Effects of nicorandil on QT prolongation and myocardial damage caused by citalopram in rats.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

The outcomes of favipiravir exposure in pregnancy: a case series.

PURPOSE: As in vitro and in vivo studies reported antiviral efficacy against RNA viruses, favipiravir, a pyrazinecarboxamide derivative, has become one of the treatment options for COVID-19 in some countries including Turkey. Preclinical studies demonstrated the risk for teratogenicity and embryotoxicity. Hence, the drug is contraindicated during pregnancy. Although limited in numbers, case-based evaluations indicate that favipiravir might not be a major teratogen in human pregnancies. This study aimed to present and analyze the outcomes of favipiravir exposure during pregnancy. METHODS: In this case series, the outcomes of nine pregnancies that were referred to the Teratology Information Service of Dokuz Eylul University Faculty of Medicine, Department of Medical Pharmacology between 01 April 2020 and 30 November 2021 were retrospectively evaluated. RESULTS: One spontaneous abortion, two elective terminations, one preterm live delivery and five term live deliveries were detected. The premature newborn was reported dead on the 5th day of neonatal intensive care unit admission. Physiological jaundice and transient respiratory distress were recorded in two term infants. One term infant was antenatally diagnosed with renal pelviectasis, but the findings resolved postnatally without requiring intervention. CONCLUSION: The data indicate that favipiravir is not likely to be a major teratogen. Yet, it is not possible to draw a definite conclusion due to methodological limitations. Favipiravir exposures during pregnancy should be followed up closely and the outcomes should be reported consistently.

Effect of the selective mitochondrial KATP channel opener nicorandil on the QT prolongation and myocardial damage induced by amitriptyline in rats.

OBJECTIVES: The aim of this study is to evaluate the protective effect of nicorandil, a selective mitochondrial KATP channel opener, on QT prolongation and myocardial damage induced by amitriptyline. METHODS: The dose of amitriptyline (intraperitoneal, i.p.) that prolong the QT interval was found 75 mg/kg. Rats were randomized into five groups the control group, amitriptyline group, nicorandil (selective mitochondrial KATP channel opener, 3 mg/kg i.p.) + amitriptyline group, 5-hdyroxydecanoate (5-HD, selective mitochondrial KATP channel blocker, 10 mg/kg i.p.) + amitriptyline group and 5-HD + nicorandil + amitriptyline group. Cardiac parameters, biochemical and histomorphological/immunohistochemical examinations were evaluated. p < 0.05 was accepted as statistically significant. KEY FINDINGS: Amitriptyline caused statistically significant prolongation of QRS duration, QT interval and QTc interval (p < 0.05). It also caused changes in tissue oxidant (increase in malondialdehyde)/anti-oxidant (decrease in glutathione peroxidase) parameters (p < 0.05), myocardial damage and apoptosis (p < 0.01 and p < 0.001). While nicorandil administration prevented amitriptyline-induced QRS, QT, QTc prolongation (p < 0.05), myocardial damage and apoptosis (p < 0.05), it did not affect the changes in oxidative parameters (p > 0.05). CONCLUSIONS: Our results suggest that nicorandil, a selective mitochondrial KATP channel opener, plays a protective role in amitriptyline-induced QT prolongation and myocardial damage. Mitochondrial KATP channel opening and anti-apoptotic effects may play a role in the cardioprotective effect of nicorandil.

Antivenom use in bite and sting cases presenting to a public hospital.

