WO2019153099A1 - Composé et procédé pour optimiser la transplantation des organes solides vascularisés et réduire le dysfonctionnement de ces derniers - Google Patents

Composé et procédé pour optimiser la transplantation des organes solides vascularisés et réduire le dysfonctionnement de ces derniers Download PDF

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WO2019153099A1
WO2019153099A1 PCT/CL2018/050009 CL2018050009W WO2019153099A1 WO 2019153099 A1 WO2019153099 A1 WO 2019153099A1 CL 2018050009 W CL2018050009 W CL 2018050009W WO 2019153099 A1 WO2019153099 A1 WO 2019153099A1
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ala
patients
transplant
transplantation
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Claudio Alejandro INCARDONA
Héctor Eduardo CHULUYAN
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Gador Limitada
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • This invention relates to a "COMPOUND AND PROCEDURE FOR OPTIMIZING THE TRANSPLANTATION OF THE VASCULARIZED SOLID ORGANS AND REDUCING THE DYSFUNCTION OF THEMSELVES", especially in the stages of ablation, transplantation and post-transplantation in order to optimize the functional recovery time. of the graft and the clinical parameters of short-term patients preferably undergoing renopancreatic, renal and hepatic transplants.
  • a syndrome called “reperfusion syndrome” may occur, which manifests as a decompensation of the transplant recipient.
  • SPR perfusion syndrome
  • Immunosuppressive induction treatment tries to avoid the phenomenon of graft rejection, and in fact it succeeds.
  • this treatment is not effective to achieve a rapid functional recovery of the graft.
  • the strategies are based on the use of continuous perfusion machines, but these are not implemented in all transplant centers and are very expensive due to the inputs that must be replaced after each operation.
  • the methods used today to recover the graft's early function are based on improving preservation techniques and reducing ischemia times. This last aspect is not always possible because of what the whole organ procurement process implies.
  • the preservation method used to minimize damage at the time of transfer and Organ preservation is the static hypothermic preservation whose foundation is the suppression of cellular metabolism by hypothermia at 4 ° C.
  • hypothermia alone is not enough for proper preservation, so it is necessary to irrigate the organ with special solutions before, during and after storage.
  • preservation solutions were chosen for a purpose. First, it is necessary to avoid cellular edematization due to the inactivity of the Na / K-ATPase pump. This is achieved using preservation liquids that have a low concentration of sodium and high potassium. Ionic solutions with extracellular composition are also used. Also, preservation liquids contain impervious substances for the cell based on simple sugars, lactobionate and trisaccharides to maintain a plasma-like osmolality (310 mOsm / kg). In addition, ischemia generates tissue acidosis, for this reason it is necessary that preservation solutions have buffer substances that maintain the pH closest to the physiological pH.
  • MPH hypothermic perfusion machine
  • drugs such as chloroquine or chlorpromazine have been administered to prevent mitochondrial dysfunctions and phospholipid degradation during ischemia.
  • one of the main targets of action should be the production of oxydryl radicals.
  • tocopherol to minimize the effects of reactive oxygen species was described.
  • the most commonly used antioxidant in experimental and clinical models is N-acetylcysteine (NAC).
  • NAC N-acetylcysteine
  • Table 1 Electrolytic composition (in mmol / l) of the main preservation solutions.
  • thioctic acid or alpha lipoic acid ALA
  • ALA is a naturally occurring compound created in the mitochondria from octanoic acid as a precursor. It is a powerful natural antioxidant that has activity in both aqueous and lipid media.
  • ALA acts both intra and extracellularly and has two isomeric forms. Due to these properties it has a wide potential for pharmacological action. Its main biological role is as a cofactor in mitochondrial enzymes such as a-ketoglutarate dehydrogenase and pyruvate dehydrogenase. ALA also appears to be involved in the production of acetyl-CoA, through oxidative decarboxylation of pyruvate. In vivo, ALA can be reduced in dihydrolipoic acid (ADHL) which has a greater antioxidant action.
  • ADHL dihydrolipoic acid
  • Both ALA and ADHL have chelating capacity of metals (Fe 2+ , Cu 2+ and Cd 2+ ) and neutralized from reactive oxygen species but only ADHL is able to regenerate endogenous antioxidants (glutathione and vitamin E, C) and repair tissue damage caused by reactive oxygen species.
  • endogenous antioxidants glutthione and vitamin E, C
  • repair tissue damage caused by reactive oxygen species.
