Evaluation of ß-adrenergic ligands for development of pharmacological heart failure and transparency models in zebrafish.

Cardiovascular toxicity represents one of the most common reasons for clinical trial failure. Consequently, early identification of novel cardioprotective strategies could prevent the later-stage drug-induced cardiac side effects. The use of zebrafish (Danio rerio) in preclinical studies has greatly increased. High-throughput and low-cost of assays make zebrafish model ideal for initial drug discovery. A common strategy to induce heart failure is a chronic ß-adrenergic (ßAR) stimulation. Herein, we set out to test a panel of ßAR agonists to develop a pharmacological heart failure model in zebrafish. We assessed ßAR agonists with respect to the elicited mortality, changes in heart rate, and morphological alterations in zebrafish larvae according to Fish Embryo Acute Toxicity Test. Among the tested ßAR agonists, epinephrine elicited the most potent onset of heart stimulation (EC50 = 0.05 mM), which corresponds with its physiological role as catecholamine. However, when used at ten-fold higher dose (0.5 mM), the same compound caused severe heart rate inhibition (-28.70 beats/min), which can be attributed to its cardiotoxicity. Further studies revealed that isoetharine abolished body pigmentation at the sublethal dose of 7.50 mM. Additionally, as a proof of concept that zebrafish can mimic human cardiac physiology, we tested ßAR antagonists (propranolol, carvedilol, metoprolol, and labetalol) and verified that they inhibited fish heart rate in a similar fashion as in humans. In conclusion, we proposed two novel pharmacological models in zebrafish; i.e., epinephrine-dependent heart failure and isoetharine-dependent transparent zebrafish. We provided strong evidence that the zebrafish model constitutes a valuable tool for cardiovascular research.

The cytotoxic and apoptotic effects of beta-blockers with different selectivity on cancerous and healthy lung cell lines.

ß-blockers having specific affinities to ß-adrenergic receptors are routinely used to treat cardiovascular problems. Additionally, it has been demonstrated that these drugs can be effective in treating apoptosis-related diseases. The current study was conducted to investigate the cytotoxic and apoptotic effects of ß-1 selective esmolol, ß-2 selective ICI-118,551, and non-selective nadolol blockers on the cancerous and healthy lung cells. MTT test was used to evaluate cytotoxicity. Apoptotic actions were examined by using Annexin V-FITC/PI assay, JC-1 staining, ROS test, and the determination of the caspase-4 and -9, Bcl-2, Bax, Bax/Bcl-2, and JNK levels. Although the MRC-5 showed greater resistance than A549 cells, the ß-blockers at 150-250 µM exhibited different levels of cytotoxic effect on both lung cell lines. Esmolol was found to be the most ineffective blocker and the increases in Bcl-2 protein levels were appeared to be effective in resistance to this drug. The increases in reactive oxygen species (ROS) together with the increase in caspase-4 and Bax protein levels have been shown to play a role in ICI-118,551 induced lung cell death. Nadolol was the most effective blocker increasing the total apoptotic cell population in both lung cells, which was based on both mitochondrial and endoplasmic reticulum stress. When the selectivities of the ß-blockers are considered, it seems that ß-2 specific antagonism predominantly mediated the death of lung cells, and the overwhelming factors causing apoptosis mainly varied depending on the selectivity of the blockers.

Antiarrhythmic effect of antazoline in experimental models of acquired short- and long-QT-syndromes.

