WO2022018707A1 - Infusion solution comprising arginine hydrochloride and levocarnitine for treatment and prevention of diseases in pregnant women and promotion of fetal development during pregnancy - Google Patents
Infusion solution comprising arginine hydrochloride and levocarnitine for treatment and prevention of diseases in pregnant women and promotion of fetal development during pregnancy Download PDFInfo
- Publication number
- WO2022018707A1 WO2022018707A1 PCT/IB2021/056731 IB2021056731W WO2022018707A1 WO 2022018707 A1 WO2022018707 A1 WO 2022018707A1 IB 2021056731 W IB2021056731 W IB 2021056731W WO 2022018707 A1 WO2022018707 A1 WO 2022018707A1
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- WIPO (PCT)
- Prior art keywords
- drug
- arginine
- tivor
- levocarnitine
- fetal
- Prior art date
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- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 title claims abstract description 24
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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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
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Definitions
- the invention relates to the field of medicine, namely to the means for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
- Preeclampsia in pregnant women is a manifestation of either hypertension after the 20th week of pregnancy in a woman whose blood pressure was normal before, or an increase in hypertension that existed before the 20th week of pregnancy, or development of proteinuria, or both, and may be accompanied with the signs of other organs/systems impairment in the pregnant woman body.
- This disease affects both a mother and a fetus. The disease can result in the simultaneous manifestation of increased systemic vascular resistance, increased propensity of platelets to aggregate, increased activation of the coagulation system, as well as endothelial dysfunction.
- the method of treatment of preeclampsia in pregnant women depends on the degree of threat to the woman and fetus, the duration of pregnancy and the degree of the fetal development. It is recommended to use antihypertensive drugs and magnesium sulfate (see article titled DIAGNOSIS, EVALUATION AND MANAGEMENT OF HYPERTENSIVE DISORDERS IN PREGNANCY: BASIC CONCLUSIONS. Clinical Practical Guide of the Society of Obstetricians and Gynecologists of Canada, 2014//Reproductive Endocrinology.-2014.-N° 4(18).- P.74-85.). Drugs based on nifedipine, hydralazine, labetalol are used as antihypertensive drugs. In mild disease, at gestational age ⁇ 34 weeks, outpatient or hospital treatment is possible. However, careful monitoring of the pregnant woman and fetus is required.
- fetal distress is diagnosed according to the results of monitoring the fetal heart rate and recording of fetal cardiac abnormalities, compilation and analysis of its biophysical profile, observation of umbilical cord blood flow and record of umbilical cord blood flow disorders.
- - diabetic angiopathy occlusive vascular disorders in the placental area, microthrombosis
- umbilical factors umbilical cord prolapse and compression, the true node of the umbilical cord, umbilical cord entanglement
- the utility model patent of Ukraine UA 44055 U (description of utility model patent published on 10.09.2009) describes a method of treating antenatal fetal distress including the use of anticoagulants with a drug containing polyunsaturated fatty acids, 2 times a day, with meals, for 29-30 days.
- Intrauterine growth restriction syndrome is diagnosed in the fetus and neonates who have low birth weight or low body weight and height for their gestational age.
- the variety of causes determines the heterogeneity of the pathogenesis of intrauterine growth restriction syndrome.
- Intrauterine growth restriction can develop at different stages of the fetal development. Thus, low birth weight in a full-term neonate indicates that the factor that restricted the fetal intrauterine growth was acting during the last 2-3 months of pregnancy, but if at the same time there is a deficit in body length (below the 10th percentile for this period of pregnancy), then unfavorable conditions for the fetus developed in the II trimester of pregnancy.
- the first type of intrauterine growth restriction is called hypotrophic, the second - hypoplastic.
- hypotrophic type of fetal intrauterine growth restriction is severe toxicosis at the second half of pregnancy due to placental insufficiency, and for hypoplastic type is multiple pregnancy, familial low birth weight, adolescent mother, minor nutritional deficiencies without deep hypovitaminosis.
- Indications for the use of the known drug are coronary heart disease, acute myocardial infarction, and conditions after acute myocardial infarction, as well as angina.
- the known drug in the form of the infusion solution contains arginine and levocarnitine as active ingredients.
- Arginine is one of the main drugs in the treatment of coronary heart disease.
- substances of the so-called class of metabolic correctors such as inhibitors of oxidation of free fatty acids, which affect the activity of enzymes involved in biochemical reactions, are also widely used.
- levocarnitine also known as L-carnitine.
- Arginine (d-guanidine-a-aminovaleric acid) is a basic a-amino acid, the L- form of which is a semi-essential amino acid. Arginine interacts with SH groups (nitrate receptors) in vascular smooth muscle cells, including coronary arteries, to form nitric oxide (NO), which is similar in structure and action to ERF.
- SH groups nitrate receptors
- arginine dilates arterioles and peripheral veins, reduces total peripheral vascular resistance, reduces venous outflow, and dilates pulmonary vessels, which reduces resistance in the small circulation and leads to regression of the symptoms in case of pulmonary edema, and reduces end-diastolic pressure and ventricular volume, thereby reducing myocardial oxygen demand.
- Arginine also dilates the coronary arteries and prevents their spasm, reduces the diastolic tension of the ventricular wall, resulting in improved coronary blood flow in the ischemic area.
- Nitric oxide (NO) which is synthesized from L-arginine by the endothelium, is of great importance in maintaining adequate placental blood flow.
- Nitric oxide (NO) synthesized by endothelial cells, has been shown to be a regulator of vascular tone and an inhibitor of platelet aggregation. NO prevents the development of vascular spasm, improves microcirculation by relaxing vascular smooth muscle and improving of the blood rheological properties. Lack of NO leads to impaired microcirculation and contributes to the development of hypoxia, placental insufficiency, threatened abortion, intrauterine growth restriction and preeclampsia.
- L-arginine normalizes placental blood flow by restoring vascular tone and improving the blood rheological properties. This leads to the normalization of uterine tone, improved blood circulation in the umbilical artery and placenta, and intrauterine fetal growth.
- Levocarnitine is a natural substance synthesized in the body, related to B vitamins, thus, it is called a vitamin-like substance. In the human body it is present in the tissues of the striated muscles and liver. It is a factor in metabolic processes that support the activity of acetyl coenzyme A. Levocarnitine facilitates the entry of long-chain fatty acids into the mitochondria of cells, thus providing a substrate for oxidation and energy production, which significantly improves the restoration of heart muscle cells in myocardial infarction. Levocarnitine inhibits the formation of atherosclerotic plaques in blood vessels and promotes the resorption of the plaques that have already formed. Thus, due to its properties, levocarnitine reduces the contribution of the above factors, such as hyperlipidemia, high-calorie diet, obesity, diabetes, smoking, hypodynamia, and age, to the development of coronary heart disease.
- levocarnitine due to the function of levocarnitine, such as the transport of fatty acids (FA) through the membranes of intracellular organelles, they oxidize with the formation of the energy and "building materials" necessary for the development of the nervous system and the growing organism.
- FA fatty acids
- fatty acids are the main source of the energy because, unlike glucose, they can oxidize at low oxygen blood level, but require large amounts of levocarnitine. Therefore, the synthesis of levocarnitine and fetus need for levocarnitine is in increasing progression.
- FA oxidation occurs in the " ancient" organelles of the cell, such as oxisomes, peroxisomes, and later in the young ones, such as mitochondria.
