Analysis of Toxicity Effects of Buspirone, Cetirizine and Olanzapine on Human Blood Lymphocytes: in Vitro Model.

BACKGROUND: The current study investigates the cytotoxicity mechanism of common drugs with piperazine ring such as cetirizine, olanzapine and buspirone on human lymphocytes. METHODS: The viability of lymphocytes, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, lysosomal integrity, content of glutathione and lipid peroxidation was determined. RESULTS: Buspirone and cetirizine showed more toxicity than olanzapine on human lymphocytes with an IC50 value of 200 µg/ml, after 6 h of incubation. Significant ROS formation, MMP collapse, lipid peroxidation, lysosomal damage and elevation of glutathione disulfide (GSSG) were observed in treated lymphocytes concentrations (4, 20, 40 µg/ml) of buspirone and cetirizine. CONCLUSION: Our results show the exposure of human lymphocytes with buspirone and cetirizine, which usually happens during the poisoning, triggers oxidative stress and organelle damages. Our study suggests that using antioxidants, mitochondrial and lysosomal protective agents can protect blood lymphocytes, from probable side effects of these highly consumed medications.

Effects of single and combined exposure of pharmaceutical drugs (carbamazepine and cetirizine) and a metal (cadmium) on the biochemical responses of R. philippinarum.

In the aquatic environment, organisms are exposed to complex mixtures of contaminants which may alter the toxicity profile of each compound, compared to its toxicity alone. Pharmaceutical drugs (e.g. carbamazepine (CBZ) and cetirizine (CTZ)) and metals (e.g. cadmium (Cd)) are among those contaminants that co-occur in the environment. However, most studies concerning their toxicity towards aquatic species are based on single exposure experiments. Thus, the present study aimed to evaluate single and combined effects of Cd and CBZ or CTZ (single conditions: Cd, CTZ, CBZ; combined conditions: CTZ + Cd, CBZ + Cd) on biomarkers related to oxidative stress and energy metabolism in the edible clam Ruditapes philippinarum, by exposing the organisms for 28 days to environmentally relevant concentrations of these contaminants. The biomarkers studied were: i) the electron transport system activity, protein and glycogen contents (indicators of organisms' metabolic status and energy reserves); ii) lipid peroxidation and the ratio between reduced and oxidized glutathione (indicators of oxidative stress); iii) superoxide dismutase and catalase activities (enzymes indicators of antioxidant defence) and iv) activity of glutathione S-transferases (family of enzymes indicators of biotransformation capacity). Results obtained showed that the uptake of Cd and CBZ was not affected by the combined presence of the contaminants. However, for CTZ, the uptake was higher in the presence than in the absence of Cd. Concerning toxicity data, in general, the combined exposures (CTZ + Cd, CBZ + Cd) had lower biological effects than the contaminants alone. Nevertheless, our data showed that despite the low concentrations tested, they were enough to exert biological effects that differed between single and combined treatments, evidencing the need to conduct more co-exposure studies to increase the environmental relevance of the gathered data.

Effects of carbamazepine and cetirizine under an ocean acidification scenario on the biochemical and transcriptome responses of the clam Ruditapes philippinarum.

Several works evaluated the toxicity of pharmaceutical drugs and climate related changes in invertebrates but few explored the combined effects of both stressors, namely considering their mode of action (MoA). Carbamazepine (CBZ) and cetirizine (CTZ) are pharmaceutical drugs detected in the environment and the toxicity derived from the combined effects of these drugs with ocean acidification (OA) is poorly explored. Thus, the present study investigated the biochemical parameters related to an oxidative stress response and the transcription of genes related to the MoA of CBZ (1.0 µg/L) and CTZ (0.6 µg/L) in the clam Ruditapes philippinarum chronically exposed (28 days) to control (7.8) and low (7.5) pH conditions. The results obtained showed that despite the clams accumulated both drugs, at low pH the clams exposed to CTZ decreased drug concentration and BCF values (CTZ uptake: 2.0 ±â€¯0.5 ng/g fresh weight; BCF: 3.8 ±â€¯0.9) in comparison with clams exposed to control pH (CTZ uptake: 2.9 ±â€¯0.3 ng/g fresh weight; BCF: 5.5 ±â€¯0.6). No oxidative stress was induced by the exposure to CBZ or CTZ at each pH level, but the transcription of several genes related with the MoA (neurotransmission, immunity and biomineralization) was altered by low pH, drug exposure and the combination of both stressors. At both pH conditions, CBZ increased the transcription of GABA receptor gene (neurotransmission) and CTZ led to a decrease of Perlucin gene (biomineralization) transcription. The transcription of MyD88 gene (immunity) decreased at low pH (7.5) combined with drug exposure (CBZ or CTZ). Thus, it was highlighted that the interaction of drug exposure and low pH conditions can change bivalves' sensitivity to drugs or alter drugs toxicity.

