Screening a novel class of anticoagulants for multi-organ toxicity using Fischer 344 rats: involvement of clinical and anatomic pathologists in the early drug development process

BACKGROUND: Veterinary clinical and anatomic pathologists play a critical role in assessing the safety of new molecules. The process for evaluation of candidate molecules in drug discovery may vary markedly, depending on the unique characteristics of the compound class. OBJECTIVES: The goal of this report is to describe the evaluation process for assessing the potential toxicity of 2 anticoagulant compounds that were representative of molecules tested in early screening studies in Fisher rats, and to use these studies as an example of the strategic approach used by veterinary pathologists in pharmaceutical safety assessment. METHODS: Groups of 3 rats were given vehicle alone or one of several doses of compound A or B by oral gavage daily for 4 consecutive days. Survival; clinical signs; body and organ weight measurements; hematologic, coagulation, and clinical biochemical testing; and gross and histologic findings at necropsy were assessed. Transmission electron microscopy was used to characterize unique findings in the liver of rats treated with compound B. RESULTS: Both compounds caused dose-dependent prolongation of the prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin clotting time (TCT). Hepatobiliary and intestinal toxicity were identified by alterations in serum chemistry data, and by histopathologic findings. Electron microscopy and tissue inorganic phosphorus analysis revealed phospholipidosis in rats treated with compound B. CONCLUSIONS: Pharmacologically mediated or "on target" effects for these molecules were characterized by dose-progressive prolongation of the PT, APTT, and TCT. Nonpharmacologically mediated or "off-target" toxicity consisted of hepatoxicity and enterotoxicity. These liabilities required that scientists alter the original molecular scaffold to reach the desired therapeutic target and minimize toxicity.     

埃普利诺菌素研究进展

埃普利诺菌素(Eprinomectin，EPR)是一种高效、低残留的抗寄生虫药物，应用于奶牛和肉牛时无需体药期。本文就EPR的开发情况、物理化学性质、生物学特性、痕量检测、药物动力学、药剂学、药效学及毒理学等方面的研究进展进行了综述。     

云南贯众驱猪蛔虫活性成分的鉴定及其体外杀虫试验研究

通过研究云南贯众(Cyrtomium yunnanense)的化学成分,用硅胶和凝胶柱色谱进行分离,根据理化性质、波谱特征鉴定结构。结果从其甲醇提取物中分离并鉴定了4个化合物:山奈酚-3,7-a-L-二鼠李糖苷(Kaempferol 3,7-a-L-Dirhamnopyranoside)(1),山奈酚-3-a-L-(4-O-乙酰基)鼠李糖基-7-a-L-鼠李糖苷[Kaempferol3-a-L-(4-O-acetyl)rhamnopyranoside-7-a-L-rhamnopyranoside](2),山奈酚-3-a-L-(2,4-二乙酰基)鼠李糖苷-7-a-L-鼠李糖苷[Kaempferol3-a-L-(2,4-Di-O-acetyl)rhamnopyranoside-7-a-L-rhamnopyranoside](3),β-谷甾醇(β-Sitosterol)(4)。利用猪蛔虫24孔NUNC细胞培养板,对云南贯众中提取分离的四种化合物的抗蠕虫活性进行检测,并作离体毒理试验,利用纤毛虫检测器来计数死活虫卵。结果4个化合物中,化合物2效果最佳,其次是化合物4、化合物1,化合物3最差。4个化合物均为首次从云南贯众中分离得到的单体,化合物2有望开发成为一种新的驱蛔虫药。     

恩拉霉素的研究进展

概述了恩拉霉素的理化特性、药效学、毒理学和临床应用研究进展,展望了今后恩拉霉素的研究方向.     

A risk assessment of atrazine use in California: human health and ecological aspects

