WO1998033813A2 - Procede permettant d'accelerer la guerison de brulures - Google Patents

Procede permettant d'accelerer la guerison de brulures Download PDF

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WO1998033813A2
WO1998033813A2 PCT/US1998/002049 US9802049W WO9833813A2 WO 1998033813 A2 WO1998033813 A2 WO 1998033813A2 US 9802049 W US9802049 W US 9802049W WO 9833813 A2 WO9833813 A2 WO 9833813A2
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seq
group
tyr
active agent
ala
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PCT/US1998/002049
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WO1998033813A3 (fr
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Kathleen E. Rodgers
Gere Dizerega
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University Of Southern California
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Priority to AU66500/98A priority Critical patent/AU6650098A/en
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Publication of WO1998033813A3 publication Critical patent/WO1998033813A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to methods for use in accelerating the healing of human wounds caused by thermal injuries and methods for use in accelerating growth factor release, neovascularization, re-epithelialization and extracellular matrix production at the site of a human thermal injury wound.
  • Thermal injury in mammalian tissue results in tissue disruption and coagulation of the microvasculature at the wound face (U.S. Patent Application No. 5,629,292; hereby incorporated by reference in its entirety). Repair of such tissue represents an orderly, controlled cellular response to injury. All soft tissue wounds, regardless of size, heal in a similar manner. Tissue growth and repair are biologic systems wherein cellular proliferation and angiogenesis occur in the presence of an oxygen gradient. The sequential morphological and structural changes that occur during tissue repair have been characterized in great detail and have in some instances been quantified
  • the cellular morphology of a wound consists of three distinct zones (U.S. Patent Application No. 5,629,292).
  • the central avascular wound space is oxygen deficient, acidotic and hypercarbic, and has high lactate levels.
  • Adjacent to the wound space is a gradient zone of local anemia (ischemia) that is populated by dividing fibroblasts.
  • Behind the leading zone is an area of active collagen synthesis characterized by mature fibroblasts and numerous newly-formed capillaries (i.e., neovascularization).
  • angiogenesis angiogenesis
  • angiogenic agents are in general unable to fulfill the long-felt need of providing the additional biosynthetic requirements of tissue repair.
  • pharmacological agents Despite the need for more rapid healing thermal injuries, to date there has been only limited success in accelerating wound healing with pharmacological agents.
  • the present invention provides methods for accelerating thermal wound healing in humans, by applying an effective amount of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof or All AT type 2 receptor agonists to the thermal wound.
  • AI angiotensinogen
  • AI analogues AI fragments and analogues thereof
  • angiotensin II All
  • All analogues All fragments or analogues thereof or All AT type 2 receptor agonists
  • kits for accelerating thermal wound healing in humans comprising an effective amount of angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, All, All analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists for healing a thermal wound, and instructions for using the amount effective of active agent as a therapeutic.
  • the kit further comprises a pharmaceutically acceptable carrier.
  • the kit further comprises a means for delivery of the active agent to a human, including, but not limited to, bandages, wound dressings, aerosol sprays and lipid foams.
  • FIG. 1 is a bar graph representation of the percentage of burns healed as a function of time post-burn.
  • FIG. 2 is a line graph representation of the area of the burn as a function of days post burn.
  • FIG. 3 is a bar graph representation of the number of blood vessels in the burn section at various times after burn injury
  • FIG. 4 is a bar graph representation of the number of blood vessels in the burn field at various times after burn injury.
  • FIG. 5 is a bar graph representation of the number of proliferating cells at the edge of the burn as a function of time post-burn.
  • FIG 6 is a bar graph representation of the number of proliferating cells in control burns and treated burns as a function of time.
  • FIG. 7 is a bar graph representation of the number of cyclin positive cells in the hair follicles at the edge of the burn after treatment with various All analogues.
  • FIG. 8 is a bar graph representation of the number of cyclin positive cells in the hair follicles at the burn site after treatment with various All analogues.
  • FIG. 9 is a bar graph representation of the number of vascular channels at the site of thermal injury 7 days after treatment with various All analogues.
  • angiotensinogen angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists.
  • AI angiotensin I
  • AI analogues AI fragments and analogues thereof
  • angiotensin II All
  • AT 2 type 2 receptor agonists All AT 2 type 2 receptor agonists.
  • various nonpeptidic agents e.g., peptidomimetics having the requisite AT2 agonist activity are further contemplated for use in accordance with the present invention.
  • angiotensin The biological formation of angiotensin is initiated by the action of renin on the plasma substrate angiotensinogen ⁇ Circulation Research. 60:786-790 (1987); Clouston et al., Genomics 2:240-248 (1988); Kageyama et al., Biochemistry 23:3603-3609; Ohkubo et al., Proc. Natl. Acad. Sci. 80:2196-2200 (1983); all references hereby incorporated in their entirety).
  • the substance so formed is a decapeptide called angiotensin I (AI) which is converted to All by the converting enzyme angiotensinase which removes the C-terminal Ffis-Leu residues from AI [DNA SEQ ID: 38]. All is a known pressor agent and is commercially available.
  • TGF- ⁇ transforming growth factor-beta
  • AII(l-7) All residues 1-7) or other fragments of All to evaluate their activity.
  • AII(l-7) elicits some, but not the full range of effects elicited by All (Pfeilschifter, et al., Eur. J. Pharmacol. 225:57-62 (1992); Jaiswal, et al, Hypertension 19(Supp. II):II-49-II-55 (1992); Edwards and Stack, J. Pharmacol.
