Zoran Segrt

Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats

Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

A near-fatal case of acute poisoning by amitraz/xylene showing atrial fibrillation

Amitraz has become a significant cause of acute poisoning because of its wide use in veterinary medicine during the last decade. The majority of published cases of amitraz poisoning have dealt with children, while severe life-threatening poisoning in adults is very rare. In this report, the clinical and laboratory features in a case of acute poisoning by amitraz and xylene in an adult are presented. A 72-year-old man accidentally swallowed about 40 g of Mitac 20, a commercial formulation of amitraz dissolved in xylene. The ingested dose was estimated to be about 10 g of amitraz and 35 g of xylene. Initial symptoms were dizziness and nausea, followed by coma, respiratory insufficiency, miosis, and hyperglycemia. As an α2-adrenergic agonist, amitraz usually causes bradycardia, but the present patient showed atrial fibrillation with rapid ventricular response, which was successfully treated by digoxin. Amitraz itself and xylene metabolites were confi rmed in his blood and urine, respectively, by instrumental analysis. Supportive and symptomatic measures were taken over 3 days, and the patient recovered fully despite the significant ingested amounts of amitraz and xylene.

Benzodiazepine poisoning in elderly

BACKGROUND/AIM Benzodiazepines are among the most frequently ingested drugs in self-poisonings. Elderly may be at greater risk compared with younger individuals due to impaired metabolism and increased sensitivity to benzodiazepines. The aim of this study was to assess toxicity of benzodiazepines in elderly attempted suicide. METHODS A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collected data consisted of patients characteristics (age, gender), benzodiazepine ingested with its blood concentrations at admission, clinical findings including vital signs and Glasgow coma score, routine blood chemistry, complications of poisoning, details of management, length of hospital stay and outcome. According the age, patients are classified as young (15-40-year old), middle aged (41-65-year old) and elderly (older than 65). RESULTS During a 2-year observational period 387 patients were admitted because of pure benzodiazepine poisoning. The most frequently ingested drug was bromazepam, the second was diazepam. The incidence of coma was significantly higher, and the length of hospital stay significantly longer in elderly. Respiratory failure and aspiration pneumonia occurred more frequently in old age. Also, flumazenil was more frequently required in the group of elderly patients. CONCLUSION Massive benzodiazepines overdose in elderly may be associated with a significant morbidity, including deep coma with aspiration pneumonia, respiratory failure, and even death. Flumazenil is indicated more often to reduce CNS depression and prevent complications of prolonged unconsciousness, but supportive treatment and proper airway management of comatose patients is the mainstay of the treatment of acute benzodiazepine poisoning.

Severe acute caffeine poisoning due to intradermal injections: mesotherapy hazard.

INTRODUCTION Caffeine is indicated in the treatment of migraine headaches, as well as neonatal apnea and bradycardia syndrome. In mild poisoning, the most prevalent symptoms are nausea, vomiting, diarrhea, tremor, anxiety and headache. In more severe cases, symptoms consist of heart rythym abnormalities, myocardial infarction and seizures. Due to its common lipolytic effect, caffeine is used in mesotherapy, usually in combination with drugs of similar effect. We presented a patient with acute iatrogenic caffeine poisoning. CASE REPORT A 51-year-old woman, with preexisting hypertension and hypertensive cardiomyopathy was subjected to cosmetic treatment in order to remove fat by intradermal caffeine injections. During the treatment the patient felt sickness, an urge to vomit, and a pronounced deterioration of general condition. Upon examination, the patient exhibited somnolence, hypotension and nonsustained ventricular tachycardia, which was sufficient enough evidence for further hospitalization. On admission to the intensive care unit the patient was anxious with increased heart rate, normotensive, with cold, damp skin, and visible traces of injection sites with surrounding hematomas on the anterior abdominal wall. Paroxysmal supraventricular tachycardia (PSVT) on electrocardiographic monitoring was found. The laboratory analysis determined a lowered potassium level of 2.1 mmol/L (normal range 3,5 - 5.2 mmol/L), and a toxicological analysis (liquid chromatography with ultraviolet detection) proved a toxic concentration of caffeine in plasma - 85.03 mg/L (toxic concentration over 25 mg/L). On application of intensive therapy, antiarrhythmics, and substitution of potassium, as well as both symptomatic and supportive therapy, there was a significant recovery. The patient was discharged without any sequele within four days. CONCLUSION A presented rare iatrogenic acute caffeine poisoning occured due to massive absorption of caffeine from the subcutaneous adipose tissue into the circulation when injected directly into the tiny blood vessels, as evidenced by hematoma formation. Poisoning manifestations were registered in gastrointestinal, CNS (anxiety, somnolence) and cardiovascular (hypotension, ventricular tachycardia and nonsustained PSVT) system. In this era of mesotherapeutic treatment promotion, one should keep in mind toxic prevention, with application being carried out exclusively in a specialized institution.

