Evaluation of Clinical Efficiency of Cardioprotective Therapy in Patients with Acute Myocardial Infarction

Aim. To evaluate the efficiency of cardioprotective therapy using intravenous metoprolol in combination with a high dose of atorvastatin in the prevention of myocardial remodeling (MR) and heart failure (HF) in patients with acute ST-segment elevation myocardial infarction (STEMI).Material AND methods. A prospective study included 100 STEMI patients who underwent primary percutaneous intervention (PCI). Depending on the regimens of drug cardioprotection, three groups of patients were formed: the first (2014–2015) — 34 patients who received 80 mg atorvastatin as a part of the basic therapy on the first day of STEMI, then 20–40 mg/day for 30 days. The second group (2017–2018) — 34 patients who received atorvastatin 80 mg/day for a month from the onset of STEMI. The third group (2018–2019) — 32 patients who received intravenous metoprolol tartrate (5–15 mg) and atorvastatin 80 mg/day before PCI for a month from the onset of STEMI. On days 1 and 2 of STEMI and one month later, patients were assessed for serum levels of cardiac biomarkers; on the 1st, 7th days and one month later, echocardiographic studies (EchoCG) were performed. At the end of the observation, clinical and imaging outcomes (MR and HF) were assessed, which were compared with the dynamics of biomarkers between the groups of patients.Results. The combined use of atorvastatin 80 mg/day for a month from the onset of STEMI and a single intravenous injection of metoprolol tartrate (5–15 mg) in the acute phase of STEMI before PCI showed the most significant effects in the prevention of the development of structural and functional myocardial disorders and clinically severe heart failure, and also caused the minimal serum activity of cardiomarkers in the third group of patients in comparison with the first and second groups of patients without this drug combination. Also, correlations between biomarkers and echocardiography indicators were established in the third group of patients who received cardioprotective therapy.Conclusion. The combined use of high-dose atorvastatin for a month with a single intravenous injection of metoprolol tartrate in acute STEMI before PCI prevents the formation of MR and clinically significant HF in the post-infarction period. Comprehensive dynamic assessment of cardiac biomarkers and echocardiography parameters within a month after post-STEMI is a highly informative tools for monitoring the efficiency of cardioprotective therapy.

Stem cells from human exfoliated deciduous teeth attenuate mechanical allodynia in mice through distinct from the siglec-9/MCP-1-mediated tissue-repairing mechanism

The effects of stem cells from human exfoliated deciduous teeth (SHED) on mechanical allodynia were examined in mice. A single intravenous injection of SHED and conditioned medium from SHED (SHED-CM) through the left external jugular vein significantly reversed the established mechanical allodynia induced by spinal nerve transection at 6 days after injection. SHED or SHED-CM significantly decreased the mean numbers of activating transcription factor 3-positive neurons and macrophages in the ipsilateral side of the dorsal root ganglion (DRG) at 20 days after spinal nerve transection. SHED or SHED-CM also suppressed activation of microglia and astrocytes in the ipsilateral side of the dorsal spinal cord. A single intravenous injection of secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 had no effect on the established mechanical allodynia, whereas a single intravenous injection of protein component(s) contained in SHED-CM with molecular weight of between 30 and 50 kDa reversed the pain. Therefore, it may be concluded that protein component(s) with molecular mass of 30–50 kDa secreted by SHED could protect and/or repair DRG neurons damaged by nerve transection, thereby ameliorating mechanical allodynia.

Toxicological characteristics of a medicinal product for veterinary «Ketoprofen 10%» in laboratory animals (acute toxicity)

In the course of the studies, the toxicological properties of the medicinal product for veterinary «Ketoprofen 10%» in laboratory animals were studied. With a single intragastric administration of the drug to rats, the LD50 value calculated by the Kerberian method was 333,3 mg/kg. At the same time, the LD50 value by the Miller and Tainter method was 358,1±159,8 (198,3 ÷ 518,0) mg/kg. After a single intravenous injection of the study drug to rats, the LD50 value calculated by the Kerberian method was 351,1 mg/kg. The LD50 calculated by probit analysis according to Miller and Tainter was 349,7±167,5 (182,3 ÷ 517,2) mg/kg. Taking into account the obtained LD50 value in rats with intragastric administration and according to the generally accepted hygienic classification, the drug belongs to the 3rd hazard class – moderately hazardous substances (GOST 12.1.007-76). Intragastric administration of the drug to mice made it possible to obtain an LD50 value of 6249,4 mg/kg (according to Kerber). The LD50 calculated by probit analysis according to Miller and Tainter was 7725,0±2646,5 (5078,5 ÷ 10) mg/kg. Taking into account the data obtained on mice and according to the generally accepted hygienic classification, the drug belongs to the 4th hazard class – low-hazard substances (GOST 12.1.007-76). The coefficient of species sensitivity was more than 17, which indicates a pronounced species resistance to ketoprofen in mice compared to rats.

The pharmacokinetics of the injectable dosage form of GK-2 in rabbits

The pharmacokinetics of the nerve growth factor mimetic GK-2 (dimeric dipeptide mimetic of the 4-th loop NGF, a derivative of fluoro-substituted 5-[2-(5-fluoropyrid-3-yl) -ethyl)]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole) in rabbits after a single intravenous injection of an injectable dosage form at dose 24 mg (7,8-8,7 mg/kg). GK-2 concentrations in the blood plasma were determined by high-performance liquid chromatography with massspectrometric detection. GK-2 can be attributed to "short-lived" drugs, since the half-life from the rabbits blood plasma was 0.9±0.1 h.