  • active angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, All, All analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists of particular interest in accordance with the present invention are characterized as comprising a sequence consisting of at least three contiguous amino acids of groups R ] -R 8 in the sequence of general formula I
  • X-R A -R B - wherein X is H or a one to three peptide group and a peptide bond between R ⁇ and R B is labile to aminopeptidase A cleavage;
  • R is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr;
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Nal and Gly;
  • R 6 is His, Arg or 6- ⁇ H 2 -Phe;
  • R 7 is Pro or Ala
  • R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr, excluding sequences including R 4 as a terminal Tyr group.
  • Compounds falling within the category of AT2 agonists useful in the practice of the invention include the AH analogues set forth above subject to the restriction that R 6 is p-NH 2 -Phe.
  • R ⁇ is suitably selected from Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me 2 Gly, Pro, Bet, Glu(NH 2 ), Gly, Asp(NH ) and Sue.
  • R B is suitably selected from Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys. Particularly preferred combinations for R A and R B are Asp-Arg, Asp-Lys, Glu-Arg and Glu-Lys.
  • Particularly preferred embodiments of this class include the following: AH, AIII or AII(2-8), ArgNal-Tyr-Ile-His-Pro-Phe [SEQ ID ⁇ O:2]; AII(3-8), also known as desl-AHI or AJV, Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:3]; AII(l-7), Asp-Arg-Val-Tyr-Ile-His-Pro [SEQ ID NO:4]; AII(2-7).
  • Arg-norLeu-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 12] and Arg-Val- Tyr-norLeu-His-Pro-Phe [SEQ ID NO:13].
  • Still another preferred embodiment encompassed within the scope of the invention is a peptide having the sequence Asp- Arg-Pro-Tyr-Ile-His-Pro-Phe [SEQ ID NO:31].
  • AII(6-8), His-Pro-Phe [SEQ ID NO: 14] and AII(4-8), Tyr-Ile-His-Pro-Phe [SEQ ID NO: 15] were also tested and found not to be effective.
  • R 2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;
  • R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr;
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
  • R 6 is His, Arg or 6-NH 2 -Phe;
  • R 7 is Pro or Ala
  • R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr.
  • a particularly preferred subclass of the compounds of general formula II has the formula
  • R 2 , R 3 and R 5 are as previously defined.
  • Particularly preferred is angiotensin III of the formula Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2].
  • Other preferred compounds include peptides having the structures Arg-Val-Tyr-Gly-His-Pro- Phe [SEQ ID NO: 17] and Arg-Val-Tyr-Ala-His-Pro-Phe [SEQ ID NO: 18].
  • the fragment AII(4-8) was ineffective in repeated tests; this is believed to be due to the exposed tyrosine on the N-terminus.
  • R may be involved in the formation of linear or nonlinear hydrogen bonds with R 5 (in the gamma turn model) or R 6 (in the beta turn model).
  • R 3 would also participate in the first turn in a beta antiparallel structure (which has also been proposed as a possible structure).
  • beta and gamma branching are equally effective in this position.
  • a single hydrogen bond may be sufficient to maintain a relatively stable conformation.
  • R 3 may suitably be selected from Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr.
  • R 4 is preferably selected from Tyr, Thr, Tyr (PO ) 2 , homoSer, Ser and azaTyr.
  • Tyr is particularly preferred as it may form a hydrogen bond with the receptor site capable of accepting a hydrogen from the phenolic hydroxyl (Regoli, et al. (1974), supra).
  • an amino acid with a ⁇ aliphatic or alicyclic chain is particularly preferred
  • Gly is suitable in position R 5 , it is preferred that the amino acid in this position be selected from He, Ala, Leu, norLeu, Gly and Val.
  • the amino acid in this position be selected from He, Ala, Leu, norLeu, Gly and Val.
  • angiotensinogen angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AH), AH analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists of particular interest in accordance with the present invention
  • R 6 is His, Arg or 6-NH 2 -Phe.
  • the unique properties of the imidazole ring of histidine are believed to contribute to its particular utility as R 6 .
  • conformational models suggest that His may participate in hydrogen bond formation (in the beta model) or in the second turn of the antiparallel structure by influencing the orientation of R 7 .
  • R 7 should be Pro in order to provide the most desirable orientation of R 8 .
  • both a hydrophobic ring and an anionic carboxyl terminal appear to be particularly useful in binding of the analogues of interest to receptors; therefore, Tyr and especially Phe are preferred for purposes of the present invention.
  • Analogues of particular interest include the following: TABLE 2 Angiotensin II Analogues
  • polypeptides of the instant invention may be synthesized by any conventional method, including, but not limited to, those set forth in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co., Rockford,
  • peptides are synthesized according to standard solid-phase methodologies, such as may be performed on an Applied Biosystems Model 430A peptide synthesizer (Applied Biosystems, Foster City, Calif), according to manufacturer's instructions. Other methods of synthesizing peptides or peptidomimetics, either by solid phase methodologies or in liquid phase, are well known to those skilled in the art.
  • a method for accelerating thermal wound healing in humans comprises applying an effective amount of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AH), AH analogues, AH fragments or analogues thereof or All AT 2 type 2 receptor agonists to the thermal wound.
  • AI angiotensinogen
  • AI analogues AI fragments and analogues thereof
  • AH angiotensin II
  • AH AH analogues
  • AH fragments or analogues thereof All AT 2 type 2 receptor agonists
  • the compounds of the present invention can significantly accelerate the healing of thermally injured tissue at nanomolar levels in vivo.
  • the optimum concentration for a given formulation may be readily determined empirically.
