Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.

[Assessment of the efficacy of mexidol in the combination with hyperbaric oxygen in acute ischemic stroke]. / Otsenka éffektivnosti primeneniia meksidola v sochetanii s giperbaricheskoi oksigenatsiei u bol'nykh v ostreishem periode ishemicheskogo insul'ta.

To study the efficacy of mexidol in the combination with hyperbaric oxygenation (HBO) in comparison with the standard HBO sessions in patients with acute ischemic stroke. One hundred and twelve patients were examined. In the main group, 48 patients underwent HBO and received treatment with mexidol. The control group consisted of 64 people who underwent the standard HBO sessions only. The use of combination therapy (HBO+mexidol) leads to the significantly more rapid normalization of acute phase indices which are correlated with neurological deficit reduction.

[Dynamics of eeg and psychophysiological indicators of acute poisoning neurotoxicants on the stage of rehabilitation on the background of different methods of treatment]. / Dinamika elektroentsefalograficheskikh i psikhofiziologicheskikh pokazatelei pri ostrykh otravleniyakh neirotoksikantami na etape reabilitatsii na fone razlichnykh metodov lecheniya.

AIM: To evaluate the dynamics of functional activity of brain structures underlying cognitive functions in patients with encephalopathy due to poisoning with neurotoxicants on the stage of rehabilitation. MATERIAL AND METHODS: Fifty-six patients were examined. The main group consisted of 40 patients treated with intravenous injections with mexidol (n=10), combination of mexidol with non-pharmacological methods - mesodiencephalic modulation (MDM) (n=10), hyperbaric oxygenation (HBO) (n=10) and the combination of MDM and HBO (n=10). The comparison group included 16 people. All patients underwent neurophysiological (EEG, auditory event-related potentials) and neuropsychological examinations. RESULTS: Marked EEG changes were noted in all patients. The domination of disturbances of functional activity on the diencephalic or mesodiencephalic levels was observed. After treatment, positive changes were found in 60% of patients. The positive dynamics was observed in 80% patients when the combination of mexidol, MDM and HBO was used. The negative dynamics was noted in 5 (12,5%) of patients of the main group, in particular when mexidol only was used. The results of the primary neuropsychological study revealed that cognitive impairment of different severity was found in 97,5% of patients of the main group and 100% of patients of the comparison group. After treatment, performance on neuropsychological tests improved by 62,5%, N200 and P300 latencies reduced, while the amplitudes increased, in the patients of the main group. CONCLUSION: The use of mexidol, MDM and HBO in the treatment of patients with encephalopathy due to poisoning with neurotoxicants on the stage of rehabilitation improved the indicators of functional brain activity and cognitive functions.

Systematic review of stimulant and nonstimulant laxatives for the treatment of functional constipation.

BACKGROUND: Constipation is an uncomfortable and common condition that affects many, irrespective of age. Since 1500 BC and before, health care practitioners have provided treatments and prevention strategies to patients for chronic constipation despite the significant variation in both medical and personal perceptions of the condition. OBJECTIVE: To review relevant research evidence from clinical studies investigating the efficacy and safety of commercially available pharmacological laxatives in Canada, with emphasis on studies adopting the Rome criteria for defining functional constipation. SEARCH METHODS: PubMed, Medline, Embase and Evidence-Based Medicine Reviews databases were searched for blinded or randomized clinical trials and meta-analyses assessing the efficacy of nonstimulant and stimulant laxatives for the treatment of functional constipation. RESULTS: A total of 19 clinical studies and four meta-analyses were retrieved and abstracted regarding study design, participants, interventions and outcomes. The majority of studies focused on polyethylene glycol compared with placebo. Both nonstimulant and stimulant laxatives provided better relief of constipation symptoms than placebo according to both objective and subjective measures. Only one study compared the efficacy of a nonstimulant versus a stimulant laxative, while only two reported changes in quality of life. All studies reported minor side effects due to laxative use, regardless of treatment duration, which ranged from one week to one year. Laxatives were well tolerated by both adults and children.

[Effect of intravenous laser irradiation on some blood biochemical indicators in the acute stage of lacunar infarcts].