- a very important, vital product of FA oxidation in hypoxia is the formation and accumulation of endogenous carbon dioxide in the blood of the fetus before the birth. Due to carbon dioxide, the neonate takes the first and all subsequent breaths in his life, because without it the access of oxygen from the air into the human body is almost impossible. In addition to the energy supply to the fetus, levocarnitine is involved in the most important processes of formation and development of the brain and spinal cord, as well as autonomic nervous system.
- neurotransmitter nerve impulse conduction
- acetylcholine performs acetylcholine functions, laying the foundations of neuromuscular reception, forming and "training" neurotrophic cholinergic (acetylcholine-controlled) structures, and parasympathetic nervous system.
- the object of the invention is to increase the effectiveness of the combination therapy (both treatment and prevention) of the diseases in pregnant women and fetal development during pregnancy, increase the effectiveness of the treatment of the fetal distress, reduce the number of neonates with intrauterine growth restriction, expand the range of drugs for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
- the object is achieved by use of an infusion solution comprising arginine hydrochloride and levocarnitine, wherein 1 ml of the solution for infusion comprise 42 mg of arginine hydrochloride and 20 mg of levocarnitine, for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
- the diseases of pregnant women and fetal development during pregnancy are preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction.
- the infusion solution is used to treat preeclampsia in pregnant women.
- the infusion solution is used for the prevention or treatment of fetal distress.
- the infusion solution for infusion is used to prevent intrauterine growth restriction.
- the infusion solution is used in the combination therapy of the diseases in pregnant women and fetal development during pregnancy.
- the infusion solution for infusion is used in the combination therapy of preeclampsia in pregnant women.
- the infusion solution for infusion is used in the combination therapy of fetal distress.
- the infusion solution for infusion is used in the combination therapy of intrauterine growth restriction.
- TIVOR-L drug which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution, for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy, in particular preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction, and the feasibility of such use, preclinical trial was conducted.
- the aim of the preclinical trial was to study the effectiveness of the known TIVOR-L drug, which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution, for the treatment and prevention of preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction.
- the trial design was as follows.
- preeclampsia According to a directive of the International Society for the Study of Hypertension in Pregnancy, clinical features of preeclampsia include severe hypertension after 20th week of gestation, proteinuria with or without edema and changes in laboratory parameters, as well as kidney, liver and brain impairment.
- NO nitric oxide
- Powerful NO vasodilator is synthesized from L-arginine by nitric oxide synthase (NOS).
- L-NAME N-nitro-L-arginine methyl ester
- TIVOR-L drug which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution;
- the first comparative drug which is a solution of arginine hydrochloride and contains 42 mg of arginine hydrochloride in 1 ml;
- the second comparative drug which is a solution of levocarnitine and contains 20 mg of levocarnitine in 1 ml;
- Group 1 included non-pregnant rats treated with saline (10 animals).
- Group 2 (negative control) included pregnant rats treated with saline (10 animals).
- Group 3 included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight (10 animals).
- Group 4 included pregnant rats administered with L- NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and the solution of arginine hydrochloride in the amount of 420 mg/kg of body weight (10 animals).
- Group 5 included pregnant rats administered with L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and the solution of levocarnitine in amount of 800 mg/kg of body weight (10 animals).
- Group 6 included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and TIVOR-L drug in the amount of 210 mg/kg of body weight on arginine basis, 0.5 ml/100 g of body weight (10 animals).
- Group 7 included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and TIVOR-L drug in the amount of 420 mg/kg of body weight equivalent on arginine basis, 1 ml/100 g of body weight (10 animals).
- Group 8 (L-NAME + TIVOR-L 840 mg/kg) included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and TIVOR-L drug in the amount of 840 mg/kg of body weight equivalent on arginine basis, 1.5 ml/100 g of body weight (10 animals).
- Pregnancy modeling using monitoring the animal estrous cycle and subsequent fertilization with the identification of the first day of fertilization based on the presence of sperm in the animal vaginal swab was performed before the trial.
- Pregnant and virgin nonlinear animals were housed individually in standard metabolic cells, which allowed urine to be collected, and food and water intake to be recorded throughout the trial.
- One arterial and one venous catheter were implanted on the 14th day of gestation (delivery days are 21 to 22).
- Group 4 Group 5, Group 6, Group 7 and Group 8 animals were administered with solution of arginine hydrochloride, levocarnitine, and TIVOR-L drug simultaneously with the start of administration of L-NAME solution, according to the above group scheme.
- Abnormalities of fetal developmental and fetal distress were assessed by weighing neonates and assessing neonatal mortality. Measurements of the average blood pressure of non-anesthetized animals that was not restricted in their movements were performed daily, at a fixed time, using an electronic manometer and a pressure transducer.
- kidneys Histological analysis of the kidneys was performed 4 days after the start of the solutions administration. The animals were anesthetized, and both kidneys were removed and weighed, the left kidney being treated for microscopic examination. The coronary sections of the kidneys were fixed in 10% formalin and imbedded into paraffin blocks. The sections (thickness 3 pm) were dyed. The sections were examined on a blinded basis for lesions of the glomerular zone.
- Preeclampsia is characterized by hypertension, proteinuria, as well as impairment of the kidneys and liver of the mother, and, consequently, possible abnormalities of the fetal development.
- body weight of the females receiving L-NAME (Group 3) was less than body weight of the pregnant animals in control Group 2 that received saline, which reflects a significant intrauterine growth restriction.
- mice treated with TIVOR-L in addition to L-NAME nitric oxide synthase blocker showed a significant increase in body weight, indicating normalization of the metabolic processes and impact on fetal weight restoration (see Table 1).
- L-NAME did not cause significant changes in water intake in pregnant rats compared with the animals in the negative control group (Group 2). Additionally, there was no significant difference between the animals in the control groups (Groups 2 and 3) and the animals in the groups that received arginine hydrochloride and levocarnitine (Groups 4 and 5), respectively, and the animals in the groups that received TIVOR-L (Groups 6, 7 and 8). However, with no significant difference in water intake for the pregnant animals of different groups, the animals receiving individual L-NAME (Group 3) demonstrated significantly decreased daily urination (see Table 1), compared with the pregnant animals receiving only saline (Group 2).
- the animals in the groups receiving TIVOR-L drug demonstrated a statistically significant restoration of the average urine volume compared with the Group 3 animals and the Group 4 and 5 animals, which may indicate normalization of the renal function due to lowering of the blood pressure caused by restoration of the blood nitric oxide level.
- the obtained data of mean systolic blood pressure (SBP) indicate the antihypertensive effect of arginine, levocarnitine and TIVOR-L drug.
- SBP mean systolic blood pressure
- the effect of TIVOR-L drug was more pronounced, compared with the similar effect of individual arginine and individual levocarnitine (see Table 1).
- the most pronounced pharmaceutical effect of TIVOR-L drug according to urine volume and mean systolic blood pressure is seen when administered in an amount of 420 mg/kg of body weight on arginine basis.
- the increase of TIVOR-L drug dose did not enhance the pharmaceutical effect.
- Kidney impairment is one of the main prognostic markers in preeclampsia progression.
- the animal kidney condition was analyzed by histological analysis, and by the level of proteinuria, namely by urinary albumin level. Inhibition of nitric oxide synthesis can cause glomerular capillary hypertension, which leads to sclerotic lesions of the kidney glomerular zone. Histological samples showed that the administration of L-NAME to Group 3 animals was accompanied by severe morphological changes in the kidney glomerular zone. Glomerular capillary lumens were segmentally occluded by intraluminal masses of eosinophilic composition. Extraglomerular lumens were filled with protein.
