may be deleterious to the eye.
  • Lawrence et al in Exp. Eye Res . , 54(4), 105-107 (1992) discuss the break down of the anatomic barriers between the anterior segment of the eye and the blood stream during inflammation elicited by MDP.
  • Kufoy et al (Exp . Eye Res . , 50(2), 189-195 (1990)) also studied modulation of the blood aqueous barrier by MDP and Waters et al ( Infect . Immun .
  • muramyl dipeptide is known to have a deleterious effect on the eye and the same may also have been expected of its derivatives.
  • administering to a patient suffering from an ophthalmic condition an effective amount of a muramyl peptide derivative.
  • a muramyl peptide compound in the preparation of an agent for the treatment of ophthalmic diseases or conditions.
  • a muramyl peptide compound has a clear meaning to those skilled in the art. In particular, it refers to a compound containing one or more sugar residues, at least one of the sugar residues, which will often be a muramic acid residue, being substituted with
  • Muramyl peptide compounds may be peptido- glycans which are capable of enhancing the cellular antigenicity response in mammals and which are prototype muramyl dipeptide (MDP) or analogues or derivatives
  • the ophthalmic conditions in which muramyl peptide compounds may be of use include conjunctivitis; disorders of the cornea such as keratitis; disorders of the 25 eyelids; dryness of the eyes and eye injuries.
  • Muramyl peptide compounds have been found to be particularly useful in the treatment of conditions such as keratitis and keratouveitis, particularly when caused 30 by a viral, bacterial or chlamydia infection.
  • keratitis One relatively common form of keratitis is that caused by Herpes simplex and known as Herpetic stromal keratitis.
  • herpetic keratouveitis may also be caused by the Herpes simplex virus and muramyl peptide compounds have now been shown to be particularly effective in the treatment of both of these conditions.
  • muramyl peptide compounds are useful in the treatment of keratouveitis because, as discussed above, prototype muramyl peptide is known to cause uveitis.
  • muramyl peptide compounds are effective as antiviral agents.
  • an additional benefit is that they are capable of preventing or reducing the extent of the corneal scarring which often accompanies the condition. It has been found that when administered to patients suffering from herpetic stromal keratitis, muramyl peptide compounds enhanced resolution of stromal involvement and increased the rate of vision improvement.
  • muramyl peptide compounds confer this surprising and beneficial effect is not absolutely clear.
  • One suggestion is that it could arise from the antiviral effects of the compounds since more rapid clearance of virally infected cells could reduce the period of infection and thus the potential for scarring.
  • An alternative theory is that the muramyl peptide compounds may down regulate the activity of inflammatory cytokines and therefore inhibit the stimulation of fibroblasts and the deposition of scar tissue.
  • the effectiveness of the invention is not affected by the accuracy or otherwise of either of these theories.
  • muramyl peptide derivatives will also be useful in a method of treating or preventing corneal scarring associated with ophthalmic disease, the method comprising administering to a patient suffering from ophthalmic disease an effective amount of a muramyl peptide compound.
  • a muramyl peptide compound in the preparation of an agent for the treatment or prevention of corneal scarring associated with ophthalmic disease.
  • a muramyl peptide compound will assist in the treatment of any ophthalmic condition from which scarring is likely to result but the ophthalmic diseases mentioned above are those in which muramyl peptide compounds are particularly useful for the prevention of scarring.
  • muramyl peptide compounds are particlarly effective when used in combination with a second drug which is used for the treatment of the condition but which cannot reduce or prevent scarring in the way in which a muramyl peptide compound can.
  • a product containing a muramyl dipeptide and a second drug as a combined preparation for simultaneous, separate or sequential use in the treatment of an ophthalmic disease or condition in a third aspect of the invention.
  • the second drug may be any substance which is useful in the treatment of an ophthalmic condition: such substances are well known to those skilled in the art of ophthalmic medicine and include antiviral agents, anti-bacterial agents, steroids and nonsteroidal anti-inflammatory drugs .
  • the present invention will also be useful in a method for the treatment of an ophthalmic condition, the method comprising administering to a patient suffering from an ophthalmic condition an effective amount of a muramyl peptide compound in combination with an effective amount of a second drug.
