Melatonin and its bioisosteres as potential therapeutic agents for the treatment of retinopathy of prematurity.

We conducted a study on the impact of intraperitoneal injections of melatonin and its three bioisosteres (compounds 1-3) on the development of oxygen-induced retinopathy in newborn rats during a 21-day experiment. It was demonstrated that melatonin and its analogues 1-3 effectively reduce the total protein concentration in the vitreous body of rat pups, decrease concentration of VEGF-A, and lower the level of oxidative stress (as indicated by normalization of antioxidant activity in the vitreous body). Melatonin and its analogues 1-3 equally normalize the level of VEGF-A. Analogues 1 and 2 even exceed melatonin in their ability to reduce protein influx into the vitreous body. However, analogue 2 had no effect on antioxidant activity, while analogues 1 and 3 caused a significant increase in this parameter, with analogue 3 even slightly exceeding melatonin. Thus, it can be concluded that analogues 1-3 are comparable to melatonin and can be utilized as potential therapeutic agents for the treatment of retinopathy of prematurity.

Enalaprilat as a new means of preventing the development of retinopathy of prematurity.

In a rat model of experimental retinopathy of prematurity (ROP), the safety of enalaprilat and its effect on the level of angiotensin-converting enzyme (ACE) and angiotensin-II (AT-II) in the vitreous body and retina were investigated. The study was performed on 136 newborn Wistar rat pups divided into 2 groups: group A - experimental (animals with ROP, n=64) and group B - control (n=72). Each group was further divided into 2 subgroups: A0 and B0 (n=32 and n=36, respectively) - animals that did not receive injections of enalaprilat, and A1 and B1 (n=32 and n=36, respectively) - animals treated with daily intraperitoneal (i.p.) injections of enalaprilat (0.6 mg/kg of body weight). This treatment started on day 2 and lasted either to day 7 or to day 14 in accordance with the therapeutic scheme. Animals were taken out of the experiment on day 7 and day 14. In samples of the vitreous body and retina, the content of ACE and AT-II was determined by enzyme immunoassay. On day 7 in subgroups A1 and B1 the levels of ACE and AT-II in the vitreous did not differ, while on day 14 were lower than in subgroups A0 and B0, respectively. Changes in the parameters studied in the retina were somewhat different from those found in the vitreous body. On the seventh day, the level of ACE in the retina of animals of subgroup B1 did not differ significantly from subgroup B0, and in subgroup A1 it was increased compared to subgroup A0. On day 14, its significant decrease was noted in subgroups A1 and B1 as compared with subgroups A0 and B0. At the same time, the level of AT-II in the retina of rat pups of subgroup B1 was lower than in subgroup B0, both on day 7 and day 14. On day 7, the concentration of AT-II, as well as the concentration of ACE, increased in subgroup A1 as compared to subgroup A0. On day 14, this parameter in subgroup A1 was significantly lower as compared to subgroup A0, but significantly higher than in subgroup B1. It should be noted that i.p. injections of enalaprilat, increased a death rate of animals of both groups. The use of enalaprilat, starting from the preclinical period of the ROP development, led to a decrease in the activity of the renin-angiotensin system (RAS) in ROP animals at the onset of retinopathy in the experimental model used. This opens up prospects for considering enalaprilat as a means of preventing the development of this pathology; however, the recognized high toxicity of the drug requires further studies and correction of the timing of its administration and dosage in order to achieve a balance of efficacy and safety of use in order to prevent the development of ROP in children.

Poplar tree (Populus balsamifera L.) as indicator of mercury emission from a point source.

The article provides original data on the ecological and geochemical characteristics of the distribution of Hg in the leaves and annual rings of balsam poplar (P. balsamifera L.) in the zone of influence of lithium production (Novosibirsk). In 2017 high Hg concentration (1300 ng/g) in the poplar leaves was recorded in the northeastern part of the city near the industrial facility of the lithium plant. The investigation showed a clear trend of increased Hg accumulation in the poplar leaves during the growing season. The maximum average Hg content was detected in the leaf litter in 2006 (1153-2425 ng/g). However, the average Hg content in the soil is 294 ng/g, which is significantly lower than the threshold limit value (2100 ng/g). Studies of changes in the content of Hg with the height of the crown of the tree revealed an increase in the upwind side of the emission source, the concentration of Hg in the leaves is on average 1.5 times higher than on the side of the "wind shadow". Hg in poplar leaves, leaf litter, and soils is mainly found in free and physically bonded forms - the most mobile, prone to increased migration, transformation and methylation under environmental conditions. According to the Hg content in the poplar cores, an increase in the Hg input near the source was established with the beginning of Li production - in the period 1967-1985 years (441 ng/g) with a subsequent decrease to 6 ng/g in 2000-2017.