  • ALA is not only an anti-oxidant but also a substance with anti-inflammatory activity.
  • ALA proved to be protective in several experimental models, such as hepatic and renal reperfusion ischemia damage and acute pancreatitis.
  • intraperitoneal administration of 100 mg / kg of ALA in animals that suffered 45 min of renal ischemia due to renal pedicle occlusion was able to reverse the deleterious effects of ischemia, such as increased serum creatinine, IL -1 b, IL-6 and TNF- a, among others.
  • intraperitoneal administration of ALA prevented the deregulation of aquaporins and sodium transporters, which is observed in renal reperfusion and attenuated increased expression of endothelin-1, which leads to renal dysfunction.
  • high dose administration of ALA 100 mg / kg was performed before ischemia and immediately before the reperfusion period.
  • ALA supplements are relatively safe in doses consumed in humans.
  • the doses of 600mg / day and 1800mg / day had no side effects for a period of 1-6 months.
  • After oral intake it is widely excreted by the kidney and is metabolized in the liver with a high hepatic first pass effect.
  • ALA was observed to decrease hepatic IRI after hepatic occlusion and resection.
  • diabetes-induced complications including polyneuropathy and cataract formation.
  • DGF graft function delay
  • the DGF is described as a discrepancy between the functional capacity of the graft and the physiological needs of the recipient, being a form of acute renal failure resulting in post-transplant oliguria. About 30-50% of kidney transplants suffer from DGF. However, in our country the number of patients with DGF amounts to 60-70%. With respect to the relationship between DGF and graft survival, it is known that the half-life of a kidney with DGF is 8.6 years compared to the half-life of 14.1 years of a kidney without DGF. The use of AAL would reduce the incidence of DGF.
  • DPI primary graft dysfunction
  • DTI early graft dysfunction
  • NFP primary non-function
  • DTI refers to a malfunction of the graft within the first week post-transplant by analyzing altered laboratory results, including alanine aminotransferase, aspartate aminotransferase, prothrombin time, lactate and serum ammonium, among others [3- 9]. While the NFP has a more severe implication that is associated with a catastrophic clinical and laboratory deterioration. It is characterized by hepatic necrosis, increased serum transaminases, coagulopathy, increased lactate levels, hemodynamic instability, hypoglycemia, respiratory and renal failure. Unlike DTI, which is a condition with potential recovery, NFP can lead to graft failure, emergency retransplantation or death of the recipient. In this type of transplant, it is necessary to emphasize that liver preservation is more critical than that of the kidney, since, since an organ replacement machine is not available, it is essential that the graft functions return immediately after the transplant.
  • the inventors provide a supplementary product that contains an active substance of alpha lipoic or thioctic acid (ALA) (C 8 H- H O 2 S 2 ) to the donor and / or the perfusion of the organs to be transplanted with ALA together with the administration of ALA in the first two days post-transplant allows to reduce early graft dysfunction.
  • ALA alpha lipoic or thioctic acid
  • our invention does not imply modifying the usual therapies and procedures in solid organ transplantation, but rather incorporating a supplementary product to the same ALA to improve clinical parameters in the short and long term.
  • ALA either in the donor and / or in the organ to be transplanted and the transplant recipient in the first two days after transplantation, improves the graft's early function, backed by the changes observed in inflammatory mediators to local level as systemic.
  • the procedure for administration of ALA is carried out in the following manner, whose stages are: a) Administer to the donor, particularly in the operating room prior to the surgical procedure of the transplant, an active substance of alpha lipoic acid (ALA) in amounts between 400 to 1000 mg, preferably 600 mg diluted in 100 my physiological solution that is passed for 30 minutes, together with the infusion of 1 vial of vitamin B (Bagó B1 B6 B12 or Becozym) endovenous; b) Slowly and continuously introduce to the organ to transplant a solution from the University of Wisconsin (UW), HTK (Bretschneider or Custodiol solution) or Eurocollins (EC) containing an active substance of alpha lipoic acid (ALA) in amounts between 400 at 1000 mg, preferably 600 mg diluted in 500 ml of physiological solution between 30-60 minutes prior to transplantation; and c) Incorporate into the receptor, an active substance of alpha lipoic acid (ALA) comprised in amounts between 400 to 1000 mg, preferably 600 mg diluted in
  • Figure 1 shows the patients with liver transplantation of the Rama Control and Rama treated with ALA groups who suffered or not having post-reperfusion (SPR).
