A peripherally restricted P2Y 12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

Brott, David; Andersson, Håkan; Stewart, Jane; Ewart, Lorna; Christoph, Greg; Harleman, Johannes H.; Armstrong, Duncan; Kinter, Lewis B.

doi:10.1016/j.toxrep.2014.11.010

Cited by 12 publications

(10 citation statements)

References 49 publications

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“…The other ( 282 ) showed a variety of tumors, such as thyroid follicular cell adenomas, adrenal pheochromocytomas, hepatocellular adenomas, and endocrine-related tumors such as uterine adenocarcinomas, ovarian adenomas, and mammary gland adenomas. Two platelet aggregation inhibitors had a different tumor response; the first was TN, whereas the other compound was FN because of a dopaminergic action as a secondary pharmacological effect ( 42 ). These compounds were not categorized related to pharmacology (NC).…”

Section: Resultsmentioning

confidence: 99%

Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

et al. 2016

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In an exercise designed to reduce animal use, we analyzed the results of rat subchronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumor outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred forty-three of the 239 compounds not inducing putative preneoplastic lesions in the subchronic study did not induce tumors in the carcinogenicity study [true negatives (TNs)], whereas 96 compounds were categorized as false negatives (FNs) because tumors were observed in the carcinogenicity study. Of the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumors in the carcinogenicity study [true positives (TPs)], and 19 only showed preneoplastic lesions in subchronic studies but no tumors in the carcinogenicity study [false positives (FPs)]. In addition, we then re-assessed the prediction of the tumor outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN). For 67 compounds, the presence of cellular hyperplasia as evidence for proliferative action could be found (TP). Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92% and the ability to detect carcinogens at 98%. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorized as FN and 1 as FP), thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological properties of compounds in relation to potential class effects, both in the negative and positive direction. A high negative and a high positive predictivity will both result in waiving the need for conducting 2-year rat carcinogenicity studies, if this is accepted by Regulatory Authorities, which will save large numbers of animals and reduce drug development costs and time.

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Section: Resultsmentioning

confidence: 99%

Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

et al. 2016

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“…For example, the anti-thrombotic clopidogrel (OR 10.14, FDR = 0.009) disrupts neural plasticity likely by inhibiting microglial-neural interactions [ 48 ]. Individuals admitted for psychiatric reasons may be particularly susceptible to perturbation of neural plasticity by clopidogrel and alternative anti-thrombotic agents with reduced ability to cross the blood-brain-barrier, such as Ticagrelor [ 49 ], should be considered. Drug repositioning [ 39 , 40 ] of the hypertension medication sodium nitroprusside has been demonstrated to have a beneficial impact on schizophrenia patients [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological risk factors associated with hospital readmission rates in a psychiatric cohort identified using prescriptome data mining

Shameer

Perez‐Rodriguez

Bachar

et al. 2018

BMC Med Inform Decis Mak

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BackgroundWorldwide, over 14% of individuals hospitalized for psychiatric reasons have readmissions to hospitals within 30 days after discharge. Predicting patients at risk and leveraging accelerated interventions can reduce the rates of early readmission, a negative clinical outcome (i.e., a treatment failure) that affects the quality of life of patient. To implement individualized interventions, it is necessary to predict those individuals at highest risk for 30-day readmission. In this study, our aim was to conduct a data-driven investigation to find the pharmacological factors influencing 30-day all-cause, intra- and interdepartmental readmissions after an index psychiatric admission, using the compendium of prescription data (prescriptome) from electronic medical records (EMR).MethodsThe data scientists in the project received a deidentified database from the Mount Sinai Data Warehouse, which was used to perform all analyses. Data was stored in a secured MySQL database, normalized and indexed using a unique hexadecimal identifier associated with the data for psychiatric illness visits. We used Bayesian logistic regression models to evaluate the association of prescription data with 30-day readmission risk. We constructed individual models and compiled results after adjusting for covariates, including drug exposure, age, and gender. We also performed digital comorbidity survey using EMR data combined with the estimation of shared genetic architecture using genomic annotations to disease phenotypes.ResultsUsing an automated, data-driven approach, we identified prescription medications, side effects (primary side effects), and drug-drug interaction-induced side effects (secondary side effects) associated with readmission risk in a cohort of 1275 patients using prescriptome analytics. In our study, we identified 28 drugs associated with risk for readmission among psychiatric patients. Based on prescription data, Pravastatin had the highest risk of readmission (OR = 13.10; 95% CI (2.82, 60.8)). We also identified enrichment of primary side effects (n = 4006) and secondary side effects (n = 36) induced by prescription drugs in the subset of readmitted patients (n = 89) compared to the non-readmitted subgroup (n = 1186). Digital comorbidity analyses and shared genetic analyses further reveals that cardiovascular disease and psychiatric conditions are comorbid and share functional gene modules (cardiomyopathy and anxiety disorder: shared genes (n = 37; P = 1.06815E-06)).ConclusionsLarge scale prescriptome data is now available from EMRs and accessible for analytics that could improve healthcare outcomes. Such analyses could also drive hypothesis and data-driven research. In this study, we explored the utility of prescriptome data to identify factors driving readmission in a psychiatric cohort. Converging digital health data from EMRs and systems biology investigations reveal a subset of patient populations that have significant comorbidities with cardiovascular diseases are more likely to be readmitted. Further, the...

