WO2007124331A2 - Utilisations cardioprotectrices et autres de la cible des inhibiteurs de la rapamycine (m-tor) chez les mammifères - Google Patents

Utilisations cardioprotectrices et autres de la cible des inhibiteurs de la rapamycine (m-tor) chez les mammifères Download PDF

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WO2007124331A2
WO2007124331A2 PCT/US2007/066910 US2007066910W WO2007124331A2 WO 2007124331 A2 WO2007124331 A2 WO 2007124331A2 US 2007066910 W US2007066910 W US 2007066910W WO 2007124331 A2 WO2007124331 A2 WO 2007124331A2
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rapamycin
patient
heart
reperfusion injury
risk
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Rakesh Kukreja
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Virginia Commonwealth University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines

Definitions

  • m-TOR mammalian target of rapamycin
  • the invention generally relates to medicine, especially cardiac medicine, and especially relates to medicine relating to ischemia/reperfusion injury particularly in the heart but also elsewhere.
  • IPC ischemic preconditioning
  • the invention provides a method of protecting against necrosis and/or apoptosis in cardiomyocytes, comprising: administering (such as, e.g., administering via an intraperitoneal administration route, etc.) to a patient having a population of cardiomyocytes an effective dose of a protective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor.
  • a protective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor.
  • the invention in another preferred embodiment provides a method of preconditioning a patient against myocardial infarction, comprising: opening mitochondrial KATP channels in the patient by administering (such as, e.g., administering via an intraperitoneal administration route, etc.) to the patient an effective amount of a substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor), such as, e.g., an inventive method of preconditioning a patient against myocardial infarction wherein the substance is administered to the patient following ischemia/reperfusion injury in the heart (such as, e.g., an ischemia/reperfusion injury resulting from coronary bypass surgery and/or angioplasty in the heart); etc.
  • administering such as, e.g., administering via an intraperitoneal administration route, etc.
  • mTOR mammalian target of rapamycin
  • the invention provides a cardio-protective method in a post-heart attack patient, comprising: after the patient has experienced a heart attack of a heart muscle of the patient, administering (such as, e.g., administering via an intraperitoneal administration route, etc.) to the patient an effective amount (such as, e.g., an amount sufficient to protect against ischemia/reperfusion injury (such as, e.g., ischemia/reperfusion injury that results from coronary bypass surgery and/or angioplasty in the heart) of a cardioprotective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor; such as, e.g., inventive cardio-protective methods wherein, after the administering step, the heart muscle undergoes ischemia and/or reperfusion having a less-damaging effect to the heart muscle than if the cardio-protective substance had not been administered
  • the invention in a further preferred embodiment provides a protective method in a post-heart attack patient, comprising: after the patient has experienced a heart attack, administering to the patient an effective amount of a protective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor, and thereby protecting a tissue selected from the group consisting of: heart, brain, liver, kidney, lung, gut, skeletal muscle, pancreas, retina and intestinal tissue wherein the protecting comprises reducing an effect to the tissue from ischemia/reperfusion injury.
  • a protective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor
  • the invention provides a protective method in an at-risk patient (such as, e.g., a post-heart attack patient; a patient who has suffered head trauma; a patient at risk of cardiovascular disease and a patient who has suffered stroke; etc.), comprising: administering to the patient an effective amount of a protective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor, and thereby protecting a tissue selected from the group consisting of: heart, brain, liver, kidney, lung, gut, skeletal muscle, pancreas, retina and intestinal tissue wherein the protecting comprises reducing an effect to the tissue from ischemia/reperfusion injury.
  • a protective substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor
  • the invention also provides another preferred embodiment which is a protective method in a post-heart attack patient, comprising: administering to a patient who has experienced a heart attack an amount of a substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor, wherein the amount is an amount effective to prevent a process of heart remodeling.
  • a substance selected from the group consisting of: rapamycin; everolimus; a rapamycin analogue; and a mammalian target of rapamycin (mTOR) inhibitor wherein the amount is an amount effective to prevent a process of heart remodeling.