  • a concentration of active agent suitable for use in accordance with the present invention ranges from about 0.1 nanograms per kilogram to about 1 milligrams per kilogram.
  • the compounds of the present invention may be administered by any suitable route, including, but not limited to, orally, parentally, by inhalation spray, rectally, transdermally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally.
  • the angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions).
  • the compounds of the invention may be applied in a variety of solutions. Suitable solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the peptide, and are not harmful for the proposed application. In this regard, the compounds of the present invention are very stable but are hydrolyzed by strong acids and bases.
  • the compounds of the present invention are soluble in organic solvents and in aqueous solutions at pH 5-8.
  • the angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
  • angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, All analogues, AH fragments and analogues thereof and or AH AT 2 type 2 receptor agonists can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
  • the dosage regimen for thermal wound healing with angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists is based on a variety of factors, including the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely by a physician using standard methods.
  • Dosage levels of the order of between 0.1 ng/kg and 1 mg/kg angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists per body weight are useful for all methods of use disclosed herein.
  • angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists are administered to a patient with a partial thickness burn (i.e.: second-degree burn) to trunk, back, upper arm, upper leg of at 10 cm in area or more, and having a total body burn ⁇ 40% twice daily for between 1 and 30 days.
  • a partial thickness burn i.e.: second-degree burn
  • Any type of application means may be employed that permits the influx of the active agents into the thermally-injured tissue over a period of time.
  • an aqueous solution could be applied to the wound tissue through a gauze bandage or strip, or such a solution could be formulated so that a timed perfusion may be obtained (using liposomes, ointments, micelles, etc.)
  • a timed perfusion may be obtained (using liposomes, ointments, micelles, etc.)
  • Methods for the production of these formulations with the compounds of the present invention are apparent to those of ordinary skill in the art.
  • concentration of active agent employed is not critical, as the tissue-repairing effect is present even when the compounds are present in nanomolar quantities.
  • a matrical or micellar solution is employed with the active agent present in a concentration of at least 0.1 micrograms per milliliter.
  • the active agent is present in a semi-solid polyethylene glycol polymer sold under the trademark HYDRON by Hydro Med Sciences, New Brunswick, New Jersey.
  • the active agent is present in a micellar solution sold under the trade name PLURONICS F108 by BASF, Ludwigshafen, Germany. Under room temperature conditions, this solution is a liquid, but when applied to warm tissue the solution forms a gel that permits infusion of the active agent into the thermally injured tissue over a period of several days.
  • compositions include carboxymethyl cellulose preparations, crystalloid preparations (e.g., saline, Ringer's lactate solution, phosphate-buffered saline, etc.), viscoelastics, polyethylene glycols, polypropylene glycols and wound dressings (e.g., bandages, etc.).
  • crystalloid preparations e.g., saline, Ringer's lactate solution, phosphate-buffered saline, etc.
  • viscoelastics e.g., polyethylene glycols, polypropylene glycols and wound dressings (e.g., bandages, etc.).
  • the angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonist is administered topically.
  • a suitable topical dose of active ingredient of angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof and/or AH AT 2 type 2 receptor agonists is preferably between about 0.1 ng/ml and about 1 mg/ml administered twice daily.
  • the active ingredient may comprise from 0.0001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5%o w/w, and more preferably from 0.01% to 1% of the formulation.
  • transdermal means including, but not limited to, transdermal patches may be utilized to deliver the angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH analogues, AH fragments or analogues thereof or AH AT 2 type 2 receptor agonists to the treatment site.
  • Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier including, but not limited to, a cellulose medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the thermal wound of a wearer.
  • kits for accelerating thermal wound healing in humans comprising an effective amount of angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, AH analogues, All fragments or analogues thereof or AH AT 2 type 2 receptor agonists for healing a thermal wound, and instructions for using the amount effective of active agent as a therapeutic.
  • the kit further comprises a pharmaceutically acceptable carrier, such as those adjuvants described above.
  • the kit further comprises a means for delivery of the active agent to a human.
  • Such devices include, but are not limited to matrical or micellar solutions, bandages, wound dressings, aerosol sprays, lipid foams, transdermal patches, topical administrative agents, polyethylene glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (e.g., saline, Ringer's lactate solution, phosphate-buffered saline, etc.), viscoelastics, polyethylene glycols, and polypropylene glycols.
  • matrical or micellar solutions include, but are not limited to matrical or micellar solutions, bandages, wound dressings, aerosol sprays, lipid foams, transdermal patches, topical administrative agents, polyethylene glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (e.g., saline, Ringer's lactate solution, phosphate-buffered saline, etc.), viscoelastics, polyethylene glycols, and polypropylene glycols.
  • crystalloid preparations
  • the means for delivery may either be impregnated with the effective amount of angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AH, All analogues, AH fragments or analogues thereof or AH AT 2 type 2 receptor agonists for healing a thermal wound, or may be separate from the compounds, which are then applied to the means for delivery at the time of application to a thermal wound.
  • kits of the invention may be used in the form of a first aid kit for thermal injuries, which would be suitable for use in settings including, but not limited to, hospitals, ambulances and other emergency vehicles, schools, and the home.
  • the invention may be better understood with reference to the accompanying
  • Example Nos. 1 and 2 presented below demonstrate the general utility of the invented method for accelerating healing in thermally injured tissue.
  • Example No. 3 discloses how the method of the invention can be used to promote healing of thermally injured human tissue.