Aims: Antazoline is a first-generation antihistamine with antiarrhythmic properties. This study examines potential electrophysiological effects of antazoline in short-QT-syndrome (SQTS) and long-QT-syndrome (LQTS). Methods and results: Sixty-five rabbit hearts were Langendorff-perfused. Action potential duration at 90% of repolarization (APD90), QT-interval, spatial dispersion (DISP), and effective refractory period (ERP) were measured. The IK, ATP-opener pinacidil (1 µM, n = 14) reduced APD90 (-14 ms, P < 0.01), QT-interval (-14 ms, P < 0.01), and ERP (-11 ms, P < 0.01), thus simulating acquired SQTS. Additional infusion of 20 µM antazoline prolonged repolarization. Under baseline conditions, ventricular fibrillation (VF) was inducible in 5 of 14 hearts (10 episodes) and in 5 of 14 pinacidil-treated hearts (21 episodes, P = ns). Antazoline significantly reduced induction of VF (0 episodes, P < 0.05 each). Further 17 hearts were perfused with 100 µM sotalol and 17 hearts with 300 µM erythromycin to induce acquired LQTS2. In both groups, prolongation of APD90, QT-interval, and ERP was observed. Spatial dispersion was increased (sotalol: +26 ms, P < 0.01; erythromycin: +31 ms, P < 0.01). Additional infusion of antazoline reduced DISP (sotalol: -22 ms, P < 0.01; erythromycin: -26 ms, P < 0.01). Torsade de pointes (TdP) occurred in 6 of 17 sotalol-treated (22 episodes, P < 0.05 each) and in 8 of 17 erythromycin-treated hearts (96 episodes P < 0.05 each). Additional infusion of antazoline completely suppressed TdP in both groups (P < 0.05 each). Acquired LQTS3 was induced by veratridine (0.5 µM, n = 17) and similar results were obtained (APD90: +24 ms, P < 0.01, QT-interval: +58 ms, P < 0.01, DISP: +38 ms, P < 0.01). Torsade de pointes occurred in 10 of 17 hearts (41 episodes, P < 0.05 each). Antazoline significantly reduced TdP (2 of 17 hearts, 4 episodes, P < 0.05 each). Conclusion: Antazoline significantly reduced induction of VF in an experimental model of acquired SQTS. In three experimental models of acquired LQTS, antazoline effectively suppressed TdP.

Chronic exposure to the ß-blocker metoprolol reduces growth and alters gene expression of gonadotropins and vitellogenin in Nile tilapia (Oreochromis niloticus).

Knowledge of the occurrence and impacts of human pharmaceuticals in the aquatic environment is increasing since many years. Ecotoxicological studies mainly focus on acute effects though; chronic exposure studies are still rare. ß-adrenergic receptor antagonists (ß-blockers) are widely detected in the aquatic environment and likely alter the physiology of aquatic vertebrates due to a well-conserved adrenergic system. In this study, Nile tilapia (Oreochromis niloticus) were exposed to four different concentrations (4×10-10M, 4×10-9M, 4×10-8M and 4×10-7M) of metoprolol (ß1-blocker) from fertilized egg until 80 days post-hatch. Hatching and survival were not affected but growth was reduced almost dose-dependently after 30 and 80 days post-hatch. Histopathological evaluation of the gills revealed the tendency of mild alterations with proliferation of mucous/chloride cells and infiltration by leucocytes as the main findings. The transcriptional responses of both pituitary gonadotropins (luteinizing hormone and follicle stimulating hormone) as well as the estrogenic biomarker vitellogenin indicated moderately altered endocrine processes due to metoprolol exposure at the concentrations chosen. In contrast, hepatic detoxification mechanisms displayed only little to no effects. Based on this study, the overall toxicity of metoprolol in fish at environmentally relevant concentrations seems to be rather low.

Assessing the environmental hazard of individual and combined pharmaceuticals: acute and chronic toxicity of fluoxetine and propranolol in the crustacean Daphnia magna.

Pharmaceuticals are widespread emerging contaminants and, like all pollutants, are present in combination with others in the ecosystems. The aim of the present work was to evaluate the toxic response of the crustacean Daphnia magna exposed to individual and combined pharmaceuticals. Fluoxetine, a selective serotonin re-uptake inhibitor widely prescribed as antidepressant, and propranolol, a non-selective ß-adrenergic receptor-blocking agent used to treat hypertension, were tested. Several experimental trials of an acute immobilization test and a chronic reproduction test were performed. Single chemicals were first tested separately. Toxicity of binary mixtures was then assessed using a fixed ratio experimental design. Five concentrations and 5 percentages of each substance in the mixture (0, 25, 50, 75, and 100%) were tested. The MIXTOX model was applied to analyze the experimental results. This tool is a stepwise statistical procedure that evaluates if and how observed data deviate from a reference model, either concentration addition (CA) or independent action (IA), and provides significance testing for synergism, antagonism, or more complex interactions. Acute EC50 values ranged from 6.4 to 7.8 mg/L for propranolol and from 6.4 to 9.1 mg/L for fluoxetine. Chronic EC50 values ranged from 0.59 to 1.00 mg/L for propranolol and from 0.23 to 0.24 mg/L for fluoxetine. Results showed a significant antagonism between chemicals in both the acute and the chronic mixture tests when CA was adopted as the reference model, while absence of interactive effects when IA was used.

Pharmacokinetic-pharmacodynamic analyses of antihypertensive drugs, nifedipine and propranolol, in spontaneously hypertensive rats to investigate characteristics of effect and side effects.

