Antioxidative Activity of 1,3,5-Triazine Analogues Incorporating Aminobenzene Sulfonamide, Aminoalcohol/Phenol, Piperazine, Chalcone, or Stilbene Motifs.

A series of 1,3,5-triazine analogues, incorporating aminobenzene sulfonamide, aminoalcohol/phenol, piperazine, chalcone, or stilbene structural motifs, were evaluated as potential antioxidants. The compounds were prepared by using step-by-step nucleophilic substitution of chlorine atoms in starting 2,4,6-trichloro-1,3,5-triazine. Reactions were catalyzed by Cu(I)-supported on a weakly acidic resin. The radical scavenging activity was determined in terms of %inhibition activity and EC50, using the ABTS method. Trolox and ascorbic acid (ASA) were used as standards. In the lowest concentration 1 × 10-4 M, the %inhibition activity values at 0 min were comparable with both standards at least for 10 compounds. After 60 min, compounds 5, 6, 13, and 25 showed nearly twice %inhibition (73.44-87.09%) in comparison with the standards (Trolox = 41.49%; ASA = 31.07%). Values of EC50 at 60 min (17.16-27.78 µM) were 5 times lower for compounds 5, 6, 13, and 25 than EC50 of both standards (trolox = 178.33 µM; ASA = 147.47 µM). Values of EC50 correlated with %inhibition activity. Based on these results, the presented 1,3,5-triazine analogues have a high potential in the treatment of illnesses caused or related to oxidative stress.

Glucose Metabolism in Cancer and Ischemia: Possible Therapeutic Consequences of the Warburg Effect.

The Warburg effect states that the main source of energy for cancer cells is not aerobic respiration, but glycolysis-even in normoxia. The shift from one to the other is governed by mutually counteracting enzymes: pyruvate dehydrogenase and pyruvate dehydrogenase kinase (PDK). Anaerobic metabolism of cancer cells promotes cell proliferation, local tissue immunosuppression, resistance to hypoxic conditions, and metastatic processes. By switching glucose back to oxidative metabolism, these effects might be reversed. This can be achieved using PDK inhibitors, such as dichloroacetate. Patients suffering from ischemic conditions might benefit from this effect. On the other hand, the ß-blockers (adrenergic ß-antagonists) often used in these patients appear to improve cancer-specific survival, and nonselective ß-blockers have been shown to promote glucose oxidation. Might there be a link?

Creatine and creatine pyruvate reduce hypoxia-induced effects on phrenic nerve activity in the juvenile mouse respiratory system.

Adequate concentrations of ATP are required to preserve physiological cell functions and protect tissue from hypoxic damage. Decreased oxygen concentration results in ATP synthesis relying increasingly on the presence of phosphocreatine. The lack of ATP through hypoxic insult to neurons that generate or regulate respiratory function, would lead to the cessation of breathing (apnea). It is not clear whether creatine plays a role in maintaining respiratory phrenic nerve (PN) activity during hypoxic challenge. The aim of the study was to test the effects of exogenously applied creatine or creatine pyruvate in maintaining PN induced respiratory rhythm against the deleterious effects of severe hypoxic insult using Working Heart-Brainstem (WHB) preparations of juvenile Swiss type mice. WHB's were perfused with control perfusate or perfusate containing either creatine [100µM] or creatine pyruvate [100µM] prior to hypoxic challenge and PN activity recorded throughout. Results showed that severe hypoxic challenge resulted in an initial transient increase in PN activity, followed by a reduction in that activity leading to respiratory apnea. The results demonstrated that perfusing the WHB preparation with creatine or creatine pyruvate, significantly reduced the onset of apnea compared to control conditions, with creatine pyruvate being the more effective substance. Overall, creatine and creatine pyruvate each produced time-dependent degrees of protection against severe hypoxic-induced disturbances of PN activity. The underlying protective mechanisms are unknown and need further investigations.

Effects of novel maleimide derivatives on cell cultures with different properties.