  • the second drug may be selected from the group consisting of antiviral agents, antibacterial agents, steroids and nonsteroidal anti-inflammatory drugs.
  • Agents which are particularly suitable in this aspect of the invention include acyclovir, idoxuridine, chloramphenicol, chlortetracycline, fusidic acid, gentamycin, neomycin, oflaxacin, polymixin, tetracycline, tobramycin, betamethasone, clobetasone, dexamethasone, fluormethiolone, hydrocortisone, prednisolone and flurbiprofen. Of these, acyclovir or idoxuridine are preferred.
  • R 1 represents a hydrogen atom or a Ci-C jj acyl group
  • R 2 represents a hydrogen atom or a C J -C JJ acyl group
  • R 3 represents a hydrogen atom or a Ci-Cg alkyl group
  • R 4 represents a Ci-Cj ! alkyl group or a C 6 or C 10 aryl group
  • R 5 represents a hydrogen atom
  • R represents the residue of an amino acid or a linear peptide built up of from 2 to 6 amino acid residues, at least one of the residues being optionally substituted with a lipophilic group;
  • Preferred acyl groups for R 1 and R 2 are C x -C 5 acyl groups such as acetyl; it will be appreciated that the carbon count in the acyl group does not include the carbonyl moiety.
  • Preferred alkyl groups for R 3 are C ⁇ C * alkyl groups such as methyl and ethyl.
  • R preferably represents a mono-, di- or tri-peptide.
  • the proximal peptide residue (or the only peptide residue, if there is only one) is preferably that of an L-amino acid. Examples include:
  • L-alanyl is preferred, as is L-threonyl.
  • the next amino acid from the proximal end of the peptide is preferably of the D-configuration. It is preferably acidic and may be D-glutamic or D-aspartic acid or a mono-, di- or mixed C ⁇ C ⁇ (preferably C ⁇ C alkyl ester, amide or C ⁇ C, alkyl amide thereof. (The expression “mixed” is illustrated when one carboxyl group is amidated and the other esterified. D-isoglutamine and D- glutamate are preferred.
  • a third amino acid residue from the proximal end of the chain is preferably of the L- configuration, as indicated above in relation to the proximal amino acid residue.
  • L-alanyl and L-lysyl are preferred.
  • the amino acid residue or linear peptide is optionally substituted with at least one lipophilic group.
  • the lipophilic group may be a C 10 -C 22 acyl group such as stearoyl or a di- (C 10 -C 22 acyl) -s ⁇ -glycero-3' -hydroxy- phospheryloxy-group wherein for example each of the C 10 -C 22 acyl groups can be a palmitoyl group.
  • the lipophilic group may alternatively (or in addition, as more than one substitution may be present) be a C l -C 1Q ester group, such as a C 2 -C 6 ester group: a butyl ester is an example.
  • muramyl dipeptides within the scope of general formula I include: muroctasin, otherwise known as MDP-Lys (L18) (N 2 - (N- acetylmuramyl-L-alanyl-D-isoglutaminyl) -N 6 -stearoyl- L-lysine) ;
  • MTP-PE N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L- alanyl-2- (1' ,2' -dipalmitoyl-sn-glycero-3' -hydroxy- phosphoryloxy)ethylamide, monosodium
  • t-MDP N-acetylmuramyl-L-threonyl-D-isoglutamine
  • t-MDP The preparation of t-MDP can be prepared by methods known in the art.
  • Patent publications which give details of the preparations of muramyl peptide compounds generally include BE-A-0834753, BE-A-0834754, BE- A-0847103, BE-A-0849214, DE-A-2710455, DE-A-2922533, DE- A-2747379, DE-A-2912865, FR-A-2355505, FR-A-2358159, FR- A-2375249, EP-A-0004512, EP-A-0002677, JP-A-54063016, JP- A-54073729, JP-A-55019236, US-A-4082735 and US-A-4082736.
  • the preparation of prototype muramyl dipeptide is disclosed in DE-A-2450355 and US-A-4235771.
  • R represents a residue of an amino acid or a linear peptide built of from 2 to 6 amino acid residues, at least one of the residues being optionally substituted with a lipophilic group;
  • n 1 or 2
  • R Preferred values for R are as described above in relation to general formula I. It is particularly preferred that the peptide R correspond to the peptide in prototype MDP (L-Ala-D-isoGln) . Alternatively, in another preferred embodiment, R may represent L-Ala-D-Glu.
