• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Aqueous crystalloid solution isotonic between those containing na, k and cl2 and use thereof as a vasodilator. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2651717A1
    申请号:ES201631021
    申请日:2016-07-26
    公开日:2018-01-29
    发明作者:Shander ARYEH；Lara OLLER DUQUE
    申请人:Lara OLLER DUQUE；
    IPC主号:
    专利说明:

    DESCRIPTION

    Isotonic crystalloid aqueous solution

    The present invention relates to an isotonic crystalloid aqueous solution. 5

    Background of the invention

    Hemorrhagic shock is a very important cause of mortality, the administration of crystalloid solutions can reduce the severity and duration of shock. 10

    Different compositions are known that can be used in cases of blood loss as a substituent thereof.

    For example the document of Dubick M.A. et al, “Hypotensive resuscitation of casualties in 15 the far forward combat environment: effects of select crystalloids and colloids on signal transduction mediators in a swine model of severe hemorrhage” published in Selected topics in electronic and systems (2006); Vol. 42: 394-400, describes three solutions, one of them colloid, Hextend, another HBOC (hemoglobin-based oxygen carriers), polyHeme and another, crystalloid. These solutions do not contain nitrate ions in their composition. twenty

    In the paper by Ozkän et al "Comparison of the effect of hypertonic saline and crystalloid infusions on haemodynamic parameters during haemorrhagic shock in dogs" published in The Journal of International Medical Research, 2001, vol. 29: 508-515, a comparative trial on the efficacy of two crystalloid solutions in the recovery of dogs subjected to hemorrhagic shock is described. The crystalloids compared are, on the one hand, a Ringer lactate solution, as a standard treatment and on the other hand, a hypertonic saline solution consisting of a 7.5% saline solution of sodium chloride. None of the solutions described contain nitrate ions.
     30
    It would be interesting to develop a new aqueous solution that achieves better results than the known solutions.

    Description of the invention
     35
    The present invention describes an isotonic crystalloid aqueous solution with the presence of
    nitrate ions or nitrite ions or mixture of them.

    In the present description "crystalloid aqueous solution" refers to a solution of ionic solutes that is used to replenish liquids, mainly blood, which does not present colloid osmotic pressure per se. 5

    When the present invention refers to isotonic solutions, it refers to solutions where the osmolarity in said solution is similar to that of the extracellular fluid of the body, preferably blood, and does not alter the volume of blood cells.
     10
    A first aspect of the invention relates to an isotonic crystalloid aqueous solution comprising Na + ions in a range between 50 and 200 mmol / L, K + ions in a range between 0.1 and 10 mmol / L, Cl- ions a range between 50 and 200 mmol / L that has nitrate ions or nitrite ions or mixture thereof in a range between 0.0001mmol / l and 1mmol / L. fifteen

    The solution of the present invention does not alter the osmotic balance of the cells.

    An advantage of the presence of nitrate ions or nitrite ions or mixture thereof, is that when the solution is perfused to a mammal, these ions partially degrade to nitric oxide, which produces a vasodilation effect at the capillary level that allows better perfusion and oxygenation of tissues. For example, this can be very useful in recovering subjects who are suffering from hemorrhagic shock.

    Blood has been the fluid traditionally used to treat those patients who have suffered a massive loss of it with an impact on microcirculation and secondary metabolic dysfunction, but it presents risks and is not always effective. The solution of the invention allows the microcirculation to be restored thanks to the presence of nitrates or nitrites that after their infusion into the systemic circulation become nitric oxide (NO), thanks to the nitrate-nitrite-nitric oxide route as set forth in multiple Scientific dissemination articles 30 such as Sruti Shiva's "Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function" paper published in Redox Biology 1 (2013) 40-44 or Eddie Weitzberg et al. Titled “Nitrate-Nitrite-Nitric Oxide Pathway. Implications for Anesthesiology and Intensive Care ”published in Anesthesiology 2010; 113: 1460-75. The generation of nitric oxide in a context of capillary dysfunction, allows the restoration of the collapsed capillaries, preserving perfusion and therefore, oxygenation of tissues.
    Therefore, the solution of the present invention is capable of generating nitric oxide, restoring the microcirculation without deterioration on the macrocirculation, or toxic effects.