Pharmaceutical Expenditure and Burden of Non-communicable Diseases in Serbia

In the low- and middle-income countries some non-communicable diseases (NCDs), such are cardiac diseases, strokes, chronic lung diseases, certain cancers, and diabetes, tend to overtake the morbidity and mortality of poverty diseases (Adams and Butterly, 2015; Jakovljevic and Getzen, 2016). Such diseases, conditionally labeled as diseases of affluence (Nutrition Health Topics, 2016), are growing rapidly in the developing countries, making almost 80% of deaths due to NCDs (New WHO report: deaths from noncommunicable diseases on the rise, with developing world hit hardest, 2011). Until a century ago, infectious diseases were the leading cause of morbidity and mortality worldwide. For example, in the United States at the beginning of the twentieth century, the crude death rate for the infectious diseases amounted to 800 per 100,000 population per year, reaching nearly 1000 during influenza pandemic at the end of the WWII. Afterwards, significant drop in the morbidity and mortality due to infectious causes was noticed, mostly as a consequence of a variety of the conducted preventive measures in sanitation and hygiene area, vaccination strategies and the development of different antimicrobial agents (Achievements in Public Health, 1900–1999: Control of Infectious Diseases, 1999; Wang et al., 2016). Due to the globalization, the flow rate of people, ideas and financial capital increased worldwide (Jakovljevic et al., 2016).

Gastroprotective effects of amifostine in rats treated by T-2 toxin

Abstract Cytoprotector amifostine (AMI) was given in a dose of 50, 100 or 150 mg/kg ip in rats treated with several highly toxic doses of T-2 toxin. The best survival rate (24 h and 7 days after treatment) was obtained with AMI50 (50 mg/kg ip). After T-2 intoxication, a peak in the mean number of gastric lesions (petechiae and ulcerations) was reached on the third day (26.40 ± 6.24). Administration of AMI50 reduced, almost completely, the total number of gastric lesions in rats acutely poisoned by 0.5 LD50 T-2 (1.5 mg/kg sc), starting with day 1 after intoxication (5.60 ± 3.42).

economic evaluation of Pharmacogenetic Tests in Patients Subjected to Renal Transplantation: A Review of Literature

Renal transplantation is the treatment of choice for the patients with end-stage renal failure. Genetic factors, among others, can influence variability in response to immunosuppressive drugs. Nowadays, due to restrictive health resources, the question arises whether routine pharmacogenetic analyses should be done in the renal transplant recipients or not. The aim of this literature review was to present the up-to-date information considering the economic feasibility of pharmacogenetic testing in patients subjected to renal transplantation. The organization United Network for Organ Sharing in the US estimated that total costs per renal transplant concerning these analyses were

Determination of flumazenil in serum by liquid chromatography-mass spectrometry: Application to kinetics study in acute diazepam overdose.

334,300 in 2014. Pharmacogenetic testing prior to treatment initiation could be helpful to predict and assess treatment response and the risks for adverse drug reactions. This kind of testing before treatment initiation seems to be one of the most promising applications of pharmacokinetics. Although pharmacogenetic tests were found to be a cost-effective or cost-saving strategy in many cases, some authors represent another opinion. However, if the real costs of renal transplantation are recognized, the application of these tests in the standard daily practice could be considered more realistic, which additionally emphasizes the importance of future studies assessing their cost effectiveness.