  • Example 1 Evaluation of All in a Guinea Pig Burn Model
  • Hartley guinea pigs (500 g males) were used for this study. Four burns were administered per animal. The guinea pigs were anesthetized with intramuscular ketamine/rompum and the hair on the back was removed with a thioglycollate depillatory. Four deep, partial thickness burns (50 seconds, 75 degrees C, 18 mm diameter brass rods) were placed on the back of the guinea pig. The burns were treated with one of the following: placebo (10% LV CMC) or 100 ug AH in vehicle. The guinea pigs were bandaged with a 25 mm Hill Top Chamber covered with Tegaderm (3M).
  • the animals were then allowed to recover and were given Bupronex analgesic as they awoke. Bupronex was given each day for 3 days after bum injury. The animals were treated daily for 10 days with placebo or 100 ⁇ g/ml AIL The guinea pigs were rebandaged on days 1, 2, 3, 4, 6, 8, and 10 after burning. On the days that the bandages were removed, the bum was gently washed with warm sterile water to remove any remaining material. As the scabs came off the bums were photographed for measurement of re-epithelialization. At a rate of one per day the guinea pigs were sacrificed and the burn sites were placed in formalin for histologic preparation and immunohistochemistry.
  • Procurement of guinea pigs and bum treatment were as described in Example 1 , except that only 2 bums were applied per animal.
  • the animals were treated for 7 days with placebo, 100 ⁇ g/ml AH, or 100 ⁇ g/ml of an AH analogue (Table 3).
  • Each analogue was tested on a group of six guinea pigs. Table 3. Designation for Analogues
  • Primary safety parameters will be: blood pressure changes and changes in laboratory values.
  • a secondary parameter will be the effect of treatment on the rate of bum site re-epithelialization.
  • a patient will participate in the double-blind treatment period for a maximum of 10 days followed by an observation period of 11 days or until the wound is 100% re— epithelialized.
  • Patients who satisfy the inclusion/exclusion criteria will be eligible for enrollment. After a biopsy to confirm that bum (wound) is partial thickness, a study number will be assigned to the patient. Each patient will be prospectively randomized to one of the three treatments. Such patients who enter the study and are subsequently excluded due to bum depth or drop out will be replaced so that a total of 60 patients (20 each group) will complete the study.
  • Group 1 5 ml glass vial containing 2 ml of:
  • the final dmg product will be formed by addition of the following diluent, under aseptic conditions at a ratio of 1 part of treatment solution to 4 parts diluent.
  • Eligible patients will be placed randomly into one of three treatment groups.
  • the randomization list will be computer generated. This list will be used to assign
  • Wound dressings for the bum site under evaluation will be changed a minimum of twice daily, i.e., once in the morning and once in the evening during administration of study dmg (10 days).
  • the study medication or placebo will be applied twice daily with a gloved hand, during the morning and evening dressing change. Additional treatment of other burned areas will be performed as per the standard ward protocol. After cessation of the study drug administration, the dressing will be changed once daily during the observation period (up to 11 additional days).
  • the volume of study medication to be applied to the bum will be determined from the dimensions of the bum measured at the screening visit. Once the volume is calculated, that volume will be applied twice daily throughout the 10 day treatment period. To calculate the volume, multiply the length and width of the bum to obtain the surface area in cm 2 . The surface area will be expressed to two decimal places. Multiply the surface area by 0.044 ml/cm 2 . This calculation will be rounded to one decimal place. The result is the volume that will be applied.
  • the individual doses will be prepared by an unblinded third party.
  • the final delivered drag product in the clinical setting will be mixed under aseptic conditions at a ratio of: 1 part (20%) Angiotensin II or Placebo solution to 4 parts (80%) CMC diluent.
  • CMC diluent will be separately drawn into sterile syringes, connected via a sterile syringe connector and mixed back and forth from one syringe to the other until uniform. A minimum of 10 mixes is necessary for homogeneity. The entire contents will be transferred to one of the syringes and capped and labeled. Twenty such doses will be prepared as described for each subject for the entirety of the study and stored at
  • the screening period will be defined as the time elapsed between the patient's signing the
  • Informed Consent and when the study medication is initially dispensed.
  • the maximum duration of the screening period will be 12 hours. Patients may be treated with placebo during the screening period.
  • the following procedures will be performed prior to enrollment into the doubleblind portion of the study: a. A signed patient informed consent will be obtained; b. The patient will be evaluated for fulfillment of inclusion/exclusion criteria (See Appendix F for procedure on assessing bums); c. Pain will be assessed using visual analogue pain scale. (See appendix G). d. A biopsy (1 x 3 mm) of two areas of the bum will be performed. (See Appendix H for procedures) e.
  • Wound cultures for B streptococcus and staphylococcus will be taken after debridement and before initial dressing of the wound.
  • Biweekly surface bum wound cultures will be obtained by the nurse and sensitivities determined if necessary; j .
  • the initial surgical debridement must be performed no more than 6 hours prior to patient randomization and the date and time documented on the case report form. If blisters, they must be completely unroofed and excised to reveal perfused wound margins. If an infection is present, the patient will be treated appropriately; k.
  • Photo-documentation At least two (2) 35 mm color, photographic slides of the wound will be taken initially after debridement 2.