  • Fig. 4 Representative images of adult mouse cardiomyocytes showing effect of rapamycin on myocyte viability.
  • A Normal isolated cardiac myocytes;
  • B Myocytes subjected to 40 min of simulated ischemia (SI) and 1 h of reoxygenation (RO). Cell necrosis is evident by the increased number of tryptan-positive blue myocytes.
  • C Pretreatment with 100 nM rapamycin reduces the number of tryptan- blue positive myocytes demonstrating improved cell viability.
  • Fig. 6 Effect of rapamycin on inhibition of apoptosis in cardiomyocytes.
  • Cells were treated with rapamycin (25, 50, or 100 nM) for 1 h followed by 40 min of simulated ischemia (SI) and 18 h of reoxygenation (RO). Apoptotic nuclei were observed using the TUNEL assay. Apoptotic cell death was markedly increased after SI-RO (*P ⁇ 0.001 vs. control). Rapamycin pretreatment reduced TUNEL-positive nuclei compared to SI-RO alone (fP ⁇ 0.001) demonstrating less apoptotic cell death. DETAILED DESCRIPTION OF THE PREFERRED
  • rapamycin being a known composition.
  • "Rapamycin” herein means the chemical nucleus commonly known by that name and includes a compound comprising a rapamycin chemical nucleus.
  • the rapamycin chemical nucleus has chemical formula C 51 H 79 NO 13 .
  • Rapamycin is sometimes called "Sirolimus.” Rapamycin is commercially available.
  • the novel uses disclosed herein for rapamycin may be extended to other compounds related to rapamycin such as, e.g., rapamycin analogues.
  • rapamycin analogues examples are, e.g., compounds called rapamycin analogues in the literature (such as, e.g., everlimus); compounds derived from rapamycin; compounds having substantial structure similarity to rapamycin; etc.
  • "Ischemia/reperfusion injury” means the injury inflicted as a result of restoring oxygenated blood in the tissue following a period of no-blood flow. Examples of ischemia/reperfusion injury are, e.g., heart attack, stroke, etc.
  • mTOR rapamycin
  • rapamcyin an enzyme serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.
  • An example of an mTOR inhibitor is rapamcyin.
  • Opening mitochondrial KATP channels means the opening of pores in the mitochondrial membrane that facilitate movement of potassium ion under the control of ATP, which is essential for performing cellular functions.
  • Protecting herein means that the extent or magnitude of an undesirable effect (such as, e.g., undesirable necrosis; undesirable apoptosis; undesirable ischemia/ reperfusion injury) is reduced.
  • Preconditioning a patient against myocardial infarction means protecting the heart tissue from dying as a result of deprivation of oxygen or ischemia.
  • Rapamycin has been shown to protect the heart muscle after experimentally induced heart attack in mice. Rapamycin is now considered an antibiotic that inhibits protein synthesis through mammalian target of rapamycin (mTOR) signaling.
  • mTOR mammalian target of rapamycin
  • This inventive example concerns the role of the drug rapamycin and other mTOR inhibitors (including analogous compounds everolimus) in protection against ischemia/reperfusion (I/R) injury.
  • rapamycin induces potent preconditioning-like effect against myocardial infarction through opening of mitochondrial K ATP channels. Therefore rapamycin may be used as a therapeutic strategy to limit infarction, apoptosis and remodeling following I/R injury in the heart.
  • mTOR inhibitor rapamycin inventively has been used for reducing myocardial infarct size following experimentally-induced heart attack (ischemia) in mice. Also, in this example, it has been shown that rapamycin reduces cardiomyocyte apoptosis (programmed cell death) following simulated ischemia/ reoxygenation.
  • mTOR inhibitors may be used to treat ischemia/reperfusion injury resulting from procedures including coronary bypass surgery and angioplasty in the heart.