BACKGROUND: To evaluate the distribution of bite and sting cases presenting to a district public hospital and the use of antivenom in scorpion sting and snake bite cases. METHODS: The demographic characteristics of patients with bites/stings reporting to a public hospital in 2014, the agent involved, the season of reporting, severity of clinical findings during presentation, and use of antivenom in scorpion sting and snake bite cases were evaluated retrospectively. χ2 test was used for statistical analysis. RESULTS: Bite and sting cases comprised 0.5% of all the patients reporting to the hospital's emergency department, with scorpion sting cases comprising almost half (54.2%) of these hospital presentations, followed by Hymenoptera (bee and wasp) sting (30.8%) and snake bite (5.5%) cases. Unnecessary antihistamine administration was found to be significantly high in asymptomatic patients (p=0.00006). Furthermore, antivenom use was found to be significantly high in patients with scorpion sting and snake bite despite the absence of systemic or local indications (p<0.0001, χ2=80.595). CONCLUSION: The study results showed that antivenom was used in scorpion sting and snake bite cases even when it was not indicated. Therefore, primary practitioners should be provided training for management of envenomation cases and should be made aware of the updated guidelines and references to raise their knowledge levels.

A Comparison of the Effectiveness of Silibinin and Resveratrol in Preventing Alpha-Amanitin-Induced Hepatotoxicity.

Amanita phalloides species mushrooms containing alpha-amanitin (α-AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of α-AMA-induced hepatotoxicity. We investigated the effects of resveratrol on α-AMA-induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with α-AMA (α-AMA + SR) or 12 (α-AMA + 12R) or 24 (α-AMA + 24R) hr after α-AMA administration. Silibinin (5 mg/kg) (α-AMA + Sil) and normal saline (α-AMA + NS) were given simultaneously with α-AMA. We found that liver transaminase levels in α-AMA + SR and α-AMA + 12R groups and histomorphologic injury score in the α-AMA + SR, α-AMA + 12R, α-AMA + 24R and α-AMA + Sil groups were significantly lower than that of the α-AMA + NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase-3 immunopositivity in the liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in a reduction in cell viability induced by α-AMA in THLE-2 and THLE-3 hepatocytes. Neither resveratrol nor silibinin was found to be effective in increasing cell viability decreased by α-AMA + NS. As a conclusion, resveratrol was found to be effective in α-AMA-induced hepatotoxicity with its anti-inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings.

Correlation between Amitriptyline-Induced Cardiotoxic Effects and Cardiac S100b Protein in Isolated Rat Hearts.

BACKGROUND: Amitriptyline is an important cause of mortality due to its cardiovascular toxicity. AIMS: To investigate the changes in levels of cardiac S100b protein on amitriptyline-induced cardiotoxicity and also to examine the correlation between amitriptyline-induced cardiotoxic effects and cardiac S100b protein in an isolated rat heart model. STUDY DESIGN: Animal experimentation, isolated heart model. METHODS: After a stabilization period, isolated hearts were randomized to two groups (n=5 and n=7). In the control group, isolated hearts were subjected to an infusion of 5% dextrose for 60 minutes. In the amitriptyline group, 5.5×10-5 M amitriptyline was infused for 60 minutes to achieve amitriptyline toxicity. After the infusion period, heart tissues were removed for histological examination. RESULTS: In comparison to control treatment, amitriptyline infusion decreased left ventricular developed pressure (LVDP), dp/dtmax and heart rate (HR) and significantly prolonged QRS duration (p<0.05). The semiquantitative scores for S100b protein levels in amitriptyline-infused hearts were higher than in the control group (p<0.01). At the end of the experiment, in the amitriptyline-infused group, significant correlations were found between LVDP and S100b protein scores (r=-0.807, p=0.003) and between QRS duration and S100b protein scores (r=0.859, p=0.001). CONCLUSION: Our results indicate that the S100b protein may be a helpful indicator or biomarker in studying the cardiotoxic effects of amitriptyline.

Effects of 2-Hydroxypropyl-Beta-Cyclodextrin on Cardiovascular Signs of Amitriptyline Poisoning in a Rat Model.

