Medium-term antifungal effects of methylene blue versus flavin mononucleotide in the treatment of moderate toenail onychomycosis.

BACKGROUND: Methylene blue (MB) and flavin mononucleotide (FMN)-mediated photodynamic therapy (PDT) have demonstrated local antimicrobial effect, but no direct comparative study has been published so far for the treatment of toenail onychomycosis. OBJECTIVES: To directly compare the short and medium-term efficacy of MB versus FMN as photosensitizers in PDT for toenail onychomycosis by applying them in a 40% w/w urea cream in two different dye concentrations. METHODS: Forty toenails with distal and lateral subungual moderate onychomycosis due to dermatophyte fungi were randomised to receive 10 weekly sessions of PDT mediated by four topical formulations including MB or FMN at two different concentrations: Group I: 0.1% w/w MB; Group II: 2% w/w MB; Group III: 0.1% w/w FMN; and Group IV: 2% w/w FMN. Photographs were used for onychomycosis severity index (OSI) estimation allowing clinical assessment at any point of the study. Microscopic and microbiological evaluations were carried out at baseline, 27- and 35-week follow-ups. Side effects were recorded along with patient satisfaction. RESULTS: At week 27, mycological cure rates were 60%, 30%, 50% and 40% and complete cure rates were 0%, 20%, 10% and 20%, for Groups I, II, III and IV respectively. At week 35, mycological cure rates were 70%, 70%, 70% and 60% and complete cure rates were 30%, 50%, 70% and 30%, for Groups I, II, III and IV respectively. All cream formulations were safe and patients were fairly satisfied. CONCLUSIONS: Results of the present work confirm PDT as a therapeutic alternative for onychomycosis. Although all cream formulations were safe and effective, with a good degree of satisfaction, higher cure rates were obtained with 2% w/w MB cream and 0.1% w/w FMN cream.

Roseoflavin, a Natural Riboflavin Analogue, Possesses In Vitro and In Vivo Antiplasmodial Activity.

The ability of the human malaria parasite Plasmodium falciparum to access and utilize vital nutrients is critical to its growth and proliferation. Molecules that interfere with these processes could potentially serve as antimalarials. We found that two riboflavin analogues, roseoflavin and 8-aminoriboflavin, inhibit malaria parasite proliferation by targeting riboflavin metabolism and/or the utilization of the riboflavin metabolites flavin mononucleotide and flavin adenine dinucleotide. An additional eight riboflavin analogues were evaluated, but none were found to be more potent than roseoflavin, nor was their activity on target. Focusing on roseoflavin, we tested its antimalarial activity in vivo against Plasmodium vinckei vinckei in mice. We found that roseoflavin decreased the parasitemia by 46-fold following a 4 day suppression test and, on average, increased the survival of mice by 4 to 5 days. Our data are consistent with riboflavin metabolism and/or the utilization of riboflavin-derived cofactors being viable drug targets for the development of new antimalarials and that roseoflavin could serve as a potential starting point.

[Variants of postoperative delirium suppression in elderly patients.]

To study the effectiveness of the inclusion of Cytoflavin in the management of postoperative delirium treating in elderly patients. Analyzed the results of treatment of 89 elderly patients (65-74 years) who, according to similar emergency indications, underwent surgery and postoperatively showed signs of delirium (according to the DDS scale ≥8 points). Depending on the treatment regimen, the patients were divided into three groups: in the first (n=32) group, bromodihydrochlorophenylbenzodiazepine was administered intravenously (1-5 min) in a dose of 1 mg in the 1st group (n=32) to the group (patients of the 2nd group (n=28) with the same purpose and at the same time cytoflavin was injected: 10 ml of the drug in dilution per 200 ml of 10% glucose solution intravenously at a rate of 140 drops (7 ml) per minute. Patients of 3rd group (n=29) were injected with ethylmethylhydroxypyridine succinate intravenous (within 5-7 min) at a dose of 200 mg. The condition was assessed using the SOFA, DDS and RASS scales. The inclusion of drugs with antioxidant/membrane-protective action (Cytoflavin and ethylmethylhydroxypyridine succinate) in the treatment regimen of postoperative delirium in the elderly increases the effectiveness of treatment, which is manifested in more rapid relief of the condition. When comparing the efficacy of Cytoflavin and ethylmethylhydroxypyridine succinate, it was noted that in a number of indicators (restoration of spontaneous breathing, improvement after the first dose and complete relief of signs of delirium) both drugs showed comparable results, however, when assessing the depth of sedation (on the RASS scale), Cytoflavin was more effective (p=0,001).The obtained results of the effectiveness of cytoflavin in combination with good patient tolerance allows us to recommend the inclusion of the drug in the treatment regimens of this pathology.