  • n 1
  • GMDP N-acetyl-D-glucosaminyl- (01-4) -N-acetylmuramyl-L-alanyl- D-isoglutamine
  • This compound (Compound II in US-A-4395399) , also known as glycopin, has already undergone preclinical toxicity testing and pharmacokinetic investigations required for licensing for clinical use in the USSR (as it then was) .
  • the acute toxicity in mice, measured by the LD 50 test is 7 g/kg.
  • This figure shows the compound to be almost an order of magnitude less toxic than muroctasin which has an LD 50 value in mice of 625 mg/kg.
  • the pyrogenicity of GMDP is sufficiently low to make it suitable for use in the present invention, and not to have prevented its clinical evaluation for other purposes, it may in some circumstances be preferable to use an even less pyrogenic analogue.
  • Such an analogue is available, and is N-acetyl-D-glucosaminyl- (Sl-4) -N- acetylmuramyl-L-alanyl-D-glutamic acid (GMDP-A) , which is Compound III in US-A-4395399, and whose structure is as follows:
  • GMDP-LL N-acetyl-D-glucosaminyl- (Sl-4) -N acetylmuramyl-L-alanyl ⁇ L-isoglutamine
  • GMDP-LL N-acetyl-D-glucosaminyl- (/31-4) -N acetylmuramyl-L-alanyl- D-glutamine n-butyl ester (GMDP-OBu) which has the structure:
  • GMDP-Lys N-acetyl-D-glucosaminyl- (Sl-4) -N acetylmuramyl-L-alanyl- D-isoglutaminyl-L-lysine (GMDP-Lys) which has the structure:
  • N-Acetyl-D-glucosaminyl- (/31--4) -N-acetylmuramyl-L-alanyl- D-glutamic acid dibenzyl ester which has the structure:
  • N-Acetyl-D-glucosaminyl- (01--4) -N- acetylmuramyl -N-methyl- L-alanyl -D-isoglutamine which as the structure:
  • N-Acetyl-D-glucosaminyl- ( / S1--4) -N-acetylmuramyl- (/S1--4) - N-acetyl-D-glucosaminyl- ( / 31--4) -N-acetylmuramyl-bis- (L- alanyl-D-glutamic acid) which has the structure:
  • GMDPA N-Acetyl-D-glucosaminyl- (j ⁇ l--4) -N- acetylmuramyl- (/31--4) - N-acetyl-D-glucosaminyl- (/31--4) -N-acetylmuramyl-bis- (L- alanyl-D-isoglutaminyl-L-lysine) which has the structure:
  • N-acetyl-D-glucosaminyl- (01--4) -N- acetylmuramyl- (/31--4) N-acetyl-D-glucosaminyl- ( / S1--4) -N-acetylmuramyl-bis- [L alanyl-D-isoglutaminyl-N € - stearoyl -L-lysine] :
  • GMDP-tuftsin E N-Acetyl-D-glucosaminyl- (/31--4) -N-acetyl-muramyl-L- alanyl- ⁇ -D-isoglutaminyl -L-threonyl -L-lysyl -L-prolyl-L- arginine which has the structure :
  • N e [N-Acetyl-D-glucosaminyl- ( ⁇ l--4) -N-acetyl-muramyl-L- alanyl- ⁇ -D-isoglutaminyl] - L- lysyl -L- hist idyl -L-glycine amide which has the structure :
  • N-Acetyl-D-glucosaminyl- (S1--4) -N- acetylmuramyl- L-alanyl - D- isoglut aminyl -L-glutamyl -L- tryptophan which has the structure:
  • N-acetylmuramyl -L-threonyl -D-isoglutamine which has the structure :
  • N-acetylmuramyl -L-alanyl -D-glutamine n-butyl ester which has the structure :
  • the most preferred compound is GMDP followed by GMDP-A, and murabutide.
  • Glucosaminyl-muramyl dipeptides within the scope of general formula II can be prepared relatively cheaply and in reasonably large quantities by the process disclosed in US-A-4395399.