- NO is a very unstable molecule
- NO2- nitrites
- NO3- nitrates
- thrombocytopenia is associated with a preeclamptic condition due to increased aggregation and adhesion of platelets to the damaged endothelium.
- thrombocytopenia is associated with a preeclamptic condition due to increased aggregation and adhesion of platelets to the damaged endothelium.
- For Group 3 animals there was a statistically significant decrease in platelets in the blood as a result of the infusion of L-NAME. Decreased platelets indicate the onset of the so-called HELLP syndrome, which is caused by vascular endothelium impairment in preeclampsia.
- TIVOR-L administered to the animals with preeclampsia (Group 6, 7 and 8 animals) was found to lead to a statistically significant increase in fetal growth rates compared to Group 4 and 5 animals that received individual arginine and individual levocarnitine (see Table 4).
- TIVOR-L drug has the greatest embryoprotective effect, because, in addition to the restoration of the fetal body weight, which prevents intrauterine growth restriction in preeclampsia, it protects the offspring from death in preeclampsia that leads to fetal distress and subsequent death. This effect can be associated with lowering mean blood pressure, restoration of the kidney function and reduction of the pro-inflammatory processes on the endothelial walls by restoring nitric oxide level.
- TIVOR-L drug comprising arginine hydrochloride and levocarnitine has a pronounced embryoprotective effect on the fetus and mother by activating the nitric oxide system and optimizing the energy balance of the cells, which is manifested in the restoration of nitric oxide blood level, subsequent restoration of mean systolic blood pressure, normalization of renal function, normalization of fetal development, reduction of fetal distress and reduction of mortality in neonates.
- TIVOR-L drug has a more pronounced protective effect and has an unexpected technical result.
- the data show that pharmaceutical effects of arginine and levocarnitine amplify each other in TIVOR-L drug and create a synergistic effect.
- potentiation In pharmacology, a specific case of synergism, in which the effect of the simultaneous use of two or more active substances exceeds the estimated total effect of the use of each of these substances individually, is called potentiation.
- the pharmaceutical effect for the first comparative drug was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 4 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
- the pharmaceutical effect for the second comparative drug was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 5 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
- the pharmaceutical effect for the dose of TIVOR-L drug 210 mg/kg on arginine basis was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 6 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
- the pharmaceutical effect for the dose of TIVOR-L drug 420 mg/kg on arginine basis was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 7 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
- the pharmaceutical effect for the dose of TIVOR-L drug 840 mg/kg on arginine basis was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 8 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
- the expected total pharmaceutical effect of co-administration of the first comparative drug (arginine) and the second comparative drug (levocarnitine) was then calculated by summing the pharmaceutical effects of the first comparative drug and the second comparative drug.
- the difference between the pharmaceutical effect of the different doses of TIVOR-L and the estimated expected total pharmaceutical effect of co-administration of the first comparative drug and the second comparative drug was then calculated. If the pharmaceutical effect of TIVOR-L exceeded the estimated expected total pharmaceutical effect of the co-administration of the first comparative drug and the second comparative drug, it can be concluded that there is the potentiation of arginine action and levocarnitine action.
- the use of two comparative drugs and different doses of TIVOR-L drug led to the increase in the animal average body weight.
- the maximum possible pharmaceutical effect is 17 g.
- the pharmaceutical effect of 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 7 g, which is 41.2% of 17.
- the pharmaceutical effect of 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 47.1% of 17.
- the pharmaceutical effect of 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 10 g, which is 58.8% of 17.
- the pharmaceutical effects were calculated for each determined animal body condition parameter.
- the increase in animal urine volume was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 31.8%, and the percentage of pharmaceutical effect for levocarnitine drug is 9.1%.
- the decrease in animal mean systolic blood pressure was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 44.6%, and the percentage of pharmaceutical effect for levocarnitine drug is 17.9%.
- the decrease in the animal albumin urinary level was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 36.3%, and the percentage of pharmaceutical effect for levocarnitine drug is 10.6%.
- the restoration of the animal nitrate (NO 3 ) blood level was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 20.5%, and the percentage of pharmaceutical effect for levocarnitine drug is 10.6%.
- the restoration of the animal nitrite (NO 2- ) blood level was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 24.2%, and the percentage of pharmaceutical effect for levocarnitine drug is 9.4%.
- the increase in the animal platelet blood level was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 27.7%, and the percentage of pharmaceutical effect for levocarnitine drug is 6.2%.
- the increase in the mean fetal weight was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 41.3%, and the percentage of pharmaceutical effect for levocarnitine drug is 10.2%.
- the increase in the offspring survival was observed when using each comparative drug and TIVOR-L.
- the percentage of pharmaceutical effect for arginine drug is 45.7%, and the percentage of pharmaceutical effect for levocarnitine drug is 35.7%.
- the calculations for each animal body condition parameter during the trial clearly show the potentiation effect of the simultaneous arginine action and levocarnitine action in the known TIVOR-L drug.
- Tables 1-4 show that the known TIVOR-L drug, which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution, has a more significant therapeutic effect when compared with the drugs containing individual arginine and individual levocarnitine, and its use gives an unexpected technical result, such as the use of the known TIVOR-L drug provides a synergistic effect, such as potentiation effect of arginine hydrochloride action and levocarnitine action.
- the technical result achieved by the invention is the increase in the effectiveness of the therapy (both treatment and prevention) of the diseases in pregnant women and fetal development during pregnancy, increase in the effectiveness of the treatment of fetal distress, reduce in the number of the neonates with intrauterine growth restriction, expand of the range of the drugs for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
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Abstract
The invention relates to the means for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy. The invention provides the use of a solution for infusion comprising arginine hydrochloride and levocarnitine, wherein 1 ml of the solution for infusion comprises 42 mg of arginine hydrochloride and 20 mg of levocarnitine, for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy. The technical result achieved by the invention is the increase in the effectiveness of the therapy (both treatment and prevention) of the diseases in pregnant women and fetal development during pregnancy, increase in the effectiveness of the treatment of fetal distress, reduce in the number of the neonates with intrauterine growth restriction, expand of the range of the drugs for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
Description
INFUSION SOLUTION COMPRISING ARGININE HYDROCHLORIDE AND LEVOCARNITINE FOR TREATMENT AND PREVENTION OF DISEASES IN PREGNANT WOMEN AND PROMOTION OF FETAL DEVELOPMENT DURING PREGNANCY
FIELD OF THE INVENTION
The invention relates to the field of medicine, namely to the means for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
BACKGROUND OF THE INVENTION
Preeclampsia in pregnant women (formerly called toxemia in pregnant women) is a manifestation of either hypertension after the 20th week of pregnancy in a woman whose blood pressure was normal before, or an increase in hypertension that existed before the 20th week of pregnancy, or development of proteinuria, or both, and may be accompanied with the signs of other organs/systems impairment in the pregnant woman body. This disease affects both a mother and a fetus. The disease can result in the simultaneous manifestation of increased systemic vascular resistance, increased propensity of platelets to aggregate, increased activation of the coagulation system, as well as endothelial dysfunction. The reason is dysfunction of the placenta or impairment of the placenta implantation, which is confirmed by the rapid cessation of this condition after childbirth. Functional and morphological changes occur in the kidneys of pregnant women, glomerular filtration decreases, and symptoms of kidney impairment may appear.