[Substantiation of the drug «Cytoflavin¼ application and cognitive-behavioral therapy in complex treatment of deforming coxarthrosis in elderly patients.]

The article presents the results of a study of the effectiveness of the addition of a standard course of conservative therapy to 104 patients of the older age group with coxarthrosis deforming the drug «Cytoflavin¼ and cognitive-behavioral therapy courses. It was found that such scheme increases the effectiveness of therapeutic interventions, which manifests itself as the improvement of the mental and physical components of quality of life by reducing pain and increasing the functionality of some of the affected hip. At the heart of positive clinical effect is a decrease in processes of inflammation and reduction of tension of regulatory processes in the organism.

[Modern approaches to components of therapy of patients with diabetes mellitus operated on for malignant neoplasms of small pelvic organs]. / Sovremennye podkhody k komponentam terapii bol'nykh sakharnym diabetom, operiruemykh po povodu zlokachestvennykh novoobrazovanii organov malogo taza.

The purpose of this study was assessment of the effect of cytoflavin preparation inclusion in surgical treatment of patients with malignant neoplasms of small pelvic organs and diabetes mellitus. A prospective examination of 51 patients aged 56 to 76 years suffering from diabetes mellitus and malignant neoplasms of the pelvic organs was performed. Patients were divided into two groups: the first group consisted of 27 patients whose adaptive potential was characterized by tension of adaptation mechanisms, the second one - 24 patients with poor adaptation. In turn, in each group, patients were divided into subgroups depending on the treatment regimen: in the main subgroup of the first group (14 people) the treatment program was supplemented with cytoflavin (10 ml 2 times a day), in the main subgroup of the second group were 13 patients with cytoflavin supplement (20 ml 2 times a day). Patients of control groups underwent standard therapy. State of energy deficiency was assessed by methemoglobin, carbohemoglobin, P50, oxygen delivery, consumption and extraction. Concentration of glucose, lactate, lactate dehydrogenase was assessed. The results of the study showed clear relationship between the nature of changes in transport and oxygen consumption, adaptation adaptive reactions, allowing to identify mechanisms that characterize formation of various types of energy deficiency in perioperative period in patients with malignant diseases of the pelvic organs and diabetes. Use of cytoflavin contributed to a qualitative and effective correction of energy deficiency as well as reduction in the patients stay in the hospital.

SURGICAL PREVENTION AND TREATMENT OF POSTOPERATIVE HYPOPARATHYROIDISM IN PATIENTS OPERATED ON THYROID GLAND.

The objective of the research was to develop and evaluate the algorithm of prevention and treatment of postoperative hypoparathyroidism (PHPT) based on determining parathyroid glands (PTG) viability and the use of antihypoxant-antioxidant therapy in the postoperative period. The research was based on the results of a comprehensive examination and treatment of 60 patients who were operated for thyroid gland diseases. The patients underwent inpatient treatment at the surgical department of Ivano-Frankivsk Central City Clinical Hospital and Ivano-Frankivsk Regional Oncology Center from 2015 to 2017. We proposed an algorithm for surgical prevention and treatment of PHPT during thyroid gland surgeries which consisted in the following. We performed a visual assessment of PTG intraoperatively and evaluated each gland from 0 to 3 points according to the degree of its viability affection. If the gland was evaluated at 0-2 points, we left it in situ, since there was a high probability of maintaining its function. If it was evaluated at 3 points, its autotransplantation was performed. Cytoflavin drug was applied in a dose of 10 ml per 200 0.9% NaCl intravenously once a day during 7 days in the postoperative period for the purpose of antihypoxant-antioxidant therapy. 2 groups of patients were formed in order to evaluate the effectiveness of the algorithm. Each group consisted of 30 people. Patients of Group I underwent surgery on thyroid gland according to generally accepted rules. Patients of Group II underwent interventions according to the above-mentioned algorithm. The use of our proposed algorithm (intraoperative assessment of PTG viability and antihypoxant-antioxidant therapy in the postoperative period) significantly reduces the frequency of permanent PHPT justifying indications to its application.