A risk assessment of the triazine herbicide atrazine has been conducted by first analyzing the toxicity database and subsequently estimating exposure. Margins of safety (MOS) were then calculated. Toxicity was assessed in animal studies and exposure was estimated from occupational and dietary sources. In acute toxicity studies, atrazine caused developmental toxicity in the rabbit [no observed effect level (NOEL) 5 mg kg(-1) day(-1)] and cardiotoxicity in a dog chronic study (NOEL 0.5 mg kg(-1) day(-1)); cancer (mammary glands) resulted from lifetime exposure. The mammary tumors, which occurred specifically in female Sprague-Dawley rats, were malignant, increased in a dose-dependent manner and were also observed with other, related triazines. Evidence for a genotoxic basis for these tumors was either equivocal or negative. Triazines have been shown to be clastogenic in Chinese hamster ovary cells, in vitro, but without showing a convincing dose/response relationship. Atrazine can be converted into genotoxic N-nitrosoatrazine in the environment or the digestive system, suggesting that N-nitrosamines derived from triazines could be oncogenic. However, it was concluded that N-nitrosotriazines are unlikely to play a significant role in triazine-induced rat mammary gland tumors. An endocrine basis for the mammary tumors, involving premature aging of the female SD rat reproductive system, has been proposed. A suppression of the luteinizing hormone surge during the estrus cycle by atrazine leads to the maintenance of elevated blood levels of 17beta-estradiol (E2) and prolactin. The mechanism for tumor development may include one or more of the following: the induction of aromatase (CYP19) and/or other P450 oxygenases, an antagonist action at the estrogen feedback receptor in the hypothalamus, an agonist action at the mammary gland estrogen receptor or an effect on adrenergic neurons in the hypothalamic-pituitary pathway. None of these has been excluded as a target because there has been a lack of a rigorous attempt to address the mechanism of action for mammary tumors at the molecular level. The potential occupational exposure to atrazine was assessed during mixing, loading and application. Absorbed daily dosage values were 1.8-6.1 microg kg(-1) day(-1). The MOS values (animal NOEL/human exposure) for short-term (acute) exposure were 820-2800. Longer-term occupational exposure and risk were also calculated. Detectable crop residues are generally absent at harvest. Theoretical calculations of acute dietary exposure used tolerance levels, along with secondary residues, and water, for which there is a maximum contamination level; atrazine plus the three main chlorotriazine metabolites were combined. MOS values were above 2000 for all population subgroups. Dietary exposure to atrazine is therefore extremely unlikely to result in human health hazard. Recent publications have reported a possible feminization of frogs, measured in laboratory and field studies. This is assumed to be due to the induction of aromatase, but no measurements of enzyme activity have been reported. In field studies, the water bodies with the greatest numbers of deformed frogs sometimes had the lowest concentrations of atrazine. Other studies have also cast doubt on the feminization theory, except perhaps at very high levels of atrazine. Epidemiology studies have investigated the possibility that atrazine may result in adverse effects in humans. Although some studies have claimed that atrazine exposure results in an elevated risk of prostate cancer, the published literature is inconclusive with respect to cancer incidence.     

The use of intravenous lipid emulsion as an antidote in veterinary toxicology

Objective – To review the use of IV lipid emulsion (ILE) for the treatment of toxicities related to fat‐soluble agents; evaluate current human and veterinary literature; and to provide proposed guidelines for the use of this emerging therapy in veterinary medicine and toxicology. Data Sources – Human and veterinary medical literature. Human Data Synthesis – Human data are composed mostly of case reports describing the response to treatment with ILE as variant from mild improvement to complete resolution of clinical signs, which is suspected to be due to the variability of lipid solubility of the drugs. The use of ILE therapy has been advocated as an antidote in cases of local anesthetic and other lipophilic drug toxicoses, particularly in the face of cardiopulmonary arrest and unsuccessful cardiopulmonary cerebral resuscitation. Veterinary Data Synthesis – The use of ILE therapy in veterinary medicine has recently been advocated by animal poison control centers for toxicoses associated with fat‐soluble agents, but there are only few clinical reports documenting successful use of this therapy. Evidence for the use of ILE in both human and veterinary medicine is composed primarily from experimental animal data. Conclusions – The use of ILE appears to be a safe therapy for the poisoned animal patient, but is warranted only with certain toxicoses. Adverse events associated with ILE in veterinary medicine are rare and anecdotal. Standard resuscitation protocols should be exhausted before considering this therapy and the potential side effects should be evaluated before administration of ILE as a potential antidote in cases of lipophilic drug toxicoses. Further research is waranted.     

4‐Methylpyrazole as a treatment in naturally occurring ethylene glycol intoxication in cats

Objective – To describe the clinical experience and therapeutic use of fomepizole (4‐methylpyrazole [4‐MP]) in 3 cats with naturally occurring ethylene glycol (EG) toxicity. Case or Series Summary – All cats were documented to be EG positive by an ethylene glycol test kit. This report describes the dose of 4‐MP used, available clinicopathological data, and clinical progression during hospitalization. All patients survived to discharge. New or Unique Information Provided – IV use of 4‐MP at 125 mg/kg as an initial dose and 31.25 mg/kg at 12, 24, and 36 hours is safe and effective for treatment of naturally occurring EG toxicity in cats. Increased HCO₃ concentrations were noted after IV use of 4‐MP. This is the first report documenting the successful treatment of naturally occurring EG intoxication in cats with 4‐MP.     

费菜的临床应用及其研究进展

费菜是可药、可食和可观赏的重要植物,在民间广泛应用.现总结了费菜化学成分、药理学、毒理学、细胞及分子生物学、生理学等方面的研究进展,报道了与费菜相关的专利以及正品费菜鉴定情况,为费菜的进一步开发和研究提供参考.