OBJECTIVE: To investigate the dynamics of lipid metabolism, C-reactive protein (CRP), lipid peroxidation and antioxidant system in lacunar infarction (LI) in chronic cerebral ischemia. MATERIAL AND METHODS: Two groups of patients were studied. The main group included 31 patients who received intravenous laser irradiation of blood (ILIB) with semiconductor laser (wavelength - 0.67 microns, the power output - 3-2 mW) in addition to standard treatment. Patients of the control group (n=22) received only standard treatment. RESULTS: A statistically significant decrease in total cholesterol levels to normal values due to the significant reduction of the content of antiatherogenic fraction of cholesterol (high-density lipoprotein and atherogenic low-density lipoprotein cholesterol) was found in the main group after treatment. The reduction in atherogenic cholesterol fractions in both groups was associated with the decrease in apolipoprotein B level. The level of CRP was higher than normal in the main and control groups of patients before and after treatment, which indicated the risk of vascular diseases in patients with LI. After treatment, superoxide dismutase activity returned to normal values. In patients of the main group, the catalase activity increased while the level of reduced glutathione did not change and lipid peroxidation products remained on the high level. CONCLUSION: Additional antioxidant therapy is needed for these patients.

Pediatric constipation in the emergency department: evaluation, treatment, and outcomes.

OBJECTIVES: Limited knowledge exists surrounding the pharmacologic management of pediatric constipation in the emergency department (ED) setting and the success of interventions. Our primary objective was to determine whether enema administration is associated with 7-day ED revisits for persistent symptoms. Secondary objectives focused on assessing other predictors of ED revisits. METHODS: We conducted a retrospective cohort study of children <18 years old, diagnosed as having constipation (International Classification of Diseases-10 codes F98.1 nonorganic encopresis, K59.0 constipation) in a pediatric ED in Toronto, Canada, between November 2008 and October 2010. RESULTS: A total of 3592 visits were included; 6% (n = 225) were associated with a revisit. Children with revisits more frequently had vomiting (28% vs 17%, P = 0.001), more pain (5.7 ±â€Š3.6 vs 4.6-3.6 of 10, P = 0.01), and underwent more blood tests (19% 05, 11%, 95% confidence interval [CI] of the difference 3%-14%] and diagnostic imaging (62% vs 47%, 95% CI of the difference 9%-22%). Children administered an enema were 1.54 times more likely to revisit the ED than those who did not receive an enema (8.6% vs 5.5%, 95% CI of the difference 1.1%-5.2%, P = 0.001). Type of enema administered varied by age (P < 0.001). Regression analysis identified the following independent predictors of revisits: diagnostic imaging (odds ratio [OR] 1.54, 95% CI 1.15-2.06), vomiting (OR 1.45, 95% CI 1.07-1.98), enema administration (OR 1.40, 95% CI 1.05-1.88), and significant medical history (OR 1.26, 95% CI 1.04-1.53). CONCLUSIONS: Enema administration and diagnostic imaging are associated with revisits in children diagnosed with constipation. Their role in the ED management of pediatric constipation requires further evaluation.

[Endoscopic treatment of chemical burns to the stomach with mucosa ulceration and necrosis].

The prevalence of acute poisoning with caustic substances in Russia is higher than in other countries and is reported by different authors as accounting for 10-32% cases among the patients admitted to acute poisoning treatment centres. Especially unfavorable prognosis is considered for necrotizing burns to the stomach that increase the risk of severe complications leading to disability of patients. The study aimed at improving the treatment of necrotizing chemical burn to the stomach by the infusion of a 5% Mexidole solution into the edges of a burn lesion at different stages of the treatment course. The paper presents the outcomes of patients who sustained chemical burns to the stomach with mucosa ulceration and necrosis, and provides an assessment of early endoscopic treatment effect.

[Myocardial cytoprotectors, a reserve therapeutic modality for patients with stable angina of effort].

The study included 1418 patients with FC I-IV stable angina of effort (42.4% men and 57.6% women, mean age 74.6 +/- 1.2 years). The possibility to supplement standard therapy with myocardial cytoprotectors (trimetasidin, mexidol, qudesan) was estimated in 4 groups of patients from the severity of pain syndrome, chronic cardiac insufficiency, and heart rhythm disturbances.

[Pharmacological neuroprotection against brain damage in ischemiai/reperfusion experiment].

Experiment carried out on laboratory animals (rats) were aimed at comparative evaluation of the effect of several neuroprotective drugs under the conditions of model brain ischemia-reperfusion. The experimental methods included staining of brain tissue sections by hematoxiline-eosine, Nissl staining, and expression of NOS1, NOS3, TRAIL by imunnohistological means. The intensity of damage in various parts of brain and the nature of apoptosis without neuroprotection and with popular neuroprotectors (cytoflavin, actovegin, mexidol) and a test drug at the stage ofpreclinical trial (AKF-90-7) were evaluated. Characteristic cytotoxic (coagulative pycnomorphic and colliquative necrosis of neurons) and vascular (hemostasia, erythropedesis) changes were revealed. The neuroprotective effectof drugs decreases in the following order: AKF-90-7 > cytoflavin > actovegin > mexidol.