To investigate the relationship between the pharmacokinetics (PK) and effects and/or side-effects of nifedipine and propranolol, simultaneous examination of their PK and pharmacodynamics (PD), namely blood pressure (BP), heart rate (HR), and QT interval (QT), were assessed in spontaneously hypertensive rats as a disease model. Drugs were infused intravenously for 30 min, then plasma PK and hemodynamic effects were monitored. After general two-compartmental analysis was applied to the plasma data, PD parameters were calculated by fitting the data to PK-PD models. After nifedipine administration, the maximal hypotensive effect appeared about 10 min after starting the infusion, then BP started to elevate although the plasma concentration increased, supposedly because of a negative feedback mechanism generated from the homeostatic mechanism. After propranolol administration, HR decreased by half, and this bradycardic effect was greater than that with nifedipine. Wide variation in QT was observed when the propranolol concentration exceeded 700 ng/mL. This variation may have been caused by arrhythmia. Prolongation of QT with propranolol was greater than that with nifedipine, and bradycardia was slower than the concentration increase and QT prolongation. The characteristically designed PK-PD model incorporating a negative feedback system could be adequately and simultaneously fitted to both observed effect and side-effects.

Acute toxicities of pharmaceuticals toward green algae. mode of action, biopharmaceutical drug disposition classification system and quantile regression models.

The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water).

Transcriptional Responses in Adult Zebrafish (Danio rerio) Exposed to Propranolol and Metoprolol.

ß-adrenergic receptor blockers (ß-blockers) are widely detected in the aquatic environment; however, the effects of these pharmaceuticals on aquatic organisms remain uncertain. In this study, adult zebrafish were exposed to two different ß-blockers, propranolol and metoprolol, for 96 h. After exposure, the transcriptional responses of genes encoding the ß-adrenergic receptor (i.e., adrb1, adrb2a, adrb2b, adrb3a and adrb3b), genes involved in detoxification and the stress response (i.e., hsp70, tap, mt1 and mt2), and genes related to the antioxidant system (i.e., cu/zn-sod, mn-sod, cat and gpx) were examined in the brain, liver and gonad. Our results show that both propranolol and metoprolol exposure changes the mRNA level of ß-adrenergic receptors, indicating clear pharmacological target engagement of the ß-blockers. The transcription of genes related to antioxidant responses and detoxification process were induced, suggesting that ß-blocker exposure can activate the detoxification process and result in oxidative stress in fish. Moreover, the transcriptional responses displayed substantial tissue- and gender-specific effects. Considering the environmental concentrations of propranolol and metoprolol, these results suggest that these pharmaceuticals are unlikely to pose a risk to fish. However, the impacts in prolonged exposure, along with other possible side effects due to ß-adrenergic receptor blockade, should be further assessed.

Occupational airborne contact dermatitis from benzodiazepines and other drugs.

BACKGROUND: Healthcare workers (or relatives) crushing drug tablets for patients with difficulties in swallowing are at risk of developing sensitization via airborne exposure. Tetrazepam, in particular, is increasingly being described as an important occupational allergen in this regard, although other drugs are also involved. OBJECTIVES: To identify the allergenic culprits in 4 patients, namely 2 nurses, 1 pharmacy assistant, and 1 spouse, who all regularly crushed tablets of systemic drugs and presented with severe airborne dermatitis. METHODS: The patients were patch tested with all of the drugs that they handled, as well as with potential cross-sensitizing molecules. RESULTS: All 4 patients reacted to tetrazepam and other benzodiazepines, some of which they had not previously come into contact with, which favours cross-reactivity rather than concomitant sensitization. These patients also had positive reactions to several other non-structurally related drugs for which, in some cases, there was no history of exposure. CONCLUSIONS: Subjects having to crush drugs, in either an occupational or a non-occupational context, and who present with dermatitis suspected of being airborne-induced, should be patch tested with all contacted medicaments, as well as with possible cross-reacting molecules. Prevention by the use of crushing devices and protective measures (gloves and masks) when medications are handled should be advised.

Toxicity and enantiospecific differences of two ß-blockers, propranolol and metoprolol, in the embryos and larvae of zebrafish (Danio rerio).