  • mTOR inhibitors can be used to avoid or ameliorate the adverse effects of myocardial infraction including cardiac hypertrophy and heart failure.
  • the mTOR inhibitors can be used to protect ischemia-related injury in other organs including brain, heart, liver, intestine, kidney, lung, gut, spleen, pancreas, nerves, spinal cord, retinal tissue, vasculature, and skeletal muscle. Rapamycin has now been shown to have a preconditioning-like protective effect in the mouse heart.
  • Rapamycin is an antibiotic derived from Streptomyces hygroscopius, and for many years has been primarily used as an immunosuppressant in the treatment of organ rejection in transplant recipients (Morris RE. Prevention and treatment of allograft rejection in vivo by rapamycin: molecular and cellular mechanisms of action.
  • rapamycin's anti-growth properties have been utilized for cardiovascular benefit as stents impregnated with rapamycin effectively reduce coronary restonosis (Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban HE, Perm M et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.
  • the proposed mechanism for the anti- proliferative effect of rapamycin is based on its ability to bind to its intracellular receptor, the FK506 binding protein (FKBP 12) (Marks AR. Cellular functions of immunophilins. Physiol Rev 1996; 76(3):631-649.)
  • FKBP 12 FK506 binding protein
  • the rapamycin/FKBP12 complex is an inhibitor of the mammalian target of rapamycin (mTOR), a 290-kDa Ser/Thr kinase that controls mammalian protein translational processes that are central to cell growth (Schmelzle T, Hall MN. TOR, a central controller of cell growth.
  • Rapamycin prevents DNA and protein synthesis, in large part, by regulation of p70S6 kinase (p70S6K) phosphatase, leading to arrest of the cell cycle at the Gl /S interface (Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995; 76(3):412-417.) Additionally rapamycin modulation of the mTOR kinase plays key roles in nutrient regulation (Cardenas ME, Cutler NS, Lorenz MC, Di Como CJ, Heitman J. The TOR signaling cascade regulates gene expression in response to nutrients.
  • rapamycin-eluting stents have become a vital tool for native coronary artery revascularization and also demonstrate favorable outcomes for treatment of saphenous vein graft lesions (Ge L, Iakovou I, Sangiorgi GM, Chieffo A, Melzi G, Cosgrave J et al. Treatment of saphenous vein graft lesions with drug- eluting stents: immediate and midterm outcome. J Am Coll Cardiol 2005; 45(7):989- 994) and in-stent restonosis (Holmes DR, Jr., Teirstein P, Satler L, Sketch M, O'Malley J, Popma JJ et al.
  • rapamycin is newly shown to induce a preconditioning-like protective effect in the intact heart and adult cardiomyocyte subjected to ischemia/reperfusion. Furthermore, the results of this example show that rapamycin induced cardioprotection is mediated by opening of the mitochondrial ATP-sensitive potassium channel (mitoK ATP channel).
  • Rapamycin was purchased from Sigma-Aldrich (St. Loius, MO) and was dissolved in DMSO (Sigma-Aldrich) for intraperitoneal injection (final DMSO concentration ⁇ 1%). Unless specified otherwise, all other chemicals including 5- hydroxydecanoate (5-HD), trypan blue dye and triphenyltetrazolium chloride (TTC) were obtained from Sigma-Aldrich.
  • the heart was retrogradely perfused at a constant pressure of 55 mmHg with modified Krebs-Henseleit (K-H) solution containing (in mM) 118 NaCl, 24 NaHCO 3 , 2.5 CaCl 2 , 4.7 KCl, 1.2 KH 2 PO 4 , 1.2 MgSO 4 , 11 glucose, and 0.5 EDTA.
  • K-H modified Krebs-Henseleit
  • the perfusion solution was continuously gassed with 95% O 2 + 5% CO 2 (pH ⁇ 7.4) and warmed by a heating/cooling bath.
  • the heart temperature was continuously monitored and maintained at 37°C throughout the experiment.