[SUBSTANTIATION OF INDICATIONS FOR BIOFEEDBACK THERAPY AND CYTOFLAVIN APPLICATION IN TREATMENT OF OSTEOCHONDROSIS NEUROLOGICAL COMPLICATIONS IN ELDERLY PATIENTS].

The aim of the study was to assess the impact of cytoflavin and bioflavin therapy on the dynamics of clinical and psychophysiological status of patients with Osteochondrosis. 150 patients with osteochondrosis of a backbone were investigated. The patients were divided into two groups using method of randomization: the main group - 75 patients - and control group -75 patients. All patients received a standard treatment (non-steroidal anti-inflammatory drugs, myorelaxants, chondroprotectors, as well as physiotherapy). The main group in addition to standard treatment received biofeedback therapy and cytoflavin. The results showed that cytoflavin and biofeedback therapy significantly enhanced the positive effect of standard treatment and significantly increased the quality of life of patients. It is recommended to treat elderly patients with neurological complications of spinal osteochondrosis with Cytoflavin in combination with biofeedback therapy Before prescribing biofeedback therapy and Cytoflavin it is necessary to take into account a number of positive and negative predictors of their effectiveness in reducing severity of pain syndrome.

[Peculiarities of clinical and psychophysiological status of elderly patients with osteochondrosis.]

We conducted a study of 220 patients in polyclinic № 91 in St. Petersburg. It was revealed that elderly patients with osteochondrosis are characterized by a high prevalence and severity of osteochondrosis against the background of metabolic disorders in the structures of the spine. At the same time, the actual condition of the spine does not always determine the severity of the pain syndrome. The effect of osteochondrosis on the development of comorbid pathology has been clarified. The ways of correction of the clinical and psychophysiological status of elderly patients with osteochondrosis such as appointment of Cytoflavin, behavioral therapy and biofeed back therapy are suggested.

[THE EFFECT OF CYTOFLAVIN ON PARAMETERS OF THE LEFT VENTRICULAR SYSTOLIC FUNCTION IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION.]

The effect of cytoflavin on parameters of the left ventricular systolic function (LVSF) during acute myocardial infarction was studied in a group of 46 patients which received this drug (in addition to standard therapy) intravenously as 20 mL of Polysan solution (St. Petersburg, Russia) diluted in 250 mL of 5% glucose solution once a day 30 min before coronary artery recanalization. The control group of 60 patients received only standard therapy. The drug effectiveness was evaluated in terms of LVSF parameters including the ejection fraction, end-diastolic volume, and end-systolic volume. The introduction of cytoflavin to pati- ents led to (i) increase in the ejection fraction of left ventricle by 7.9% as compared to patients of the control group and (ii) decrease in the end-diastolic and end-systolic volume of the left ventricle on 7th day of hospitalization by 10.6% and 17.9%, respectively (p < 0.05). The addition of cytoflavin to standard the- rapy significantly reduced the level of troponin I on the 7th day in patients with acute myocardial infarction down to 81% relative to the control and the activity of creatine kinase by 35% (p < 0.05). The inclusion of cytoflavin in the treatment of patients with acute myocardial infarction should be considered as pathoge- netically proved, clinically justified, and promising therapy.

[EFFICACY OF CYTOFLAVIN IN COMPLEX TREATMENT OF DIABETIC FOOT SYNDROME].