Ecotoxicity of the antihistaminic drug cetirizine to Ruditapes philippinarum clams.

Cetirizine (CTZ) is an antihistaminic drug present in the aquatic environment, with limited information on its toxicity to organisms inhabiting this system. This study intended to evaluate the effects of CTZ on oxidative stress and energy metabolism biomarkers in the edible clam Ruditapes philippinarum after a 28days exposure to environmentally relevant CTZ concentrations (0.0, 0.3, 3.0, 6.0 and 12.0µg/L). The results obtained showed that CTZ was accumulated by clams reaching maximum concentrations (up to ~22ng/g FW) at the highest CTZ exposure concentrations (6.0 and 12.0µg/L). The bioconcentration factor (average maximum values of ~5) decreased at 12.0µg/L reflecting a reduction in clams uptake or increase of excretion capacity at this condition. The present study revealed that, in general, clams decreased the metabolic potential after exposure to CTZ (decrease in electron transport system activity), a response that led to the maintenance of glycogen content in organisms exposed to CTZ in comparison to control values. Our findings also showed that, CTZ did not exert significant levels of oxidative injury to clams. However, comparing the control with the highest exposure concentrations (6.0 and 12.0µg/L) a significant increase of the antioxidant enzyme superoxide activity (~53 and ~44%) was observed in clams exposed to CTZ. Moreover, a tendency to increase lipid peroxidation (~14 and ~9%) and carbonyl groups on proteins (~11 and ~3%) was observed in clams exposed to CTZ (6.0 and 12.0µg/L) compared to control condition. Overall the present study suggests that toxic impacts may be induced in R. philippinarum if exposed for longer periods or higher CTZ concentrations.

H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice.

We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)-/- mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE-/- mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.

An NMR investigation of the structure, function and role of the hERG channel selectivity filter in the long QT syndrome.

The human ether-a-go-go-related gene (hERG) voltage-gated K(+) channels are located in heart cell membranes and hold a unique selectivity filter (SF) amino acid sequence (SVGFG) as compared to other K(+) channels (TVGYG). The hERG provokes the acquired long QT syndrome (ALQTS) when blocked, as a side effect of drugs, leading to arrhythmia or heart failure. Its pore domain - including the SF - is believed to be a cardiotoxic drug target. In this study combining solution and solid-state NMR experiments we examine the structure and function of hERG's L(622)-K(638) segment which comprises the SF, as well as its role in the ALQTS using reported active drugs. We first show that the SF segment is unstructured in solution with and without K(+) ions in its surroundings, consistent with the expected flexibility required for the change between the different channel conductive states predicted by computational studies. We also show that the SF segment has the potential to perturb the membrane, but that the presence of K(+) ions cancels this interaction. The SF moiety appears to be a possible target for promethazine in the ALQTS mechanism, but not as much for bepridil, cetirizine, diphenhydramine and fluvoxamine. The membrane affinity of the SF is also affected by the presence of drugs which also perturb model DMPC-based membranes. These results thus suggest that the membrane could play a role in the ALQTS by promoting the access to transmembrane or intracellular targets on the hERG channel, or perturbing the lipid-protein synergy.

Murine chronotoxicity to the antiallergic agent, cetirizine.

Cetirizine is a second-generation histamine H1-receptor antagonist used in the treatment of allergic diseases. The aim of the study was to assess whether cetirizine toxicity estimated by, for example, death, body loss, and leucopenia, is circadian rhythm dependent. A total of 210 male Swiss mice, aged 9 weeks, were synchronized for 3 weeks to 12-hour light (i.e., rest span)/12-hour dark (i.e., activity span) cycles. The drug was administered per os (orally). Each lethal (DL(50) = 750 mg/kg) and sublethal (DT(50) = 55 mg/kg) dose was administered to comparable groups of animals at six different circadian time points (1, 5, 9, 13, 17, and 21 hours after light onset; HALO). The death rate was dosing time dependent (P <0.001). Drug dosing at 5 HALO resulted in maximum mortality (76.75%), whereas dosing at 17 HALO resulted in the lowest mortality rate (16.7%). Cosinor analyses validated a statistically significant circadian rhythm in death rate (P < 0.008). Changes in body weight after cetirizine administration were dosing time dependent (P < 0.01), with the dosing time of least effect (-0.7% loss) at 17 HALO and of greatest effect (-7% loss) at 5 HALO. Cosinor analyses validated a statistically significant circadian rhythm in body loss (P < 0.05). A statistically significant decrease in leukocyte number varied, according to antihistamine dosing time (P < 0.01), with the dosing time of least leucopenia (≈-17%) at 17 HALO and of greatest leucopenia (≈-28%) at 5 HALO. The results show that cetirizine dosing time at the midactivity (dark) span seems to be optimal, since it corresponds to the best tolerance.