  • Ventricular function was measured by a force-displacement transducer (model FT03, Grass) attached to the apex with a no. 5 surgical thread and a rigid metal hook. The resting tension of the isolated heart was adjusted to -0.30 g. Ventricular developed force was continuously recorded with a PowerLab 8SP computerized data acquisition system connected to the force transducer. Coronary flow rate was calculated by timed collection of the perfusate. The hearts were not paced. 2.4. Experiment protocol for drug pretreatment and cardiac ischemia- reperfusion
  • mice were injected with either rapamycin (0.25 mg/kg, IP) or volume-matched DMSO (solvent for rapamycin) 30 minutes prior to heart isolation.
  • the hearts were isolated and subjected to 30 min of stabilization on a Langendorff system.
  • the hearts were randomized to either continued K-H buffer perfusion or intracoronary infusion of 100 ⁇ M 5 -HD (at a previously established dose (Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, Figueredo V et al.
  • Preconditioning limits mitochondrial Ca(2+) during ischemia in rat hearts: role of K(ATP) channels.
  • the heart was immediately removed from the Langendorff apparatus, weighed, and frozen at -20 0 C.
  • the frozen heart was manually cut into seven to eight transverse slices of approximately equal thickness ( ⁇ 0.8 mm) and stained by incubation in 10% TTC for 30 min at room temperature ( ⁇ 22°C).
  • TTC buffer was then replaced with 10% formaldehyde, and the slices were fixed for 4-6 hours before infarct area and risk zone were measured using computer morphometry (Bioquant 98).
  • the risk area was calculated as total ventricular area minus the area of the cavities.
  • the infarct size was calculated as a percentage of the risk area.
  • mice ventricular cardiomyocytes were isolated using an enzymatic technique reported in Das A, Xi L, Kukreja RC.
  • Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis.
  • the aortic opening was cannulated onto a Langendorff perfusion system (Xi et al., supra) and heart was retrogradely perfused (37 0 C) at a constant pressure of 55 mmHg for ⁇ 5 min with a Ca 2+ -free bicarbonate-based buffer containing (in mM): 120 NaCl, 5.4 KCl, 1.2 MgSO 4 , 1.2 NaH 2 PO 4 , 5.6 glucose, 20 NaHCO 3 , 10 2,3-butanedione monoxime, and 5 taurine, which was continuously gassed with 95%O 2 + 5%CO 2 .
  • the enzymatic digestion was commenced by adding collagenase type II (Worthington, 0.5 mg/mL each) and protease type XTV (0.02 mg/mL) to the perfusion buffer and continued for ⁇ 15 min. 50 ⁇ M Ca + was then added in to the enzyme solution for perfusing the heart for another 10-15 min. The digested ventricular tissue was cut into chunks and gently aspirated with a transfer pipette for facilitating the cell dissociation. The cell pellet was resuspended for a 3 -step Ca 2+ restoration procedure ⁇ i.e. 125, 250, 500 ⁇ M Ca 2+ ).
  • the freshly isolated cardiomyocytes were then suspended in minimal essential medium (pH 7.35-7.45) containing 1.2 mM Ca 2+ , 12 mM NaHCO 3 , 2.5% fetal bovine serum and 1% penicillin-streptomycin.
  • the cells were then plated onto 2-chamber slides, which were pre-coated with 20 ⁇ g/mL mouse laminin in PBS + 1% penicillin- streptomycin for 1 hour.
  • the cardiomyocytes were cultured in the presence of 5% CO 2 for 1 hour in a humidified incubator at 37 0 C, which allowed cardiomyocytes to attach to the slide surface prior to the experimental protocol.
  • the cultured cardiomyocytes were incubated under 37 0 C and 5% CO 2 , for 1 hour with or without 25, 50 or 100 nM rapamycin. Cardiomyocytes were subjected to simulated ischemia (SI) for 40 minutes by replacing the cell medium with an "ischemia buffer" which contained (in mM): 118 NaCl, 24 NaHCO 3 , 1.0 NaH 2 PO 4 , 2.5 CaCl 2 -2H 2 O, 1.2 MgCl 2 , 20 sodium lactate, 16 KCl, 10 2-deoxyglucose (pH adjusted to 6.2) similar to those previously published (Das et al., supra.)
