Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy.

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study's objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.

Assessment of hospitalizations of patients after intoxication with organophosphates used in agriculture.

INTRODUCTION: Clinical manifestation of organophosphates toxicity may be differentiate and include cholinergic toxidrome, intermediate syndrome, OP-induced delayed polyneuropathy to chronic OP-induced neuropsychiatric disorder (OPIDN). Patients symptoms, along with decrease in cholinesterase serum level, determines the possible diagnosis of organophosphate poisoning. OBJECTIVE: The aim of the study was to present the clinical manifestation and cholinesterase level changes in intoxication with organophosphorus compounds in patients. MATERIAL AND METHODS: A data base was created by analysis of the hospital documents of 34 patients hospitalized due to organophosphate intoxication. Statistical analysis involved frequency tables with percentage values, the application of non-parametric Chi-square test and parametric t-Student test (with homogeneity of variance Levine test). The level of static significance was set to p=0.05. RESULTS: In fatal hospitalizations (20.6%), cholinesterase level was significantly lower (265.87 U/l) than in other patients (4254.78 U/l; p<0.05). Similarly, levels of cholinesterase were decreased in group of patients with acute respiratory failure (999.79 U/l vs 4943.86 U/l in other patients; p<0.05), patients with multi-organ dysfunction syndrome (244.13 U/l vs 4914.89 U/l in other patients; p<0.05) and those with cardiac arrest (547 U/l vs 4636.25 U/l in other patients). A statistically significant difference was also observed in cholinesterase level of patients who required mechanical ventilation (548.17 U/l vs 5219.71 U/l in other group). The study revealed that 29.4% of poisonings were suicidal. CONCLUSIONS: The management of a patient with organophosphate poisoning remains challenging and requires continuous control. A significant step in the diagnostic process is the assessment changes in both the clinical picture and cholinesterase level.

Severe carbamates intoxication of 43-year-old farmer - case report.

INTRODUCTION: Carbamate insecticides are methyl carbamic acid esters and reversible cholinesterase inhibitors. In contrast to the long-term action of organophosphate insecticides, this complex undergoes rapid hydrolysis. CASE REPORT: A suicidal poisoning by exposure to carbofuran in a 43-year-old farmer is reported. The patient had a sudden respiratory and cardiac arrest in the mechanism of bradycardia asystole. He was additionally diagnosed with metabolic acidosis and massive aspiration pneumonia. After applied treatment, the patient's general condition improved - alignment of efficiency of both respiratory and circulatory efficiency were reached. CONCLUSION: Carbofuran is one of the most toxic carbamate insecticides. It is therefore important to react quickly and choose the right treatment. Differentiation between organophosphate and carbamate intoxication is essential.

[Hyponatremia in toxicological practice].

Hyponatremia, defined as a serum sodium <135 mmol/l, is the most common clinical disorder of water and electrolyte balance. Hyponatremia occurs in approximately 15-20% of hospitalized patients and up to 20% of patients in critical condition. It can lead to a wide range of clinical symptoms, from mild to even life-threatening, and is associated with increased mortality and longer duration of hospitalization in patients affected by many different syndromes. The diagnosis and treatment of hyponatremia in patients' is still a major problem. Hyponatremia is a disorder observed commonly in toxicological practice. It most often occurs in people who abuse alcohol, narcotics - mainly ecstasy, drugs, as well as the so-called water intoxication in athletes and the people who are mentally ill. In view of the complex pathomechanisms and a variety of symptoms observed in poisoned patients, hyponatremia should be considered as one of the reasons and the exponent of the general condition of the patient.

[Genetically modified food--unnecessary controversy?]. / Zywnosc genetycznie modyfikowana--niepotrzebne kontrowersje?

Fast development of genetic engineering and biotechnology allows use of genetically modified organisms (GMO) more and more in different branches of science and economy. Every year we can see an increase of food amount produced with the use of modification of genetic material. In our supermarkets we can find brand new types of plants, products including genetically modified ingredients or meat from animals fed with food containing GMO. This article presents general information about genetically modified organisms, it also explains the range of genetic manipulation, use of newly developed products and current field area for GMO in the world. Based on scientific data the article presents benefits from development of biotechnology in reference to modified food. It also presents the voice of skeptics who are extremely concerned about the impact of those organisms on human health and natural environment. Problems that appear or can appear as a result of an increase of GMO are very important not only from a toxicologist's or a doctor's point of view but first of all from the point of view of ordinary consumers--all of us.