    A second aspect of the invention relates to the solution of the invention for use as a medicament. 5

    A third aspect of the invention relates to the solution of the invention for use as a vasodilator.

    The solution described in the present invention is preferably useful in cases of hemorrhagic shock or acute normovolemic hemodilution.

    Therefore another aspect of the present invention is the solution of the invention for use in the treatment of hemorrhagic shock or in acute normovolemic hemodilution.
     fifteen
    Finally, another aspect of the invention is the solution of the invention for use as an intravenous replacement fluid.

    Description of a preferred embodiment
     twenty
    In a preferred embodiment of the first aspect of the invention, the solution further comprises Mg2 + in a range between 5 and 20 mmol / L.

    In a second preferred embodiment of the first aspect of the invention the solution comprises Ca2 + ions in a range between 1 and 10 mmol / L. 25

    In a third preferred embodiment of the first aspect of the invention the nitrate ions or nitrite ions or mixtures thereof is in a range between 0.0001 mmol / L and 0.06 mmol / L. More preferably between 0.001 mmol / L and 0.06mmol / L.
     30
    Preferably the pH of the solution is between 5 and 10. More preferably between 7 and 9. In a particular embodiment the pH of the solution of the invention is 8.2. In a particular embodiment, the solution of the invention has a solubility coefficient of 0.006ml O2 / mmHg pO2 in a plasma dl at 36 ° C.
     35
    In a more preferred embodiment the aqueous solution of the invention has metals
    Selected from: Li, be, B, Al, Si, P, Sc, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Br, Rb, Sr, Y, Zr, Mo, Pd, Ag , Sn, Sb, I, Cs, Ba, Ce, Au, Tl, Pb, Bi, Th and U.

    Examples
     5
    In the examples, the solution of the invention, Plasmalyte and fresh whole blood (less than 20 days of storage) was used. The compositions of the solutions used are shown below.

    Table 1 shows the composition of the solution of the invention used in the tests. 10

     mmol / L
     Na +  128.51
     K +  2.7
     Mg2 +  12.32
     Ca2 +  3,082
     Cl-  164
     SO4-2  6.47
     HCO3-  0.836
     NO3-  <0.0484

    Table 2 shows the composition of the Plasmalyte solution used in the examples (data extracted from Lira et al. Ann Intensive Care, 2014).
     fifteen
     mmol / L
     Na +  140
     K +  5
     Mg2 +  1.5
     Cl-  98
     Acetate  27
     Gluconate  2. 3
     Osmolority  294
    The examples were made with pigs. All animals are of the same genetic crossing, all females and in a specific weight range. The protocol consists in the extraction of between 40-60% of the estimated vollemia according to calculations (volemia is on average 7%
    of weight) to take them to a lactic acid greater than 5 mmol / L that correlates with a tissue oxygen debt of 75.2 mL / kg or greater according to Rixen et al in their article “A pig hemorrhagic shock model: oxygen debt and metabolic acidemia as indicators of severity ”. Since the circulating volemia of each animal ranges from 55ml / kg to 74 ml / kg and the volume of extraction is not as decisive as the speed in which it is extracted and the tolerance of the animal to hypoxia, we aim to reach a degree of tissue oxygen debt indicated above. Then a volumetric replacement was performed with the solution of the invention (the volume of blood drawn was infused three times (ratio 3: 1), and lactic acid washing was measured in the minutes after replacement (T0 = just after replacement) , T15 = 15 minutes after replacement, T30 = 30 minutes after replacement, T1h = one hour after 10 replacement, T2h = two hours after replacement) and the intestinal microcirculation was analyzed with a micro scan paying special attention to the proportion of perfused capillaries expressed as a percentage (small PPV: proportion of perfused small vessels, in Spanish proportion of perfused capillaries%).
     fifteen
    During the shock a fall of the PPV was observed and about 60 minutes after the replacement a 100% PPV was observed in all the measured areas, demonstrating the ability of the solution of the invention to open those capillaries collapsed during the hemorrhagic shock and do it in a homogeneous way.
     twenty
    Likewise, this quantitative analysis of the microcirculation was accompanied by an efficient lactic acid wash that is the clinical expression of what was seen in the microcirculation.