The paper is focused on pilot study of effects of novel synthetic protein kinase inhibitors-maleimide derivatives in different concentrations on normal, transformed and multipotent cell lines. Influence on cell proliferation and morphological characteristics has been demonstrated. The chosen agents cause antiproliferative effect on transformed cells and are not cytotoxic to normal cell lines. Moreover, different maleimide derivatives' effects on multipotent cells in attached and floating states has been shown. Described results can be used for further research of the maleimide derivatives as antitumor agents.

In vitro permeation of micronized and nanonized alaptide from semisolid formulations.

This study is focused on in vitro permeation of the original Czech compound, a skin/mucosa tissue regeneration promoter, known under the international nonproprietary name "alaptide," in micronized and nanonized forms. Alaptide showed a great potential for local applications for treatment and/or regeneration of the injured skin. The above mentioned technological modifications influence the permeation of alaptide through artificial or biological membranes, such as PAMPA or skin. The permeation of micronized and nanonized form of alaptide formulated to various semisolid pharmaceutical compositions through full-thickness pig ear skin using a Franz cell has been investigated in detail. In general, it can be concluded that the nanonized alaptide permeated through the skin less than the micronized form; different observations were made for permeation through the PAMPA system, where the micronized form showed lower permeation than the nanonized alaptide.

Bioactive compounds from Schisandra chinensis - Risk for aquatic plants?

Schisandra chinensis is a potential plant for production of nutrient supplements due to adaptogens content. The dominant bioactive substance, lignan schisandrin, has positive effects on human health, but it can cause possible allelopathic effects in relation to other plants. S. chinensis is not native to European ecosystems, and its ecotoxicological properties have not been verified yet. Lemna minor was selected as a model aquatic plant to test its potential impact on the aquatic environment. Crude water extract from S. chinensis fruits, simulating the natural soaking of active substances in a surface water body, was used in treatments from 0.045 to 45 mg/L (according to the content of schisandrin as the dominating lignan). During seven days of cultivation, the growth (number of plants, leaf area, fresh weight) and photosynthetic activity of L. minor fronds were assessed. In low treatments (0.045 and 0.09 mg/L), the extract of S. chinensis did not cause any changes in duckweed growth parameters or photosynthetic performance. Higher treatments (0.45 and 0.9 mg/L) caused significant limitations in plants' number, total leaf area, and fresh weight. The photosynthetic parameters (basal chlorophyll fluorescence, quantum yields) were affected only by 0.9 mg/L. The highest treatment, 45 mg/L, exhibited extreme toxicity to duckweed plants causing their death during the first five days of cultivation. Schisandrin and other bioactive substances extractable from S. chinensis fruits can negatively impact water biota in the case of massive contamination of surface water.

Potential toxicity of Schisandra chinensis to water environment: acute toxicity tests with water crustaceans.

Fruits of Schisandra chinensis, an East Asian liana plant, are currently more and more used to produce nutrient supplements that positively affect human health due to the content of various secondary metabolites. On the other hand, these substances because of their bioactivity can cause possible allelopathic or toxic effects concerning other organisms (algae, plants, animals). But the ecotoxicological properties of S. chinensis outside its area of origin have yet to be sufficiently verified. Two crustaceans, Daphnia magna and Thamnocephalus platyurus, were selected as model aquatic organisms to test the potential impact of S. chinensis active compounds on the aquatic environment. Crude water extract from S. chinensis fruits, simulating the natural leakage of active substances in water, was tested in treatments from 0.0045 to 45 mg/L (according to the content of schisandrin as the dominating lignan). Effective concentration (EC50) causing 50% lethal effect for D. magna was established to 0.0448 mg/L after 24 h and 0.0152 mg/L after 48 h. EC50 for T. platyurus reached 0.4572 mg/L after 24 h, i.e. more than ten times higher than for D. magna. This study showed that the potential environmentally relevant concentrations of S. chinensis bioactive compounds could represent a severe risk to aquatic ecosystems.