  • Inclusion Criteria a. Patients will be between the ages of 10 and 75 years old;
  • b. Sex male or female; c. Have a partial thickness thermal bum to trunk, back, upper arm, upper leg of at least 10 cm 2 in area; d. Have a total body bum ⁇ 40%o and under reasonable medical judgment will be expected to successfully complete study participation; e. Are compliant and deemed to be reliable in following study requirements. Patients must have adequate assistance or be able to ensure adherence to the study medication, treatment and dressing change schedules; f. Have given written informed consent;
  • n Patients with prior history of diabetes mellitus requiring insulin; n. Patients with chronic renal insufficiency if the seram creatinine during screening is 2.5 mg/dL or greater; o. Patients with chronic active hepatitis, cirrhosis or severe ongoing liver dysfunction, as determined from medical history, physical exam and/or liver function tests (e.g., ALT, AST>2x upper limit of normal); p. Bum wound areas to head, neck, joints, hands, feet, perineum and fasciotomy sites will be excluded as study sites; q. Presence of beta hemolytic streptococcal infection or positive culture; r. Receiving hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) therapy; s. A resting diastolic blood pressure at bed rest on admission exceeding 95 mm
  • Hg on 3 consecutive readings at least 15 minutes apart; t. History of chronic hypertension or receiving anti-hypertension medication; u. Past radiation therapy; v. Current use of corticosteroid, immunosuppressive, chemotherapeutics
  • Twice daily application of study medication will begin on day 1 and will continue daily through and include day 10.
  • the application of study medication will coincide with the a.m. and p.m. dressing changes (See appendix J for Clinical Procedures in Series II).
  • Patients will be assessed daily as follows: a. Assess level of pain using visual analog scale prior to administration analgesic. b. Pain medication administered as required and recorded. c. Dressing removed as needed. d Dimension of the bum documented and assessed for re-epithelialization; e. Percent of surface exudate and surface re-epithelialization of burn visually estimated and recorded. f. Photo-documentation of wound. g. Exudate removed. h. Treatment of wound. i. Record blood pressure, pulse and respiration 15 and 45 minutes posttreatment. j. Record drag dispensing and patient compliance. k. Document adverse events. 1. Record concomitant medication.
  • the patient will complete the study when 100% re-epithelialization has occurred. If the wound has shown either no improvement or has deteriorated during 10 days of double-blind treatment, or converts to a full thickness bum, the patient will be discontinued from the study and treated as determined by the investigator. Three patients from each dose group will have plasma levels determined. As to not unblind the study, a third party representative will select three patients from each dose group for venous blood sampling. Samples will be obtained from each of these patients pretreatment and at 15 minutes posttreatment with the first dose. AH blood levels will be determined.
  • CRF's case report forms
  • results of the study will be presented utilizing descriptive statistics and making comparisons between treatment groups with respect to demographic, efficacy and safety parameters.
  • Descriptive statistics by treatment group for continuous variables will consist of sample sizes, means, standard deviations, standard errors of least squares means, medians, and minimum and maximum values.
  • Inferential analyses for continuous variables will utilize appropriate analysis of variance (ANOVA) models.
  • ANOVA analysis of variance
  • Descriptive statistics for time to re-epithelialization in particular will consist of both means and medians by treatment group along with appropriate measures of dispersion, while survival analysis techniques will be utilized for treatment group comparisons.
  • primary emphasis will be placed on the analysis of the Intent-to-Treat (ITT) population of all patients receiving any study medication and from whom any post-baseline data is available.
  • Demographic analyses and summary statistics by treatment group will be presented on the following parameters at baseline; age, race, gender, height, weight, medical history, concomitant medications, vital signs, clinical laboratory parameters and dimensions of the target bum.
  • Patient accounting by treatment group will be displayed at each visit, and the proportion of patients terminating prematurely for any reason, as well as due to adverse events and due to lack of efficacy, will be statistically compared between treatment groups. The results of the latter two analyses will be highlighted in both safety and efficacy discussions. Patient accounting will also include summary statistics on exposure to drag over time.
  • the primary efficacy parameter will be time to complete re-epithelialization of the target wound. Differences among treatment groups in this parameter will be analyzed utilizing survival analysis and allowing for correct statistical treatment of right-censored observations.
  • the survival distribution functions will be estimated by the Kaplan-Meier method. Inferential comparisons between each active treatment group and placebo of survival functions will be made utilizing nonparametric rank tests and a likelihood ratio test. The effects of other covariates such as the baseline dimension of the bum will also be tested in this model.
  • Comparisons between each active dose group and placebo on the proportion of patients with complete re- epithelialization of the target wound by day 10, day 21 and at the final follow-up will be performed utilizing both Fisher's Exact Test and Cochran-Mantel-Haenszel's test adjusted for investigators as strata. Changes in estimated bum area will also be analyzed for differences between placebo and active treatment groups utilizing appropriate analysis of variance (ANOVA) models including terms for treatment, investigator, the two-way interaction, and adjusted for relevant covariates as required.
  • ANOVA analysis of variance
  • Time points for the analysis of safety parameters will be at day 10, day 21 and at the final follow-up visit where data are available to make those analyses possible.
  • the proportion of patients in each treatment group reporting adverse events will be reported and analyzed by preferred term, by body system and by severity and relationship to study medication as assessed by the investigator.
  • Adverse events will first be coded using the WHO dictionary to allow grouping into preferred terms and body systems. Proportions of patients terminating prematurely due to adverse events will be compared statistically. Blood chemistries will be available only at screening and termination. Summary statistics will be displayed and analyses based on mean changes from screening values, on tabulations of shifts from screening values, and on clinically significant deviations from laboratory normal ranges. Mean changes from screening values in vital signs will also be displayed and analyzed by treatment group. Pharmacokinetic data (Series II) will be reviewed with clinical parameters such as blood pressure to determine if a correlation exists.