  • the cells were incubated under hypoxic conditions at 37 0 C during the entire SI period by adjusting the tri-gas incubator to 1-2% O 2 and 5% CO 2 . Reoxygenation (RO) was accomplished by replacing the ischemic buffer with normal medium under normoxic conditions. Assessment of cell necrosis and apoptosis was performed at 1 hour and
  • TUNEL terminal deoxynucleotidyl transferase mediated nick end labeling
  • HR heart rate
  • DF developed force
  • RFP rate-force product
  • CF coronary flow.
  • Baseline function (developed force and rate-force product) was similar between the RAPA and DMSO pretreated groups.
  • the DMSO pretreated group that received 5- HD infusion during stabilization (DMS0+5-HD) had an elevated developed force prior to 5-HD infusion, compared to the other three groups (P ⁇ 0.05).
  • DMS0+5-HD 5- HD infusion during stabilization
  • infusion of 5-HD led to a decrease in rate-force product in the RAPA+5-HD group (PO.05).
  • Infarct size in the DMSO treated mice was 28.2 ⁇ 1.3% of risk area which was consistent with previously reported results (Wang X, Yin C, Xi L, Kukreja RC. Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice. Am J Physiol Heart Circ Physiol 2004; 287(5):H2070-H2077.) Pretreatment with rapamycin reduced infarct size (down to 10.1 ⁇ 2.8%) compared to DMSO controls (a 64% decrease, PO.001).
  • rapamycin has greatly increased during the past few years with the introduction of rapamycin-eluting coronary stents. While the anti-hypertrophic effects of rapamycin have been well described (Schmelzle, supra), conventionally other properties of this pharmacological agent are poorly understood.
  • the preconditioning-like effect of rapamycin in the mouse heart is a new discovery, disclosure and invention. More specifically, it has now been shown that intraperitoneal administration of rapamycin induces cardioprotection as demonstrated by significant reduction in infarct size. Furthermore, these finding have been replicated at the cellular level by showing that rapamycin directly protected against cardiomyocyte necrosis and apoptosis following ischemia-reoxygenation injury.
  • Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up- regulating the insulin-like growth factor receptor/insulin receptor substrate- 1/phosphatidylinositol 3-kinase cascade.
  • MoI Cancer Ther 2005; 4(10): 1533-1540.) O'Reilly and colleagues replicated these findings in a variety of tumor cell lines (Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
  • anisomycin has also been shown to induce acute and delayed preconditioning effect in the heart, mediated by opening of mitoKATP (Baines CP, Liu GS, Birincioglu M, Critz SD, Cohen MV, Downey JM. Ischemic preconditioning depends on interaction between mitochondrial KATP channels and actin cytoskeleton. Am J Physiol 1999; 276(4 Pt 2):H1361-H1368; Zhao TC, Taher MM, Valerie KC, Kukreja RC. p38 Triggers late preconditioning elicited by anisomycin in heart: involvement of NF-kappaB and iNOS . Circ Res 2001 ; 89(10):915-922.)
  • endogenous nitric oxide NO
  • exogenous NO is cardioprotective (Nakano A, Liu GS, Heusch G, Downey JM, Cohen MV.
  • Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning.
  • rapamycin but not cyclosporine, treatment inhibited the development of intimal hyperplasia and increased the expression of iNOS in a rat aortic allograft model (Pham SM, Shears LL, Kawaharada N, Li S, Venkataramanan R, Sehgal S. High local production of nitric oxide as a possible mechanism by which rapamycin prevents transplant arteriosclerosis.