The study involved 97 patients with severe diabetic foot syndrome (DFS) subcompensated type 2 diabetes. All patients were available mediacalcification foot and lower leg arteries of different severity. Depending on the treatment, all patients were divided into 2 groups by stratified randomization. The І group received standard therapy, which is indicated for the DFS. A ІІ group of patients additionally received basic therapy drug Cytoflavin 10 ml 0,9% NaCl 200 ml for 10 days, followed by transfer to tablet form Cytoflavin 2 tablets 2 times per day orally for one month. We noted a positive trend of treatment of patients who, in addition to standard therapy received the drug Cytoflavin. Thus, the use of complex surgical treatment of patients with mixed form of DFS Cytoflavin reduces the severity of distal polyneuropathy, improves oxygenation of tissues and restores the enzyme activity of antioxidant system, that manifested neuroprotective, antioxidant and anti-hypoxic effects of drugs, which substantiates the indications for its use in the this pathology.

[TACTICS OF CHOOSING COGNITIVE DYSFUNCTION THERAPY IN THE POSTOPERATIVE PERIOD].

The aim of the study is to formulate the tactics of assigning adequate neuroprotective therapy to patients with postoperative cognitive dysfunctions on the basis of subtracting the indicator of the total cognitive deficiency. To achieve this goal, we conducted a study of cognitive function in patients of different age groups: young age, middle age, elderly age with acute surgical pathology before surgery and at 1, 7, 30 days after surgery compared with preoperative data. Methods of research. The study of the cognitive sphere: scale MMSE, test drawing hours, test "10 words", battery tests for frontal dysfunction, method Schulte. The indicator of the total cognitive deficiency was calculated.  The results of the study of cognitive function made it possible to formulate a scheme for the use of citicoline and cytoflavin in a complex of therapeutic programs. In each age group, on the seventh day of the study, there were patients with different dynamics of cognitive function recovery for the preoperative period. This allowed us to develop and propose a formula for calculating the total cognitive deficit, which makes it possible to formulate appropriate tactics for managing patients in the subsequent period in each specific case. We determine the values ​​of the percentage deviations of each study result from the norm and the indicator of the total cognitive deficit by the sum of the values ​​of the percentage deviation from the norm of the results of the study of cognitive impairment.

[The effectiveness of the combined use of energomonitor antioxidant and cognitive psychotherapy in the treatment of generalized periodontitis in elderly patients].

The aim of the study was to evaluate the effect of combined use of Cytoflavin and cognitive therapy on the dynamics of psychosomatic status and effectiveness of the treatment of generalized periodontitis in elderly patients. The results of treatment of 103 patients aged 60 and older were analyzed. All patients received standard therapy for 10-14 days depending on the severity of the process. In addition, the patients of the main group (51 patients) received Cytoflavin: 2 tabs. 2 times a day with an interval between doses of 8-10 hours for 25 days, and cognitive therapy aimed at training alternative realistic way of life perception. Treatment results were monitored by PMA, Russell periodontal index (PI), Green-Vermillion hygienic index. Psychosomatic dynamics was assessed by means of Spielberger anxiety scale and SUN" methods of before and after a month of treatment. The inclusion in the treatment regimen of Cytoflavin and cognitive therapy had a positive impact: reduction of PMA by 61.8%, PI by 45.3% and Green-Vermillion index by 39.8%. The psychosomatic tests proved anxiety level decrease by 28.7% in terms of "reactive" anxiety and 31.5% in terms of "personal" anxiety, emotional status (21.2%), activity (21.7%) and mood (21.8%) improvement.

Comparative evaluation of contemporary methods of treatment and rehabilitation of post-apoplexy patients.

The study was aimed to compare efficiency of optimized and combined treatment and rehabilitation in post-apoplexy patients, using standard therapy, cytoflavin and COBS-training. The study involved 51 patients in early (n = 25) and late (n = 26) recovery periods after CVA. Reference groups included patients in early (n = 15) and late (n = is) recovery periods, receiving basic therapy. Evaluations included thepatients' complaints change, activity index (Bartel scale), neurologic state (NIHSS scale), static and locomotory disorders intensity (M.E. Tinetti scale), ultrasound dopplerography, MALDI-TOF-TOF mass spectrometry of serum. Implementation of cytoflavin and COBS-training in CVA patients in early recovery period resulted in better life quality, decrease in neurologi deficit, less static and locomotory disorders, increased average blood velocity, RI, PI on ICA siphon and lower average blood velocity, RI, PI on MCA in comparison with reference groups and CVA patients in late recovery period. Findings are molecular groups of cellular apoptosis, autophagy, necroptosis, ER stress in serum -. explanation of additional links of cytoflavin and COBS-training action mechanism in post-apoplexy patients.

