Prophylactic role of α-lipoic acid and vitamin E against zinc oxide nanoparticles induced metabolic and immune disorders in rat's liver.

OBJECTIVES: Potential health hazard is associated with the wide use of nanoparticles. The prophylactic role of either α-lipoic acid (α-lip) or vitamin E (vit E) against the toxic effect of zinc oxide nano-particles (ZnO-NPs) induced metabolic disorder, inflammation and DNA damage in rat livers was studied. MATERIALS AND METHODS: ZnO-NPs were administered orally using two doses (600 mg and 1 g/kg body weight/day for 5 conscutive days). Some biomarkers of tissue damage, metabolic disorder, and DNA damage were investigated to explore the protective mechanisms of α-lip or vit E against ZnO-NPs induced hepatotoxicity. RESULTS: Co-administration of either α-lip (200 mg/kg body weight) or vit E (100 mg/kg body weight) daily for three weeks to ZnO-NPs intoxicated rats, significantly down-modulated the marked increase in serum ALT (marker of liver damage) and also serum glucose level (marker of metabolic disorder) as well as the pro-inflammatory biomarkers including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and immunoglobin G (IGg). Reduced glutathione level was decreased while caspase3 level was elevated in liver tissues of ZnO-NPs treated group compared with intoxicated one. Moreover histopathological examination of liver tissue supported the previous biochemical markers. Furthermore, ZnO-NPs induced hepatic oxidative DNA damage. CONCLUSIONS: Either α-lip or vit E proved to be hepatoprotective agents against ZnO-NPs toxicity because they ameliorated metabolic and immune disorders related to liver damage and modulated the previous measured parameters.

Induction of inflammation, DNA damage and apoptosis in rat heart after oral exposure to zinc oxide nanoparticles and the cardioprotective role of α-lipoic acid and vitamin E.

Although zinc oxide nanoparticles (ZnO-NP) are being used on a wide scale in the world consumer market, their potential hazards on humans remain largely unknown. The present study was aimed at investigating the oral toxicity of ZnO-NP in 2 dose regimen (600 mg/kg and 1 g/kg body weight for 5 consecutive days) in rats. In addition, the protective role of either α-lipoic acid (Lipo) or vitamin E (Vit E) against this cardiotoxic effect of ZnO-NPs was assessed. Results revealed that, co-administration of Lipo (200 mg/Kg body weight) or Vit E (100 mg/Kg body weight) daily for 3 weeks to rats intoxicated with ZnO-NPs (in either of the 2 dose regimen) significantly ameliorated the cardiotoxic effect of these nanoparticles. As, both agents significantly reduced the increase in serum cardiac injury markers including troponin-T, creatine kinase-MB (CK-MB), and myoglobin. Additionally, Lipo and Vit E significantly decreased the increase in serum pro-inflammatory biomarkers level including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP). Moreover, either of the 2 used agents successfully alleviated the alteration in nitric oxide (NO) and vascular endothelial growth factor (VEGF) in ZnO-NPs in sera of intoxicated group. They also significantly reduced the increase in cardiac calcium concentration and the consequent oxidative deoxyribonucleic acid (DNA) damage, as well as the increase in cardiac caspase-3 activity of intoxicated rats. Conclusively, these results indicate that early treatment with either α-lipoic acid or vitamin E may offer protection against cardiac tissue injury induced by the deleterious toxic impacts of ZnO-NPs.

Comparison of mecA polymerase chain reaction with phenotypic methods for the detection of methicillin-resistant Staphylococcus aureus.

In the present study, several conventional methods to detect methicillin-resistant Staphylococcus aureus (MRSA) were compared with polymerase chain reaction (PCR) detection of mecA gene-positive isolates. Cefoxitin E-test was also evaluated as a possible phenotypic method of MRSA detection. Oxacillin agar screen and PBP2' latex agglutination methods were found to be more sensitive than oxacillin and cefoxitin disk-diffusion methods. Cefoxitin disk diffusion was found to be the most specific. A combination of oxacillin agar screening with cefoxitin disk diffusion, or oxacillin disk diffusion with PBP2', improved sensitivity and specificity. Cefoxitin E-test with the current break points had low sensitivity and specificity (33.3% and 75%, respectively) for the detection of MRSA. However, changing the break points to or= 6 microg/ml for sensitive and resistant, respectively, greatly improved both. Changing the 30-microg cefoxitin disk-diffusion break points to