[Silibinin and its hepatoprotective action from the perspective of a toxicologist]. / Sylibinina i jej dzialanie hepatoprotekcyjne z punktu widzenia toksykologa.

Silibinin is the most active component of a complex of flavonoids -silymarin contained in fruit milk thistle (Sylibum marianum). Its mechanism of action is complex and highly beneficial in protecting hepatocytes. On the one hand this compound blocks the penetration of various toxins (for example amanitin) into the hepatocytes not allowing in this way for the cell death and on the other hand, it prevents apoptosis through intracellular. It protects the liver from oxidative intracellular free radicals by increasing the activity of enzyme superoxide dismutase and peroxidase, as well as by increasing the concentration of glutathione and the activity of the peroxidase. Silibinin strengthens and stabilizes the cell membranes, inhibits the synthesis of prostaglandins associated with the lipid peroxidation and promotes regeneration of liver through the stimulation of protein synthesis and effect on the production of new hepatocytes. A particularly interesting topic from the perspective of a toxicologist is the application of silibinin in Amanita phalloides poisoning. Clinical trials conducted in this respect are very encouraging. The other beneficial application of silibinin is in therapy of the alcoholic liver cirrhosis. The evidence shows that the use of silymarin leads to a significant reduction in liver-related mortality and even reduction in the number of patients with encephalopathy in the course of the disease. Application of silibinin goes beyond liver disease and expands in the direction of cancer and even diabetes. What is interesting is the fact, that the substance of herbal origin occurring in the environment is so strong, favorable, beneficial and multidirectional. Science has contributed to improving the bioavailability of silibinin thus making it more effective.

[Severe rhabdomyolysis syndrome in the course of alcohol withdrawal syndrome and hyponatremia]. / Ciezki zespól rabdomiolizy w przebiegu alkoholowego zespolu odstawienia i hiponatremii.

Rhabdomyolysis and associated kidney failure is a medical problem, often faced by doctors working in the centers of toxicology. Its most common cause is mechanical damage to the muscles, but predisposing factors include a big group of other pathologies and clinical conditions, including: electrolyte imbalance, immobility, infections, drug or psychoactive substances poisoning. The article presents an example of a patient with severe rhabdomyolysis syndrome caused by an alcohol withdrawal syndrome. Based on our experience and scientific studies of other clinical centres the paper presents various causes of muscle damage, including the iatrogenic effects of ethanol intoxication treatment. The article explains the importance of a proper and quick treatment which prevents damage of internal organs, including kidney failure.

[Severe tricyclic antidepressants poisoning--a case study]. / Ciezkie zatrucie trójcyklicznymi antydepresantami--opis przypadku.

Long QT syndrome is a disease characterized by periodic or constant prolongation of QT interval and attacks of ventricular polymorphic tachycardia known as torsade de pointes. It may appear as a result of various medicines application, both anti-arrhythmic and non-cardiovascular. Currently, a list of medicines which may cause proarrhythmic action in consequence of QT prolongation is long and constantly updated. It contains tricyclic antidepressants, which are the most toxic antidepressants currently used and are often the cause of poisoning and hospitalization on toxicology wards. The paper presents the case of a 20-year-old man, treated in the clinical toxicology ward, after severe poisoning with tricyclic antidepressants. The patient, treated many times in our toxicology centre, had very high concentration of tricyclic antidepressants in the serum (2768 ng/ml). The concentration above 1000 ng/ml indicates serious life-threatening poisoning. Very severe symptoms of cardiotoxicity were observed: in ECG - wide QRS (160 ms) with heart rate 120-150 per minute, ventricular tachycardia, periodically polymorphic, prolongation of QT interval, hypotonia (80/60 mm Hg) and also recurrent attacks of seizures. Also metabolic/respiratory acidosis was stated (pH - 7.089; pCO2 - 56.9 mm Hg, HCO3 - 16.8 mmol/l). Gastric lavage, activated charcoal were administered, symptomatic and supportive treatment according to the intensive therapy rule was applied, including sodium bicarbonate, magnesium sulfate and vasopressors intravenous infusion. High concentration of the drug, unknown after ingestion and significantly developed symptoms of cardiotoxicity caused, that the treatment was ineffective. The case described shows that treatment of severe poisoning with tricyclic antidepressants and induced acquired long QT syndrome is still a challenge.

[Impact of internet on poisoning with psychoactive substances in young people]. / Wplyw internetu na zatrucia substancjami psychoaktywnymi u ludzi mlodych.