Novel riboswitch-binding flavin analog that protects mice against Clostridium difficile infection without inhibiting cecal flora.

Novel mechanisms of action and new chemical scaffolds are needed to rejuvenate antibacterial drug discovery, and riboswitch regulators of bacterial gene expression are a promising class of targets for the discovery of new leads. Herein, we report the characterization of 5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione (5FDQD)-an analog of riboflavin that was designed to bind riboswitches that naturally recognize the essential coenzyme flavin mononucleotide (FMN) and regulate FMN and riboflavin homeostasis. In vitro, 5FDQD and FMN bind to and trigger the function of an FMN riboswitch with equipotent activity. MIC and time-kill studies demonstrated that 5FDQD has potent and rapidly bactericidal activity against Clostridium difficile. In C57BL/6 mice, 5FDQD completely prevented the onset of lethal antibiotic-induced C. difficile infection (CDI). Against a panel of bacteria representative of healthy bowel flora, the antibacterial selectivity of 5FDQD was superior to currently marketed CDI therapeutics, with very little activity against representative strains from the Bacteroides, Lactobacillus, Bifidobacterium, Actinomyces, and Prevotella genera. Accordingly, a single oral dose of 5FDQD caused less alteration of culturable cecal flora in mice than the comparators. Collectively, these data suggest that 5FDQD or closely related analogs could potentially provide a high rate of CDI cure with a low likelihood of infection recurrence. Future studies will seek to assess the role of FMN riboswitch binding to the mechanism of 5FDQD antibacterial action. In aggregate, our results indicate that riboswitch-binding antibacterial compounds can be discovered and optimized to exhibit activity profiles that merit preclinical and clinical development as potential antibacterial therapeutic agents.

[Performance evaluation of integrated cytoprotective therapy of different duration in patients with cerebral infarction].

The paper reviews the preliminary results of a multicenter randomized clinical research. The aim of the study was to determine the optimal duration of different types of energy-correction therapy. 99 case report forms of patients with cerebral infarction were reviewed with their prior envelope randomization into three groups. Patients in the first group (experimental group), consisting of 32 patients, as part of combined therapy received ascorbic acid (5% solution twice a day in a recommended dosage of 20 ml/day for 20 days); the second group (37 patients) received 10 ml of cytoflavin intravenously by drop infusion twice a day for 10 days; the third group received cytoflavin for 20 days (from day 1 to day 10 - 20 ml a day, from day 11 to day 20 - 10 ml a day). The average NIH scale score on admission was 14.9 ± 2.6. Prescription of cytoflavin came with average 1.7 - 1.8 time regression (p < 0.05) of the volumes of cerebral ischemia in the of cases of the 10- and 20-day courses of treatment, while there were no significant morphologic changes in the ascorbic acid group. These results correlated with the best dynamics and outcomes of the neurological and performance status of patients receiving cytoflavin. Despite the lack of significant general differences in the clinical and morphological data of the second and third groups, the patients with underlying grave medical condition in the 20-day cytoflavin group (with NIH score of 14-20 points on admission) tended to have improved neurologic status parameters in comparison with the experimental group and the 10-day cytoflavin group. These results attest to the advantages of personalized antioxidant energy-correction therapy.

[PREVENTION AND CORRECTION OF PULMONARY COMPLICATIONS FOR SEVERE ACUTE PANCREATITIS].