[Pathogenetically oriented approach to prevention of retinopathy of prematurity (experimental study)]. / Patogeneticheski orientirovannaya profilaktika retinopatii nedonoshennykh (eksperimental'noe issledovanie).

Intraperitoneal injections of exogenous melatonin during the development of the retinal vascular system in experimental rats has been shown in a number of experimental studies on the model of EROP to prevent the appearance of histological signs of the development of experimental retinopathy of prematurity (EROP), stabilize the blood-retinal barrier and have a pronounced antioxidant effect, but pathogenetic basis for these phenomena hasn't been studied. PURPOSE: To study the influence mechanism of melatonin and its analogues on the development of EROP at the preclinical stage of the pathological process to substantiate new approaches to prevention of ROP. MATERIAL AND METHODS: The study included 42 Wistar rat pups (84 eyes) divided into 6 groups: control group, experimental group (rat pups with EROP), experimental groups who underwent injections of melatonin and its analogues K-148, AL-3, K-096. The pups were euthanized on day 7 (4-5 pups from each group at each study period), binocular enucleation was performed, and the content of hypoxia-induced factor1α (HIF-1α) and VEGF-A was determined in retinal samples. RESULTS: The intraperitoneal injections of melatonin and its analogs led to a significant decrease in the level of HIF-1α and VEGF-A in the retina of the rat pups of the experimental group until the beginning of pathological vasoproliferation. CONCLUSION: Melatonin and its analogues are able to prevent the development of EROP by reducing the level of angiogenic factors in the retina of rat pups at the stage of existing avascular zones, which allows for them to be considered as a new promising approach to preventing the development of ROP.

The Role of Catecholamines in the Development of Pathological Retina Neovascularization in an Experimental Model of Retinopathy of Prematurity in Rats.

This work is dedicated to proving our hypothesis that catecholamines and their metabolites play a crucial role in the development of retinopathy of prematurity, which leads to progressive uncontrollable vascularization in the retina, leading to blindness. The study was performed in an animal model of retinopathy of prematurity, which was achieved by hyperoxygenation in rats on postnatal days 7, 14, 21, and 30. The content of catecholamines and their metabolites in the retina of rats was determined by high performance liquid chromatography with electrochemical detection. It was shown that, in the rats with retinopathy, the content of L-DOPA on days 21 and 30 was decreased as compared to the control, whereas the content of noradrenaline on day 14 life increased compared to the control. However, we did not observe changes in the content of dopamine in the experimental animals relative to the control in any period studied. Given the published data on the involvement of catecholamines in the regulation of vasculogenesis in the retina in normal state, our data on the changes in the catecholamine metabolism in the retina in the model of retinopathy of prematurity can be regarded as evidence of the important role of catecholamines in the pathogenesis of this severe disease.

[Melatonin as a new promising agent for the treatment and prevention of retinopathy of prematurity]. / Eksperimental'noe issledovanie vozmozhnosti primeneniya melatonina v lechenii i profilaktike retinopatii nedonoshennykh.

AIM: To evaluate the effect of exogenous melatonin on the blood-retinal barrier and oxidative status of the vitreous in rats with oxygen-induced retinopathy (OIR) and analyze its prospects in the treatment and prevention of retinopathy of prematurity (ROP). MATERIAL AND METHODS: The study was performed on 48 Wistar rat pups (96 eyes) divided into 4 groups 12 animals each: OIR group, melatonin group and two control groups. In order to induce retinopathy, rat pups and does were placed in an incubator for 14 days after birth. Oxygen concentration in the incubator changed from 60 to 15% every 12 hours. The controls for this experiment were rats that grew under normoxic conditions (21%). The two other groups of rats were injected with 30 ml intraperitoneal melatonin (Sigma-Aldrich) in sterile 0.05 M phosphate buffer (pH 7.4) at a dose of 10 mg/kg for 14 days starting on day 1. The pups were killed on days 7 (n=16), 14 (n=16), and 18 (n=16). Binocular enucleation was performed in all cases. The total protein level and antioxidative activity (AOA) were then measured in vitreous samples. RESULTS: Oxygen-induced retinopathy had two phases and was accompanied by a sharp increase in the vitreal AOA and total protein. After intraperitoneal melatonin injections made during the period of early OIR-associated vascular changes, the said parameters were decreased down to near-control values at any times during the follow-up period. CONCLUSION: Exogenous melatonin, due to its strong antiangiogenic and antioxidant activity, helps stabilize the blood-retinal barrier in OIR.