The aim of this study was to investigate the efficacy of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) as an antidotal treatment for the in vivo cardiovascular effects of amitriptyline poisoning. Experiments were carried out on 33 Wistar rats. To evaluate cardiovascular effects of HPBCD, rats were infused with dextrose or HPBCD. In the poisoning model, amitriptyline (0.94 mg/kg/min) was infused until the mean arterial blood pressure (MAP) dropped to 50 % of the baseline. Following amitriptyline infusion, dextrose, low-dose HPBCD (4.19 mg/kg/min), or high-dose HPBCD (16.76 mg/kg/min) was infused, and MAP, heart rate (HR), and electrocardiogram were recorded for 60 min. Hearts were examined for tissue damage and apoptosis. HPBCD infusion alone did not yield significant difference for MAP, HR, QRS duration, QT interval, and cardiac tissue damage when compared to dextrose (p > 0.05). In the poisoning model, MAP and HR decreased, while QRS duration and QT interval prolonged significantly following amitriptyline infusion (p < 0.0167). Dextrose, low-dose HPBCD, and high-dose HPBCD infusion similarly corrected MAP, HR, QRS duration, and QT interval values at the end-experiment time point (p > 0.05). Histological scores for tissue damage and apoptosis showed no significant difference between the groups (p > 0.05). Based on our results, HPBCD did not show cardiovascular toxicity, while it was not more effective than dextrose for the treatment of amitriptyline poisoning. Further antidotal studies of cyclodextrins with higher doses and/or binding affinities are needed for poisonings.

The Effects of the Adenosine Receptor Antagonists on the Reverse of Cardiovascular Toxic Effects Induced by Citalopram In-Vivo Rat Model of Poisoning.

BACKGROUND: Citalopram is a selective serotonin reuptake inhibitor that requires routine cardiac monitoring to prevent a toxic dose. Prolongation of the QT interval has been observed in acute citalopram poisoning. Our previous experimental study showed that citalopram may be lead to QT prolongation by stimulating adenosine A1 receptors without affecting the release of adenosine. AIMS: We examined the effects of adenosine receptor antagonists in reversing the cardiovascular toxic effects induced by citalopram in rats. STUDY DESIGN: Animal experimentation. METHODS: Rats were divided into three groups randomly (n=7 for each group). Sodium cromoglycate (20 mg/kg) was administered to all rats to inhibit adenosine A3 receptor mast cell activation. Citalopram toxicity was achieved by citalopram infusion (4 mg/kg/min) for 20 minutes. After citalopram infusion, in the control group (Group 1), rats were given an infusion of dextrose solution for 60 minutes. In treatment groups, the selective adenosine A1 antagonist DPCPX (Group 2, 8-cyclopentyl-1,3-dipropylxanthine, 20 µg/kg/min) or the selective A2a antagonist CSC (Group 3, 8-(3-chlorostyryl)caffeine, 24 µg/kg/min) was infused for 60 minutes. Mean arterial pressure (MAP), heart rate (HR), QRS duration and QT interval measurements were followed during the experiment period. Statistical analysis was performed by ANOVA followed by Tukey's multiple comparison tests. RESULTS: Citalopram infusion reduced MAP and HR and prolonged the QT interval. It did not cause any significant difference in QRS duration in any group. When compared to the control group, DPCPX after citalopram infusion shortened the prolongation of the QT interval after 40, 50 and 60 minutes (p<0.01). DPCPX infusion shortened the prolongation of the QT interval at 60 minutes compared with the CSC group (p<0.05). CSC infusion shortened the prolongation of the QT at 60 minutes compared with the control group (p<0.05). CONCLUSION: DPCPX improved QT interval prolongation in citalopram toxicity. The results of this study show that mechanism of cardiovascular toxicity induced by citalopram may be related adenosine A1 receptor stimulation. Adenosine A1 receptor antagonists may be used for the treatment of citalopram toxicity.

A Case Report of Toxic Brain Syndrome Caused by Methyl Bromide.

Methyl bromide (CH3Br) is a halogenated aliphatic hydrocarbon that may cause acute and chronic toxicities. We describe a case of a 44-year-old male patient who developed toxic brain syndrome (TBS) and central nervous system (CNS) toxicity after exposure to CH3Br by inhalation. Toxicity began with progressive nervousness, dysarthria and coordination disorder. The complaints on admission to the hospital were speech defect, balance disorder, consciousness disorder and involuntary movements. The patient was treated symptomatically in the intensive care unit (ICU), and organic reasons were excluded. Findings in the magnetic resonance imaging were considered secondary demyelination related to systemic intoxication. Because of the CH3Br, alkylates the crucial sulfhydryl-containing enzymes, N-acetylcysteine was used as a source of sulfhydryl groups for the treatment of the patient. He was hospitalised for nearly 1.5 months in the ICU.

