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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Effect of subacute methyl parathion administration on the pharmacokinetics and pharmacodynamics of nifedipine in rats.

Families living in agricultural areas may submitted to repeated exposure of methyl parathion (MP) that has been widely used as an agricultural insecticide. MP inhibits cytochrome P450 enzymes and has the potential to alter pharmacokinetic profiles of therapeutic agents that are metabolized in the liver. The aim of the present study is to investigate the possibility that the increased pharmacokinetic and pharmacodynamic effects of nifedipine is due to the inhibition of the metabolism after repeated administration of low doses of MP in rats. Male rats received commercial formulation of diluted MP (1/100 LD(50) or 1/25 LD(50), n=6) or tap water (control, n=5) via gastric gavage (0.5ml) for 14 days. On the 15th day, the carotid artery and jugular vein were cannulated for measurement of cardiovascular parameters and blood sampling, respectively. Nifedipine was administered 3mg/kg via the cannula inserted in the duodenum of the rat. Subacute MP administration did not change pharmacokinetic AUC((0-240)), C(max), t(max), t(1/2)) and pharmacodynamic (mean arterial pressures and heart rates) parameters of nifedipine. These findings provide evidence that repeated exposure of low doses of commercial MP did not affect the elimination of nifedipine which might be due to the lack of inhibition of CYP3A in rats.

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.

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.

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.

Turkish coffeehouse kahvehane is an important tobacco smoke exposure area in Turkey.

This study was undertaken to investigate the extent of environmental tobacco smoke (ETS) exposure in coffeehouses, as these are commonly frequented public places in Turkey. From 86 coffeehouses in the 3 districts, 59 coffeehouse workers and 35 hospital staff members (as a control group) were evaluated. Participants answered a questionnaire about demographics, working characteristics, smoking behavior, and ETS exposure during their daily life lives. The amount of nicotine in hair was determined by using gas chromatography/mass spectrometry (GC/MS). The mean hair nicotine level of the nonsmoker and smoker coffeehouse workers were 23.2 +/- 12.3 microg/g and 62.5 +/- 49.8 microg/g, respectively. Among the hospital staff, mean hair nicotine levels were 4.5 +/- 6 microg/g in nonsmokers and 30.6 +/- 14 microg/g in smokers. Working in coffeehouses has a marked effect on hair nicotine levels and potential adverse health effects.

The effects of gender and menopause on serum lidocaine levels in smokers.

It has been established that human cytochrome P450 (CYP) enzymatic activity is affected by gender, or by hormonal factors such as the menopause in women. Gender differences have a more pronounced effect on cytochrome (CYP) 3A4 isoenzyme activity, whereas cytochrome (CYP) 1A2 isoenzyme activity is mainly induced by chronic smoking. Lidocaine is frequently used in the treatment of hemodynamic changes following laryngoscopy and tracheal intubation during general anesthesia, and is metabolized by CYP3A4 and CYP1A2 isoenzymes in the liver. The aim of this study was investigate the effects of gender and menopause on serum lidocaine levels in smokers under general anesthesia. Six men, six premenopausal women and six postmenopausal women were enrolled in the study and received i.v. lidocaine (1 mg/kg) 1 minute before they underwent general anesthesia. Serum lidocaine concentrations were measured using the EMIT method at 1, 5, 10, 20, 40 and 60 minutes post-administration. Statistical analyses were performed using the Mann-Whitney U-test. No statistically significant differences were found regarding the area under curve (AUC(0-60) microg/mL/min), elimination half-life (t1/2 [min]) of lidocaine and in the measured levels of serum lidocaine at any time point between the study groups (p > 0.05). These results suggest that gender and menopause may have no significant effect on serum lidocaine levels in smokers.