The effects of a sodium and a calcium channel blocker on lethality of mice injected with the yellow scorpion (Leiurus quinquestriatus) venom

Scorpion venom toxins generally produce similar effects by mainly acting on sodium channels, and to a lesser extent, on potassium, calcium, and chloride channels. This leads to increased release of neurotransmitters and mediators, resulting in a cascade of pathological events, involving the central nervous system, the autonomic nervous system, the cardiovascular and the respiratory system, eventually leading to death. The objective of this paper was to discover whether a sodium channel blocker, lidocaine, or a calcium channel blocker, verapamil, would prolong the survival of mice injected with the venom from the common yellow scorpion Leiurus quinquestriatus quinquestriatus (LQQ). For this purpose, mice were divided into 2 groups, each injected with a different venom dose (250 or 300 µg.kg-1, s.c.). Subgroups (n=10) from each group were given venom alone; different doses of lidocaine (4, 10, 15, or 20 mg.kg-1); or several doses of verapamil (0.01, 0.03, 0.1, 0.3, or 1 mg.kg-1). All doses of lidocaine and verapamil were intravenously administered 3 minutes before, 1, 5, and 15 minutes after venom injection. Percent surviving after 24 hours was recorded in addition to the time of death. In general, lidocaine significantly prolonged survival at the dose of 10 mg.kg-1 (P<0.05 and P<0.01, versus low and high dose of venom, respectively) or 15 mg.kg-1 (P<0.01 and P<0.001, versus low and high dose of venom, respectively; Covariance Wilcoxon survival statistics), especially when injected before the venom or in the early stages of envenomation. On the other hand, in all doses administered, verapamil was either toxic or showed non-significant results. Lidocaine, the sodium channel blocker, appears to play an important role in the protection from lethality of mice injected with LQQ venom, and significantly prolonged the survival time of mice whether injected before or in the early stages of envenomation.(AU)

Effects of two newly synthesized analogues of lidocaine on rat arterial blood pressure and heart rate.

Two new analogues of lidocaine were synthesized at the College of Pharmacy, King Saud University: compound I (Methyl-2-[2-(N,N-diethylamino) acetamido]-3-cyano-4,5-dimethylbenzoate) and compound II (Methyl-2-[2-(piperidino) acetamido]-3-cyano-4,5-dimethylbenzoate). Their influence on the arterial blood pressure and the heart rate of urethane-anaesthetized rats was studied and compared with the actions of lidocaine. Compounds I, II and lidocaine induced significant dose-dependent decreases in the arterial blood pressure and heart rate, which usually returned to basal values within 3-5 min. There were significant differences in the potency of the three compounds in producing their effects on blood pressure and heart rate (P< 0.0001, ANOVA). Compound II was 14 and 6 times more potent in reducing blood pressure and 8 and 2 times more capable of reducing the heart rate than lidocaine and compound I, respectively. The results of this study also indicated the ineffectiveness of antagonists of autonomic, histaminergic and 5-HT receptor, and various vasodilators in blocking the actions of the three compounds on blood pressure and heart rate. Pretreatment with CaCl(2)significantly reduced the hypotension and bradycardia induced by the three compounds, suggesting the involvement of calcium channels, probably of the L type. Several possible mechanisms are postulated. In conclusion, the results direct attention to the capability of the two new compounds to decrease blood pressure and heart rate; affects that may have clinical potential.

The effects of lignocaine on actions of the venom from the yellow scorpion "Leiurus quinquestriatus" in vivo and in vitro.