  • Figure 2 shows the relative expression in biopsies of liver transplanted patients that receives an organ perfused with ALA and whose recipient has received ALA.
  • Figure 3 shows the plasma levels of SLPI and PAP in liver transplant patients. Liver transplanted patients receive perfused organs (RT Group) or not with ALA (RC Group).
  • Figure 4 shows that patients with simultaneous reopancreatic transplantation who receive an organ perfused with ALA and whose recipient has received ALA have lower early graft dysfunction, greater graft and patient survival compared to untreated patients.
  • Figure 5 shows the relative expression of inflammatory mediators in renal and pancreatic biopsies of renopancreatic transplanted patients treated with ALA.
  • Figure 6 shows the cytokine plasma levels in renopancreatic transplanted patients measured in samples obtained in the pre-transplant (Pre-Tx) and 12 h post-transplant.
  • Figure 7 shows the plasma levels of PAP (pancreatitis indicator protein) and SLPI in pre-transplant renopancreatic transplant patients, immediately after the act surgical (time 0 h post-Tx) and 12 hours after transplantation in group C, R and DR.
  • PAP pancreatitis indicator protein
  • Figure 8 shows the plasma levels of amylase, lipase, glucose, creatinine and urea.
  • Figure 9 shows the% of DGF, the dialysis requirements and the hospitalization time of the patients receiving kidneys perfused with ALA and are treated with ALA during the first post-transplant days.
  • this syndrome is evaluated within the operating room as persistent hypotension (TA> 30% the values of the anhepatic phase), asystole or arrhythmias that trigger hemodynamic instability, with the need for continuous infusion of vasopressors. Appearance of prolonged (more than 30 minutes) or recurrent fibrinolysis (reappearance of fibrinolysis 30 minutes after it has been resolved).
  • qPCR was performed on biopsies of liver transplant patients from the RC (control) and RT (treated) group.
  • the graph shows the relative expression of mRNA (2 L (- AACt)) in the biopsies of the RT patient group vs the biopsies of the RC group. Data are represented as the mean ⁇ SD * p ⁇ 0.05. Mann-Whitney test. It is observed that the levels of the transcripts of Birc2, Sestrin2, IkBa, HIF-1 a, GATA3, CCR1, IL-6 and IL-8 were similar in both groups of patients. Higher levels of SLPI were also observed in the biopsies of treated patients, although this difference was not statistically significant. However, the levels of PHD1 and 2 and REG3a / PAP transcripts were significantly lower in the treated group (RT) compared to those in the RC group, indicating that perfusion of the organ with ALA protects it from hypoxia suffered during surgical procedure.
  • the data is represented as the mean ⁇ SD in (A) and (B). * p ⁇ 0.05.
  • SLPI alarmine Another of the proteins analyzed in the plasma of the transplanted patients was the SLPI alarmine. An expression pattern similar to that of PAP can be observed in the Figure; that is, only patients in the DR group presented significantly lower levels of SLPI, at 12 hours after surgery, compared to the levels found at 0 hours, suggesting that both proteins, being proteins of acute phase, they would be indicating that the treatment with ALA generates an environment with a lower degree of damage of the organism during the transplant.
  • SRP kidney-pancreas transplantation
  • the patients included were people between 18 and 65 years of age, recipients of SRP transplants. All patients received as induction therapy Timoglobulin (1.5 mg / kg for five days) and Solumedrol; and as maintenance therapy a triple immunosuppression (tacrolimus with levels of 10-12 ng / ml, prednisone 4 mg / day and mycophenolate sodium 1,440 mg / day).
  • the patients were randomly divided into three groups: 1) Control: patients who were not treated with ALA; 2) R-ALA: patients who were given a dose of ALA (600 mg) immediately before the surgical procedure; and 3) DR-ALA: patients who in addition to receiving a dose of ALA (600 mg) immediately before the surgical procedure, such as the group Previously, they also received organs from cadaveric donors who were given ALA (600 mg) at the time of procurement.
  • the objective of the administration of ALA was to reduce the unfavorable effect of the EROs that occur throughout the process known as IRI, which begins in the donor and continues in the recipient. This experimental design of comparing the DR-ALA group with the R-ALA group was aimed at unraveling the impact of EROs that occur during the different stages of the IRI process.