  • Adverse Events Any adverse event, including both observed or volunteered problems, complaints, or symptoms, will be recorded on the Adverse Event CRF. The need to capture this information is dependent upon whether the adverse event is associated with the use of the study medication. Adverse events resulting from concurrent illnesses or reactions to concurrent medications will also be recorded. Each adverse event will be evaluated for duration, intensity and relationship with the study medication or other causes. The intensity of the adverse event will be characterized as mild, moderate or severe as follows:
  • MILD events are usually transient, requiring no special treatment, and do not interfere with the participant's daily activities.
  • MODERATE events traditionally introduce a low level of inconvenience or concern to the participant and may interfere with daily activities, but are usually ameliorated by simple therapeutic measures.
  • the maximum intensity rating for the event will be listed. If the intensity category changes over a number of days, then these mini-events or changes will be recorded separately (i.e., having distinct onset days).
  • the investigator will use the criteria below as a guideline for determining the relationship of the adverse event to the study drug: a. A temporal relationship exists between the event and the use of the drag. b. Re-administration of study medication results in reappearance or worsening of the reaction: c. Previous experience with the suspected drag resulted in a similar reaction: d. The event is not related to any concomitant disease, preexisting condition, other drag therapy, or environmental factor.
  • Case Report Forms will be signed and dated by the investigator or a designated representative and filled out in black ink. If an entry on a CRF requires change, the correction will be made as follows: a. A single line will be drawn through the incorrect entry. b. The date will be entered and the change initialed. White-out or erasure on CRF's will not be permitted under any circumstances. c. All fields and blanks will be completed. The following abbreviations will be used when values or answers cannot be provided:
  • Venous blood samples will be obtained for: a. Hematology tests: hemoglobin, WBC, including differential and platelet count. b. Seram chemistries: glucose, total bilirubin, creatinine, alkaline phosphatase,
  • BUN SGOT c.
  • Urine pregnancy test if the patient is female and of child-bearing potential.
  • a subject may be entered on the basis of a negative urine test (sensitive to at least 50 mlU/ml). Urinalysis; a microscopic examination of sediment for RBC and WBC will be conducted.
  • the abrasion will be created utilizing the Chamber-Scarification Test (Frosh et al., 1976). Each volunteer will receive 1 (one) scarified site on the mid-volar surface of each forearm. (Frosch and Kligman, Contact Dermatitis 2(6): 314-324, 1976.)
  • Abrasion procedure will be performed at the selected site.
  • the dose volume will be calculated and recorded on the appropriate CRF page. This volume will be used throughout the dosing period;
  • Step 1 Hands will be washed thoroughly and sterile gloves will be used;
  • Step 2 An appropriate volume of study medication will be applied.
  • the medication should form a continuous film covering the entire area including the margins;
  • Step 3 The abrasion will be covered with a clean bandage and an over wrap;
  • Step 4 Dressings will be changed twice daily. Study medication will be applied after examination by the clinical investigator during scheduled visits to the clinic; Step 5. Blood pressure will be monitored 15 and 45 minutes posttreatment.
  • Partial thickness (PT) burns are characteristically red and painful with blisters and subcutaneous edema. This red color blanches on pressure in the early post-bum period. Because the deepest levels of cutaneous sensitivity to pinprick lie at approximately the level of the deepest epidermal derivatives, a useful diagnostic screening test is the penetration of skin by a fine needle. A 25 gauge sterile needle will be gently rubbed over the bum site until patient indicates presence of discomfort. If no sensation is elicited, the needle will be gently inserted through the burned skin until pain is elicited up to the hub of the needle (where bevel ends). If no pain is elicited the needle will be withdrawn and the test site assessed for bleeding. If no bleeding occurs the test will be repeated. If bleeding occurs in the absence of pain the site will be considered as full thickness and not suitable as a studysite.
  • a PT bum site for study will be selected by the principal investigator.
  • One study site per patient will be selected from the upper arm, upper leg, chest, abdomen, back or buttock areas.
  • the site will be > 10 cm 2 .
  • After initial debridement the wound will be biopsied. The biopsy will be used to confirm that the bum is a partial thickness injury.
  • the superficial epidermis when present, shows full thickness coagulative necrosis;
  • the underlying papillary dermis and superficial reticular dermis shows degeneration and homogenization of the collagen bundles with coagulative necrosis of fibroblasts;
  • Occasional arterioles and medium sized veins of the superficial reticular dermis may remain patent with viable endothelial cells; Adnexal structures of the skin show coagulative necrosis of the superficial hair shafts but the base of hair shafts and deep pilo-sebaceous complexes show viable epithelial cells;
  • the deep reticular dermis shows preservation of the collagen pattern. Scattered fibroblasts can be identified;
  • Blood vessels of the deep reticular dermis are patent and show intact muscle and endothelial layers.
  • Acute third degree burn The superficial epidermis, when present, shows full thickness coagulative necrosis;
  • the adnexal structures of the skin show coagulative necrosis of the entire structures including the base of hair shafts and of pilo-sebaceous complexes deep in the reticular dermis; Both the papillary dermis and superficial and deep reticular dermis show degeneration and homogenization of the collagen bundles with coagulative necrosis of most fibroblasts;
  • Visual Analog Pain Scale will be used to determine the amount of pain the patient is experiencing prior to administration of any analgesic before treating the bum site
  • the biopsy site will be aseptically prepared after debridement and soap and water washes.
  • the two areas representative of the bum are e biopsied sharply in a 1 X 3-mm ellipse after injection of 1%> lidocaine.
  • the wound is sutured closed using a vertical mattress interrupted technique with a 3-0 nylon suture.