  • the preparation disclosed is based on the extraction and purification of the disaccharide component from the bacterium Micrococcus lysodecticus and its subsequent chemical linkage to a dipeptide synthesised for example by conventional peptide chemistry.
  • the disaccharide may equally well be chemically synthesised using standard sugar chemistry.
  • Muramyl peptide compounds in the invention has been demonstrated using oral administration.
  • the formulation in this instance consisted of tablets containing pharmaceutically acceptable excipients, namely lactose, starch, polyvidone, magnesium stearate and talc.
  • Muramyl peptide compounds may be formulated for sustained and/or delayed delivery if desired. Gastric coating is another option.
  • a daily oral dosage in the range of from 0.1 to 50 mg per day (or per unit dose) may be found acceptable, with a range of 0.5 to 50 mg being preferred.
  • a daily dosage of 1 to 20 mg is considered optimal.
  • duration of administration may be varied. The duration will of course depend to some extent on dosage level, i.e. lower dose results in longer required duration of dosage. In general terms, the duration of dosage will be in the range of 1-60 days, preferably l-30days and most preferably 1-14 days.
  • administration need not necessarily be daily: Example 2 presented herein used a regimen of GMDP once per day for three days, three days without administration of GMDP, and then GMDP once per day for a further three days. Other variations, for instance every other day, can also be used.
  • muramyl peptide compounds are intended for the treatment of ophthalmic conditions, it is also possible for them to be formulated for topical administration to the eye.
  • Such a formulation will generally contain pharmaceutically acceptable excipients etc usually found in such formulations.
  • compositions comprising a muramyl peptide compound together with a pharmaceutically acceptable excipient or carrier; characterised in that the composition is formulated for topical administration to the eye.
  • compositions When formulated for topical administration to the eye, the compositions may comprise one or more muramyl peptides in a pharmaceutically acceptable opthalmic ointment or cream.
  • the formulation can be in the form of drops which will contain appropriate buffers and preservatives common in the art and known to the skilled man.
  • a daily dosage in the range of from 0.1 to 100 mg per day (or per unit dose) for topical compositions may be found to be acceptable, with a range of 0.5 mg to 50 mg per day (or per unit dose) being preferred.
  • a daily dosage of 1 to 20 mg is considered to be optimal.
  • FIGURE 1 is a plot showing a comparison of the effects of the muramyl peptide compound GMDP and a placebo on the resolution of the symptoms of ophthalmic herpes infection.
  • FIGURE 2 is a plot showing a comparison of the effects of the muramyl peptide compound GMDP and a placebo on the epithelial healing in patients suffering from dendritic keratitis.
  • FIGURE 3 is a plot showing a comparison of the effects of the muramyl peptide compound GMDP and placebo in the incidence of complete clearing of clinical symptoms in patients with herpetic stromal keratitis.
  • the first group displayed dendritic herpetic keratitis (DK) with stromal lesion (13 patients) and the second group, herpetic keratouveitis (KU) (12 patients) .
  • DK dendritic herpetic keratitis
  • KU herpetic keratouveitis
  • SUBSTITUTESHEET(RULE26 ⁇ Examination of the eye included testing of visual acuity, eye biomicroscopy after staining with fluorescein, internal eye examination, testing of intraocular pressure by means of Maklokov's tonometer and, if not possible due to the eye condition, by means of palpation.
  • Immunological examination included: taking of scrapings from the conjunctiva of the infected eye; sampling tear liquid of the infected and non-infected eye; blood samples.
  • Table 1 Main characteristics of control and GMDP treated groups.
  • a second clinical trial was performed in a way broadly similar to that described in example 1.
  • a total of 60 patients with herpetic stromal keratitis were enrolled in the study, and randomised (2 groups of 30) to treatment with GMDP tablets or identical placebo.
  • Dosage was 20mg GMDP per day, and administration was according to the following schedule: GMDP or placebo once per day for three days, three days rest (no GMDP/placebo) , GMDP or placebo once per day for three days.
  • stromal involvement (superficial, deep, corneal oedema, descemetitis) , corneal ulceration (punctate, area) , interior eye involvement (precipitates, hypopion, ulceris) , hyperaemia (conjunctival and pericorneal) .
  • Results showed that GMDP treatment enhanced resolution of most clinical symptoms and accelerated improvement of visual acuity.