WHO Recommendations for Prevention and treatment of pre-eclampsia and eclampsia. - World Health Organization, 2017, NICE Guideline. Hypertension in pregnancy: diagnosis and management. - National Institute for Health and Care Excellence, 2019, and Guideline 00559 FIGO. Gestational hypertension (preeclampsia). - International Federation of Gynecology and Obstetrics, 2017, describe the use of doses of aspirin in the range 75-150 mg per day starting from 12th week of gestation for the prevention and treatment of preeclampsia in pregnant women.
The method of treatment of preeclampsia in pregnant women depends on the degree of threat to the woman and fetus, the duration of pregnancy and the degree of the fetal development. It is recommended to use antihypertensive drugs
and magnesium sulfate (see article titled DIAGNOSIS, EVALUATION AND MANAGEMENT OF HYPERTENSIVE DISORDERS IN PREGNANCY: BASIC CONCLUSIONS. Clinical Practical Guide of the Society of Obstetricians and Gynecologists of Canada, 2014//Reproductive Endocrinology.-2014.-N° 4(18).- P.74-85.). Drugs based on nifedipine, hydralazine, labetalol are used as antihypertensive drugs. In mild disease, at gestational age <34 weeks, outpatient or hospital treatment is possible. However, careful monitoring of the pregnant woman and fetus is required.
According to the Clinical Protocol on Obstetrics "Fetal Distress during Pregnancy and Childbirth", approved by the order of the Ministry of Health of Ukraine dated 27.12.2006 N° 900, all disorders of the fetus functional status are referred to as "fetal distress". This term has come to be used as a generic term for all the fetus functional disorders, formerly referred to as "chronic fetal hypoxia" and "acute fetal hypoxia." Fetal distress is diagnosed according to the results of monitoring the fetal heart rate and recording of fetal cardiac abnormalities, compilation and analysis of its biophysical profile, observation of umbilical cord blood flow and record of umbilical cord blood flow disorders. Determining the reasons of the fetal cardiac abnormalities, its biophysical profile and umbilical cord blood flow using modern noninvasive methods of research may be very problematic. Publications and literature indicate that fetal distress is characterized by impaired functional status of the fetus due to acute or repeated restriction of oxygen access to the fetus or impaired ability of the fetus to use oxygen in cellular metabolism (metabolic acidosis). Depending on the rate of fetal distress progression, it is divided into:
• chronic fetal distress that develops due to the constant effect of a pathogenic factor (anemia in pregnant women, intrauterine infection (IUI), hypertension in pregnant women, etc.);
• acute fetal distress that develops due to acute disorders of uterine-placental and placental-fetal circulation (placental abruption, umbilical factors, acute maternal hypotension (anaphylactic shock), uterine rupture, uterine tetany).
Etiological factors that can lead to fetal distress are divided into:
1) Preplacental factors that include conditions leading to:
- impairment of oxygen transport to the uterus and placenta;
- cardiovascular and pulmonary pathology of the mother;
- anemia in pregnant women Hb <100 g/L;
- hypertension in pregnant women, hypotension in pregnant women, preeclampsia with a predominance of the hypertensive component,
- previous inflammatory diseases of the endometrium and abortion, as a consequence of pathological changes in the spiral arteries and in the placental area;
- diabetic angiopathy (occlusive vascular disorders in the placental area, microthrombosis);
- overdue pregnancy and preeclampsia (microthrombosis, trophoblastic embolism and peripheral vasospasm in the area of the spiral arteries).
2) Placental factors:
- primary placental insufficiency (small placenta, placental hemangiomas, etc.);
- premature abruption of the normally located placenta;
- hyperplasia of the placenta due to an infectious toxic agent at the late stages.
3) Postplacental factors:
- umbilical factors (umbilical cord prolapse and compression, the true node of the umbilical cord, umbilical cord entanglement);
- congenital anomalies of cardiovascular system in the fetus, congenital disorders of nervous regulation in the fetus.
The observations in the publications suggest that in the vast majority of cases, the factors of fetal distress are placental factors that are associated with the circulation.
The utility model patent of Ukraine UA 44055 U (description of utility model patent published on 10.09.2009) describes a method of treating antenatal fetal distress including the use of anticoagulants with a drug containing polyunsaturated fatty acids, 2 times a day, with meals, for 29-30 days.
Intrauterine growth restriction syndrome is diagnosed in the fetus and neonates who have low birth weight or low body weight and height for their gestational age. The variety of causes determines the heterogeneity of the pathogenesis of intrauterine growth restriction syndrome. Intrauterine growth restriction can develop at different stages of the fetal development. Thus, low birth weight in a full-term neonate indicates that the factor that restricted the fetal intrauterine growth was acting during the last 2-3 months of pregnancy, but if at the same time there is a deficit in body length (below the 10th percentile for this period of pregnancy), then unfavorable conditions for the fetus developed in the II trimester of pregnancy. The first type of intrauterine growth restriction is called hypotrophic, the second - hypoplastic. The most common cause of the hypotrophic type of fetal intrauterine growth restriction is severe toxicosis at the second half of pregnancy due to placental insufficiency, and for hypoplastic type is multiple
pregnancy, familial low birth weight, adolescent mother, minor nutritional deficiencies without deep hypovitaminosis.
The literature and publications note that the most common cause of intrauterine growth restriction is placental insufficiency. The connection between the severity of placental insufficiency in pregnant women and the degree of intrauterine growth restriction was shown, and the treatment of placental insufficiency was shown to reduce fetal intrauterine growth restriction.
Prevention of intrauterine growth restriction in pregnant women uses conventional treatment and prevention measures, including hormonal correction, vitamin therapy, use of antioxidants, antispasmodics and antiplatelet agents, sedatives, tocolytic drugs, antibacterial drugs, and vasoactive drugs. The patent US 8389483 B2 (description of the invention was published on 05.03.2013) describes a method of preventing intrauterine growth restriction due to placental vascular insufficiency, including intravenous bolus of 50-100 cubic meters of at least 10-20% of hypertensive glucose to a pregnant woman two or three times a day.
There is a known TIVOR-L drug, which is an infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution (see patient leaflet of TIVOR-L drug on the website at http:/7mozdocs.kjev.ua/1ikiview.php?id=38804). Indications for the use of the known drug are coronary heart disease, acute myocardial infarction, and conditions after acute myocardial infarction, as well as angina.
The known drug in the form of the infusion solution contains arginine and levocarnitine as active ingredients. Arginine is one of the main drugs in the treatment of coronary heart disease. In cardiac therapy substances of the so- called class of metabolic correctors, such as inhibitors of oxidation of free fatty acids, which affect the activity of enzymes involved in biochemical reactions, are also widely used. A known representative of these inhibitors is levocarnitine (also known as L-carnitine).
Arginine (d-guanidine-a-aminovaleric acid) is a basic a-amino acid, the L- form of which is a semi-essential amino acid. Arginine interacts with SH groups (nitrate receptors) in vascular smooth muscle cells, including coronary arteries, to form nitric oxide (NO), which is similar in structure and action to ERF. Due to its properties, arginine dilates arterioles and peripheral veins, reduces total peripheral vascular resistance, reduces venous outflow, and dilates pulmonary vessels, which reduces resistance in the small circulation and leads to regression of the symptoms in case of pulmonary edema, and reduces end-diastolic pressure and ventricular volume, thereby reducing myocardial oxygen demand. Arginine also dilates the coronary arteries and prevents their spasm, reduces the diastolic
tension of the ventricular wall, resulting in improved coronary blood flow in the ischemic area.