These days young people use internet as a source of information. Internet offers knowledge that can be used not only for school education but also to obtain information about usage and effects of psychoactive substances. Recent research shows that young people more often use internet websites and chat rooms to exchange knowledge and experience with chemicals and everyday products used as intoxicants, for example: nutmeg, nonprescription medications, metal cleaning liquid or feminine hygiene products. This article shows the extend of knowledge young people can gain from popular internet websites. Information on the web is presented as appealing, attractive and encouraging. From a toxicologist point of view it is extremely important to be familiar with those new threats because more and more often we have to treat young patients with a serious poisoning from usage of experimental intoxicating substances.

[Severe digoxin poisoning a case study]. / Ciezkie zatrucie digoksyna--opis przypadku.

Digitalis glycosides are among the oldest drugs used in cardiology. Nowadays, due to the limited indications for their use (advanced heart failure, usually concomitant with atrial fibrillation), cases of poisoning induced by this class of drugs are rarely observed. Digoxin produces a positive inotropic and bathmotropic effect on the heart, but has a negative chronotropic and dromotropic effect. Cardiac glycosides have a narrow therapeutic window, so digitalis treatment can easily lead to symptoms of overdose. In patients taking digoxin, the drug therapeutic level should be maintained at 1-2 ng/ml; the toxic effects occur at concentrations > 2.8 ng/ml and are mainly related to disturbances of cardiac function and of the circulatory system, as well as gastrointestinal symptoms and CNS disturbances. We present, a 45-years-old patient who was hospitalized following the ingestion with suicidal intent of 100 0.25 mg tablets of digoxin. In spite of rapidly applied gastric irrigation and administration of activated charcoal, the drug level in the patient's blood was estimated at 12.0 ng/ml. During her stay on the ward, typical symptoms of severe poisoning were observed: from gastric symptoms (severe nausea, vomiting) to numerous severe arrhythmias and conduction disturbances. Type I, II and III AV blocks were detected, as well as numerous ventricular and supraventricular extrasystoles. These conduction disorders required the use of temporary endocardial pacing. Due to the unavailability of specific antidotes (antidigitalis antibodies) and lack of efficient methods of extracorporeal elimination of the drug, symptomatic treatment comprising the correction of electrolyte disturbances and heart rate control remains the most effective.

[Methanol poisoning in a 61-year old male with recently diagnosed diabetes--a case report]. / Zatrucie metanolem u 61-letniego mezczyzny ze swiezo wykryta cukrzyca--opis przypadku.

The aim of this paper is to present a case of a 61-year-old male transferred to the Regional Center of Clinical Toxicology from the Department of Endocrinology with suspected methanol poisoning. The patient presented symptoms of diabetes with extreme hyperglycemia >1600 mg/dl and nonketotic hyperosmolar coma. Laboratory tests showed metabolic/respiratory acidosis, methanol 80 mg/dl, ethanol 0.47 g/l, creatinine 3.5 mg/dl, urea 140 mg/dl, lactic acid 4.11 mmol/l, myoglobin >1000 ng/ml, HbA1C >14.5%. During a few days prior to the hospitalization the patient was drinking a great amount of fruit juices and milk (a dozen or so litres per twenty four hours). The eventuality of metabolizing glucose and aspartame into methanol is known from professional literature. The possibility of excessive consumption of aspartame and its metabolites causing methanol poisoning in the presented patient was considered.

[Myocardial infarction secondary to carbon monoxide poisoning--a study of two cases]. / Zawal serca w przebiegu zatrucia tlenkiem wegla--opis dwóch przypadków klinicznych.

The carbon monoxide poisoning still remains a main cause of fatal poisoning. The carbon monoxide poisoning occurs after inhalation of carbon monoxide. Carbon monoxide binds strongly to molecules, such as cytochrome oxidase, myoglobin, hemoglobin, causing hypoxia of tissues and organs. Carbon monoxide converts hemoglobin to carboxyhemoglobin and makes transport of oxygen through the body impossible and causes severe hypoxia. The only treatment is administering 100% oxygen or providing hyperbaric oxygen therapy. The central nervous system and heart are the most sensitive to hypoxia. We present the cases of two young people with no history of chronic diseases (a 24-year-old man and a 39-year-old woman) who were diagnosed NSTEMI in the course of severe carbon monoxide poisoning. Both poisoning cases were severe, both patients were unconscious when they were admitted to our hospital. We observed elevation of serum troponin level and changes in ECG (e.g. atrial fibrillation) significant for myocardial infarction.