The risk presented by ß-blockers on aquatic organisms remains uncertain, particularly given the enantiospecific differences in toxicity of chiral ß-blockers. In this study, the toxicity of two ß-blockers, propranolol and metoprolol, was determined. The 96-h LC50 of propranolol in the zebrafish larvae was 2.48 mg/L, whereas 50 mg/L metoprolol did not result in death. Both ß-blockers decreased the heart rate and hatching rate and increased the mortality of the zebrafish embryos. Among these indicators, the heart rate was the most sensitive. However, the acute larval and embryo toxicity results displayed no enantioselectivity. Additionally, the transcriptional response of the genes encoding the ß-adrenergic receptors and those involved in other physiological processes, including the antioxidant response, detoxification, and apoptosis, in zebrafish larvae exposed to the ß-blockers was examined. Although the changes in gene transcription were fairly minor, significant enantioselectivity was observed for ß-blockers, suggesting that the transcriptional response was more sensitive for the evaluation of enantiospecific toxicity. Based on these results, the pharmaceutical drugs were not expected to pose a risk to fish; however, this conclusion should not be considered final. These results also demonstrated that the enantiospecific toxicity of chiral ß-blockers should be investigated when performing an ecological risk assessment.

Formulation study of a patch containing propranolol by design of experiments.

OBJECTIVE: To evaluate the feasibility of a transdermal patch containing propranolol (PR). METHOD: Skin penetration enhancers (SPEs) able to improve the skin permeability of PR were selected and a quality by design approach was applied to the development of the patch by a 2(4) full factorial design. The permeation profile of PR from the formulations was assessed in in vitro permeation studies performed by using Franz diffusion cells and human epidermis as membrane. Finally, skin irritation was evaluated by the Draize test. RESULTS: N-methyl pyrrolidone (NMP) resulted as the best SPE: in addition, the critical factors influencing the PR diffusion through the human epidermis when loaded in the patch resulted in the matrix thickness (X1, p = 0.0957) and PR content (X3, p = 0.0004) which improved the flux; conversely, NMP lacked its enhancement effect when loaded in the patch and the increase in its concentration (X4, p = 0.006) affected the drug permeation through human epidermis. The flux of optimal formulation was 12.7 µg/cm(2)/h. On the basis of the steady-state concentration and clearance of PR, the estimated patch surface was 100-120 cm(2), since the activity of PR is related to its Senantiomer and no in vivo bioconversion occurs. CONCLUSION: A patch containing (S)-PR was prepared and the (S)-PR flux (13.3 µg/cm(2)/h) permitted to confirm the suitability of a transdermal administration of PR. In particular, the use of a 50 µm thick methacrylic matrix containing 8% (S)-PR and 15% NMP can allow to develop a patch non-irritating to the skin, in order to ensure a constant permeation flux of PR over 48 h.

The combined effect of furosemide and propranolol on GSH homeostasis in ACHN renal cells.

OBJECTIVES: Propranolol, a beta-adrenergic blocker, is used in the treatment of a large number of cardiovascular diseases such as hypertension and arrhythmias. Propranolol, in combination with furosemide, is used to treat hypertensive disorders although their side effect profile is not very obvious. In present study, the effects of the drugs furosemide and propranolol were in corporately investigated both on glutathione homeostasis and their antioxidant effect on ACHN cells. METHODS: The cytoxicities and antioxidant effects of these two clinically important drugs on human kidney cell lines were evaluated using MTT following by the determination of glutathione reductase (GR) and glutathione peroxidase (GPx) activities and measuring the level of reduced glutathione (GSH). RESULTS: Propranolol induced a significant cytotoxic effect at 100 µM, while furosemide was cytotoxic at doses of 250 and 1000 µg/ml. A slight increase in GPx and GR activities and GSH level was observed with propranolol and furosemide treatment alone, while the two drugs together caused a significant increase in GPx and GR activities (35% and 42%, respectively) and GSH content (35%) in ACHN cell lysates (p < 0.05). CONCLUSIONS: Our results demonstrate that although high doses of furosemide and propranolol are cytotoxic, co-administration of low doses may improve the antioxidant defense in patients undergoing treatment with these two important drugs.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo.

A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of ß-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of ß-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate.

Nebivolol treatment increases splanchnic blood flow and portal pressure in cirrhotic rats via modulation of nitric oxide signalling.