According to the modern concept in obstetrics, much attention is paid to the role of the vascular endothelium in the pathogenesis of gestational complications of the mother and fetus. Generalized endothelial dysfunction leads to the development of placental insufficiency, preeclampsia, fetal hypoxia (fetal distress syndrome) and intrauterine growth restriction.
At chronic placental insufficiency transport, trophic, endocrine, metabolic and other important functions of the placenta are impaired. Nitric oxide (NO), which is synthesized from L-arginine by the endothelium, is of great importance in maintaining adequate placental blood flow. Nitric oxide (NO), synthesized by endothelial cells, has been shown to be a regulator of vascular tone and an inhibitor of platelet aggregation. NO prevents the development of vascular spasm, improves microcirculation by relaxing vascular smooth muscle and improving of the blood rheological properties. Lack of NO leads to impaired microcirculation and contributes to the development of hypoxia, placental insufficiency, threatened abortion, intrauterine growth restriction and preeclampsia.
L-arginine normalizes placental blood flow by restoring vascular tone and improving the blood rheological properties. This leads to the normalization of uterine tone, improved blood circulation in the umbilical artery and placenta, and intrauterine fetal growth.
Levocarnitine is a natural substance synthesized in the body, related to B vitamins, thus, it is called a vitamin-like substance. In the human body it is present in the tissues of the striated muscles and liver. It is a factor in metabolic processes that support the activity of acetyl coenzyme A. Levocarnitine facilitates the entry of long-chain fatty acids into the mitochondria of cells, thus providing a substrate for oxidation and energy production, which significantly improves the restoration of heart muscle cells in myocardial infarction. Levocarnitine inhibits the formation of atherosclerotic plaques in blood vessels and promotes the resorption of the plaques that have already formed. Thus, due to its properties, levocarnitine reduces the contribution of the above factors, such as hyperlipidemia, high-calorie diet, obesity, diabetes, smoking, hypodynamia, and age, to the development of coronary heart disease.
Additionally, due to the function of levocarnitine, such as the transport of fatty acids (FA) through the membranes of intracellular organelles, they oxidize with the formation of the energy and "building materials" necessary for the development of the nervous system and the growing organism. In an oxygen- and glucose-depleted environment where the fetus develops, fatty acids are the main source of the energy because, unlike glucose, they can oxidize at low oxygen
blood level, but require large amounts of levocarnitine. Therefore, the synthesis of levocarnitine and fetus need for levocarnitine is in increasing progression. At the early stages of the development FA oxidation occurs in the "ancient" organelles of the cell, such as oxisomes, peroxisomes, and later in the young ones, such as mitochondria. A very important, vital product of FA oxidation in hypoxia is the formation and accumulation of endogenous carbon dioxide in the blood of the fetus before the birth. Due to carbon dioxide, the neonate takes the first and all subsequent breaths in his life, because without it the access of oxygen from the air into the human body is almost impossible. In addition to the energy supply to the fetus, levocarnitine is involved in the most important processes of formation and development of the brain and spinal cord, as well as autonomic nervous system. At the initial stage of development, it is the only neurotransmitter (nerve impulse conduction) and, having a structural similarity to acetylcholine, it performs acetylcholine functions, laying the foundations of neuromuscular reception, forming and "training" neurotrophic cholinergic (acetylcholine-controlled) structures, and parasympathetic nervous system.
SUMMARY OF THE INVENTION
The object of the invention is to increase the effectiveness of the combination therapy (both treatment and prevention) of the diseases in pregnant women and fetal development during pregnancy, increase the effectiveness of the treatment of the fetal distress, reduce the number of neonates with intrauterine growth restriction, expand the range of drugs for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
The object is achieved by use of an infusion solution comprising arginine hydrochloride and levocarnitine, wherein 1 ml of the solution for infusion comprise 42 mg of arginine hydrochloride and 20 mg of levocarnitine, for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
In addition, according to one of the embodiments of the invention, the diseases of pregnant women and fetal development during pregnancy are preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction.
In addition, according to one of the embodiments of the invention, the infusion solution is used to treat preeclampsia in pregnant women.
In addition, according to one of the embodiments of the invention, the infusion solution is used for the prevention or treatment of fetal distress.
In addition, according to one of the embodiments of the invention, the infusion solution for infusion is used to prevent intrauterine growth restriction.
In addition, according to one of the embodiments of the invention, the infusion solution is used in the combination therapy of the diseases in pregnant women and fetal development during pregnancy.
In addition, according to one of the embodiments of the invention, the infusion solution for infusion is used in the combination therapy of preeclampsia in pregnant women.
In addition, according to one of the embodiments of the invention, the infusion solution for infusion is used in the combination therapy of fetal distress.
In addition, according to one of the embodiments of the invention, the infusion solution for infusion is used in the combination therapy of intrauterine growth restriction.
DETAILED DESCRIPTION OF THE INVENTION
To determine the possibility of using the known TIVOR-L drug, which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution, for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy, in particular preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction, and the feasibility of such use, preclinical trial was conducted.
The aim of the preclinical trial was to study the effectiveness of the known TIVOR-L drug, which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution, for the treatment and prevention of preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction.
The trial design was as follows.
According to a directive of the International Society for the Study of Hypertension in Pregnancy, clinical features of preeclampsia include severe hypertension after 20th week of gestation, proteinuria with or without edema and changes in laboratory parameters, as well as kidney, liver and brain impairment. One of the key factors of this pathology is confirmed to be the inhibition of the synthesis of nitric oxide (NO) vasodilator. Powerful NO vasodilator is synthesized from L-arginine by nitric oxide synthase (NOS). Chronic inhibition of NOS by N- nitro-L-arginine methyl ester (L-NAME) in pregnant rats leads to the dose- dependent development of hypertension in combination with proteinuria, renal vasoconstriction, thrombocytopenia and maternal and fetal mortality. This emphasizes the importance of this molecule in pregnancy and is a useful preclinical model for assessing the role of NO in pregnancy and developing new drugs for the prevention and treatment of preeclampsia. In view of this, the trial on the TIVOR-L drug, the pharmacodynamic effect of which is related to the presence
of levocarnitine and arginine hydrochloride, and its effect on the clinical characteristics of preeclampsia, increase of nitric oxide synthesis in endothelial cells and the fetus condition, was conducted.
To compare the pharmaceutical effects of individual arginine, individual levocarnitine, and combined arginine and levocarnitine (the known pharmaceutical composition), a preclinical trial was conducted on pregnant rats with chronic NOS inhibition by N-nitro-L-arginine methyl ester (abbreviated as L-NAME).
The following solutions were used for the trial:
- the known TIVOR-L drug, which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution;
- the first comparative drug, which is a solution of arginine hydrochloride and contains 42 mg of arginine hydrochloride in 1 ml;
- the second comparative drug, which is a solution of levocarnitine and contains 20 mg of levocarnitine in 1 ml;
- the solution of L-NAME nitric oxide synthase blocker containing L-NAME in saline in the amount of 10 mg/ml.
The trial was conducted on 8 groups of animals:
Group 1 (intact control) included non-pregnant rats treated with saline (10 animals).
Group 2 (negative control) included pregnant rats treated with saline (10 animals).
Group 3 (positive control) included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight (10 animals).
Group 4 (L-NAME + arginine) included pregnant rats administered with L- NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and the solution of arginine hydrochloride in the amount of 420 mg/kg of body weight (10 animals).
Group 5 (L-NAME + levocarnitine) included pregnant rats administered with L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and the solution of levocarnitine in amount of 800 mg/kg of body weight (10 animals).