Inhibitory effect of adenosine on intimal hyperplasia and proliferation of smooth muscle cells in a carotid arterial anastomosis animal model.

PURPOSE: The effect of adenosine (9-ß-0-ribifuranosyladenine) on the endothelial cell proliferation and neointimal hyperplasia is investigated in the rabbit carotid artery anastomosis model. METHODS: Twenty-eight New Zealand white rabbits were arranged in four groups of seven animals each. The right carotid arteries of each animal were transsected and re-anastomosed. The left sides remained as control. In Group A, no medication was used. In Group B, subcutaneous Adenosine was applied for 3 days. In Group C, the same dose was applied for 7 days, and in Group D for 21 days. After 28 days, the luminal diameters, luminal areas, intima/media ratios were all measured by using histopathological evaluation. FINDINGS: The mean luminal diameters and areas of the four groups were smaller than the control ones. Massive thickening of smooth muscle cell proliferation and dense intensifying in the connecting tissues were observed most prominently in Group A, in decreasing degrees within other groups. Intima/media ratio was highest in Group A. Scoring the quantity of e-NOS positive staining also revealed a significant difference between the experimental groups and their control associates. CONCLUSION: The process of endothelial cell proliferation and neointimal hyperplasia can be significantly reduced by the use of adenosine.

The role of adenosine receptors and endogenous adenosine in citalopram-induced cardiovascular toxicity.

AIM: We investigated the role of adenosine in citalopram-induced cardiotoxicity. MATERIALS AND METHODS: Protocol 1: Rats were randomized into four groups. Sodium cromoglycate was administered to rats. Citalopram was infused after the 5% dextrose, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; A1 receptor antagonist), 8-(-3-chlorostyryl)-caffeine (CSC; A2a receptor antagonist), or dimethyl sulfoxide (DMSO) administrations. Protocol 2: First group received 5% dextrose intraperitoneally 1 hour prior to citalopram. Other rats were pretreated with erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; inhibitor of adenosine deaminase) and S-(4-Nitrobenzyl)-6-thioinosine (NBTI; inhibitor of facilitated adenosine transport). After pretreatment, group 2 received 5% dextrose and group 3 received citalopram. Adenosine concentrations, mean arterial pressure (MAP), heart rate (HR), QRS duration and QT interval were evaluated. RESULTS: In the dextrose group, citalopram infusion caused a significant decrease in MAP and HR and caused a significant prolongation in QRS and QT. DPCPX infusion significantly prevented the prolongation of the QT interval when compared to control. In the second protocol, citalopram infusion did not cause a significant change in plasma adenosine concentrations, but a significant increase observed in EHNA/NBTI groups. In EHNA/NBTI groups, citalopram-induced MAP and HR reductions, QRS and QT prolongations were more significant than the dextrose group. CONCLUSIONS: Citalopram may lead to QT prolongation by stimulating adenosine A1 receptors without affecting the release of adenosine.

Demographic and Clinical Characteristics of Theophylline Exposures between 1993 and 2011.