    Lactic levels of up to 10 descend to 4 mmol / L in two hours and in a short time 25 more, lactic acid was taken in the normal range. At 24h, 48h and 72h the animal is standing, eating, eliminating feces and urinating, with good oxygenation and ventilation, with a lactic inferior or equal to the baseline in all measurements and ions in range.

    A negative control group was added with one of the crystalloids that is commonly used in practice, Plasmalyte®. An isotonic and balanced solution. The animal was taken to a Lactic acid greater than 5 mmol / L as the established protocol and subsequently the Plasmalyte infusion was performed (ratio 3: 1). Lactic acid remained elevated during the 2h of observation and at 3h it was still at 6 mmol / L.
     35
    This result already shows a clear difference with respect to the solution of this
    invention.

    At the microcirculation level there were areas with 17% PPV explaining why lactic levels did not decrease as observed with the solution of the present invention. At 24h the animal was standing, with little appetite and marked weakness. The attention was drawn by an inspiratory stridor, with respiratory difficulty and abdominal circulation. In auscultation there was a marked bilateral hypophonitis. In arterial blood gas, the oxygen saturation by hemoglobin was 89% and the pO2 was 60 mmHg with an oxygen flow of 5 liters. All this seemed to indicate that the animal was suffering from acute lung edema. After sacrificing the animal, samples were taken from different organs; At the intestinal level, 10 loop edema was observed, not being so in the solution group of the present invention and in the whole blood group. The superiority of the solution of the present invention with respect to Plasmalyte® is clear. Lactic acid at 24 hours remained above the basal lactic acid being a clear indicator that the restoration of microcirculation was not achieved. fifteen

    The solution of the present invention was compared with the transfusion of fresh whole blood (less than 20 days stored at 5 ° C) applying a 1: 1 ratio that would be the ideal treatment for these cases of hemorrhagic shock. The results were similar in terms of the analysis of microcirculation and lactic acid washing. During the hemorrhagic shock, the 20 PPV dropped and after the resuscitation with blood we reached a PPV of 100%, not being so in all the measured areas, in some cases a 50% PPV persisted at the hour being normal at 2 o'clock. The lactic exceeded 5 mmol / L and also returned to normal in just over two hours. The animal looked good at 24 hours, the oxygenation and ventilation data were adequate, it was eating, eliminating feces, urinating and with good respiratory dynamics.

    Draws attention to the non-inferiority of the new crystalloid with respect to fresh whole blood in relation to microcirculation. The results have not been isolated cases, but have been repeated successively in each and every one of the animals included in the trial.



     35



    Table 3 shows the results in an animal treated with the solution of the invention. 32 kg animal with an estimated volume of 2,200 mL. 40% of the volume is removed by exceeding the threshold of a lactic acid of mmol / L. 5