Investigation of substituted 6-aminohexanoates as skin penetration enhancers.

Skin penetration enhancers are compounds used to facilitate the transdermal delivery of drugs that are otherwise not sufficiently permeable. Through a synthetic route implementing two series of esters, we generated transdermal penetration enhancers by a multi-step reaction with substituted 6-aminohexanoic acid. We present the synthesis of all newly prepared compounds here with structural confirmation accomplished by (1)H NMR, (13)C NMR, IR and mass spectroscopy (MS). The lipophilicity (logk) of all compounds was determined via RP-HPLC and their hydrophobicity (logP/ClogP) was also calculated using two commercially available programs. Ab initio calculations of geometry and molecular dynamic simulations were employed to investigate the 3-dimensional structures of selected compounds. The transdermal penetration-enhancing activity of all the synthesized esters were examined in vitro and demonstrated higher enhancement ratios than oleic acid. Compounds 2e (C(10) ester chain) and 2f (C(11) ester chain) exhibited the highest enhancement ratios. It can be concluded that the series non-substituted at the C((2)) position by a ω-lactam ring showed significantly higher activity than those with azepan-2-one. None of the prepared compounds penetrated through the skin. All of the investigated agents demonstrated minimal anti-proliferative activity using the SK-N-MC neuroepithelioma cell line (IC(50)>6.25µM), suggesting these analogs would have a low cytotoxic profile when administered in vivo as chemical penetration enhancers. The correlation between the chemical structure of the studied compounds and their lipophilicity is discussed in regards to transdermal penetration-enhancing activity.

Synthesis, physico-chemical properties and penetration activity of alkyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxopyrrolidin-1-yl)hexanoates as potential transdermal penetration enhancers.

Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. The series of seven esters of substituted 6-aminohexanoic acid as potential transdermal penetration enhancers was formed by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC method for the lipophilicity measurement and their lipophilicity (logk) was determined. Hydrophobicities (logP/ClogP) of the studied compounds were also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio/DFT calculations of geometry. All the synthesized esters were tested for their in vitro transdermal penetration enhancer activity. The relationships between the lipophilicity and the chemical structure (SLR) of the studied compounds as well as the relationships between their chemical structure and transdermal penetration activity are mentioned.

Investigating the activity of 2-substituted alkyl-6-(2,5-dioxopyrrolidin-1-yl)hexanoates as skin penetration enhancers.

Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC and their lipophilicity (logk) was determined. The hydrophobicity (logP/ClogP) of the studied compounds was also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio calculations of geometry and molecular dynamic simulations. All the synthesized esters were tested for their in vitro transdermal penetration-enhancing activity and showed higher enhancement ratios than oleic acid. The highest enhancement ratios were exhibited by compound 5f (C((2)) substituted with piperidine-2-one, C(11) ester chain) and 5a (C((2)) substituted with piperidine-2-one, C(6) ester chain). The series with a ω-lactam ring (piperidin-2-one; 5a-g), showed slightly higher activities than those with morpholine (6a-6g). All of the agents showed minimal anti-proliferative activity (IC(50) >6.25µM), indicating they would have low cytotoxicity when administered as chemical penetration enhancers. The relationships between the lipophilicity and the chemical structure of the studied compounds, as well as the correlation between their chemical structure and transdermal penetration-enhancing activity, are discussed.

Indol-2-Carboxylic Acid Esters Containing N-Phenylpiperazine Moiety - Preparation and Cholinesterase-inhibiting Activity.