BACKGROUND: Acute and chronic exposure to theophylline can cause serious signs and symptoms of poisoning. Additionally, with a narrow therapeutic range, toxicity could be observed even with therapeutic doses of theophylline. Epidemiological data on theophylline exposures in our country are extremely limited. The results of our study may improve the clinical management of theophylline poisoning in our country and elsewhere. AIMS: To present aetiological and demographic features, clinical findings and treatment attempts with regard to theophylline exposures reported to Dokuz Eylül University Drug and Poison Information Center (DPIC), between 1993 and 2011. STUDY DESIGN: Descriptive study. METHODS: The data regarding demographics, date, time, type of exposure, route of and reason for exposure, signs and symptoms upon admission, clinical management and outcome were retrospectively evaluated. RESULTS: The DPIC recorded 88,562 poisoning calls between 1993 and 2011; 354 (0.4%) of them were due to theophylline exposure. The mean age of all cases was 24.1±15.4 (range between 1 month and 90 years). Females dominated all age groups (72.6%, 257 females). Intentional exposure was significantly higher in women than in men (88.2% vs. 68.2% for all age groups; p<0.001 for children; p<0.001 for adults; p<0.001 for all age groups). While 60.5% of the cases had no symptoms, severe signs of toxicity were present in 1.9% of theophylline exposure cases during the telephone inquiry. Signs and symptoms were found to be significantly more prevalent in adults than in children (p<0.01). The serum theophylline level was regarded as toxic in 74% (65 toxic levels) of theophylline measured cases. Clinical signs and symptoms were found to be significantly prevalent in cases with toxic theophylline levels (p<0.001). The rate of gastrointestinal decontamination procedures was higher than that of recommended gastrointestinal decontamination procedures by DPIC (83% and 66%, respectively). There were two fatalities (4.6%) associated with chronic theophylline toxicity and theophylline overdose in an acute setting for suicide (a 90 year-old and 25 year-old, respectively). CONCLUSION: Although most of the theophylline exposure cases had no symptoms, some reported serious signs and symptoms of poisoning such as hypokalaemia, tachycardia and hyperglycaemia. DPICs have an important role in the management of theophylline exposure without unnecessary gastrointestinal decontamination procedures.

Adenosine-mediated cardiovascular toxicity in amitriptyline-poisoned rats.

We investigated the contribution of endogenous adenosine to amitriptyline-induced cardiovascular toxicity in rats. A control group of rats was pretreated with intraperitoneal (i.p.) 5% dextrose and received intravenous 0.94 mg/kg/min of amitriptyline for 60 minutes. The second and third groups of rats pretreated with i.p. 10 mg/kg of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, and i.p. 1 mg/kg of S-(4-nitrobenzyl)-6-thioinosine (NBTI), a facilitated adenosine transport inhibitor, received 5% dextrose and amitriptyline infusion, respectively. Outcome parameters were mean arterial pressure (MAP), heart rate (HR), QT and QRS durations, and plasma adenosine concentrations. Plasma adenosine concentrations were increased in all groups. In the control group, amitriptyline decreased MAP and HR and prolonged QT and QRS durations after 10 minutes of infusion. In EHNA/NBTI-pretreated rats, amitriptyline prolonged QRS duration at 10 and 20 minutes. In EHNA/NBTI pretreated rats, amitriptyline-induced MAP, HR reductions, and QRS prolongations were more significant than that of dextrose-infusion-induced changes. Our results indicate that amitriptyline augmented the cardiovascular effects of endogen adenosine by increasing plasma levels of adenosine in rats.

Effects of terlipressin in a rat model of severe uncontrolled hemorrhage via liver injury.

BACKGROUND: Animal experiments and clinical studies have shown that vasopressin infusion in cases of uncontrolled hemorrhagic shock is a promising treatment. However, there are only a few studies regarding the application of terlipressin in hemorrhagic cases. This study was designed to evaluate the effects of terlipressin vs controlled fluid resuscitation on hemodynamic variables and abdominal bleeding in a rat model of uncontrolled hemorrhage via liver injury. METHODS: A total of 21 average weight 250 ± 30 g Wistar rats were used. A midline celiotomy was performed, and approximately 65% of the median and left lateral lobes were removed with sharp dissection. After creation of the liver injury, rats were randomized into 1 of 3 resuscitation groups, the control group, Lactated Ringer's (LR) group, and terlipressin group, with 7 rats in each group. Blood samples were taken from rats for arterial blood gas analysis. At the end of the experiments, free intraperitoneal blood was collected on preweighed pieces of cotton, and the amount of free blood was determined by the difference in wet and dry weights. RESULTS: In response to resuscitation, the terlipressin group demonstrated a significant elevation in mean arterial pressure (MAP). Blood loss was greater in the LR group compared with the control group (12.8 ± 1.9 mL vs 8.2 ± 0.7 mL, P < .05). At the end of the experiments, 5 rats in the control group, 5 in the LR group, and 2 in the terlipressin group died. The average survival rates were 28.6%, 28.6%, and 71.4%, respectively. CONCLUSIONS: Compared with the control group, intravenous terlipressin bolus after liver injury contributed to an increase in MAP and survival rates without increasing abdominal bleeding.