[Possibilities of the application of antioxidants and antihypoxants in a complex therapy of obsessive conditions in different mental disorders].

Based on the study of 84 patients with a syndrome of persistence within obsessive-compulsive neurosis (OCN) and generalized tic disease (GTD), we found the dysfunction of humoral and cellular immune reactions with the disturbance of regulation of hypophysis-adrenal and hypophysis-thyroid systems. The complex psychopharmacological effect of mexidol, thymogen and hyperbaric oxygenation was significantly higher compared to traditional therapy (neuroleptics and benzodiazepine anxiolytics) applied to patients with OCN and GTD.

Factors affecting outcomes in colonoscopy.

There are many factors that influence successful outcomes in colonoscopy. The aims of this study were to evaluate these factors and determine ways to improve outcomes. All participants (N=229) who underwent planned colonoscopy between July and September 2004 were retrospectively included. Participants included 118 men and 111 women with a mean age of 59 years. Completion rate was 92%. Reasons of failure included poor bowel preparation (2.2%, p< .025), bowel looping (2.2%, p< .025), participant discomfort (1.3%), and obstructing lesion (1.3%). Mean midazolam dose was 3.8 mg. Three participants (1.3%) had midazolam alone, and all had complete colonoscopy. One hundred thirty-three participants (60.7%) had additional meperidine, with a completion rate of 94%. Eighty three participants (37.9%) had additional meperidine and Buscopan, with a completion rate reduced to 89.2%. There was no correlation between sedatives used and completion rate. Completion rate of colonoscopy in our unit was acceptable at 92%. A combination of midazolam and meperidine gave the best completion rates (94%). The two main reasons for incompletion were poor bowel preparation and excessive bowel looping.

Efficacy of neuroprotectors in patients with tension headaches.

Studies were performed on 126 patients with chronic tension headache (CTH). Patients were divided into two groups - an experimental group (64 patients) and a control group (62). Control patients received standard treatment (tizanidine, fluoxetine, vinpocetin, and manual acupressure of active points in the trapezius muscles and the temporomastoid area of the head); the experimental group also received Mexidol. Clinical and neurophysiological studies, including electromyography, were performed before and after treatment. Comparison of the treatment outcomes in the two groups showed that inclusion of Mexidol into the complex therapy of chronic CTH led to faster and more marked clinical effects.

A review of current issues underlying colon cleansing before colonoscopy.

The present review examines four current issues related to the efficacy, patient tolerance and safety of the following bowel cleansing agents: oral sodium phosphate (NaP), polyethylene glycol (PEG) and magnesium citrate (Pico-Salax, Ferring Pharmaceuticals Inc, Canada), an agent recently made available in Canada. MedLine and PubMed databases were systematically searched to identify studies related to the efficacy of altered PEG solutions combined with adjunct treatments; the efficacy, tolerability and safety of Pico-Salax; the association between nephrocalcinosis, and chronic renal failure and oral NaP use; and the role of diet. Although lower volume PEG solutions combined with adjuvant agents were generally associated with better patient tolerance, their efficacy was varied and interpretation of this end point is complicated by study design issues. There are very few reported studies of Pico-Salax, and as a result, there are insufficient data to draw conclusions about the efficacy of this agent. The available data suggest that Pico-Salax may be better tolerated by patients, than oral NaP and PEG solutions. There is a paucity of hemodynamic monitoring data pre- and postadministration, but the available data suggests that this small-volume osmotic agent could cause subclinical contraction of the intravascular space. Recent case reports suggest an association between nephrocalcinosis and oral NaP ingestion, but to date, these reports have been confined to a single centre. Preliminary studies suggest that this is not a widespread problem, but more studies are needed. There are only a few studies examining diet and patient tolerability, but they do suggest that diet may be liberalized with some cleansing regimens to enhance tolerability without decreasing efficacy. The present review highlights current controversies and advances in colon cleansing before colonoscopy, and also identifies areas for further study.

[Efficacy of the use of antioxidant preparation mexidol in comprehensive treatment of inflammatory diseases of parodontium].

Examination of 90 patients (52 women and 38 men) in the age range from 25 to 60 with chronic generalized parodontitis of medium severity was done. All examined were divided into 4 groups; 1st - was control, in 3 of them antioxidant preparation mexidol in different forms was used, the. The exercised comprehensive study and treatment of the mentioned above pathology of medium severity with the use of mexidol let us conclude that in comprehensive therapeutical treatment it is necessary to include not only local but also general mexidol use. For mexidol action prolongation it is recommended to use for teeth cleaning the tooth pastes with mexidol.