  • Circ Res 2004; 94(4):420-432 as well as pharmacological agents (Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ. Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res 1999; 84(7):846-851; Ockaili RA, Bhargava P, Kukreja RC. Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial K(ATP) channel. Am J Physiol Heart Circ Physiol 2001; 280(5):H2406-H2411; Wang Y, Kudo M, Xu M, Ayub A, Ashraf M.
  • Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. J MoI Cell Cardiol 2001; 33(11):2037-2046; Ockaili R, Salloum F, Hawkins J, Kukreja RC. Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits.
  • rapamycin induced mTOR inhibition enhances compensatory upregulation of upstream survival kinases, such as PI3K and Akt (Gursoy et al., supra; Oldenburg et al., supra; Shi et al., supra.)
  • upstream survival kinases such as PI3K and Akt
  • PI3K and Akt are key mediators in the activation of mitoK A ⁇ p channel
  • Akt upstream survival kinases
  • Akt upstream survival kinases
  • T-cadherin protects endothelial cells from oxidative stress-induced apoptosis. FASEB J2005; 19(12):1737-1739) and B-lymphocytic cells (Edinger et al., supra). Hypoxia-inducible factor-l ⁇ (HIF- l ⁇ ) (Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF- 1 -dependent pathways.
  • HIF- l ⁇ Hypoxia-inducible factor-l ⁇
  • mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF- 1 -dependent pathways.
  • HIF-I alpha hypoxia-inducible factor 1 alpha
  • elF4E Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. Survival signalling by Akt and eEF4E in oncogenesis and cancer therapy.
  • Rapamycin increases the cellular concentration of the BCL-2 protein and exerts an anti-apoptotic effect.
  • Eur J Cancer 2001 ; 37( 16):2121 -2128) HEK (Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115(5):577-590), multiple myeloma (Thyrell L, Hjortsberg L, Arulampalam V, Panaretakis T, Uhles S, Dagnell M et al. Interferon alpha-induced apoptosis in tumor cells is mediated through the phosphoinositide 3- kinase/mammalian target of rapamycin signaling pathway. J Biol Chem 2004;
  • rapamycin may have potential effects on myocyte proliferation.
  • Several labs have documented that the heart has an endogenous reserve of progenitor cells that have the ability to proliferate and potentially reconstitute infracted myocardium (Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S et al.
  • Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114(6):763-776; Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y et al.
  • Cardiac progenitor cells from adult myocardium homing, differentiation, and fusion after infarction.
  • rapamycin has been shown to upregulate PI3K (a critical effector in HGF mediated migration) and also likely enhance IGF-I activity (Gursoy et al., supra; Oldenburg et al., supra; Shi et al., supra).
  • Rapamycin induces preconditioning-like protective effects against myocardial infarction following ischemia-reperfusion injury through opening of mitoK ATP channels.
  • this drug reduced necrosis as well as apoptosis following simulated ischemia-reoxygenation injury in adult cardiomyocytes. Rapamycin therefore may be used as a novel therapeutic strategy to limit myocardial infarction and apoptosis following ischemia/reperfusion injury and attenuate ventricular remodeling, in addition to its well-established effect on reduction of post-stent restenosis in humans.
  • rapamycin a potent inhibitor of downstream signaling from the mammalian target of rapamycin (mTOR) proteins
  • mTOR mammalian target of rapamycin
  • mice in each group were used for infarct size assessment.
  • Three mice per group from groups 2 and 3 were used for western blotting.
  • a total of 24 male ICR mice (Body weight: 27-33g) were used.
  • the animals were anesthetized with an intraperitoneal injection of pentobarbital (70 mg/kg).
  • the animals were intubated orotracheally and ventilated on a positive-pressure ventilator.
  • the tidal volume was set at 0.2 ml, and the respiratory rate was adjusted to 133 cycles/min.
  • the surgery was carried out under sterile conditions.
  • a left thoracotomy was performed at the fourth intercostal space and the heart was exposed by stripping the pericardium to identify the left coronary artery branch.