Group 6 (L-NAME + TIVOR-L 210 mg/kg) included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and TIVOR-L drug in the
amount of 210 mg/kg of body weight on arginine basis, 0.5 ml/100 g of body weight (10 animals).
Group 7 (L-NAME + TIVOR-L 420 mg/kg) included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and TIVOR-L drug in the amount of 420 mg/kg of body weight equivalent on arginine basis, 1 ml/100 g of body weight (10 animals).
Group 8 (L-NAME + TIVOR-L 840 mg/kg) included pregnant rats administered with the solution of L-NAME nitric oxide synthase blocker comprising 0.5 mg of L-NAME in 0.05 ml per 100 g of body weight, and TIVOR-L drug in the amount of 840 mg/kg of body weight equivalent on arginine basis, 1.5 ml/100 g of body weight (10 animals).
Pregnancy modeling using monitoring the animal estrous cycle and subsequent fertilization with the identification of the first day of fertilization based on the presence of sperm in the animal vaginal swab was performed before the trial. Pregnant and virgin nonlinear animals were housed individually in standard metabolic cells, which allowed urine to be collected, and food and water intake to be recorded throughout the trial. One arterial and one venous catheter were implanted on the 14th day of gestation (delivery days are 21 to 22).
Four days later, for Group 3 animals the infusion of L-NAME solution (dissolved in sterile L-NAME saline) in amount of 0.5 mg in 0.05 ml per 100 g of body weight per hour through a catheter implanted in a hollow vein was started. Group 1 and Group 2 animals were injected with saline at a similar rate.
Group 4, Group 5, Group 6, Group 7 and Group 8 animals were administered with solution of arginine hydrochloride, levocarnitine, and TIVOR-L drug simultaneously with the start of administration of L-NAME solution, according to the above group scheme.
Infusion of the animals with these solutions was started before the birth and continued for an additional day after the birth.
Abnormalities of fetal developmental and fetal distress were assessed by weighing neonates and assessing neonatal mortality. Measurements of the average blood pressure of non-anesthetized animals that was not restricted in their movements were performed daily, at a fixed time, using an electronic manometer and a pressure transducer.
Sample collection and analysis were performed as follows.
Animal body weight, water and food intake, and urine volume were monitored daily. Urine samples collected over twenty-four hours were centrifuged
at 3000 G for 15 minutes and stored in a freezer at -20 °C before albumin chemical analysis (usually <2 weeks). Shortly before infusion, blood samples were taken into syringes from a catheter implanted in the aorta (for baseline values), and, 4 days later, to assess the effect of L-NAME on nitrate and nitrite levels, and platelet count.
Histological analysis of the kidneys was performed 4 days after the start of the solutions administration. The animals were anesthetized, and both kidneys were removed and weighed, the left kidney being treated for microscopic examination. The coronary sections of the kidneys were fixed in 10% formalin and imbedded into paraffin blocks. The sections (thickness 3 pm) were dyed. The sections were examined on a blinded basis for lesions of the glomerular zone.
Statistical analysis of the results is presented as the mean ± SEM. Comparison of the respective values for the pregnant and virgin rats was performed using the Student's test. Probability <0.05 was considered statistically significant.
The trial results show the following.
Preeclampsia is characterized by hypertension, proteinuria, as well as impairment of the kidneys and liver of the mother, and, consequently, possible abnormalities of the fetal development. There was no significant difference in food intake between the animals in control groups 2 and 3 and the animals in groups 4, 5, 6, 7 and 8. Despite almost identical food intake, body weight of the females receiving L-NAME (Group 3) was less than body weight of the pregnant animals in control Group 2 that received saline, which reflects a significant intrauterine growth restriction. The animals treated with TIVOR-L in addition to L-NAME nitric oxide synthase blocker (Groups 6, 7 and 8) showed a significant increase in body weight, indicating normalization of the metabolic processes and impact on fetal weight restoration (see Table 1).
Table 1
Effect of chronic inhibition of NO synthase with L-NAME, arginine, levocarnitine and TIVOR-L on body weight, food and water intake, urine volume, systolic blood pressure (SBP) in pregnant and virgin rats
* The changes are statistically significant for the animals in the negative control group (* p <0.05, ** p <0.01).
# The changes are statistically significant for the animals in the positive control group (# p <0.05, ## p <0.01).
The administration of L-NAME (Group 3) did not cause significant changes in water intake in pregnant rats compared with the animals in the negative control group (Group 2). Additionally, there was no significant difference between the animals in the control groups (Groups 2 and 3) and the animals in the groups that received arginine hydrochloride and levocarnitine (Groups 4 and 5), respectively, and the animals in the groups that received TIVOR-L (Groups 6, 7 and 8). However, with no significant difference in water intake for the pregnant animals of different groups, the animals receiving individual L-NAME (Group 3) demonstrated significantly decreased daily urination (see Table 1), compared with the pregnant animals receiving only saline (Group 2). This may indicate a decrease in renal blood supply, which is caused by a vasoconstrictive effect, with a decrease in the blood nitric oxide level when administering L-NAME nitric oxide synthase blocker.
The animals in the groups receiving TIVOR-L drug (Groups 6, 7 and 8) demonstrated a statistically significant restoration of the average urine volume compared with the Group 3 animals and the Group 4 and 5 animals, which may indicate normalization of the renal function due to lowering of the blood pressure caused by restoration of the blood nitric oxide level.
The obtained data of mean systolic blood pressure (SBP) indicate the antihypertensive effect of arginine, levocarnitine and TIVOR-L drug. The effect of TIVOR-L drug was more pronounced, compared with the similar effect of individual arginine and individual levocarnitine (see Table 1). The most pronounced pharmaceutical effect of TIVOR-L drug according to urine volume and mean systolic blood pressure is seen when administered in an amount of 420 mg/kg of body weight on arginine basis. The increase of TIVOR-L drug dose did not enhance the pharmaceutical effect.
Kidney impairment is one of the main prognostic markers in preeclampsia progression. The animal kidney condition was analyzed by histological analysis, and by the level of proteinuria, namely by urinary albumin level. Inhibition of nitric oxide synthesis can cause glomerular capillary hypertension, which leads to sclerotic lesions of the kidney glomerular zone. Histological samples showed that the administration of L-NAME to Group 3 animals was accompanied by severe morphological changes in the kidney glomerular zone. Glomerular capillary lumens were segmentally occluded by intraluminal masses of eosinophilic composition. Extraglomerular lumens were filled with protein. In addition, mild diffuse interstitial edema and sparse interstitial lymphocyte infiltration were observed. In histological samples of Group 6, 7 and 8 animals that were administered with TIVOR-L drug such renal changes were not observed, in contrast to Group 4 and 5 animals (administration of individual arginine and individual carnitine), for which pathological changes in the kidneys were recorded.
The presence of the urinary glomerular proteins of intermediate size, such as albumin, indicates the renal tubules impairment, which can occur in severe preeclampsia. Thus, it was found that the average daily urinary albumin excretion increased sharply in Group 3 animals (administered with individual L-NAME) from 8.3 ± 1.5 mg/24 h to 56.3 ± 14.3 mg/24 h (p <0.005). For Group 4, 5, 6, 7 and 8 animals (administered with arginine, levocarnitine, and TIVOR-L drug) there was a decrease in the urinary albumin level, and for Group 6, 7 and 8 animals (administered with TIVOR-L drug) proteinuria is least pronounced, which confirms the more pronounced nephroprotective effect of TIVOR-L drug in comparison with the individual administration of arginine and levocarnitine (see Table 2).