Is serum S100B protein a biomarker for amitriptyline-induced cardiovascular toxic effects?

The aim of this study was to assess the role of serum S100B protein as a biomarker for cardiovascular effects in an anesthetized rat model of amitriptyline toxicity. Adult male Wistar rats (n = 28) were randomized into four groups. While the control group received normal saline, the experimental groups received different doses of amitriptyline (0.625 or 0.94 or 1.25 mg/kg/min) infusion. Mean arterial pressure (MAP), heart rate (HR), electrocardiogram parameters, and serum S100B protein levels were recorded during the experiment. Linear Pearson's correlation coefficient was used to examine the association between cardiovascular parameters and serum levels of S100B protein. In the experimental groups, amitriptyline caused a significant decrease in MAP and HR (P < 0.001), a prolongation in QRS duration and QT intervals (P < 0.01), but it did not change PR intervals significantly. At the end of the experiment of the second group, a significant correlation was found between HR and serum S100B protein levels (r = -0.963, P = 0.037). At the end of the experiment of the third and fourth groups, a significant correlation between MAP, HR, all ECG parameters, and serum S100B protein levels was found. Serum S100B protein levels correlate well with amitriptyline-induced cardiovascular toxicity and can be used as a biomarker for predicting cardiovascular toxic effects of amitriptyline.

An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline.

We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P < 0.05, respectively). There was no statistically significant difference in the results of arterial blood-gas analyses among the groups (P > 0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect.

Cardiovascular medication exposures and poisonings in Izmir, Turkey: a 14-year experience.

Cardiovascular medications (CVMs) are frequently prescribed for cardiovascular diseases. The unconscious use of cardiovascular drugs may lead to severe clinical manifestations, even to death, especially when in overdose. The objective of this study is to clarify the profile of CVM exposures admitted to Department of Emergency Medicine in Dokuz Eylul University Hospital (EMDEU) between 1993 and 2006. Case demographics, type of the medication, route and reason for exposure, clinical effects and outcome were recorded. Related to the CVM exposures, 105 poisoning cases were admitted. Mean age of children and adults were 12.8 ± 1.0 and 30.1 ± 1.8, respectively. Females were dominating (77.1%). Poisoning by accident occurred mainly among children in the 0-6 age group (64.3%) and suicide attempt was predominant in the 19-29 age group (47.8%). The most common ingested CVMs admitted to EMDEU were calcium channel blockers (19.7%), beta-blockers (17.3%), angiotensin converting enzyme inhibitors and diuretics (11.8%). Most of the patients were asymptomatic (59.1%). Frequently observed symptom was altered consciousness (18.6%). Antihypertensive drugs are responsible for the most of the CVM exposures. Prospectively designed multi-centered studies are needed to reflect the epidemiological properties of cardiovascular drug exposures throughout our country and would be very valuable for the determination of preventive measures.

Effects of adenosine receptor antagonists on survival in amitriptyline-poisoned mice.