  • a ligature was then placed around the left coronary artery, and the artery was occluded by snaring with a small tube through which the ligature had been passed. After 30 minutes of ischemia, the ligature was released and the air was expelled from the chest and the surgical wounds were sutured closed. The animals were observed during recovery until fully conscious and then extubated. The animals received intramuscular doses of analgesia (buprenorphine 0.02 mg/kg) and antibiotic (Gentamicin 0.7 mg/kg). The hearts we allowed to reperfuse 24 hours before explantation.
  • analgesia buprenorphine 0.02 mg/kg
  • antibiotic Genetamicin 0.7 mg/kg
  • TTC triphenyl tetrazolium chloride
  • rapamycin may be a useful therapeutic tool to suppress I/R injury in patients with cardiovascular disease.
  • rapamycin 25, 50, or 100 nM
  • rapamycin induces preconditioning-like protective effects against myocardial infarction following ischemia-reperfusion injury through MAPK signaling.
  • This novel cardioprotective effect against ischemia/reperfusion injury is of great clinical interest because this compound is already being used in the clinical arena in transplant medicine and as a coating for drug-eluting stents.
  • This example supports the use of rapamycin as a therapeutic strategy to limit myocardial infarction and apoptosis following ischemia/reperfusion injury and attenuate ventricular remodeling.
  • cardioprotection may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • protection of brain tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • liver tissue For a person whose liver tissue is at risk for ischemia/reperfusion injury during hepatic surgical intervention, protection of liver tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • kidney tissue For a person whose kidney tissue is at risk (such as e.g., during ischemic acute renal failure), protection of kidneytissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • protection of lung tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • protection of gut tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • protection of skeletal muscle may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • protection of spleen tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • EXAMPLE 3H protection of pancreatic tissue
  • pancreatic tissue For a person whose pancreatic tissue is at risk (such as e.g., clinical pancreas transplantation), protection of pancreatic tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • EXAMPLE 31 protection of retinal tissue
  • retinal tissue For a person whose retinal tissue is at risk (such as e.g., macular edema, capillary nonperfusion, retinal neovascularization, vitreous hemorrhage, and tractional retinal detachments that often result in loss of vision), protection of retinal tissue may be undertaken by administration of rapamycin or a rapamycin analogue, such as administration via intraperitoneal route.
  • rapamycin or a rapamycin analogue such as administration via intraperitoneal route.

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Abstract

L'invention concerne de nouvelles utilisations de la rapamycine, comprenant par exemple l'effet de type préconditionnant de la rapamycine contre l'infarctus du myocarde intact ainsi que contre la nécrose et l'apoptose des cardiomyocytes. Elle concerne également d'autres utilisations de la rapamycine et d'autres inhibiteurs m-TOR, notamment chez les patients ayant subi une crise cardiaque et d'autres patients à risque d'ischémie/lésion de reperfusion.
PCT/US2007/066910 2006-04-19 2007-04-19 Utilisations cardioprotectrices et autres de la cible des inhibiteurs de la rapamycine (m-tor) chez les mammifères Ceased WO2007124331A2 (fr)

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US11099194B2 (en) 2013-01-17 2021-08-24 Astute Medical, Inc. Methods and compositions for diagnosis and prognosis of renal injury and renal failure
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US11229676B2 (en) 2013-12-03 2022-01-25 Astute Medical, Inc. Methods and compositions for diagnosis and prognosis of renal injury and renal failure
WO2016164854A1 (fr) * 2015-04-09 2016-10-13 Astute Medical, Inc. Méthodes et compositions pour le diagnostic et le pronostic d'une lésion rénale et d'une insuffisance rénale
US11243202B2 (en) 2015-04-09 2022-02-08 Astute Medical, Inc. Methods and compositions for diagnosis and prognosis of renal injury and renal failure
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CN116637110A (zh) * 2023-06-16 2023-08-25 新乡医学院 雷帕霉素在制备用于减轻瓦斯爆炸致脾脏损伤制剂中的应用

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