[STAGES OF OPIOID THERAPY OF CHRONIC PAIN IN RUSSIA: ANCIENT AND COMING].

There is history of the introduction and development of systemic and invasive opioid treatment of chronic cancer pain in Russia presented by the authors--experts with experience in thisfield over 30 years. The earliest researchers are no more among us, but their memory is still alive in the publications of the early 1980's. Along with the analysis of accumulated by Russian specialists positive clinical experience of opioids using, authors discuss main problems of organization and availability of adequate opioid therapy of chronic pain in Russia. Ways of further development ofpalliative care and pain management in oncology is discussed as well as.

[Trends in world science and practice of pain treatment].

In recent days there are two main conceptions of the treatment of strong pain. The first conception is a system multimodal analgesia and the second is a multidisciplinary therapy including invasive techniques (local nervous blockades, neuroaxial blockades, neurostimulating or drug therapy with implanted systems etc.), physical, manual, and psychological effecting on peripheral and central nervous system. A physician (anaesthesiologist, oncologist, neurologist etc.) treats the pain according to interests of a patient. Multidisciplinary pain treatment, which is recommended by the American Pain Association, requires the use of special equipment for effecting on nervous system of the patient and contains conflict of interests of managers, medical workers, equipment providing companies and other parts of the multidisciplinary process. Therefore there is a risk that commercial benefit can get a main role in the process of pain treatment, but not interests of the patient. The "industrial" approach in the pain treatment is connected with many negative outcomes such as a minimizing of the role of pain science, increasing of complications risks due to invasive techniques of the pain relief etc. Therefore an objective analysis of pain treatment outcomes is needed Helsinki Declaration of a patient safety in surgery approved by European Society of Anaesthesiology in June, 2010 requires an accounting system of critical incidents, complications and assessment of outcomes in perioperative anaesthesiological practice. The same study is very actual for Russia especially to compare a safety of the system multimodal anaesthesia/analgesia and epidural blockades in major surgery.

[The algorith of preoperative cardiovascular therapy in high risk elderly oncology patients].

The study was based on 478 oncology patients (72.1 +/- 3.6 years old) with cardiovascular comorbidities operated from 1991 to 2008 in regards of abdominal and pelvic mainly 3rd stage tumors with multimodal general anesthesia (4.2 +/- 1.6 hours). In prospective group (n = 302) all patients received cardiovascular treatment, while in retrospective group (n = 176) only 48.9% received it. The evaluation of the cardiovascular therapy effect was based on the peri-operative and postoperative HR and BP dynamics. The occurrance of noticeable bradycardia and drop of BP lower than 90/60 mm Hg was considered as a deviation. It is revealed that the cardiovascular therapy with beta adrenoblockers and calcium antagonists leads to an intraoperative bradycardia in 59.8% and 73.7% of cases, while in patients without the aforementioned therapy in 26.6% and 46.4% of cases respectively (p < 0.05). Antiarrhythmics don't have a noticeable impact on the development of bradycardia (p = 0.204). Intraoperative hypotension on the basis of ATP inhibitor treatment developed in 92.2% of patients statistically significant (p < 0.01). Monotherapy with calcium antagonists or nitrates leads to the development of hypotension in 55.2% and 41.4% of cases respectively, though in patients without the given therapy a lot more often (p < 0.05). In the case of combined calcium antagonist/nitrate therapy hypotension develops in 55.5% of cases, and in 72.3% without the therapy (p < 0.05). For the means of prevention of cardiovascular complications during the surgical treatment it is appropriate to keep the therapy with nitrates, though vasodilatives should be canceled 12 hours before the surgery.

[Prevention and treatment of postoperative pain syndrome in extensive thoracoabdominal oncological surgery].

A procedure has been developed and tested to prevent and treat postoperative pain syndrome during extensive thoracoabdominal surgery for esophageal cancer. The procedure is based on the preventive (12 hours before anesthesia and surgery) application of Durogesic (fentanyl transdermal therapeutic system (TTS)) at an opioid release rate of 50 microg/h for 72 hours. By the end of surgery and anesthesia when intravenous injection of fentanyl is stopped, analgesia continues to be maintdined due to its therapeutic dose coming from TTS. This prevents the development of acute opioid tolerance, hyperalgesia, and destabilization state in the early postanesthetic period and creates the basis for continuous multimodal postoperative analgesia in combination with nonopioid components (lornoxicam, perfalgan) and with none or minimal need for the injectable opioid. This allows an operated patient to have a comfort and stable state. A further investigation on the comparative assessment of the developed procedure with other variants of perioperative systemic and combined anesthesia-analgesia is to be conducted.