     Baseline 25% Extraction 40% Extraction Shock T0 T15 T30 FiO2 0.6 T1h FiO2 0.8 T1h FiO2 1
     TAM  72 52 34 33 59 55 50 55 50
     HR / rhythm  83 RS 172 RS 194 220 147 142 150 140 150
     SpO2  100 100 100 Does not capture 100 100 100 100 100
     EtCO2  33 30 26 24 35 35 33 32 30
     FiO2 / PEEP  0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.6 / 5 0.8 / 5 1/5
     pH  7.49 7.37 7.28 7.179 7.23 7.29 7.35 7.34 7.38
     EB  3 3.1 -1.2 -11.4 -8.7 -7.9 -5.5 -3.7 -4.8
     HCO3  26.3 26.2 21.6 16.4 18.4 19 17 21.5 20.6
     pCO2 A / V  33.4 / 39.8 / 54 23.8 / 40.6 / 47.9 38 / 46.9 35.4 / 43.9 36 / 42.7 34.1 / 43.7
     PO2  191 206 215 360 368 520 550
     Na / K  137/4 135 / 4.7 131 / 5.6 129 / 5.5 134/4 133 / 4.3 133 / 4.4 136 / 4.4 133 / 5.1
     Ca2 + / Cl  1.36 1.39 / 99 1.38 / 95 1.31 / 100 1.63 / 112 1.60 / 112 1.54 / 112 1.55 / 113 1.50 / 111
     Hb / Hto  9.5 11.9 12.4 12.2 5.7 5.8 5.3 4.4 5.8
     Lac  2.5 2.9 5.7 6.6 4.1 3.5 3.1 2.4 1.5
     SatvcO2 OER  79.5 64.5 12.2 12% 67.7 66.6% 74.8% 80.6% 53.6%
     Pvc  5 3 4 4 7 5 6 6 6
     MetHb  1.6% 1.7% 3.4% 1.3% 2.4% 2.9 2.5% 1%
     Cl  9.1 3.5 3.5 3 8 8.7 6.5 7.6 4.5
     VVS%  11% 18% 26% 24% 27% 24% 26% 24 24%
     RVYes  554 1262 727 784 473 442 553 456 704
     VSi  108 20 18 19 55 55 43 53 30
     Tª  35.4 35.4 35.2 35.1 35 35 35 34.7 34.5
     PPV intestine (%)  100 100 100 70 100 100 100 100 100
     rSO2 brain / skeletal muscle     56/54 56/50 54/47 51/38 59/55 59/56 59/56 61/58 60/56
     Diuresis                          300cc

    TAM: mean blood pressure
    HR: heart rate
    SpO2: peripheral oxygen saturation
    EtCO2: CO2 expiratory tidal 5
    FiO2: inspired oxygen fraction
    PEEP: pressure at the end of expiration
    EB: excess bases
    Hb: hemoglobin
    Hto: hematocrit 10
    SatvcO2: central venous oxygen saturation
    PVC: central venous pressure
    MetHb: methemoglobin
    IC: cardiac index
    VVS%: variation of systolic volume expressed in% 15
    RVSi: indexed systemic venous resistance
    Vsi: indexed systolic volume
    PPV: proportion of perfused capillaries expressed in%
    rSO2: regional tissue oxygen saturation. The first number refers to the cerebral and the 2nd to the muscular 20
    Diuresis: amount of urine expelled by the animal at the end of the procedure
    RS: sinus rhythm

    The oxygen solubility coefficient in the solution of the invention was measured at 36 ° C, said coefficient is 0.006 mLO2 / mm Hg O2 / dl. When compared with the coefficient of 25 solubility of oxygen in Plamalyte® which is 0.0041 mLO2 / mm Hg O2 / dl and with the coefficient of solubility of oxygen in blood plasma (undiluted) which is 0.0031
    mLO2 / mm Hg O2 / dl all measured at 36 ° C, it was verified that the solubility coefficient of the solution of the invention is superior to them, this being advantageous since it demonstrates the ability of oxygen to dissolve in the solution and thus optimize oxygen dissolved.