Many toxins from scorpion venoms activate sodium channels, thereby enhancing neurotransmitter release. The aim of the present work was to determine if the in vivo and in vitro effects of Leiurus quinquestriatus venom (LQQ) could be ameliorated by lignocaine, a sodium channel blocker. In urethane anaesthetised rabbits, LQQ venom (0.5 mg kg(-1), i.v.) caused initial hypotension and bradycardia followed by hypertension, pulmonary oedema, electrocardiographic changes indicating conduction defects, ischaemia, infarction, and then hypotension and death. Lignocaine (1 mg kg(-1) i.v. bolus initially, followed by i.v. infusion of 50 microg kg(-1) min(-1)) significantly attenuated the majority of the venom-evoked effects and reduced mortality. Addition of LQQ venom (1, 3 and 10 microg ml(-1)) to chick biventer cervicis, guinea pig ileum, and rat vas deferens preparations, increased the height of electrically-induced twitches, elevated resting tension, and caused autorhythmic oscillations. Lignocaine (3 x 10(-4)-1.2 x 10(-3) M) greatly attenuated these venom-evoked actions in the three preparations. Antagonists of appropriate neurotransmitters were also tested to determine the contribution of released transmitters to LQQ effects. Atropine significantly decreased the venom-elicited effects on guinea pig ileum preparations, while prazosin and guanethidine significantly reduced the venom's actions on rat vas deferens. In chick biventer cervicis preparations, tubocurarine and hexamethonium significantly attenuated the venom-induced effects. This study supports the hypothesis that many effects of LQQ venom involve the release of neurotransmitters and may be ameliorated by treatment with lignocaine.

The involvement of plasma kinins in the cardiovascular effects of Leiurus quinquestriatus scorpion venom in anaesthetised rabbits.

The present study was undertaken to investigate the involvement of kinins in the cardiovascular- and respiratory effects of LQQ venom. Blood pressure, heart rate, electrocardiogram (ECG) and respiration were studied in anaesthetised rabbits, in the presence and absence of aprotinin and icatibant, a B2 bradykinin antagonist. Plasma bradykinin concentrations were also measured following venom injection. LQQ venom caused a triphasic effect on blood pressure comprising an immediate fall, a pronounced rise and a progressive decline until death. Bradycardia, myocardial damage, arrhythmias, respiratory distress and pulmonary oedema were also exhibited. Pretreatment with aprotinin attenuated the venom-induced hypotension, bradycardia, ECG and respiratory changes and prolonged survival. Pretreatment of atropinized animals with icatibant gave similar protection. In animals treated with LQQ venom, plasma bradykinin was significantly higher than controls, although there was considerable inter-animal variation in plasma kinin concentrations and the elevation was seen relatively late after venom administration. The data provides some support for the hypothesis that kinins are involved in the cardiovascular and lethal effects of LQQ venom in rabbits.

Experimental treatment protocols for scorpion envenomation: a review of common therapies and an effect of kallikrein-kinin inhibitors.

Nine fatal cases from the sting of the scorpion Leiurus quinquestriatus are presented. All victims showed association of CNS and cardiovascular manifestations. Either the CNS or the cardiovascular effects could occur first in the early phases of the scorpion envenoming syndrome; the CNS manifestations, however, always preceded the terminal hypotension and cardiac arrest. Pharmacokinetic studies in rabbits following s.c. injection of the labelled venom showed that rapid absorption took place with about 70% of the maximum blood concentration reached within 15 min. Intramuscular injection of antivenom did not significantly affect the absorption of the venom or the other pharmacokinetic parameters. The total area under concentration time curve was not significantly different from that following i.v. injection, showing that nearly complete absorption of the venom from the s.c. site would occur in 7-8 hr. The i.v. infusion of venom into anaesthetized rats, at a rate comparable to the absorption rate from s.c. sites, allowed the determination of the minimum lethal dose (MLD) with reasonable accuracy. In rescue experiments, anaesthetized rats were injected s.c. with multiple MLD of venom and infused i.v. with drugs commonly used in the treatment of scorpion envenomation. The prepared potent specific antivenoms, but not the commercial polyvalent antivenom, rescued all animals from the lethal effect of the venom, even when injected late. Atropine, atropine+phentolamine, chlorpromazine, hydrocortisone and indomethacin were able, in varying degrees, to rescue some rats injected with 2 MLD of venom. Phentolamine, propranolol, hydralazine and calcium gluconate significantly prolonged the survival time, but did not rescue any animals. Chlorpheniramine, saline and 1/4 saline + 5% dextrose were without any effect. Aprotinin, the kallikrein-kinin inhibitor, was able to rescue half of the animals from the lethal action of the venom. Electrocardiographic studies showed that L. quinquestriatus venom, irrespective of the route of administration, causes myocardial ischaemia and either inferior or anterior wall infarction. This was associated with an initial moderate and a terminal severe bradycardia together with a variety of rhythm and conduction defects. Except for minor and transient electrocardiographic changes, either the prepared antivenoms or aprotinin protected rabbits and rats from the cardiac effects of the venom.