  • the treatment of the cadaveric donor was performed just before the procurement procedure, by intravenous drip (20 min) of 600 mg of ALA diluted in 250 ml of saline solution at the beginning of the ablation process, which has a total duration of approximately 90-120 minutes.
  • the choice of dose administered to donors was based on the work of Dunschede et al and Muller et al, with humans and rodents, respectively [10,1 1].
  • this dose is the dose approved by our local regulatory authorities to treat diabetic neuropathy.
  • the administration of said antioxidant is considered part of the normal organ extraction process, and therefore, no informed consent was necessary beyond that associated with organ donation.
  • the organs were stored cold until transplantation.
  • Blood samples for obtaining plasma and measuring mediators are acquired at the beginning of the surgery, after blood unlocking, 12 hours after surgery and every one or two days after transplanting for at least 14 days or until patient discharge These samples served, not only for the measurement of inflammatory mediators, but also as part of the routine determination of analytes to assess renal and pancreatic function.
  • kidney and pancreas biopsies were taken at the end of the surgery to perform a RT-qPCR study.
  • Plasma levels of IL-8, IL-1, IL-6, IL-10, TNF- ae IL-12p70 were measured in the sample before surgery and at 12 h after transplant using the “BD TM Cytometric Bead Array” kit (BD Biosciences, San Jose, CA), following the manufacturer's instructions. Both the samples and the standard curve were incubated with these reagents and then passed through a FACSCalibur flow cytometer for detection. Data analysis was carried out using FCAP Array software. Plasma SLPI levels were determined using a sandwich ELISA.
  • a human anti-SLPI mouse monoclonal antibody (1 pg / ml, R&D) was adhered to the surface of 96-well plates (high peptide binding) for 18h at 4 ° C. The plate was then blocked for 1 h at 37 ° C with 0.5% bovine serum albumin (Sigma) and 1% low-fat milk in 1 X PBS (blocking solution). Subsequently the wells were washed with 0.1% PBS / Tween 20 and the plasma and standard samples were incorporated; these were preserved for 1 h at 37 ° C. Once the incubation time was over, the second human anti-SLPI rabbit polyclonal antibody in blocking solution (1/1000) was added, leaving 1.5 h at 37 ° C.
  • bovine serum albumin Sigma
  • 1 X PBS blocking solution
  • mRNA purification was carried out using the RNeasy Mini Kit (QUIAGEN). With the biopsies a dry homogenate was performed using liquid nitrogen. This was resuspended in RLT Plus lysis buffer by using needles of different caliber for better degradation. A 3 min centrifugation was performed at 10,000 rpm. The supernatant was passed through a gDNA eliminator column (30 sec at 10,000 rpm). 70% ethanol was added to the eluate and 0.7 ml was transferred to the RNeasy column. After centrifugation (15 sec at 10,000 rpm), the eluate was discarded and the column was washed with RW1 buffer. RPE buffer was added to the column, and washed twice (15 sec and 2 min at 10,000 rpm).
  • RNA-free water was added to the column, centrifuged 1 min at 10,000 rpm and the eluate was recovered. Quantification was performed using a Nanodrop device, purity was determined by analyzing the relationship between absorbances at 260 and 280 nm. Then cDNA was obtained, using a kit "RT2 First Strancf '(QIAGEN). For this, the 50 ml obtained from RNA was centrifuged 15 sec.
  • the gDNA elimination mixture was prepared for each sample to which 700ng of RNA was added reaching a final volume of 10 ml. It was centrifuged and incubated at 42 Q C for 5 min, immediately he passed ice and allowed 1 min.
  • the RT Cocktail was prepared (according to protocol). A mixture of gDNA elimination was added 10ml Cocktail RT, incubated for 15 min at 42 Q C, and the reaction was stopped by heating at 95 Q C for 5 min. Finally, 91 ml of distilled water were added.
  • the kit used was that of SYBR GreenER qPCR SuperMix Universal (Invitrogen).
  • a Master mix was prepared for each gene, with SYBR Green, ROX reference, 5 'primer, 3' primer and ultra pure water. To 22.5 ml of each master mix was added 2.5 ml of each sample.
  • the instrument used for qPCR was a Corbett Research Rotor-Gene 6000 (QIAGEN, Valencia, CA). The cycling program used was: 5min at 50 ° C; 45 cycles of 10 seconds at 95 ° C, 15 seconds at 60 ° C and 20 seconds at 72 ° C. The specificity of the primers was checked with post-amplification agarose gel and by melting curve.