BACKGROUND: We evaluated the effects of nebivolol, a third generation beta-blocker capable of increasing NO-bioavailability on portal pressure, and on splachnic and systemic haemodynamics in a cirrhotic portal hypertensive rat model. METHODS: Male Sprague-Dawley rats underwent sham operation (SO) or bile duct ligation (BDL). When cirrhosis was fully developed, the animals were orally treated with low-dose (5 mg/kg) or high-dose (10 mg/kg) nebivolol (NEBI) or vehicle (VEH) for 7 days. Heart rate (HR), mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Portosystemic collateral blood flow (PSCBF) was quantified using radioactive microspheres. Hepatic and splanchnic NOx levels and GSH/GSSG ratios (RedOx state) were determined using commercially available kits. RESULTS: BDL-VEH rats showed increased HR, PP and PSCBF, whereas MAP was decreased compared to SO-VEH rats. Nebivolol significantly reduced HR both in SO (P < 0.001) and BDL (P < 0.001) rats. BDL-NEBI animals had significantly higher PP (15.5 vs. 12.6 mmHg; P = 0.006) and SMABF (5.3 vs. 3.7 ml/min/100g; P = 0.016) than BDL-VEH animals. The increase in PP and SMABF was noted both in low-dose and high-dose BDL-NEBI rats. While no beneficial effects on hepatic RedOx state were observed, splanchnic NOx levels were significantly increased by NEBI treatment in a dose-dependent manner. Nebivolol treatment did not affect PSCBF in SO and BDL animals. CONCLUSION: Nebivolol increases portal pressure in cirrhotic animals by increasing splanchnic blood flow via modulation of NO signalling. Portosystemic collateral blood flow remained unchanged. These data do not support the use of nebivolol for treatment of cirrhotic patients with portal hypertension.

Pharmacokinetics, pharmacodynamics and toxicity of a combination of metoprolol succinate and telmisartan in Wistar albino rats: safety profiling.

Metoprolol succinate (MET), a cardioselective ß blocker and telmisartan (TEL), an angiotensin receptor blocker were administered orally, both individually and in combination to Wistar albino rats for evaluation of their pharmacokinetics, pharmacodynamics and repeated dose oral toxicity (28 days). Pharmacokinetic study was performed by analyzing drug concentration in plasma by a developed and validated LC-MS/MS method following oral administration of MET and TEL at 2.5 mg/kg and 2.0 mg/kg dose, respectively, both individually and in combination. Antihypertensive activity of MET and TEL in above dose and manner was evaluated on artificially induced hypertension on laboratory animals. In repeated dose oral toxicity study, MET (60, 120 and 240 mg/kg/day) and/or TEL (12, 24 and 48 mg/kg/day) were administered to animals for 28 days followed by a recovery period of 14 days. Pharmacokinetic data revealed the probable absence of any pharmacokinetic interaction when co-administered. Improved blood pressure lowering effect was observed by combination therapy. Moreover, toxic effects obtained at high dose level of each treatment groups were transient and reversible and no evidence of additive toxic effects were observed due to concomitant administration. So, this combination can primarily be stated as safe which will be confirmed after clinical interaction studies in humans.

Effects of indomethacin and propranolol on Chironomus riparius and Physella (Costatella) acuta.

New analytical methods are available for detecting novel xenobiotic compounds in freshwater systems. Pharmaceuticals are suspected of having effects on freshwater biota at very low concentrations, although the nature of these effects remains unclear. Previous data from the Llobregat River revealed a positive statistical relationship between the biomass of benthic macroinvertebrates and the presence of certain non-steroidal anti-inflammatory drugs (NSAIDs) and beta-blockers. Here, experiments were conducted with the midge Chironomus riparius and the freshwater snail Physella (Costatella) acuta in sediments and water, respectively. The sediments and water were treated with the pharmaceuticals propranolol and indomethacin, with the aims of assaying the effects of these compounds on the organisms and testing the statistical relationships observed in field. The variables measured were survival; C. riparius biomass; and the carbon/nitrogen ratio, lipid content and fertility of freshwater snails. Indomethacin in treated sediments induced an increase in C. riparius biomass, whereas propranolol inhibited growth, albeit at marginal statistical significance. By contrast, indomethacin in water had no effect on any of the parameters measured in P. acuta.

Molecular interactions of polyvinyl chloride microplastics and beta-blockers (Diltiazem and Bisoprolol) and their effects on marine meiofauna: Combined in vivo and modeling study.

