Nil Hocaoglu

Early-onset pancytopenia and skin ulcer following low-dose methotrexate therapy.

Pancytopenia is a rare but serious adverse effect of low-dose methotrexate (MTX) sodium therapy, and this case report describes a very early-onset of pancytopenia and cutaneous lesions after three days of ingestion. A 64-year-old man was presented to Emergency Department with weakness, fever, poor appetite, nausea, and vomiting after he had had accidentally ingested MTX tablets (2.5 mg) twice a day for the last three days. On initial examination, several painful lesions in his oral mucosa and a cutaneous ulceration on his right foot were also observed. He had severe pancytopenia, poor kidney functions, and abnormal coagulation parameters. The blood level of MTX was found to be within therapeutic range. He was treated with leucovorine, intravenous antibiotics, and appropriate blood transfusions; he was discharged from hospital without any sequela. Pancytopenia associated with low-dose (cumulative dose of 15 mg in 3 days) MTX therapy had not been reported previously. The Naranjo probability scale showed pancytopenia and skin ulcer associated with low-dose MTX therapy as probable adverse reactions. Risk factors for pancytopenia such as renal insufficiency, hypoalbuminemia, low folate levels, concomitant infections, concomitant use of drugs, and folate supplementation were not identified in our patient. Although pancytopenia associated with low-dose MTX therapy is not expected as early as 3 days after initiation of the therapy, physicians should also be aware of this life threatening adverse effect during the very first days of MTX therapy for rheumatoid arthritis patients.

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 Ringers (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.

Effects of adenosine receptor antagonists on amitriptyline-induced QRS prolongation in isolated rat hearts.

Objective. We investigated the effects of adenosine receptor antagonists on amitriptyline-induced cardiotoxicity in isolated rat hearts. Methods. The amitriptyline concentrations that prolonged the QRS duration more than 150% (10−4 M) and 50–75% (5.5 × 10−5 M) were accepted as the control groups for two experimental protocols, respectively. In the first protocol, amitriptyline (10−4 M) was infused following pretreatment with a selective adenosine A1 receptor antagonist, DPCPX (8-cyclopentyl-1,3-Dipropylxanthine,10−4 to 10−6 M) or a selective adenosine A2a receptor antagonist, CSC (8-3-chlorostyryl-caffeine,10−4 to 10−6 M). In the second protocol, amitriptyline (5.5 × 10−5 M) was infused following pretreatment with DPCPX (10−4 M) or CSC (10−5 M). Left ventricular developed pressure (LVDP), dp/dtmax, QRS duration and heart rate (HR) were measured. Results. In the first protocol, 10−4 M DPCPX pretreatment shortened QRS duration at 50 minutes when compared to the control group (p < 0.05). In the second protocol, pretreatment with 10−4 M DPCPX shortened the QRS duration at 40, 50, and 60 minutes after amitriptyline infusion when compared to the control group (p < 0.05, p < 0.01 and p < 0.05, respectively). Pretreatment with 10−5 M CSC prolonged QRS duration at 20, 30, and 60 minutes (p < 0.05). Amitriptyline infusion following pretreatment with DPCPX or CSC did not change LVDP, dp/dtmax, or HR when compared to control in both protocols (p > 0.05). Conclusion. While 10−4 M DPCPX shortened QRS prolongation, 10−5 M CSC prolonged QRS duration in the isolated rat hearts with prolonged QRS duration induced by 5.5 × 10−5M amitriptyline. An adenosine A1 receptor antagonist, DPCPX, might shorten amitriptyline-induced QRS prolongation by activating beta adrenergic receptors.

Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats.

The aim of this study was to investigate the effect of glucagon on cardiovascular parameters in anesthetized rat model of tricyclic antidepressant overdose. Toxicity was induced by infusion of amitriptyline 0.94 mg/kg/min until a 40–45% of reduction in mean arterial pressure was observed. Amitriptyline infusion rats were then randomized into three groups. Control group of rats (group 1) received a bolus of 5% dextrose followed by the continuous infusion of dextrose, whereas treatment groups received 1 mg/kg (group 2) or 2 mg/kg (group 3) bolus doses of glucagon followed by continuous infusion (0.1 mg/kg/min) of glucagons for 60 min. Mean arterial pressure, heart rate, and electrocardiogram were recorded. Amitriptyline caused a significant decrease in mean arterial pressure and a prolongation in QRS, yet it did not change the heart rate. High-bolus dose of glucagon (2 mg/kg) followed by glucagon infusion significantly increased mean arterial pressure at 40, 50, and 60 min (P < 0.05) and shortened the prolonged QRS at 50 and 60 min (P < 0.05) when compared with control group. There was also a significant increase in heart rate. In conclusion, bolus doses followed by a continuous infusion of glucagon were found to be effective in reversing the hypotension and QRS prolongation in the rat model of amitriptyline toxicity. Further studies are needed to reveal the exact mechanism of the proposed effect.