  • the wound is dressed appropriately to await the results of the biopsy.
  • the biopsy will be analyzed to assure the wound is partial thickness.
  • the histologic criteria to evaluate bum thickness maybe seen in Appendix F.
  • Analgesics will be administered as required;
  • Surgical debridement of the bum will be performed to remove necrotic tissue fibrin, or exudate; 8. The length (longest edge-to-edge measurement), width (edge-to-edge measurement taken at the widest point perpendicular to the length measurement) and depth of the bum in centimeters will be determined and recorded in the CRF;
  • Step 1 Hands will be washed thoroughly and sterile gloves will be used; Step 2. Soiled dressings will be removed and disposed of (post day-1 treatment); Step 3. The entire wound will be cleaned and debrided;
  • Step 4 An appropriate volume of study medication will be applied.
  • the medication should form a continuous film covering the entire bum including the margins;
  • Step 5 The bum will be covered with a clean bandage and an over wrap; Step 6.
  • the dressings will be changed twice daily. Study medication will be applied after examination by the clinical investigator during scheduled visits to the clinic;
  • Step 7 Blood pressure will be monitored 15 and 45 minutes posttreatment.

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Abstract

La présente invention concerne des procédés et des équipements destinés à accélérer la guérison de brûlures chez des êtres humains, qui comportent l'étape consistant à appliquer sur la brûlure une quantité efficace d'angiotensinogène, d'angiotensine I (AI), d'analogues d'AI, de fragments d'AI et de ses analogues, d'angiotensine II (AII), d'analogues d'AII, de fragments d'AII ou de ses analogues, ou d'agonistes de récepteur d'AII AT2 de type 2.
PCT/US1998/002049 1997-02-04 1998-02-04 Procede permettant d'accelerer la guerison de brulures WO1998033813A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66500/98A AU6650098A (en) 1997-02-04 1998-02-04 Method for accelerating healing of thermal injuries

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US3716697P 1997-02-04 1997-02-04
US60/037,166 1997-02-04

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999031125A1 (fr) * 1997-12-12 1999-06-24 University Of Southern California Compositions de cicatrisation
WO2000009144A1 (fr) * 1998-08-13 2000-02-24 University Of Southern California Procede pour augmenter le debit sanguin vers le tissu ischemique
WO2000056345A2 (fr) * 1999-03-23 2000-09-28 University Of Southern California Procede pour limiter la formation de cicatrices et d'adherences
US6258778B1 (en) 1998-07-13 2001-07-10 University Of Southern California Methods for accelerating bone and cartilage growth and repair
EP1252894A1 (fr) * 2001-04-26 2002-10-30 Institut National De La Sante Et De La Recherche Medicale (Inserm) Utilisation de l'angiotensinogène et de ses dérivés pour la fabrication d'un médicament anti-angiogène
US6475988B1 (en) 1998-05-11 2002-11-05 University Of Southern California Methods to increase white blood cell survival after chemotherapy
US6498138B1 (en) 1998-03-11 2002-12-24 University Of Southern California Method of promoting production of living tissue equivalents
US6730775B1 (en) 1999-03-23 2004-05-04 University Of Southern California Methods for limiting scar and adhesion formation
US6747008B1 (en) 2000-06-19 2004-06-08 University Of Southern California Methods for treating and preventing alopecia
US6762167B1 (en) 1998-05-11 2004-07-13 University Of Southern California Methods for treating a patient undergoing chemotherapy
US6916783B2 (en) 1998-07-13 2005-07-12 University Of Southern California Methods for accelerating bone and cartilage growth and repair
US7338938B2 (en) 1999-05-10 2008-03-04 University Of Southern California Methods for treating a patient undergoing chemotherapy
US7652054B2 (en) 2001-05-31 2010-01-26 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
EP2455388A1 (fr) 2010-11-23 2012-05-23 LanthioPep B.V. Nouveaux agonistes du récepteur 2 (AT2) de type angiotensine et leurs utilisations
US8207234B1 (en) 2011-02-02 2012-06-26 University Of Southern California Methods for treating diabetic foot ulcers
CN102905719A (zh) * 2010-03-26 2013-01-30 南加利福尼亚大学 治疗复合性辐射和热损伤的方法
WO2021023698A1 (fr) 2019-08-02 2021-02-11 Lanthiopep B.V Agonistes du récepteur de l'angiotensine 2 (at2) destinés à être utilisés dans le traitement du cancer

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US5015629A (en) * 1989-06-26 1991-05-14 University Of Southern California Tissue repair
WO1995008337A1 (fr) * 1993-09-24 1995-03-30 The University Of Southern California Utilisation de l'angiotensine iii et de ses analogues pour la reparation tissulaire
WO1995008565A1 (fr) * 1993-09-24 1995-03-30 The University Of Southern California Utilisation d'analogues d'angiotensine ii pour la reparation tissulaire
WO1996014858A1 (fr) * 1994-11-14 1996-05-23 University Of Southern California Utilisation de fragments d'angiotensine ii et d'analogues de celle-ci pour la reparation des tissus
WO1996039164A1 (fr) * 1995-06-06 1996-12-12 The University Of Southern California Utilisation d'agonistes du recepteur type 2 de l'angiotensine ii dans la reparation des tissus