  • the data analysis was based on method 2 A (-AACt) with the normalization of the raw data in relation to the expression levels of the control gene, in this case GAPDH.
  • the primers of each gene were designed and evaluated by our research group.
  • the transplanted patients were evaluated to determine the renal and pancreatic function, defining renal dysfunction as a decrease in creatinine less than 70% of baseline creatinine on the seventh day post-transplant or the need for hemodialysis during the first week.
  • Clinical pancreatitis was defined as a clinical state of abdominal distension, abdominal pain, graft swelling and the need for rest of the pancreas with total parenteral nutrition. This diagnosis was made independently of this study by the doctors who were in charge of the patient and was recorded in the patient database. Survival of both the graft and the patient at 3 months post-transplant was also evaluated to determine the impact of these first events on the evolution of the transplant.
  • Liver Transplant
  • the median MELD value (which is a prognostic index used to assess the severity of liver failure) of the population was 24 points and there were no differences between the two groups.
  • Control and Treaty Of the total patients included, 13 belonged to the treated group (treated with a-lipoic acid) and 10 to the control group.
  • the administration of the drug or placebo was carried out as follows according to the group:
  • Treated Branch Donors, before the onset of cold ischemia, were given an infusion of ALA (600 mg in 50 ml of NaCI for 5 minutes) through the portal vein in order to administer it directly to the graft. Subsequently, once the transplant was carried out and prior to reperfusion, the ALA infusion into the recipient was administered by the portal vein. Then, the removal and reperfusion were carried out.
  • ALA 600 mg in 50 ml of NaCI for 5 minutes
  • Control Branch instead of ALA, both donors and recipients received the same volume of physiological solution as the treated group.
  • Induction treatment consisted of corticosteroids during surgery and Basiliximab in intensive therapy, repeating the dose of Basiliximab at 4 days.
  • Maintenance therapy consisted of: steroids (meprednisone) in decreasing doses, Tacrolimus (Prograf) and Mofetil Mycophenolate.
  • the amplification and detection of cDNA in the quantitative real-time PCR was carried out using the GoTaq® qPCR Master Mix reagent, in a 96-well format in a Stratagene Mx 3000P device.
  • the cycling program was: 95 Q C for 2 min, 40 cycles at 95 Q C for 15 seconds and 60 Q C 45 seconds. Finally, a cycle of 1 minute at 95 Q C, 30 seconds at 55 Q C and 30 seconds at 95 Q C.
  • the primers used were designed and checked by the research group. The specificity was evaluated by melting curve and run on agarose gel from the result of post-qPCR amplification. The analysis of the result was carried out by method 2 A (-AACt), using 28S as the control gene. Reg3a / PAP and SLPI levels were determined in the same manner as for simultaneous renopancreatic transplants.
  • kidney to be transplanted was perfused with a Wisconsin solution containing 600 mg of ALA (diluted in 500 ml of physiological solution) between 30-60 minutes prior to transplantation.
  • Patients in the control group only received 1 vial of vitamin B (Bagó B1 B6 B12 or Becozym) intravenously prior to the surgical procedure of renal transplantation.
  • vitamins B Bagó B1 B6 B12 or Becozym
  • induction treatment patients received ATG + MMF + Corticosteroids.
  • control group C
  • RT-qPCR was performed to determine the mRNA expression of inflammatory mediators involved in ischemia-reperfusion damage in renal and pancreatic biopsies of group C and DR.
  • transcript levels of C3, TNF-a, TGF-b, FIMOX-1 were analyzed.
  • the surgical act represents a traumatic process, causing an increase in acute phase proteins.
  • acute phase proteins and in the case of renopancreatic transplants, a protein called Reg3 / PAP stands out, whose expression increases more than 200 times during pancreatitis. For this reason, we decided to determine the plasma levels of this secretory protein in the plasma of patients treated with ALA. In all groups, the plasma PAP level measured at the end of the surgery (time 0 h post-transplant) was found to be increased in relation to the levels found in the pre-transplant (Figure 7A).
  • pancreatitis When the presence of clinical pancreatitis was evaluated, 3 cases of pancreatitis were diagnosed in the control group, one in the DR group and none in the R group ( Figure 4). Then, a three-month clinical follow-up was performed to evaluate more stringent clinical parameters such as graft and patient survival. Although the number of patients recruited and the time elapsed were very low, it was observed that there was a lower survival rate of the graft and of the patients in the control group compared to the treated groups ( Figure 4). With these results we can determine that the use of ALA did not affect graft function, nor did it prove to be a risk for graft and patient survival. Quite the contrary, some biochemical and gene parameters indicated that the administration of ALA has some beneficial effect for the graft and for the patient, at least in the short term.