     Baseline 25% extraction 55% extraction Shock T0 T15 T30 FiO2 0.6 T1h FiO2 0.8 T1h FiO2 1
     TAM  62 32 33 34 51 43 46 47 48
     HR / rhythm  98 Rs 179 RS 202 rs 200 rs 172 rs 184 192 202 197
     SpO2  100 100 No No 100 100 100 100 100
     EtCO2  34 31 26 23 46 40 39 39 40
     FiO2 / PEEP  0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.6 / 5 0.8 / 5 1/5
     pH  7.56 7.56 7.499 7.46 7.6 7.35 7.33 7.36 7.39
     EB  8.7 6.3 -0.8 -4.7 0.7 -0.1 -0.4 -0.1 1.9
     HCO3  31.8 29.8 24 21.1 26.2 24.4 24.2 23.4 25.9
     pCO2 A / V  33.9 / 43.5 31.1 / 45.6 28.8 / 46.3 26.6 / 54.2 22.4 / 57.2 45/54 47.8 / 54.2 43.6 / 55 , 2 43.7 / 54.5
     PO2  204 199 174 149 150 161 237 328 462
     Na / K  138 / 4.1 137 / 5.1 135 / 6.9 135 / 7.6 140/4 140 / 3.4 141 / 3.9 140 / 3.7 139 / 4.1
     Ca2 + / Cl  1.34 / 100 1.38 / 101 1.33 / 102 1.33 / 102 0.84 / 99 1.14 / 99 1.16 / 99 1.19 / 100 1.28 / 99
     Hb / Hto  9.5 / 29 10.8 / 33.1 12.4 12.7 / 38.8 4.9 / 14.9 8.8 / 27 8.5 / 26.1 8.3 / 25.4 8, 5/
     26.2
     Lac  1 1.7 5 7.3 5.9 6.7 7.6 7.4 5.8
     SatvcO2 OER  54.6 45.2 15.4 13 63.7 51.7 52.9 58.7 60.7
     Pvc  5 5 4 7 6 6 5 4 6
     MetHb  1.9% 1.6 -0.9 0.9 -0.4 1.1% 0.5 3.3
     Cl  10.2 2 15.2 8.4 9.2 7.9 3.7
     VVS%  18 26 32 25 31 26 31 30
     RVYes  449 1225 171 370 369 438 387
     VSi  101 11 29 81 43 47 41 30
     Tª  35.2 35.6 35.9 35.5 35.6 35.8 35.9 36.2
     PPV intestine (%)  100 100 95 95 62 87 100 72 97
     rSO2 brain / skeletal muscle  50/61 48/57 47/42 48/39 53/54 55/61 54/62 56/58 46/53
     Diuresis                          300cc
    Table 4 shows the results in an animal treated with Plasmalyte ®. Animal of 21 Kg, extraction of 55% of the estimated vollemia exceeding the lactic threshold of 5 mmol / L stipulated in the protocol.
    Table 5 shows the results in an animal treated with fresh whole blood 13 days old. Extraction of 60% of the blood volume exceeding the lactic threshold of 5 mmol / L.

     Baseline Extraction Extraction T0 T15 T30 T1h T2h FiO2 of 25% of 60% FiO2 0.6 FiO2 1 0.8 TAM 75 50 35 62 60 80 73 84 FC / rhythm 100 RS 163 Major 156 176 169 119 87 200 SpO2 100 100 No captures 100 100 100 100 100 EtCO2 31 32 33 43 41 39 35 34 FiO2 / PEEP 0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.4 / 5 0.6 / 5 0, 8/5 1/5 pH 7.48 7.515 7.46 7.329 7.4 7.41 7.49 7.53 EB 6.1 4.8 -3 -1.4 1.4 3.4 6.6 10 , 5 HCO3 29.5 28.3 22.4 23.2 25.6 26.7 29.9 33.9 pCO2 A / V 38.8 / 45.4 34.3 / 44.3 28.5 / 47 , 8 46.6 / 56.7 41.4 / 63 43.5 / 49.7 38.7 / 47 38.8 / 43.7 PO2 233 217 150 197 194 280 331 317 Na / K 138 / 4.6 135 / 4.9 131/6 136 / 4.7 137 / 4.7 137 / 4.5 137 / 4.4 136 / 4.6 Ca2 + / Cl 1.39 / 100 1.36 / 99 1.26 / 100 0.89 / 94 2.31 / 99 1.27 / 96 1.32 / 97 1.40 / 95 Hb / Hto 9.8 / 30 9.1 / 28 13 / 39.8 11.2 10.5 10.1 10.1 10.1 Lac 3.3 4.2 6.4 6.7 6.3 4.9 3.1 1.7 SatvcO2 OER 71.7% 49.5 33.7 77.3 89 , 5% 88.2% 79.2 PVC 7 4 3 4 6 7 6 7 MetHb 2% 1.4% 0.7% 1.1% 0.9% 0.8% 0.3% 1.3% Cl 7.3 3.8 3.7 13.3 16.2 11 10.7 8 VVS% 8% 14% 17% 10% 5% 8% 9% 10% RVSi 896 1029 1106 371 325 376 454 659 VSi 7 3 21 19 82 119 68 88 85 Tª 36 35.6 36 35.8 35.6 35.8 35.6 PPV intestine 100 100 92 67 79 95 100 100 (%) rSO2 brain / muscle 70/60 80/54 66 / 44 60/64 65/67 65/69 64/70 58/64 skeletal
