Effects of adenosine receptor antagonists on amitriptyline-induced vasodilation in rat isolated aorta

Background. Although we have previously demonstrated the beneficial effects of adenosine receptor antagonists in preventing cardiovascular toxicity of amitriptyline in rats, it is not clear whether adenosine receptors in heart or in vasculature are dominant. The aim of the current study was to investigate the role of adenosine A2a receptors on amitriptyline-induced vasodilation in rat isolated aorta. Methods. After determining EC80 of noradrenalin (NA) (the concentration of noradrenalin that produces 80% of maximal contractile response) as 10−5M, the IC50 value of amitriptyline was measured in rat isolated aorta (the drug concentration causing a half- maximal inhibition of contractile responses to NA); IC50 of amitriptyline was then compared in the presence of the DPCPX (a selective adenosine A1 antagonist), CSC (a selective A2a antagonist) or DMSO (a solvent for adenosine antagonists). Statistical analysis was done using the Student t test. Results. Amitriptyline-inhibited 49.9 ± 3.7 % contractile response to NA on aorta segments at 1.8 × 10−5M (IC50). While DPCPX increased amitriptyline-induced inhibition on contractile response to NA dose dependently, CSC decreased the contractile response to NA only at 10−5M. DMSO did not change amitriptyline-induced IC50. Conclusion. Adenosine A2a receptor stimulation seems to be responsible partly for amitriptyline-induced vasodilation and hypotension since the adenosine A1 antagonist, DPCPX, increased amitriptyline-induced vasodilation in rat isolated aorta.

Propafenone-induced cardiac arrest: full recovery with insulin, is it possible?

Propafenone may cause mental depression, mania, convulsion, metabolic acidosis, hypotension, prolonged QRS, atrioventricular block, and cardiac arrest if it is taken at a dose greater than recommended. There is no standard specific treatment or antidote for a propafenone overdose, and life-supporting treatments are applied in these cases. In this case report, we report a case of a 15-year-old female patient who experienced cardiac arrest after an oral propafenone overdose. She was successfully treated using cardiopulmonary resuscitation, which took approximately 1.5 hours. Dopamine infusion, sodium bicarbonate, and insulin treatment were also administered to the patient. Highdose insulin treatment may be an effective treatment of propafenone poisoning. Propafenone is a class IC antiarrhythmic agent that can be used to treat paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, and ventricular arrhythmia [1]. Hypotension, long QRS duration, atrioventricular block, convulsion, and cardiac arrest may occur after a propafenone overdose. The survival rate of patients who require cardiovascular resuscitation as a result of cardiac arrest is low [2,3]. Propafenone poisoning is a rare yet life-threatening situation, and there is no specific procedure and/or antidote used for treatment. Supportive treatments for the symptoms and conditions of the patient are recommended. Gastric lavage, a method of gastrointestinal decontamination, is not recommended, except in cases of overdose because it can increase the risk of convulsion. Activated charcoal can be used with the constraint of protecting airway patency if the time passed after poisoning is sufficient [4]. If there is no response to intravenous fluid treatment in cases of propafenone poisoning monitored for cardiac activity, alternate methods can be used, including vasopressive drug administration for hypotension, sodium bicarbonate administration for a prolonged QRS duration and metabolic acidosis, cardiopulmonary resuscitation (CPR), transient ☆ The authors report no declarations of interest. 0735-6757/

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

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Adenosine-mediated cardiovascular toxicity in amitriptyline-poisoned rats

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.

Protective Effect of an Adenosine A1 Receptor Agonist Against Metamidophos-Induced Toxicity and Brain Oxidative Stress

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.

A retrospective evaluation of analgesic exposures from Izmir, Turkey

The aim of this study was to evaluate the effects of different doses of an adenosine A1 selective agonist, phenylisopropyl adenosine (PIA), on metamidophos-induced cholinergic symptoms, mortality, diaphragm muscle necrosis, and brain oxidative stress. A LD50 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.