BACKGROUND: The indole derivatives and the N-phenylpiperazine fragment represent interesting molecular moieties suitable for the research of new potentially biologically active compounds. This study was undertaken to identify if indol-2-carboxylic acid esters containing N-phenylpiperazine moiety possess acetylcholinesterase and butyrylcholinesterase inhibitory activity. MATERIALS AND METHODS: The study dealt with the synthesis of a novel series of analogs of 1H-indole-2- carboxylic acid and 3-methyl-1H-indole-2-carboxylic acid. The structure of the derivatives was represented by the indolylcarbonyloxyaminopropanol skeleton with the attached N-phenylpiperazine or diethylamine moiety, which formed a basic part of the molecule. The final products were synthesized as dihydrochloride salts, fumaric acid salts, and quaternary ammonium salts. The first step of the synthetic pathway led to the preparation of esters of 1H-indole-2-carboxylic acid from the commercially available 1H-indole-2-carboxylic acid. The Fischer indole synthesis was used to synthesize derivatives of 3-methyl-1H-indole-2-carboxylic acid. RESULTS AND DISCUSSION: Final 18 indolylcarbonyloxyaminopropanols in the form of dihydrochlorides, fumarates, and quaternary ammonium salts were prepared using various optimization ways. The very efficient way for the formation of 3-methyl-1H-indole-2-carboxylate (Fischer indole cyclization product) was the one-pot synthesis of phenylhydrazine with methyl 2-oxobutanoate with acetic acid and sulphuric acid as catalysts. CONCLUSION: Most of the derivatives comprised of an attached N-phenylpiperazine group, which formed a basic part of the molecule and in which the phenyl ring was substituted in position C-2 or C-4. The synthesized compounds were subjected to cholinesterase-inhibiting activity evaluation, by modified Ellman method. Quaternary ammonium salt of 1H-indole-2-carboxylic acid which contain N-phenylpiperazine fragment with nitro group in position C-4 (7c) demonstrated the most potent activity against acetylcholinesterase.

Sunflower Plants as Bioindicators of Environmental Pollution with Lead (II) Ions.

In this study, the influence of lead (II) ions on sunflower growth and biochemistry was investigated from various points of view. Sunflower plants were treated with 0, 10, 50, 100 and/or 500 µM Pb-EDTA for eight days. We observed alterations in growth in all experimental groups compared with non-treated control plants. Further we determined total content of proteins by a Bradford protein assay. By the eighth day of the experiment, total protein contents in all treated plants were much lower compared to control. Particularly noticeable was the loss of approx. 8 µg/mL or 15 µg/mL in shoots or roots of plants treated with 100 mM Pb-EDTA. We also focused our attention on the activity of alanine transaminase (ALT), aspartate transaminase (AST) and urease. Activity of the enzymes increased with increasing length of the treatment and applied concentration of lead (II) ions. This increase corresponds well with a higher metabolic activity of treated plants. Contents of cysteine, reduced glutathione (GSH), oxidized glutathione (GSSG) and phytochelatin 2 (PC2) were determined by high performance liquid chromatography with electrochemical detection. Cysteine content declined in roots of plants with the increasing time of treatment of plants with Pb-EDTA and the concentration of toxic substance. Moreover, we observed ten times higher content of cysteine in roots in comparison with shoots. The observed reduction of cysteine content probably relates with its utilization for biosynthesis of GSH and phytochelatins, because the content of GSH and PC2 was similar in roots and shoots and increased with increased treatment time and concentration of Pb-EDTA. Moreover, we observed oxidative stress caused by Pb-EDTA in roots where the GSSG/GSH ratio was about 0.66. In shoots, the oxidative stress was less distinctive, with a GSSG/GSH ratio 0.14. We also estimated the rate of phytochelatin biosynthesis from the slope of linear equations plotted with data measured in the particular experimental group. The highest rate was detected in roots treated with 100 µM of Pb-EDTA. To determine heavy metal ions many analytical instruments can be used, however, most of them are only able to quantify total content of the metals. This problem can be overcome using laser induced breakdown spectroscopy, because it is able to provide a high spatial-distribution of metal ions in different types of materials, including plant tissues. Data obtained were used to assemble 3D maps of Pb and Mg distribution. Distribution of these elements is concentrated around main vascular bundle of leaf, which means around midrib.

Diazepam filled hard capsules intended for detoxification of patients addicted to benzodiazepines and Z-drugs.