    The data shows that the solution of the invention has better results than the Plasmalyte solution. It is evident in terms of metabolic, hemodynamic management and clinical status of experimental animals. In comparison with fresh blood, it is also clear, its non-inferiority, which positions it in a very advantageous situation. It is important to note that the blood that was used for experimentation is fresh whole blood, less than 20 days of storage. The blood that is usually transfused to patients takes about 40 days of storage after fragmentation into the three main components of blood, platelets, red blood cells and plasma, excluding leukocytes. The blood that has been stored for about 40 days is called "old blood" whose biochemical and structural state is far from that of fresh blood. This has a great clinical impact since the stored blood undergoes a series of biochemical changes (decrease in ATP, decrease in 2.3 DPG, decrease in nitric oxide bound to HB) and morphological (transformation of erythrocytes to spheroequinocytes) causing This stored blood has a capacity to transport limited oxygen and far from restoring perfusion, makes it worse. fifteen
    权利要求:
    Claims (8)
    [1]

    1. Isotonic crystalloid aqueous solution comprising Na + ions in a range between 50 and 200 mmol / L, K + ions in a range between 1 and 10 mmol / L, Cl- ions in a range between 50 and 200 mmol / L characterized in that 5 has nitrate ions or nitrite ions or mixtures thereof in a range between 0.0001 mmol / L and 1 mmol / L.

    [2]
    2. Isotonic crystalloid aqueous solution according to claim 1 comprising Mg2 + ions in a range between 5 and 20 mmol / L. 10

    [3]
    3. Crystalloid aqueous solution according to any of claims 1-2 comprising Ca2 + ions in a range between 1 and 10 mmol / L.

    [4]
    4. Crystalline aqueous solution according to any of claims 1-3 of the range 15 nitrate ions or nitrite ions or mixtures thereof is between 0.0001 mmol / L and 0.06 mmol / L.

    [5]
    5. Solution according to any of claims 1 to 4 for use as a medicament.
     twenty
    [6]
    6. Solution according to any of claims 1 to 4 for use as a vasodilator.

    [7]
    7. Solution according to any of claims 1 to 4 for use in the treatment of hemorrhagic shock or in acute normovolemic hemodilution.
     25
    [8]
    8. Solution according to any of claims 1 to 4 for use as an intravenous replacement fluid.




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    RU2423987C1|2009-12-31|2011-07-20|Государственное образовательное учреждение высшего профессионального образования САНКТ-ПЕТЕРБУРГСКАЯ ГОСУДАРСТВЕННАЯ ХИМИКО-ФАРМАЦЕВТИЧЕСКАЯ АКАДЕМИЯ Федерального агентства по здравоохранению и социальному развитию |Infusion solution for total blood volume replacement, hydro-electrolytic rebalancing and hematopoiesis process normalisation|
    CN103989704A|2013-02-19|2014-08-20|B.布劳恩梅尔松根股份公司|Electrolyte water solution for transfusion|
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