Toxicological effect of acetaminophen, metamizole, and nimesulide cocktail on early development of zebrafish.

IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY DARU Journal of Pharmaceutical Sciences Pub Date : 2024-07-11 DOI:10.1007/s40199-024-00528-9
Wellington Fernandes de Carvalho, Ednalva de Souza Pereira Lima, Whocely Victor de Castro, Ralph Gruppi Thomé, Hélio Batista Santos
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Abstract

Background: Several countries' most incorrectly discarded medicines are acetaminophen (ACM), metamizole (MTZ), and nimesulide (NMS). These xenobiotics easily reach the aquatic environment; such contamination is very important for the health of humans and other species, yet little explored.

Objectives: To evaluate the cocktail effect of ACM, MTZ, and NMS during zebrafish's initial development.

Methods: Zebrafish embryos 6-8 h post-fertilization (hpf) were exposed to different concentrations of ACM, MTZ, and NMS, separately, to obtain the 50% lethal concentrations (LC50). Next, the embryos were exposed to distinct concentrations of the cocktail (LC50/2, LC50/5, LC50/10, and LC50/20) in a semi-static system. Samples were analyzed 0, 24, 48, and 96 h after exposure, and the drugs' concentrations in E3 medium were assessed by high-performance liquid chromatography. For embryotoxicity evaluation, the mortality, hatching, and heart rates; total length; and pericardial and yolk sac areas were determined. In addition, body malformations, edemas, presence of pigmentation, and histopathological assessments were also recorded.

Results: The LC50 values obtained for MTZ, ACM, and NMS were 4.69 mgmL-1, 799.98 μgmL-1, and 0.92 μgmL-1, respectively. No difference was observed between the drugs' nominal and observed concentrations at each time point. The cocktail significantly induced mortality and decreased hatching in the LC50/10, LC50/5, and LC50/2 groups. Additionally, body malformations, pigmentation loss, and yolk sac and pericardial edemas were observed in the cocktail groups. The cocktail groups' larvae had decreased total length and slower heart rates compared to the controls (p < 0.05). The histopathological assessment showed that yolk sac edema promoted severe histological changes in the esophageal-intestine junction and intestine in larvae treated with cocktails. Moreover, PAS-positive structures decreased in the esophageal-intestine junction, intestine, and liver in larvae exposed to pharmaceutical cocktails.

Conclusion: This study's findings suggest the cocktail of ACM, MTZ, and NMS may be hazardous to aquatic organisms in case of environmental contamination.

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对乙酰氨基酚、甲咪唑和尼美舒利鸡尾酒对斑马鱼早期发育的毒理影响
背景:一些国家最常错误丢弃的药物是对乙酰氨基酚(ACM)、甲咪唑(MTZ)和尼美舒利(NMS)。这些异生物体很容易进入水生环境;这种污染对人类和其他物种的健康非常重要,但却很少有人对其进行研究:评估 ACM、MTZ 和 NMS 在斑马鱼初始发育过程中的鸡尾酒效应:方法:将受精后 6-8 小时的斑马鱼胚胎分别暴露于不同浓度的 ACM、MTZ 和 NMS,以获得 50% 的致死浓度(LC50)。然后,在半静态系统中将胚胎暴露于不同浓度的鸡尾酒(LC50/2、LC50/5、LC50/10 和 LC50/20)中。暴露后 0、24、48 和 96 小时对样本进行分析,并通过高效液相色谱法评估 E3 培养基中的药物浓度。在胚胎毒性评估方面,测定了死亡率、孵化率和心脏率;总长度;心包和卵黄囊面积。此外,还记录了身体畸形、水肿、色素沉着和组织病理学评估结果:MTZ、ACM和NMS的半数致死浓度分别为4.69 mgmL-1、799.98 μgmL-1和0.92 μgmL-1。在每个时间点,药物的标称浓度与观察浓度之间没有差异。在 LC50/10、LC50/5 和 LC50/2 组中,鸡尾酒能明显诱导死亡并降低孵化率。此外,在鸡尾酒组中还观察到身体畸形、色素脱失、卵黄囊和心包水肿。与对照组相比,鸡尾酒组幼虫的总长度减少,心率减慢(p 结论:鸡尾酒组幼虫的总长度和心率均低于对照组:本研究结果表明,ACM、MTZ 和 NMS 鸡尾酒可能会在环境污染的情况下对水生生物造成危害。
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DARU Journal of Pharmaceutical Sciences
DARU Journal of Pharmaceutical Sciences PHARMACOLOGY & PHARMACY-
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期刊介绍: DARU Journal of Pharmaceutical Sciences is a peer-reviewed journal published on behalf of Tehran University of Medical Sciences. The journal encompasses all fields of the pharmaceutical sciences and presents timely research on all areas of drug conception, design, manufacture, classification and assessment. The term DARU is derived from the Persian name meaning drug or medicine. This journal is a unique platform to improve the knowledge of researchers and scientists by publishing novel articles including basic and clinical investigations from members of the global scientific community in the forms of original articles, systematic or narrative reviews, meta-analyses, letters, and short communications.
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