Table 2
Effect of chronic inhibition of NO synthase with L-NAME, arginine, levocarnitine and TIVOR-L on urinary albumin level
# The changes are statistically significant for the animals in the positive control group (# p <0.05, ## p <0.01).
Since NO is a very unstable molecule, to determine NO activity the level of NO metabolites, namely nitrites (NO2-) and nitrates (NO3-), is therefore measured. According to biochemical studies, it was found that for Group 4, 6, 7 and 8 animals the administration of arginine and TIVOR-L drug led to increase of NO2- and NO3- levels in the blood, and Group 6, 7 and 8 animals (administered with TIVOR-L drug) demonstrated the most pronounced increase in NO metabolites level. Individual administration of levocarnitine to Group 4 animals did not affect NO2 and NO3- blood level (see Table 3).
Table 3
The effect of chronic inhibition of NO synthase with L-NAME, arginine, levocarnitine and TIVOR-L drug on the level of nitric oxide metabolic products and platelets in the blood
* The changes are
# The changes are statistically significant for the animals in the positive control group (# p <0.05, ## p <0.01).
Typically, thrombocytopenia is associated with a preeclamptic condition due to increased aggregation and adhesion of platelets to the damaged endothelium. For Group 3 animals, there was a statistically significant decrease in platelets in the blood as a result of the infusion of L-NAME. Decreased platelets indicate the onset of the so-called HELLP syndrome, which is caused by vascular endothelium impairment in preeclampsia. There was a statistically significant restoration of platelet level, when administering arginine and TIVOR-L drug to Group 4, 6, 7 and 8 animals, which indicates a protective effect on vascular endothelium (see Table 3), wherein administration of TIVOR-L drug gave significantly higher protective effect, than administration of arginine.
To investigate the abnormality of the fetal developmental and fetal distress, the effect of chronic inhibition of NO synthase with L-NAME, arginine, levocarnitine, and TIVOR-L on neonatal weight and offspring mortality was studied. The development of preeclampsia is associated with the risks of decreased fetal perfusion and decreased fetal growth. Significant embryoprotective effect is confirmed by data on the neonatal weight and the percentage of the offspring mortality. The infusion of L-NAME starting from the
18th day of pregnancy caused a significant intrauterine growth restriction without affecting the duration of gestation. Administration of TIVOR-L to the animals with preeclampsia (Group 6, 7 and 8 animals) was found to lead to a statistically significant increase in fetal growth rates compared to Group 4 and 5 animals that received individual arginine and individual levocarnitine (see Table 4).
The offspring mortality was studied immediately after the birth. For Group 3 animals, a significant number of neonates were stillborn, indicating a negative effect of preeclampsia on fetal development, which is associated with fetal distress. Approximately 10% of all neonates in Group 3 animals died (see Table 4). Group 6, 7, and 8 animals treated with TIVOR-L showed a statistically significant reduction in neonatal mortality, indicating a significant protective effect of TIVOR-L on pregnancy and fetal development (see Table 4).
Table 4
Effect of chronic inhibition of NO synthase with L-NAME, arginine, levocarnitine and TIVOR-L on neonatal weight and percentage of dead neonates
** p <0.01 , *** p <0.005).
# The changes are statistically significant for the animals in the positive control group (# p <0.05, ## p <0.01).
Table 4 shows that TIVOR-L drug has the greatest embryoprotective effect, because, in addition to the restoration of the fetal body weight, which prevents intrauterine growth restriction in preeclampsia, it protects the offspring from death in preeclampsia that leads to fetal distress and subsequent death. This effect can be associated with lowering mean blood pressure, restoration of the kidney
function and reduction of the pro-inflammatory processes on the endothelial walls by restoring nitric oxide level.
Above mentioned allow to conclude that TIVOR-L drug comprising arginine hydrochloride and levocarnitine has a pronounced embryoprotective effect on the fetus and mother by activating the nitric oxide system and optimizing the energy balance of the cells, which is manifested in the restoration of nitric oxide blood level, subsequent restoration of mean systolic blood pressure, normalization of renal function, normalization of fetal development, reduction of fetal distress and reduction of mortality in neonates.
Analysis of the data provided in Tables 1-4 shows that, in comparison with the drugs containing either arginine or levocarnitine, TIVOR-L drug has a more pronounced protective effect and has an unexpected technical result. The data show that pharmaceutical effects of arginine and levocarnitine amplify each other in TIVOR-L drug and create a synergistic effect.
In pharmacology, a specific case of synergism, in which the effect of the simultaneous use of two or more active substances exceeds the estimated total effect of the use of each of these substances individually, is called potentiation.
The calculation of the pharmaceutical effect for each of the drugs and conclusion whether they have the potentiation effect, was carried out according to the following technique. Initially, the maximum possible pharmaceutical effect that is the difference between the values of a body condition parameter for Group 2 animals (negative control) and Group 3 animals (positive control), was calculated.
The pharmaceutical effect for the first comparative drug (arginine) was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 4 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
The pharmaceutical effect for the second comparative drug (levocarnitine) was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 5 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
The pharmaceutical effect for the dose of TIVOR-L drug 210 mg/kg on arginine basis, was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 6 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
The pharmaceutical effect for the dose of TIVOR-L drug 420 mg/kg on arginine basis, was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 7 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
The pharmaceutical effect for the dose of TIVOR-L drug 840 mg/kg on arginine basis, was defined as the difference between the values of any one of the body condition parameters for Group 3 animals (positive control) and the corresponding parameter for Group 8 animals and was expressed as a percentage of the maximum possible pharmaceutical effect.
The expected total pharmaceutical effect of co-administration of the first comparative drug (arginine) and the second comparative drug (levocarnitine) was then calculated by summing the pharmaceutical effects of the first comparative drug and the second comparative drug. The difference between the pharmaceutical effect of the different doses of TIVOR-L and the estimated expected total pharmaceutical effect of co-administration of the first comparative drug and the second comparative drug was then calculated. If the pharmaceutical effect of TIVOR-L exceeded the estimated expected total pharmaceutical effect of the co-administration of the first comparative drug and the second comparative drug, it can be concluded that there is the potentiation of arginine action and levocarnitine action.
Thus, according to the trial, the use of two comparative drugs and different doses of TIVOR-L drug led to the increase in the animal average body weight. The maximum possible pharmaceutical effect is 17 g. The pharmaceutical effect of arginine drug is 5 g, which is 29.4% of 17, and the pharmaceutical effect of levocarnitine drug is 1 g, which is 5.9% of 17. Accordingly, the estimated expected total pharmaceutical effect of the two comparative drugs is 29.4% + 5.9% = 35.29%.
The pharmaceutical effect of 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 7 g, which is 41.2% of 17. The pharmaceutical effect of 210 mg/kg of body weight of TIVOR-L drug exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs by 41.2% - 35.29% = 5.88%.
The pharmaceutical effect of 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 47.1% of 17. The pharmaceutical effect of 420 mg/kg of body weight of TIVOR-L drug exceeds the estimated expected total pharmaceutical effect of two comparative drugs by 47.1% - 35.29% = 11.76%.
The pharmaceutical effect of 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 10 g, which is 58.8% of 17. The pharmaceutical effect of 840
mg/kg of body weight of TIVOR-L drug exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs by 58.8% - 35.29% = 23.53%.
The pharmaceutical effects were calculated for each determined animal body condition parameter.