Increased of proinflammatory cytokines levels, including interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) on severe acute pancreatitis causes vasodilatation, increased permeability of the wall, accumulation of fluid in lung tissue and pleural sinuses. Transudate from acute parapancreatyc clusters of hot liquid and abdomen falls into the chest cavity through microscopic defects in the diaphragm due to the formation of pathological pleural-peritoneal connections or the relevant pressure gradient between the abdominal and pleural cavities. Remediation and removal of acute parapancreatyc clusters combined with the use of a multicomponent drug infusion therapy Cytoflavin provide a reduction in the frequency of pulmonary complications of acute pancreatitis from 48.3 to 31.0%. Use of the drug Cytoflavin reduces the severity of endogenous intoxication and mortality from acute lung injury from 12.9 to 6.1%.

[Modern methods of energy homeostasis correction in elderly patients].

In the multicenter randomized clinical-instrumental prospective study 185 patients aged 55-75 years (mean age 68 years) with 94 men and 91 women with cerebral infarction were included. All the patients were hospitalized in the period from 6 to 24 hours from the time of the debut of clinical symptoms, 42,2% of patients scored 14 and above on NIH scale on admission. Patients were randomized into 3 groups: 1st group consisted of 64 patients treated as an antioxidant by 5% solution of ascorbic acid 2 times a day the recommended dose (20 ml/day) for 20 days; 2nd group consisted of 72 patients who received energy monitor Cytoflavin in a daily dose of 20 ml (10.0 ml/drip 2 times a day for 10 days); 3rd group consisted of 49 patients with Cytoflavin therapy extended to 20 days, moreover from 11th to 20th day the dose was 10 ml/day. Cytoflavin treatment was more efficient than ascorbic acid, which can be explained by different pharmacologic mechanisms. Treatment with Cytoflavin for 10 days resulted in a significant decrease of ischemia zone volume by 25% in average, treatment with Cytoflavin for 20 days--by 29%, which manifested in better outcomes in neurologic and functional status. Ascorbic acid demonstrated no effect on morphologic parameters. Patients having at the time of admission 18-20 points according to the NIH and treated with Cytoflavin for 20 days demonstrated significant trend towards improvement of the parameters of the neurological status.

[Efficiency of intensive care with cytoflavin in patients of advanced age in combined traumatic brain injury].

Research objective--determination of efficiency of intensive care with inclusion Cytoflavin in patients of old age in combined traumatic brain injury. A prospective controlled blind randomized study was conducted. In 1st group (21 people) the patients received a standard intensive care, in 2nd group (18 persons) Cytoflavin was included in complex intensive care. Using Cytoflavin starting from 2 days post-traumatic period (with the correction of blood circulation and respiration) had antioxidant and detoxification effects, contributed to the recovery rate of free radical and metabolic processes, reduced the degree of impairment in the structural-functional state of membranes and restored the conformational structure of membrane proteins in the earlier periods. Reduction in reactions of disadaptation led to regression of multiple organ dysfunctions, restoration the level of consciousness at an earlier date. The number of cases of severe respiratory distress syndrome decreased.

[Gerontological trends of contemporary forms of alcohol dependence. Approaches to full compensation and rehabilitation].

Quality of life has already been investigated in elderly patients with alcohol dependence. Indicators were deteriorated with long-term experience of alcohol and somatic diseases. Practice of Reamberin, Cytoflavin, Cycloferon has improved quality of life and physical status of elderly patients.

[The study of the effectiveness of drug prevention mechanisms of cardiovascular aging by cytoflavin].

The aim of the research was the search of the mechanism of Cytoflavin action in patients with isolated systolic arterial hypertension (ISAH) as the aging model. The following research methods were applied: the assessment of complaints, 24-hour arterial pressure monitoring, ultrasound diagnostic, volume sphygmography, lipid profiles and coagulogram, molecular phenotyping by MALDI-TOF-TOF-MS. The combination of Cytoflavin with standard therapy of ISAH led to the most expressed return development of clinical symptoms, the restoration of the haemodynamics, structural and geometrical parameters of cardiovascular system, indicators lipid profiles and coagulogram in the comparison with patients with ISAH, who accepted standard therapy and those of the control groups. Molecular mechanisms of Cytoflavin action, including regulation of the activity of cell signaling pathways through intermolecular interactions were found. We recommend using Cytoflavin together with the standard therapy in treatment of ISAH, which provides the action of geroprotectors for cardiovascular system.