Mesenchymal Stem Cell–Derived Exosomes Improve Functional Recovery in Rats After Traumatic Brain Injury: A Dose-Response and Therapeutic Window Study

Background. Mesenchymal stem cell (MSC)-derived exosomes play a critical role in regenerative medicine. Objective. To determine the dose- and time-dependent efficacy of exosomes for treatment of traumatic brain injury (TBI). Methods. Male rats were subjected to a unilateral moderate cortical contusion. In the dose-response study, animals received a single intravenous injection of exosomes (50, 100, 200 µg per rat) or vehicle, with treatment initiated at 1 day after injury. In the therapeutic window study, animals received a single intravenous injection of 100 µg exosomes or vehicle starting at 1, 4, or 7 days after injury. Neurological functional tests were performed weekly after TBI for 5 weeks. Spatial learning was measured on days 31 to 35 after TBI using the Morris water maze test. Results. Compared with the vehicle, regardless of the dose and delay in treatment, exosome treatment significantly improved sensorimotor and cognitive function, reduced hippocampal neuronal cell loss, promoted angiogenesis and neurogenesis, and reduced neuroinflammation. Exosome treatment at 100 µg per rat exhibited a significant therapeutic effect compared with the 50- or 200-µg exosome groups. The time-dependent exosome treatment data demonstrated that exosome treatment starting at 1 day post-TBI provided a significantly greater improvement in functional and histological outcomes than exosome treatments at the other 2 delayed treatments. Conclusions. These results indicate that exosomes have a wide range of effective doses for treatment of TBI with a therapeutic window of at least 7 days postinjury. Exosomes may provide a novel therapeutic intervention in TBI.

Potential therapeutic effects of endothelial cells trans-differentiated from Wharton’s Jelly-derived mesenchymal stem cells on altered vascular functions in aged diabetic rat model

BackgroundDiabetes mellitus in elderly represents an exceptional subset in the population vulnerable to cardiovascular events. As aging, diabetes mellitus and hypertension share common pathways, an ideal treatment should possess the ability to counter more than, if not all, the underlying mechanisms. Stem cells emerged as a potential approach for complicated medical problems. We tested here the possible role of trans-differentiated endothelial cells (ECs) in the treatment of diabetes mellitus in old rats.MethodsMesenchymal stem cells where isolated from umbilical cord Wharton’s Jelly and induced to differentiate into endothelial like-cells using vascular endothelial growth factor-enriched media. Thirty aged male Wistar albino rats were used in the present study. Rats were divided (10/group) into: control group (18–20 months old, weighing 350–400 g, received single intraperitoneal injection as well as single intravenous injection via tail vein of the vehicles), aged diabetic group (18–20 months old, weighing 350–400 g, received single intraperitoneal injection of 50 mg/kg streptozotocin, and also received single intravenous injection of saline via tail vein), and aged diabetic + ECs group (18–20 months old, weighing 350–400 g, received single intraperitoneal injection of 50 mg/kg streptozotocin, and also received single intravenous injection of 2*106 MSC-derived ECs in 0.5 ml saline via tail vein) groups. Assessment of SBP, aortic PWV, and renal artery resistance was performed. Serum levels of ET1, ANG II, IL-6, TNF-α, MDA, ROS, and VEGF were evaluated, as well as the aortic NO tissue level and eNOS gene expression. Histopathological and immunostaining assessments of small and large vessels were also performed.ResultsInduction of diabetes in old rats resulted in significant increase in SBP, aortic PWV, renal artery resistance, and serum levels of ET1, ANG II, IL-6, TNF-α, MDA, ROS, and VEGF. While there was significant decrease in aortic NO tissue level and eNOS gene expression in the aged diabetic group when compared to aged control group. ECs treatment resulted in significant improvement of endothelial dysfunction, inflammation and oxidative stress.ConclusionWe report here the potential therapeutic role of trans-differentiated ECs in aged diabetics. ECs demonstrated anti-inflammatory, antioxidant, gene modifying properties, significantly countered endothelial dysfunction, and improved vascular insult.

Comparison of protective effects of carvedilol and α-tocopherol on doxorubicin-induced cardiotoxocity

Background: Doxorubicin, an effective anticancer drug used to treat multiple solid tumours and childhood malignancies since many decades but its cardiac adverse effects limits its use in full therapeutic dose. The mechanism involved in cardiotoxicity is apoptosis of cardiomyocytes due to reactive oxidative stress. The study was conducted to compare the cardioprotective effects of carvedilol and α-Tocopherol and to detect myocardial injury at early stage.Methods: Cardiotoxicity was produced in a group of rabbits by single intravenous injection of doxorubicin; control group was treated with normal saline only. Third and fourth groups were pretreated with carvedilol 30 mg/kg bodyweight and α-Tocopherol 200 mg/kg bodyweight respectively for ten days before injection of doxorubicin.Results: Doxorubicin produced marked cardiotoxicity represented by raised levels of serum biomarkers (cTnI, LDH and CK-MB) and severe necrosis of cardiomyocytes on microscopic examination. Carvedilol and α-tocopherol pretreatment resulted in decreased serum levels of biomarkers and improved the histological picture of heart tissue.Conclusions: The outcome of doxorubicin chemotherapy can be made successful with the concurrent use of carvedilol or α-tocopherol. Although carvedilol has more pronounced cardioprotective effects perhaps due to its antioxidant activity in addition to antiapoptotic, antiproliferative and anti-inflammatory effects. Furthermore the quantitative cTnI estimation for detection of cardiotoxicity at early stage can lead to significant economic impact in management of cancer.