  • SRP post-reperfusion syndrome
  • HMOX-1 hypothalamic hormone-1
  • Several studies have described the beneficial effects of this antioxidant molecule in various animal models of IRI [14] ⁇ Highly in the kidney, a high expression of HMOX-1 seems to be associated with a poor prognosis, it should be noted that in the study of inflammatory mediators in DGF patients describe an increase in the expression of said molecule, in line with the literature [14,15].
  • the positive regulation of HMOX-1 can prevent fibrosis by inhibiting the proliferation of pancreatic starry cells, so that the result obtained in said organ would be beneficial [16].
  • the overall effect observed in the biopsies of the DR group compared to the untreated group clearly indicates a beneficial effect of AAL in the donor.
  • Donor preconditioning to reduce IRI is not a new concept [17,18].
  • treatment with steroids or administration of the soluble ligand of P-selectin to the donor with brain death increased receptor survival compared to the untreated group [18].
  • steroid treatment to the cadaveric donor reduced the expression of proinflammatory cytokines [19].
  • the DR group had a reduced expression of IL-8 and IL-6, but not the R group.
  • IL-10 considered an anti-inflammatory cytokine, showed no significant differences in any group. treaty.
  • pancreatitis Another of the markers analyzed to evaluate the efficacy of the treatment was the protein associated with pancreatitis (PAP). This protein has been detected in post-transplant pancreatic juice [21, 22] and was described as a good serum marker for pancreatic injury [23]. In patients who were treated with ALA and in turn received grafts treated, the plasma levels of PAP 12hs post-transplant were lower than that of patients who received untreated grafts and were treated with ALA at the time of surgery. On the other hand, the same pattern could be observed for the SLPI alarm. In fact, a strong direct correlation was observed between PAP and SLPI.
  • liver transplantation there is a high morbidity and mortality in the immediate post-transplant period, with severe complications due to IRI.
  • the patients were divided into a control group and a treated group (where the organ received twice the administration of ALA, as in the DR group of the renopancreatic protocol).
  • the kidney also suffers consequences in the immediate post-transplant period characterized by the so-called DGF. Therefore, it was logical to start with another clinical trial in renal transplantation to observe the effect of ALA administration. However, for this protocol it was not possible to administer ALA to the donor, but the drug could be perfused to the organ to be transplanted in the operating room, prior to transplantation.
  • the preliminary results so far obtained with ALA in renal transplantation could not demonstrate a beneficial effect on the appearance of DGF, but it could be noted that the patients of the Control Branch needed more dialysis sessions, to maintain homeostasis, compared with the active branch.
  • the results obtained from the study show that the use of ALA reduces inflammation mediators.

Abstract

La présente invention concerne un composé et un procédé pour optimiser la transplantation des organes solides vascularisés et réduire le dysfonctionnement de ces derniers, le composé contenant de 400 à 1000 mg d'acide alpha lipoïque (ALA), de préférence 600 mg de ALA et l'administration de ALA, au traitement habituel de l'immunosuppression, la perfusion du greffon avant la transplantation et au récepteur dans les deux premiers jours après la transplantation pour réduire le temps de récupération fonctionnelle du greffon et améliorer les paramètres cliniques des patients à court terme, des patients soumis à des transplantations rénopancréatiques, rénales et hépatiques.
PCT/CL2018/050009 2018-02-12 2018-02-12 Composé et procédé pour optimiser la transplantation des organes solides vascularisés et réduire le dysfonctionnement de ces derniers WO2019153099A1 (fr)

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EP0812590A2 (fr) * 1989-11-09 1997-12-17 ASTA Medica Aktiengesellschaft Utilisation de l'acide R-alpha lipoique comme cytoprotecteur
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Publication number Priority date Publication date Assignee Title
EP0812590A2 (fr) * 1989-11-09 1997-12-17 ASTA Medica Aktiengesellschaft Utilisation de l'acide R-alpha lipoique comme cytoprotecteur
CA2446573A1 (fr) * 1996-09-13 1998-03-19 Osteotech, Inc. Implant chirurgical contenant un marqueur radio-opaque resorbable

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