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“…With regard to other possible factors affecting uterine carcinogenesis in rodents, the relationship between prolactin and uterine carcinogenesis should be discussed because the long-term effects of prolactin on uterine carcinogenicity in rats are controversial 21 , 22 , 23 and the relevance of prolactin in the development of endometrial adenocarcinoma in humans has not yet been established. The function of prolactin in rats is known to be different from that in women, particularly in its role in the formation and regression of the corpus luteum.…”

Section: Discussionmentioning

confidence: 99%

“…Dopamine blocking/inhibitory chemicals modulate prolactin production in rodents 24 . Recently, a P2Y12 receptor antagonist possessing dopamine agonistic activity was shown to increase the incidence of rat uterine adenocarcinomas in carcinogenicity studies 21 . Decreased pituitary and mammary tumors and approximately 20% lower body weight were also observed.…”

Section: Discussionmentioning

confidence: 99%

Predictive modes of action of pesticides in uterine adenocarcinoma development in rats

2015

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Endometrial adenocarcinoma in the uterine corpus is a malignant cancer that occurs in menopausal women and aged rodents. Because of the similarities in pathogenesis and morphology of endometrial adenocarcinoma in rodents and humans, prediction of the modes of action (MOA) in uterine carcinogenesis is important for extrapolation of rodent data to humans. Three MOAs have been accepted as major pathways for uterine carcinogenesis in rodents: 1) estrogenic activity, 2) increased serum 17beta-estradiiol (E2) to progesterone (P4) ratio and 3) modulation of estrogen metabolism to produce 4-hydroxyestradiol via P450 induction. Inhibition of estrogen excretion and increased aromatase in situ in the tumor are also a potential pathway. Here, chemicals showing uterine carcinogenicity were chosen from approximately 300 pesticides evaluated in Japan within the past decade, and their mechanisms were predicted using parameters from mechanistic and toxicity studies. Seven pesticides increased uterine tumor formation in rats, and the pathways of 4 pesticides could be predicted based on various mechanistic studies. The MOAs of cyenopyrafen and benthiavalicarb-isopropyl were predicted to be modulation of estrogen metabolism, while those of pyriminobac-methyl and spirodiclofen were predicted to be increased E2 to P4 ratio. The driven pathways of metazosulfuron and isopyrazam could not be predicted using several mechanistic studies. No mechanistic studies have been reported for sedaxane, which has a chemical structure and toxicological profile similar to isopyrazam. Our results indicated that appropriate mechanistic studies are useful for mechanism prediction in risk assessment. From this analysis, a flowchart showing a decision tree for predictive MOAs in uterine carcinogenesis was proposed.

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A peripherally restricted P2Y 12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

Cited by 12 publications

References 49 publications

Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

Pharmacological risk factors associated with hospital readmission rates in a psychiatric cohort identified using prescriptome data mining

Predictive modes of action of pesticides in uterine adenocarcinoma development in rats

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