  • the mean time to 50% resolution of stromal involvement was 7.3 days in the placebo group and 5.8 days in the GMDP group.
  • Mean time to complete resolution was 14.9 days and 10.6 days respectively.
  • the time course of achieving complete clearing is plotted in Figure 3.
  • Analysis of the incidence of clearing at successive time points showed that between days 8 and 14 inclusive, significantly (p ⁇ 0.05) more patients receiving GMDP showed clearing than compared to the placebo group.
  • Visual acuity in the GMDP treated group reached an average of 0.60 by day 10, whereas the placebo group was only 0.49.

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Abstract

L'invention concerne des dérivés peptidiques de muramyle, à l'exemple du composé GMDP, qui trouvent une utilisation particulière dans le traitement d'ophtalmies telles que la kératite herpétique et l'uvéite kératique herpétique. Ces dérivés peptidiques sont des plus utiles pour faire se réduire une cicatrisation cornéenne susceptible de se manifester à la suite d'affections du genre de la kératite ou la prévenir. Un traitement faisant appel à des composés peptidiques de muramyle peut être administré en sus d'un traitement prescrivant d'autres remèdes.
PCT/GB1995/002237 1994-09-21 1995-09-20 Utilisation de composes peptidiques de muramyle WO1996009063A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1019970701823A KR970706015A (ko) 1994-09-21 1995-09-20 무라밀 펩티드 화합물의 용도(Use of Muramyl Peptide Compounds)
EP95932084A EP0782454A1 (fr) 1994-09-21 1995-09-20 Utilisation de composes peptidiques de muramyle
AU35274/95A AU3527495A (en) 1994-09-21 1995-09-20 Use of muramyl peptide compounds
SK366-97A SK36697A3 (en) 1994-09-21 1995-09-20 Use of muramyl peptide compounds
JP8510688A JPH10506387A (ja) 1994-09-21 1995-09-20 ムラミルペプチド化合物の使用
CZ97861A CZ86197A3 (en) 1994-09-21 1995-09-20 Use of muramyl peptide compounds
BG101325A BG101325A (en) 1994-09-21 1997-03-13 Use of muramyl peptide compounds

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GB9419011A GB9419011D0 (en) 1994-09-21 1994-09-21 Use of muramyl peptide compounds
GB9419011.3 1994-09-21

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KR (1) KR970706015A (fr)
AU (1) AU3527495A (fr)
BG (1) BG101325A (fr)
CA (1) CA2200570A1 (fr)
CZ (1) CZ86197A3 (fr)
GB (1) GB9419011D0 (fr)
HU (1) HUT77741A (fr)
IL (1) IL115391A0 (fr)
SK (1) SK36697A3 (fr)
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ZA (1) ZA957997B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005890A1 (fr) * 1995-08-08 1997-02-20 Allergan Methode permettant d'augmenter les secretions lacrymales en administrant localement un peptide de muramyle
EP2198723A1 (fr) * 2001-02-14 2010-06-23 Thomas Luger Liaisons anti-inflammatoires
US11859021B2 (en) 2021-03-19 2024-01-02 Icahn School Of Medicine At Mount Sinai Compounds for regulating trained immunity, and their methods of use
US12377054B2 (en) 2016-04-29 2025-08-05 Icahn School Of Medicine At Mount Sinai Targeting the innate immune system to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis

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Publication number Priority date Publication date Assignee Title
CN112516080B (zh) * 2018-01-23 2023-09-19 盛元医药广州有限公司 一种眼用药物组合物及其制备方法和应用

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WO1993010148A1 (fr) * 1991-11-19 1993-05-27 Peptech (Uk) Limited Composes de muramyl utilises dans le traitement de choc septique
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AU3527495A (en) 1996-04-09
GB9419011D0 (en) 1994-11-09
CZ86197A3 (en) 1997-08-13
KR970706015A (ko) 1997-11-03
JPH10506387A (ja) 1998-06-23
IL115391A0 (en) 1995-12-31
CA2200570A1 (fr) 1996-03-28
HUT77741A (hu) 1998-07-28
BG101325A (en) 1998-01-30
SK36697A3 (en) 1997-11-05
ZA957997B (en) 1997-03-24
EP0782454A1 (fr) 1997-07-09

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