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.

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 x 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 A(1) receptor antagonist, DPCPX (8-cyclopentyl-1,3-Dipropylxanthine,10(-4) to 10(-6) M) or a selective adenosine A(2a) receptor antagonist, CSC (8-3-chlorostyryl-caffeine,10(-4) to 10(-6) M). In the second protocol, amitriptyline (5.5 x 10(-5) M) was infused following pretreatment with DPCPX (10(-4) M) or CSC (10(-5) M). Left ventricular developed pressure (LVDP), dp/dt(max), 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/dt(max), 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 x 10(-5)M amitriptyline. An adenosine A(1) receptor antagonist, DPCPX, might shorten amitriptyline-induced QRS prolongation by activating beta adrenergic receptors.

A retrospective evaluation of analgesic exposures from Izmir, Turkey.

The objective of this study is to analyze exposures concerning analgesics that were reported to Dokuz Eylul University Drug and Poison Information Center (DPIC) and admitted to the Department of Emergency Medicine in Dokuz Eylul University Hospital (EMDEU) between 1993 and 2004. Demographics of the patients, characteristics of analgesic exposures, performed treatment attempts and outcome of the poisoned patients were recorded on standard data forms and were then entered into a computerized database program. Statistical analysis was performed by using the chi-square test. The DPIC recorded 55 962 poisoning calls, 48 654 (86.9%) of them related to medicines. Analgesics accounted for 16.3% (7 939 cases) of all medicine-related exposures; among them 446 exposures were admitted to EMDEU. More than half of the analgesic exposure calls and admitted cases involved adults (55.9%, 4 440). Females dominated in all age groups (70.3%, 5 578). Mean age was 20.2 +/- 11.8. The most involved analgesics were paracetamol (47.9%), propionic acid derivatives (16.1%) and salicylates (13.7%). Most of the poisonings were intentional (75.1%), especially in 19-29 years age group of adults and 13-18 years age group of children. Most of the patients reported to DPIC and admitted to EMDEU were asymptomatic (84.4% and 54.7%, respectively). Gastrointestinal decontamination methods were performed more frequently for admitted poisoning cases before hospital admission than reported poisoning cases (61% vs. 23%). Paracetamol ingestion was the most common cause of analgesic exposures reported to our DPIC. Most of the analgesic exposures reported to DPIC were asymptomatic or mild. DPICs have an important role for the referral of analgesic exposures without unnecessary gastrointestinal decontamination procedures.

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 A(2a) receptors on amitriptyline-induced vasodilation in rat isolated aorta. METHODS: After determining EC(80) of noradrenalin (NA) (the concentration of noradrenalin that produces 80% of maximal contractile response) as 10(-5)M, the IC(50) value of amitriptyline was measured in rat isolated aorta (the drug concentration causing a half- maximal inhibition of contractile responses to NA); IC(50) of amitriptyline was then compared in the presence of the DPCPX (a selective adenosine A(1) antagonist), CSC (a selective A(2a) 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 x 10(-5)M (IC(50)). While DPCPX increased amitriptyline-induced inhibition on contractile response to NA dose dependently, CSC decreased the contractile response to NA only at 10(-5)M. DMSO did not change amitriptyline-induced IC(50). CONCLUSION: Adenosine A(2a) receptor stimulation seems to be responsible partly for amitriptyline-induced vasodilation and hypotension since the adenosine A(1) antagonist, DPCPX, increased amitriptyline-induced vasodilation in rat isolated aorta.

The role of adenosine triphosphate-regulated potassium channels in propofol-induced beneficial effect on contractile function of hypercholesterolemic isolated rabbit hearts.

OBJECTIVE: To investigate the role of adenosine triphosphate-regulated potassium (KATP) channels in the propofol-induced changes in the contractile function of hypercholesterolemic rabbit hearts. METHODS: This study was carried out in the Department of Pharmacology Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey during the period January to December 2003. Twenty-two isolated rabbit hearts were grouped into 4. Group I (n=6) were infused with 50 microM propofol during a 60 minutes perfusion. Group II (n=6) were also infused with 100 microM propofol over the same period. Group III (n=5) was perfused with solutions containing 10 microM glybenclamide and group IV (n=5) 100 microM diazoxide for 5 minutes before and during a 60 minutes infusion with 100 microM propofol. RESULTS: The 50 microM propofol infusion decreased left ventricular pressure (LVP) significantly (p<0.05) but it did not change dP/dt max and dP/dt min. The 100 microM propofol infusion caused a significant increase in LVP at 20 minutes. Furthermore, a 100 microM propofol infusion resulted in a significant increase in maximal positive left ventricular pressure (dP/dt max) and maximal negative left ventricular pressure (dP/dt min) compared to baseline (p<0.05). The increase in dP/dtmax and dP/dt min induced by 100 microM propofol was inhibited by glybenclamide (p<0.05), a KATP channel blocker, but was not affected by diazoxide (p>0.05), a KATP channel opener. CONCLUSION: The activation of KATP channels seems to be one of the mechanisms by which propofol induced beneficial effect on contractility of myocardium in hypercholesterolemic rabbit hearts.