The increase in animal urine volume was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 31.8%, and the percentage of pharmaceutical effect for levocarnitine drug is 9.1%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 31.8% + 9.1% = 40.91%. The pharmaceutical effect of 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 45.5%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase of urination by 45.5% - 40.91% = 4.55%. The pharmaceutical effect of 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 63.6%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase of urination by 63.6% - 40.91% = 22.73%. The pharmaceutical effect of 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 50%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase of urination by 50% - 40.91% = 9.09%.
The decrease in animal mean systolic blood pressure was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 44.6%, and the percentage of pharmaceutical effect for levocarnitine drug is 17.9%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 44.6% + 17.9% = 62.56%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 69.2%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the decrease in mean systolic blood pressure by 69.2% - 62.56% = 6.67%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 81.3%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the decrease in mean systolic blood pressure by 81.3% - 62.56% = 18.72%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 74.4%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on decrease in mean systolic blood pressure by 74.4% - 62.56% = 11.79%.
The decrease in the animal albumin urinary level was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 36.3%, and the percentage of pharmaceutical effect for levocarnitine drug is 10.6%. The estimated expected total pharmaceutical effect of
the use of two comparative drugs is 36.3% + 10.6% = 46.88%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 54.6%, which exceeds the estimated expected total pharmaceutical effect of two comparative drugs on the increase of the albumin urinary level by 54.6% - 46.88% = 7.71%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 60.2%, which exceeds the estimated expected total pharmaceutical effect of two comparative drugs on the increase of the albumin urinary level by 60.2% - 46.88% = 13.33%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 57.3%, which exceeds the estimated expected total pharmaceutical effect of two comparative drugs on the increase of the albumin urinary level by 57.3% - 46.88% = 10.42%.
The restoration of the animal nitrate (NO3 ) blood level was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 20.5%, and the percentage of pharmaceutical effect for levocarnitine drug is 10.6%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 20.5% + 10.6% = 31.13%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 37.1%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the nitrate blood level by 37.1% - 31.13% = 5.96%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 41.7%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the nitrate blood level by 41.7% - 31.13% = 13.33%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 39.1%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the nitrate blood level by 39.1% - 31.33% = 7.95%.
The restoration of the animal nitrite (NO2-) blood level was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 24.2%, and the percentage of pharmaceutical effect for levocarnitine drug is 9.4%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 24.2% + 9.4% = 33.56%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 37.6%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the nitrite blood level by 37.6% - 33.56% = 4.03%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 53.0%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the nitrite blood level by 53.0% - 33.56% = 19.46%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 58.4%, which exceeds
the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the nitrite blood level by 58.4% - 33.56% = 24.83%.
The increase in the animal platelet blood level was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 27.7%, and the percentage of pharmaceutical effect for levocarnitine drug is 6.2%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 27.7% + 6.2% = 33.95%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 51.4%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the platelet level by 51.4% - 33.95% = 17.44%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 55.6%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the platelet level by 55.6% - 33.95% = 21.64%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 58.4%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the platelet level by 56.6% - 33.56% = 22.68%.
The increase in the mean fetal weight was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 41.3%, and the percentage of pharmaceutical effect for levocarnitine drug is 10.2%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 41.3% + 10.2% = 51.56%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 63.6%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the mean fetal weight by 63.6% - 51.56 % = 12.00%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 76.9%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the mean fetal weight by 76.9% - 51.56 % = 25.33%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is 72.4%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the mean fetal weight by 72.4% - 51.56 % = 20.89%.
The increase in the offspring survival was observed when using each comparative drug and TIVOR-L. The percentage of pharmaceutical effect for arginine drug is 45.7%, and the percentage of pharmaceutical effect for levocarnitine drug is 35.7%. The estimated expected total pharmaceutical effect of the use of two comparative drugs is 45.7% + 35.7% = 81.43%. The pharmaceutical effect 210 mg/kg of body weight of TIVOR-L drug on arginine basis is 88.6%, which exceeds the estimated expected total pharmaceutical effect
of the use of two comparative drugs on the increase in the offspring survival by 88.6% - 81.43% = 7.14%. The pharmaceutical effect 420 mg/kg of body weight of TIVOR-L drug on arginine basis is 95.7%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the offspring survival by 95.7% - 81.43% = 14.29%. The pharmaceutical effect 840 mg/kg of body weight of TIVOR-L drug on arginine basis is is 92.9%, which exceeds the estimated expected total pharmaceutical effect of the use of two comparative drugs on the increase in the offspring survival by 92.9% - 81.43% = 11.43%.
Thus, the calculations for each animal body condition parameter during the trial clearly show the potentiation effect of the simultaneous arginine action and levocarnitine action in the known TIVOR-L drug. Analysis of the trial results provided in Tables 1-4 shows that the known TIVOR-L drug, which is the infusion solution and contains 42 mg of arginine hydrochloride and 20 mg of levocarnitine in 1 ml of the solution, has a more significant therapeutic effect when compared with the drugs containing individual arginine and individual levocarnitine, and its use gives an unexpected technical result, such as the use of the known TIVOR-L drug provides a synergistic effect, such as potentiation effect of arginine hydrochloride action and levocarnitine action.
The technical result achieved by the invention is the increase in the effectiveness of the therapy (both treatment and prevention) of the diseases in pregnant women and fetal development during pregnancy, increase in the effectiveness of the treatment of fetal distress, reduce in the number of the neonates with intrauterine growth restriction, expand of the range of the drugs for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
These examples only illustrate the invention, but do not limit it.
Claims
1. Use of an infusion solution comprising arginine hydrochloride and levocarnitine, wherein 1 ml of the solution for infusion comprises 42 mg of arginine hydrochloride and 20 mg of levocarnitine, for the treatment and prevention of the diseases in pregnant women and fetal development during pregnancy.
2. The use of the infusion solution according to claim 1 , wherein the diseases in pregnant women and fetal development during pregnancy are preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction.
3. The use of the infusion solution according to claim 2, wherein the infusion solution is used to treat preeclampsia in pregnant women.
4. The use of the infusion solution according to claim 2, wherein the infusion solution is used for the prevention or treatment of fetal distress.
5. The use of the infusion solution according to claim 2, wherein the infusion solution is used to prevent fetal growth restriction.
6. The use of the infusion solution according to claim 1 , wherein the infusion solution is used in the combination therapy of the diseases in pregnant women and fetal development during pregnancy.
7. The use of the infusion solution according to claim 6, wherein the diseases in pregnant women and fetal development during pregnancy are preeclampsia in pregnant women, fetal distress, and intrauterine growth restriction.
8. The use of the infusion solution according to claim 7, wherein the infusion solution is used in the combination therapy of preeclampsia in pregnant women,
9. The use of the infusion solution according to claim 7, wherein the infusion solution is used in the combination therapy of fetal distress.
10. The use of the infusion solution according to claim 7, wherein the infusion solution is used in the combination therapy of intrauterine growth restriction.
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UA44055U (en) | 2009-06-05 | 2009-09-10 | Одесский Государственный Медицинский Университет | Method for treating antenatal distress of fetus |
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US8389483B2 (en) | 2003-06-13 | 2013-03-05 | Sumathi Paturu | Intrauterine fetal growth restriction—the treatment modalities for clinical research, and the biochemical rationale |
UA44055U (en) | 2009-06-05 | 2009-09-10 | Одесский Государственный Медицинский Университет | Method for treating antenatal distress of fetus |
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WO2017085642A1 (en) * | 2015-11-17 | 2017-05-26 | Товарыство З Обмэжэною Видповидальнистю Мэдычный Центр "Мтк" | Pharmaceutical composition |
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