A randomized controlled trial of cetirizine plus pseudoephedrine versus loratadine plus pseudoephedrine for perennial allergic rhinitis.

The purpose of this study was to compare the safety and efficacy of cetirizine plus pseudoephedrine (C+P) with loratadine plus pseudoephedrine (L+P) in the treatment of perennial allergic rhinitis. This was a double blind, randomized, parallel trial with an active control. Subjects aged 12 to 70 years with perennial allergic rhinitis for at least 2 years were enrolled and randomized to receive either of the active study medications plus a placebo resembling the other, twice daily for 4 weeks. Nasal total symptom scale (NTSS) including sneezing, rhinorrhea, nasal itching and nasal stuffiness is evaluated by subjects daily and at baseline, 2 weeks, and 4 weeks by the investigator as efficacy measurement. A total of 51 eligible patients were enrolled and 45 patients completed the treatment course. Both groups had significant reductions in NTSS after 4 weeks of treatment as assessed by the subjects, but there was no significant difference between the two groups (mean +/- SD) reduction of 4.25 +/- 2.45 with C+P vs. 3.52 +/- 2.41 with L+P, p = 0.215. As assessed by the investigator, sneezing was significantly better at 2 weeks (-1.13 vs. -0.52, p = 0.028) and nasal congestion at 4 weeks (-1.71 vs. -1.19, p = 0.031) in subjects treated with C+P compared to those treated with L+P. There were 37 treatment-related adverse events (5 in 4 subjects in the C+P group and 32 in 16 subjects in the L+P group). It was concluded that both cetirizine plus pseudoephedrine and loratadine plus pseudoephedrine are efficacious for perennial allergic rhinitis in Taiwanese subjects. Relief of sneezing and nasal congestion may be marginally better with the cetirizine preparation, which also seemed to be slightly better tolerated, although the incidence of side effects did not differ significantly.

[Circadian rhythms in the toxic effects of the histamine antagonist cetirizine in mice]. / Rythmes circadiens des effets toxiques d'un antihistaminique H1: la cétirizine chez la souris.

UNLABELLED: Cetirizine is a second generation histamine H(1) receptor antagonist used to provide symptomatic relief of allergic signs caused by histamine release. The aim of the study was to learn whether the survival and the motor incoordination (ataxia) side effect of cetirizine administration is dosing time-dependent. MATERIALS AND METHODS: A total of 240 male Swiss mice, 10 weeks of age were synchronized for 3 weeks by 12 h light (rest span)/12 h dark (activity span). Different doses of cetirizine were administered orally at fixed times during the day to determine both the sublethal (TD(50)) and lethal (LD(50)) doses, which were, respectively, 55 +/- 0.35 and 750 +/- 0.40 mg/kg. In the chronotoxicologic study a single dose of cetirizine (DL(50)) was administered to comparable groups of animals at six different circadian stages [1, 5, 9, 13, 17, 21 h after light onset (HALO)]. RESULTS: The survival was statistically significant dosing time-dependent (chi(2) = 16.73; P < 0.001). Drug dosing at 17 HALO resulted in 83.3% survival rate whereas drug dosing at 5 HALO was only 23.25%. Cosinor analysis revealed a statistically significant circadian (period approximately 24 h) rhythmic component in survival. Lowest (20%) and highest (88%) ataxia occurred when cetirizine was administered, respectively, at 17 and 5 HALO. Cosinor analysis revealed a statistically significant circadian (period approximately 24 h) rhythmic component in ataxia. CONCLUSION: Our results reveal that the best safety is shown when cetirizine is administered in the middle of the dark (activity) span of the mice, since it produces some side effects: ataxia and hyperthermia. Taking into account of the hour administration of cetirizine, improves treatment efficacy and permit the best control of allergic diseases.

Electrophysiological effects of cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome.

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

Enhanced cancer growth in mice administered daily human-equivalent doses of some H1-antihistamines: predictive in vitro correlates.

BACKGROUND: Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity. PURPOSE: We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. METHODS: Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups. RESULTS: The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor. CONCLUSION: Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo. IMPLICATION: These in vitro tests may prove valuable to screen potential tumor growth promoters.