Do adenosine receptors play a role in amitriptyline-induced cardiovascular toxicity in rats?

OBJECTIVE: The aim of the our study was to investigate the role of adenosine receptors on cardiovascular toxicity induced by amitriptyline, a tricyclic antidepressant agent. Therefore, the hypothesis of this study was that adenosine receptor antagonists would improve and/or prevent amitriptyline-induced hypotension and conduction abnormalities in an anesthetized rat model of amitriptyline intoxication. METHODS: Two separate experimental protocols were performed. Amitriptyline intoxication was induced by the infusion of amitriptyline 0.94 mg/kg/min until 40-45% reduction of mean arterial pressure (MAP). Sodium cromoglycate (10 mg/kg) was injected i.v. to inhibit the A3 receptor-mediated activation of mast cells. In protocol 1, after amitriptyline infusion, while control animals (n=8) were given dextrose solution, treatment groups received a selective adenosine A1 antagonist DPCPX (8-cyclopentyl-1,3-Dipropylxanthine, 20 microg/kg/min, n=8) or a selective A2a antagonist CSC (8-(3-chlorostyryl) caffeine, 24 microg/kg/min, n=8) for 60 minutes. In protocol 2, after the sodium cromoglycate, while control group of rats (n=8) recevied a dextrose solution, treatment groups of rats were administered DPCPX (20 microg/kg/min, n=8) or CSC (24 microg/kg/min, n=8) infusion to block adenosine A1 and A2a receptors for 20 minutes before amitriptyline infusion. After pretreatment with adenosine antagonists, all rats were given a dose of 0.94 mg/kg/min of amitriptyline infusion during 60 minutes. Outcome measures were mean arterial pressure (MAP), heart rate (HR), QRS duration and survival rate. RESULTS: In protocol 1, amitriptyline infusion significantly reduced MAP and prolonged QRS within 15 minutes. HR was not changed significantly during the experiments. While dextrose did not improve MAP and QRS prolongation, DPCPX or CSC administration developed a significant improvement in MAP compared to the dextrose group within 10 min (88.5 +/- 2.8%, 75.6 +/- 4.7% and 50.1 +/- 14.7%, p<0.01, p<0.05, respectively). Both DPCPX and CSC decreased QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.00001). In protocol 2, pretreatment with DPCPX or CSC prevented the reduction in MAP due to amitriptyline toxicity compared to rats administered dextrose infusion (99.5 +/- 2.6%, 102.4 +/- 2.6%, 81.8 +/- 5.4, p<0.01 at 30 min; 98.0 +/- 2.9%, 93.5 +/- 6.0%, 64.9 +/- 4.7, p<0.001, p<0.01 at 40 min, respectively). Pretreatment with DPCPX or CSC also prevented the QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.0001). CONCLUSION: Adenosine antagonists were found to be effective in improving hypotension, QRS prolongation and survival time in our rat model of amitriptyline toxicity. Additionally, amitriptyline-induced cardiotoxicity was abolished by pretreatment with adenosine receptor antagonists. These results suggest that adenosine receptors may have a role in the pathophysiology of amitriptyline-induced cardiovascular toxicity. Adenosine A1 and A2a receptor antagonists may be promising agents for reversing amitriptyline-induced cardiovascular toxicity.

Acute methanol poisonings reported to the Drug and Poison Information Center in Izmir, Turkey.

The demographics, sources and outcomes of methanol poisoning have not been described in Turkey. Our study identified the profile of acute methanol exposures reported to Drug and Poison Information Center (DPIC) in Izmir, Turkey, from 1993 to 2002. Data analysis included patient demographics, sources of methanol, reason for the exposure, clinical effects and outcomes of methanol poisoning. The DPIC recorded 30,485 calls concerning poisoning; 996 (3.3%) alcohol poisonings were recorded and 113 (11.3%) of them were methanol poisonings. There were 91 (80.5%) males and 22 (19.5%) females with a mean age of 34.7+/-1.3 y (range 19-65) and 4.8+/-0.9 y (range 1-18) in adults and children, respectively. The sources of methanol were eu de cologne (72.6%), spirits (10.6%) and antifreeze (2.7%). Accidental poisoning occurred in all children between 0 and 12 y old, abuse (55.7%) and intentional poisoning (27.3%) were predominant in adults. Clinical signs in all cases were central nervous system symptoms (45.1%), metabolic acidosis (23.0%), visual symptoms (21.2%) and gastrointestinal symptoms (10.6%). Sixteen patients (14.1%) died, 63 (55.8%) had complete recovery and 1 (0.9%) had irreversible visual problems. Most patients with methanol poisoning may die or present serious morbidity without appropriate treatment in a health care facility. Methanol for producing cheap "eu de colognes" in Turkey is the principal reason for severe poisoning and deaths. Public education about colognes and legislative control of cologne production are important in preventing methanol poisoning.