[Effect of mexidol on efficacy of traditional therapy of sick sinus syndrome in adolescents]. / Vliianie meksidola na éffektivnost' traditsionnoi terapii sindroma slabosti sinusovogo uzla u podrostkov.

ECG data obtained with a Holter monitor in a group of 90 adolescent patients with vegetovascular dystonia and sick sinus syndrome (SSS) showed that mexidol, intravenously instilled in a daily dose of 2-4 mg/kg over a period of 10 days in combination with a standard neurometabolic scheme results in the development of a therapeutic effect in 93-100% of patients with clinical-ECG variants I and II of the disorder. In most cases, both clinical state and ECG quality were improved and the functional capacity of myocardium was increased. Repeated courses of mexidol administration increased efficacy of the ambulatory SSS treatment on the average by 20%.

[Clinico-functional efficacy of medicinal and photon stabilization of cell membrane in patients with angina pectoris]. / Kliniko-funktsional'naia éffektivnost' medikamentoznoi i kvantovoi stabilizatsii kletochnoi membrany u bol'nykh stenokardiei.

Modification of erythrocytic membrane and the trend in clinicofunctional indices were studied in 90 patients with angina of effort (FC I-IV) in the course of treatment with a combination of membranoprotective drugs (group 1), magneto-laser radiation (group 2) and imitation of laser radiation (group 3). In patients of groups 1 and 2 the treatment resulted in stabilization of cell membrane accompanied with a hypotensive effect and increased exercise tolerance due to more effective cardiac performance.

[Antioxidant Mexidol premedication of patients with periodontitis during antihomotoxic therapy]. / Premedikatsiia antioksidantom meksidolom na fone antigomotoksicheskoi terapii u bol'nykh parodontitom.

The tranquilizing effect of antioxidant mexydol on 95 patients with chrconic generalized parodontitis against a background of various somatic diseases was evaluated. The anxiety and the efficiency of premedication were accessed according to Korach's and Spilberger's scales and according to the special psychological questionnaire. The quantitative characteristics of premedication were given baised on the psychological tests results. There was registered a definite improvement of health characteristics and of patient's mood in comparison to the initial input data as well as lower lever of their situational anxiety. This proves the tranquilizing effect of premedication with mexidol (5% amp.). The most evident dynamics of these changes can be observed among patients suffering from high initial anxiety level. The findings of the study are based on more than 2 year old history of treatment of 30 patients with traumel. 21 patients suffering from disfunction of the nervous system were given some comprehensive treatment (traumel locally orally and mexidol in injections). The clinical effect resulted in emotional stabilization of patients and reduced the time needed for their clinical treatment. The medicines were combined. No side effects were observed.

["Fast" and "slow" components of psychotropic activity of the drugs with nootropic effects]. / "Bystrye" i "medlennye" komponenty psikhotropnogo deistviia preparatov s nootropnymi svoistvami.

A clinical-pharmacological study was carried out to evaluate correlation of "fast" (nonspecific) and "slow" (specific) components of the action of the drugs with nootropic properties (piracetam, mexidol, tanacan) and to estimate their contribution to achieving therapeutic efficacy. The study was performed during 28 days using standard quantitative assay techniques in 79 patients with "Organic emotional-liable (asthenic) disorders" (F06.6, ICD-10). It was found that "fast" component of the psychotropic action of the drugs tested was presented by stimulating and anxiolytic effects, while a "slow" one--by specific nootropic activity. All these effects were fully independent with no correlation found, and this could, probably, be attributed to different mechanisms of their realization. It is shown that nootropic activity of piracetam was most significant in its therapeutic effect; and anxiolytic effect was most important for mexidol action. Meanwhile, stimulating and anxiolytic activities as well as positive influence on long-term memory were main components of tanacan effect. The results obtained show an important role of both specific and nonspecific ("fast") effects in realization of therapeutic action of the drugs with nootropic effects in patients with cognitive-mnestic and neurosis-like disorders.

[The structure of the optic nerve in experimental glaucoma and in the means for its treatment]. / Stroenie zritel'nogo nerva pri éksperimental'noi glaukome i nekotorykh sposobakh ee lecheniia.

Using light and electron microscopy disorders of structure of the optic nerve were studied in rabbits with adrenaline induced glaucoma and after the action of antioxidants (Emoxipine, Erisode) used for preventive and medical purposes. Changes in glaucoma and after administration of drugs in axons and their myelinated sheath were similar but differently pronounced in right and left eye of the same animal. Positive effect of Erisode used for preventive and medical purposes was noted. Emoxipine enhanced the disturbances in optic nerve structure.