Pharmacodynamic and pharmacokinetic effects of flumazenil and theophylline application in rats acutely intoxicated by diazepam

BACKGOUND/AIM Flumazenil is benzodiazepine receptor antagonist. It has been studied for a various indications, including reversal of sedation after surgery or diagnostic procedures, awakening of comatose patients in benzodiazepine overdose, or for symptomatic treatment of hepatic encephalopathy. Some drugs, like theophylline, may prolong its elimination half-life. Considering the long half-life of diazepam and its metabolites, concomitant use of theophylline may reduce the need for repeated dosing of flumazenil in patients with acute diazepam poisoning. The aim of this study was to introduce a reliable and accurate method for determining the concentration of flumazenil after therapeutic application in patients with acute poisoning, and using that method to assess whether the kinetics of flumazenil change in the presence of aminophylline (combination of theophylline and ethylenediamine in a 2:1 ratio) applied as concomitant therapy. METHODS Blood samples from patients with acute diazepam poisoning that received flumazenil at the dose of 0.5 mg, or the same dose with 3 mg/kg of body weight of aminophylline, were collected 1, 3, 10, 30, 60, 120 and 240 min after its intravenous administration. Samples were prepared by solid-phase extraction on Oasis HLB cartridges with ethylacetate as extracting agens. Flumazenil was determined by liquid chromatography with mass spectrometry (LC-MS) in single ionmonitoring mode at m/z 304. Separation of flumazenil from matrix compound was performed on Lichrospher RP-8 column usingthe mixture of acidic acetonitrile and 20 mM of ammonium acetatein water (55 : 45) as a mobile phase. RESULTS The applied analitycal method showed excellent recovery (94.65%). The obtained extracts were much cleaner than the extracts obtained by the sameextractant in the process of liquid-liquid extraction. The limit ofdetection of the LC-MS method described in this paper was 0.5 ng/mL and the limit of quantitation was 1 ng/mL. In the patientstreated with both flumazenil and aminophylline, the eliminationconstant for flumazenil was significantly lower and the elimination half-life was longer (p < 0.05) in comparison with the same parameters in.the patients who received flumazenil alone. CONCLUSION The applied LC-MS method for the determination of flumazenil in serum samples of patients with acute diazepam poisoning is rapid, sensitive, precise and specific. Concomitant use with theophylline significantly prolonged elimination of flumazenil during the treatment of acute poisonings with diazepam.

Acute poisoning by cardiovascular agents

BACKGROUND/AIM The majority of symptoms and signs of acute diazepam poisoning are the consequence of its sedative effect on the CNS affecting selectively poli-synaptic routes by stimulating inhibitory action of GABA. The aim of the present study was to examine the effects of combined application of theophylline and flumazenil on sedation and impaired motor function activity in acute diazepam poisoning in rats. METHODS Male Wistar rats were divided in four main groups and treated as follows: group I--with increasing doses of diazepam in order to produce the highest level of sedation and motor activity impairment; group II--diazepam + different doses of flumazenil; group III--diazepam + different doses of theophylline; group IV--diazepam + combined application of theophylline and flumazenil. Concentrations of diazepam and its metabolites were measured with LC-MS. The experiment was performed on a commercial apparatus for spontaneous motor-activity registration (LKB-Farad, Sweden). Assessment of diazepam-induced neurotoxic effects and effects after theophylline and flumazenil application was performed with rotarod test on a commercial apparatus (Automatic treadmill for rats, Ugo Basile, Italy). RESULTS Diazepam in doses of 10 mg/kg and 15 mg/kg produced long-time and reproducible pharmacodynamic effects. Single application of flumazenil or theophylline antagonized effects of diazepam, but not completely. Combined application of flumazenile and theophylline resulted in best effects on diazepam-induced impairment of motoric activity and sedation. As a result of theopylline application there was better elimination of diazepam and its metabolites. CONCLUSION Combined application of flumazenil and theophylline resulted in the best antidotal effects in the treatment of diazepam poisoned rats. These effects are a result of different mechanisms of their action, longer half-life of theophylline in relation to that of flumezenil and presumably the diuretic effect of theophylline.