[Diagnosis and risk assessment of perioperative cardiovascular complications in geriatric patients in oncological surgery].

Cardiovascular events (CVE) developing at the stages of surgical treatment in 449 geriatric (aged 72 +/- 5.8 years) cancer patients with concomitant cardiovascular diseases (CVD) were quantitatively and qualitatively analyzed. Statistical analysis was used to compare and establish a discrepancy between the results of a predictable risk by the standard scale of the international perioperative CV risk index (ICVRI) and the actually developed complications. The logistic regression method was employed to analyze the risk factors included into the ICVRI scale. The risk factors that were best in predicting the development of CVE were determined. A mathematical formula was derived to estimate the adjusted prognosis of an individual cardiovascular risk. Based on their perioperative CV risk classification, the authors constructed an algorithm of a diagnostic search and surgical preparation tactics in seriously ill cancer patients with concomitant CVD. The algorithm has been put into the routine practice of the P. A. Herzen Moscow Research Institute of Oncology, which makes it possible to improve the results of surgical treatment in geriatric patients and to expand its indications. Examples of clinically applying the algorithm are given.

[Choice of components and a method of anesthesia in geriatric cancer patients with high cardiovascular risk].

Investigations were made at surgical treatment stages in 102 cancer patients (mean age 72 +/- 5.8 years) at high cardiovascular risk, who received continuous therapy that reduced heart rate and blood pressure, in order to compensate for the course of coronary heart disease and arterial hypertension. The time course of changes in the major circulatory and metabolic parameters was analyzed in patients during operations on the abdomen and small pelvis while using three different multimodal anesthetic techniques (general intravenous anesthesia-based diazepam, propofol, fentanyl, ketamine; sevofluorane-based inhalational; combined epidural and intravenous one). The advantages and limitations of the above methods were shown in patients on cardio- and vasotropic therapies. Correcting modes (transesophageal atrial pacing, morning-dose drug withdrawal) for its possible related bradycardiac and hypotensive disorders, which reduce a risk of perioperative cardiovascular complications, are set forth.

[Intra- and postoperative correction of bradycardia by transesophageal electric stimulation].

The authors describe a case of clinical use of transesophageal pacing to correct drug-induced bradycardia during anesthesia, surgery, and in the early postoperative period in a geriatric patient with severe cardiovascular comorbidity who has been long receiving a beta-adrenoblocker. They show it possible to employ the procedure long in the therapy of bradyarrhythmias resistant to the cholinolytic atropine.

[Antioxidants treatment of severe post-operative pyoinflammatory and septic complications].

New medical human lactoferrin product called Laprot possessing antioxidant, detoxicant, anti-inflammatory immunomodulating properties was developed and registered (serial number LS-002374) in the P.A. Hertsen Institute. System (intravenous) administration of Laprot is efficacious detoxicant and anti-inflammatory treatment in patients with severe postoperative pyoinflammatory and septic complications accompanied by polyorgan failure. Local administration contributes to clinically apparent cleansing of festering wounds and cavities, regress of local pyoinflammatory processes, reduction of local purulo-necrotic processes of trachea's mucosa. Laprot administrated intravenously as in the case of topical administration is well tolerated by the patients and doesn't cause any side affects.

[Comparative assessment of methods for prevention of microvascular anastomotic thrombosis at reparative plastic surgery for cancer].

Four therapeutic-and-prophylactic drug complexes aimed at preventing microvascular anastomotic thrombosis and used as a part of anesthesiological appliance and intensive care were studied in 83 cancer patients who underwent planned extensive reparative plastic operations with microsurgical autoplasty. The drug complexes included pathogenetically substantiated special agents, such as low molecular-weight heparin (nadroparin), the gas-transport blood substitute perfluorane, the kininogenesis inhibitor (aprotinine), the nonsteroidal anti-inflammatory drug ketoprofen, the disaggregant pentoxifylline (trental), which were given in various combinations. The study of hemostatic parameters and the analysis of postoperative (hemorrhagic, necrotic) complications have demonstrated that fraxiparin-perfluorane-contrycal and fraxiparin-trental-contrycal are the most optimal therapeutic-and-prophylactic complexes to preserve the viability of autografts during oncological operations with microsurgical autoplasty.