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US5015629A (en) * 1989-06-26 1991-05-14 University Of Southern California Tissue repair
WO1995008337A1 (fr) * 1993-09-24 1995-03-30 The University Of Southern California Utilisation de l'angiotensine iii et de ses analogues pour la reparation tissulaire
WO1995008565A1 (fr) * 1993-09-24 1995-03-30 The University Of Southern California Utilisation d'analogues d'angiotensine ii pour la reparation tissulaire
WO1996014858A1 (fr) * 1994-11-14 1996-05-23 University Of Southern California Utilisation de fragments d'angiotensine ii et d'analogues de celle-ci pour la reparation des tissus
WO1996039164A1 (fr) * 1995-06-06 1996-12-12 The University Of Southern California Utilisation d'agonistes du recepteur type 2 de l'angiotensine ii dans la reparation des tissus

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7022675B2 (en) 1997-12-12 2006-04-04 University Of Southern California Wound healing compositions
US6165978A (en) * 1997-12-12 2000-12-26 University Of Southern California Wound healing composition
US6455501B1 (en) 1997-12-12 2002-09-24 University Of Southern California Wound healing compositions
WO1999031125A1 (fr) * 1997-12-12 1999-06-24 University Of Southern California Compositions de cicatrisation
US6498138B1 (en) 1998-03-11 2002-12-24 University Of Southern California Method of promoting production of living tissue equivalents
US6475988B1 (en) 1998-05-11 2002-11-05 University Of Southern California Methods to increase white blood cell survival after chemotherapy
US6762167B1 (en) 1998-05-11 2004-07-13 University Of Southern California Methods for treating a patient undergoing chemotherapy
US6916783B2 (en) 1998-07-13 2005-07-12 University Of Southern California Methods for accelerating bone and cartilage growth and repair
US6258778B1 (en) 1998-07-13 2001-07-10 University Of Southern California Methods for accelerating bone and cartilage growth and repair
AU755943B2 (en) * 1998-08-13 2003-01-02 University Of Southern California Methods to increase blood flow to ischemic tissue
US6177407B1 (en) 1998-08-13 2001-01-23 University Of Southern California Methods to increase blood flow to ischemic tissue
WO2000009144A1 (fr) * 1998-08-13 2000-02-24 University Of Southern California Procede pour augmenter le debit sanguin vers le tissu ischemique
US6730775B1 (en) 1999-03-23 2004-05-04 University Of Southern California Methods for limiting scar and adhesion formation
WO2000056345A3 (fr) * 1999-03-23 2001-01-11 Univ Southern California Procede pour limiter la formation de cicatrices et d'adherences
WO2000056345A2 (fr) * 1999-03-23 2000-09-28 University Of Southern California Procede pour limiter la formation de cicatrices et d'adherences
US7786085B2 (en) 1999-05-10 2010-08-31 University Of Southern California Method for treating a patient undergoing chemotherapy
US7338938B2 (en) 1999-05-10 2008-03-04 University Of Southern California Methods for treating a patient undergoing chemotherapy
US6747008B1 (en) 2000-06-19 2004-06-08 University Of Southern California Methods for treating and preventing alopecia
EP1252894A1 (fr) * 2001-04-26 2002-10-30 Institut National De La Sante Et De La Recherche Medicale (Inserm) Utilisation de l'angiotensinogène et de ses dérivés pour la fabrication d'un médicament anti-angiogène
WO2002087607A1 (fr) * 2001-04-26 2002-11-07 Institut National De La Sante Et De La Recherche Medicale (Inserm) Utilisation d'agt et de ses derives pour preparer des compositions pharmaceutiques anti-angiogenese
US8124638B2 (en) 2001-05-31 2012-02-28 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
US7652054B2 (en) 2001-05-31 2010-01-26 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
CN102905719A (zh) * 2010-03-26 2013-01-30 南加利福尼亚大学 治疗复合性辐射和热损伤的方法
US9272013B2 (en) 2010-03-26 2016-03-01 University Of Southern California Methods for treating combined radiation and thermal injury
JP2013523659A (ja) * 2010-03-26 2013-06-17 ユニバーシティー オブ サザン カリフォルニア 放射線および熱の複合損傷の治療方法
US20130123190A1 (en) * 2010-03-26 2013-05-16 University Of Southern California Methods for Treating Combined Radiation and Thermal Injury
WO2012070936A1 (fr) 2010-11-23 2012-05-31 Lanthiopep B.V. Nouveaux agonistes du récepteur de l'angiotensine de type 2 (at2) et leurs utilisations
EP2455388A1 (fr) 2010-11-23 2012-05-23 LanthioPep B.V. Nouveaux agonistes du récepteur 2 (AT2) de type angiotensine et leurs utilisations
US9290540B2 (en) 2010-11-23 2016-03-22 Lanthio Pep B.V. Angiotensin Type 2 (AT2) receptor agonists and uses thereof
US9707268B2 (en) 2010-11-23 2017-07-18 Lanthiopep B.V. Angiotensin type 2 (AT2) receptor agonists and uses thereof
US10214563B2 (en) 2010-11-23 2019-02-26 Lanthiopep B.V. Angiotensin type 2 (AT2) receptor agonists and uses thereof
US8207233B1 (en) 2011-02-02 2012-06-26 University Of Southern California Methods for treating diabetic foot ulcers
US8207234B1 (en) 2011-02-02 2012-06-26 University Of Southern California Methods for treating diabetic foot ulcers
US8536231B2 (en) 2011-02-02 2013-09-17 Kathleen E. Rodgers Methods for treating diabetic foot ulcers
WO2021023698A1 (fr) 2019-08-02 2021-02-11 Lanthiopep B.V Agonistes du récepteur de l'angiotensine 2 (at2) destinés à être utilisés dans le traitement du cancer

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