OBJECTIVE: We investigated the effects of adenosine receptor antagonists on survival rates in a mouse model of amitriptyline poisoning. MATERIALS AND METHODS: In the preliminary study, amitriptyline was given at doses of 75, 100, and 125 mg/ kg to mice intraperitoneally (i.p.; n = 20 for each dose) to determine the lethal dose at 50% (LD(50)). Different doses (1, 3, and 5 mg/kg) of DPCPX (selective adenosine A(1) antagonists, n = 10 for each dose, total n = 30) or CSC (selective adenosine A(2a) antagonists, n = 10 for each dose, total n = 30) were given i.p. to find the nonlethal dose. After the administration of the LD(50) dose of amitriptyline (125 mg/kg), mice were treated with DPCPX (3 mg/kg), CSC (3 mg/kg), saline, or DMSO (dimethyl sulfoxide) (n = 25 for each group). Mice were observed during a 24-hour period. RESULTS: Kaplan-Meier estimates of the 24-hour survival rate was 52% (13/25) for saline and 68% (17/25), 52% (13/25), and 40% (10/25) for the DPCPX, CSC, and DMSO groups, respectively. There was no statistically significant difference in survival rates among the groups (P > 0.05). CONCLUSIONS: Adenosine antagonists failed to increase the survival rates of amitriptyline-poisoned mice. Further studies are needed with repeated doses of adenosine antagonists.

Protective effect of an adenosine A1 receptor agonist against metamidophos-induced toxicity and brain oxidative stress.

The aim of this study was to evaluate the effects of different doses of an adenosine A(1) selective agonist, phenylisopropyl adenosine (PIA), on metamidophos-induced cholinergic symptoms, mortality, diaphragm muscle necrosis, and brain oxidative stress. A LD(50) dose of metamidophos (20 mg/kg body weight, p.o.) was followed by 1 mL/kg body weight of 0.9% NaCl or 1 mg/kg, 2 mg/kg, 3 mg/kg, or 5 mg/kg body weight PIA ip. Incidence of clinical signs including chewing, salivation, convulsion, and respiratory distress did not show any significant difference among all treatment groups (p > 0.05). PIA was found to be effective to reverse the necrotic changes in diaphragm muscle induced by metamidophos significantly in all groups. Brain Thiobarbituric Acid Reactive Substance (TBARS) levels were significantly increased after the metamidophos poisoning. Administration of 2 to 5 mg/kg body weight PIA decreased brain TBARS levels compared to 0.9% NaCl treated rats. The results indicate that, although different doses of PIA reduced the OP-induced oxidative stress and diaphragm necrosis, a single dose of PIA was not able to recover cholinergic signs and symptoms of metamidophos poisoning.

Does adenosine A(1) receptor stimulation causes QRS prolongation by blocking beta adrenergic receptors in amitriptyline poisoning?

AIMS: To investigate the role of beta receptor blockade via adenosine A(1) receptor stimulation on amitriptyline-induced QRS prolongation. METHODS: Isolated rat hearts were randomized into three groups (n=8 for each group). After pretreatment with 5% dextrose (control) or DPCPX (8-cyclopentyl-1,3-dipropylxanthine), or propranolol + DPCPX, amitriptyline infusion was given to all groups. Intact beta adrenergic receptor response was verified with a bolus dose of isoproteranol (3 x 10(-5)M). RESULTS: Amitriptyline (5.5 x 10(-5)M) infusion following pretreatment with 5% dextrose or 10(-4)M DPCPX prolonged QRS by 40-110% and 30-75%, respectively. After the beta receptor blockade with 10(-2)M propranolol bolus, amitriptyline infusion following pretreatment with DPCPX prolonged QRS by 40-130%. Amitriptyline infusion following pretreatment with DPCPX (10(-4)M) shortened the QRS at 40, 50 and 60 min significantly when compared to propranolol+DPCPX group (168.8+/-4.9%, p<0.05; 170.8+/-6.9%, p<0.01; 174.0+/-6.9%, p<0.01, respectively). Amitriptyline infusion following pretreatment with 5% dextrose prolonged QRS duration significantly at 50th minutes (209.5+/-6.1%, p<0.05) compared to DPCPX pretreatment group. CONCLUSION: DPCPX pretreatment shortened amitriptyline-induced QRS prolongation. Beta adrenergic receptor blockade enhanced QRS prolongation shortened by DPCPX pretreatment. Adenosine A(1) receptor stimulation related to beta adrenergic receptor blockade may play a role in amitriptyline-induced QRS prolongation in isolated rat hearts.