OBJECTIVES: The abuse of benzodiazepines and Z-drugs reduces the quality of life of millions of addicted people worldwide. They cannot be discontinued abruptly due to harmful withdrawal symptoms. Detoxification is usually based on replacement of short/middle acting benzodiazepines or Z-drugs by diazepam and tapering the dose over time. In order to enhance patient adherence to an individual withdrawal plan, suitable diazepam dosage forms have to be available. Hard capsules containing an exact and uniform dose could be used for the relief of symptoms caused by altering the plasma level and overcoming psychogenic stress from the dose reduction. METHODS: This work demonstrates that capsules with a content of diazepam ranging from 2.125mg to 0.492 mg (dose decreasing always by 15%) cannot be easily prepared by standard mortar technology in a pharmacy. To meet mass and content uniformity European Pharmacopoeia criteria, capsules were prepared by improved technology based on the preparation of binary blends of calcium phosphate anhydrous and diazepam in descending concentrations in a high-speed mixer (time 30 s) and densification of about 10% during filling of the capsules. RESULTS: All batches (n=20) prepared by improved technology met the requirement for content uniformity compared with only nine batches prepared by standard mortar blender technology. Based on the process capability index, none of the samples prepared by standard technology fitted pharmacopeia limits at the statistically acceptable level. On the other hand, all batches prepared by improved technology exhibited acceptable process capability index. CONCLUSIONS: We have shown that at least 99.73% of batches prepared by our improved technology would meet the pharmacopoeia limits for content uniformity and are suitable for treatment of this type of addiction.

Melatonin and breast cancer: Evidences from preclinical and human studies.

The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women. The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed.

The hypoxia-responsive long non-coding RNAs may impact on the tumor biology and subsequent management of breast cancer.

Long non-coding RNAs (lncRNAs) are DNA transcripts longer than 200 nucleotides without protein-coding potential. As they are key regulators of gene expression at chromatic, transcriptional and posttranscriptional level, they play important role in various biological and pathological processes. Dysregulation of lncRNAs has been observed in several diseases including cancer. Breast cancer is heterogeneous disease with many molecular subtypes specific in different prognosis and treatment responses. Hypoxia, a common micro-environmental feature of rapidly growing tumour is associated with metastases, recurrences and resistance to therapy. Aberrant expression of hypoxia related lncRNAs significantly correlates with poor outcomes in cancer patients, as the lncRNAs play an important regulatory role in the breast cancer-cell survival. Thus, a better understanding of lncRNAs role in the hypoxic conditions of breast cancer is crucial for precise understanding of the tumorigenesis, disease features and poor clinical outcome, especially in highly aggressive breast cancer subtypes (HER2-positive and triple-negative types). Moreover, lncRNAs may represent tumour marker predicting prognosis and therapeutic targets improving precise and personalized therapy for better patient´s survival. In this review, we summarize the recent information on lncRNAs in breast cancer with special focus on the hypoxia-responsive lncRNAs and their potential impact on the prognosis, therapy algorithms and individual outcomes. Presented data helps in better understanding of the specific mechanisms predicting new therapeutic agents and strategies for the pharmacological intervention.

Nitric oxide in the pathophysiology of retinopathy: evidences from preclinical and clinical researches.

Retinopathy is the leading cause of blindness and visual disability in working-aged people. The pathogenesis of retinopathy is an actual and still open query. Alterations contributing to oxidative and nitrosative stress, including elevated nitric oxide and superoxide production, changes in the expression of different isoforms of nitric oxide synthase or endogenous antioxidant system, have been implicated in the mechanisms how this ocular disease develops. In addition, it was documented that renin-angiotensin system has been implicated in the progression of retinopathy. Based on comprehensive preclinical and clinical researches in this area, the role of above-mentioned factors in the pathogenesis of diabetic retinopathy, hypertensive retinopathy and ischaemic proliferative retinopathy is reviewed in this study. Moreover, the genetic susceptibility factors involved in the development of the retinopathy and possible strategies that utilize antioxidants as additive therapy are also highlighted here.