The ecotoxicological effects of beta-blockers (i.e. Diltiazem and Bisoprolol) and their interactions with the microplastic polyvinyl chloride on marine meiofauna were tested in laboratory microcosms. An experimental factorial design was applied, using meiobenthic fauna collected from the Old Harbor of Bizerte (NE Tunisia), but with a main focus on the nematode communities. The meiobenthic invertebrates were exposed to two concentrations of Diltiazem and Bisoprolol, of 1.8 µg.L-1 and 1.8 mg.L-1, respectively, and one concentration of polyvinyl chloride (i.e. 20 mg.kg-1), separately and mixed. The overall meiofauna abundance was significantly reduced in all treatments, mainly that of polychaetes and amphipods. Moreover, the juveniles-gravid female ratios of the nematode communities were the lowest in the 1.8 µg.L-1 Bisoprolol treatment and for the 1.8 mg.L-1 mixture of Diltiazem and microplastics, suggesting that different dosages influence the maturity status of the examined species. The demographic results were also supported by in silico approach. The simulation of molecular interactions revealed acceptable binding affinities (up to -8.1 kcal/mol) and interactions with key residues in the germ line development protein 3 and sex-determining protein from Coenorhabditis elegans. Overall, the experimental outcome strongly indicates synergistic interactions among the beta-blockers Diltiazem and Bisoprolol and the microplastic polyvinyl chloride on marine nematode communities.

Is hypoglycemia really observed in pediatric beta-blocker intoxications? A case-control study.

BACKGROUND: Beta-blocker (BB) intoxications are common in both childhood and adulthood. In the case of poisoning, bradycardia, hypotension, ventricular dysrhythmias, mental status changes, seizures, hypoglycemia, and bronchospasm may occur. Effects on the cardiovascular system are commonly seen, but hypoglycemia is not frequently observed in clinical practice. In this study, we aimed to answer the question, "Is hypoglycemia more commonly observed in BB intoxications than in other intoxications?" METHOD: This was a case-control study conducted in a pediatric emergency department of a university hospital. The case group (Group 1) consisted of cases with BB poisonings and the control group (Group 2) consisted of cases with selective serotonin receptor inhibitor (SSRI) poisonings. Data were obtained from patient files. We recorded the blood glucose levels (BGLs) of all patients on admission to the emergency department and at the 1-, 6-, and 24-h follow-up. The amounts of BBs received by the cases were compared with the specific toxic doses of each drug. The data obtained were analyzed using the Statistical Package for the Social Sciences 22 (SPSS.22) program. Mean and standard deviation for numerical values and frequency for categorical data are reported; at test, chi-square test, and ANOVA tests were used for the analysis. RESULTS: The study comprised 40 patients (Group 1) and 40 controls (Group 2). The mean serum BGLs of patients in Group 1 at admission and at the 1-, 6-, and 24-h follow-up were 107.2 ± 46.3 mg/dl, 86.3 ± 20.1 mg/dl, 88.6 ± 28.4 mg/dl, and 86.5 ± 23.7 mg/dl, respectively. The mean values of Group 2 cases were 100 ± 39.5 mg/dl, 92.1 ± 30 mg/dl, 91±28 mg/dl, and 127.8 ± 60.7 mg/dl, respectively, at admission and at the 1-, 6-, and 24-h follow-up (p = 0.4, p < 0.001, p = 0.7, and p < 0.001, respectively). The mean BGLs of patients who were exposed to propranolol at admission and at the 1-, 6-, and 24-h follow-up were significantly lower than those of the patients who had taken different BBs in Group 1. No linear correlation was found between the percentage of exposure to BB toxic doses and BGLs. CONCLUSION: Our study showed that the BGLs of patients receiving BBs could be lower, but they were not at a level that would have serious consequences. Nevertheless, the BGLs of all cases of intoxication should be monitored closely.

Rescue extracorporeal life support for acute verapamil and propranolol toxicity in a neonate.

Extracorporeal life support (ECLS) to manage acute antiarrhythmic drugs toxicity in neonates has never been reported. Here presented is a case of venoarterial extracorporeal membrane oxygenation support in a newborn with refractory low cardiac output as a result of acute Ca-channel and ß-receptor antagonist toxicity for treatment of paroxysmal supraventricular tachycardia (SVT). Shortly after onset of ECLS, the baby recovered sinus rhythm and subsequent bouts of SVT were controlled by amiodarone infusion and repeated DC shocks. Weaning was possible on the 5th day after implant, once recovery of the left ventricular function and optimization of the antiarrhythmic medication were achieved. In neonates with severe but potentially reversible cardiac dysfunction caused by drug toxicity, ECLS can maintain cardiac output and vital organ perfusion while allowing time for drug redistribution, metabolism, and clearance.

[Hemodynamic disorders and myocrdial insufficiency after toxic doses of propranolol].

Results of an experimental study of the toxic action of propranolol on the cardiovascular system are presented. It was shown that i/p injections of propranolol (2 mg/100 g) cause circulatory insufficiency, activate free radical oxidation, and induce cardiac dysfunction.