Nano-selenium and its nanomedicine applications: a critical review.

Traditional supplements of selenium generally have a low degree of absorption and increased toxicity. Therefore, it is imperative to develop innovative systems as transporters of selenium compounds, which would raise the bioavailability of this element and allow its controlled release in the organism. Nanoscale selenium has attracted a great interest as a food additive especially in individuals with selenium deficiency, but also as a therapeutic agent without significant side effects in medicine. This review is focused on the incorporation of nanotechnological applications, in particular exploring the possibilities of a more effective way of administration, especially in selenium-deficient organisms. In addition, this review summarizes the survey of knowledge on selenium nanoparticles, their biological effects in the organism, advantages, absorption mechanisms, and nanotechnological applications for peroral administration.

Chemotherapeutic agents for the treatment of metastatic breast cancer: An update.

Breast cancer is the second greatest cause of death among women worldwide; it comprises a group of heterogeneous diseases that evolves due to uncontrolled cellular growth and differentiation and the loss of normal programmed cell death. There are different molecular sub-types of breast cancer; therefore, various options are selected for treatment of different forms of metastatic breast cancer. However, the use of chemotherapeutic drugs is usually accompanied by deleterious side effects and the development of drug resistance when applied for a longer period. This review offers a classification of these chemotherapeutic agents according to their modes of action and therefore improves the understanding of molecular targets that are affected during treatment. Overall, it will allow the clinician to identify more specific targets to increase the effectiveness of a drug and to reduce general toxicity, resistance and other side effects.

Adipokines in neurovascular diseases.

Adipose tissue is now described as an endocrine organ secreting a number of adipokines contributing to the development of inflammation and metabolic imbalance, but also endothelial dysfunction, vascular remodeling, atherosclerosis, and ischemic stroke. Leptin, adiponectin, and resistin are the most studied adipokines which play important roles in the regulation of cardiovascular homeostasis. Leptin and adiponectin mediate both proatherogenic and antiatherogenic responses. Leptin and adiponectin have been linked to the development of coronary heart disease and may be involved in the underlying biological mechanism of ischemic stroke. Resistin, a pro-inflammatory cytokine, is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. The changes in serum levels of novel adipokines apelin, visfatin are also associated with acute ischemic stroke. These adipokines have been proposed as potential prognostic biomarkers of cardiovascular mortality/morbidity and therapeutic targets in patients with cardiometabolic diseases. In this article, we summarize the biologic role of the adipokines and discuss the link between dysfunctional adipose tissue and metabolic/inflammation imbalance, consequently endothelial damage, progression of atherosclerotic disease, and the occurrence of ischemic stroke.

Antiarrhythmic effect of newly synthesized compound 44Bu on model of aconitine-induced arrhythmia -- compared to lidocaine.

The antiarrhythmic action of the newly developed compound 44Bu (an original compound that was synthesized at our Faculty of Pharmacy) was tested on a model of aconitine-induced arrhythmia and compared with the effect of lidocaine. Both tested substances were administered either as therapeutic or prophylactic agents. 44Bu was highly effective in reducing the occurrence of ventricular fibrillation from 94% to 8% by therapeutic administration, and to 0% by prophylactic administration. The overall mortality rate was significantly reduced by 44Bu from 100% to 25% in the case of therapeutic administration, and to 0% in the case of prophylactic administration. In contrast, there was not any significant difference between therapeutic and prophylactic administration of lidocaine. The occurrence of ventricular fibrillation dropped from 94% to 50% with therapeutic administration, and to 67% with prophylactic administration of lidocaine. The overall mortality rate was significantly reduced from 100% to 63% and to 67%, respectively. We conclude that the 44Bu compound is a highly effective agent in suppressing aconitine-induced arrhythmias. The antiarrhythmic effect of 44Bu was significantly more evident in comparison with lidocaine, particularly in the case of its prophylactic administration.