New consortium to share drug safety testing secrets

Abstract The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected four (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosyhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all four were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation (BDL)-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury (DILI), in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve pre-approval drug safety assessment.

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Comprehensive summary – Predict-IV: A systems toxicology approach to improve pharmaceutical drug safety testing

Toxicology in Vitro ◽

10.1016/j.tiv.2014.09.016 ◽

2015 ◽

Vol 30 (1) ◽

pp. 4-6 ◽

Cited By ~ 6

Author(s):

Stefan O. Mueller ◽

Wolfgang Dekant ◽

Paul Jennings ◽

Emanuela Testai ◽

Frederic Bois

Keyword(s):

Drug Safety ◽

Systems Toxicology ◽

Safety Testing ◽

Pharmaceutical Drug

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FDA Recommendations for Drug Safety Testing

Idea to Product ◽

10.1007/978-1-4612-0743-6_18 ◽

1996 ◽

pp. 115-118

Author(s):

Alexander W. Jordan

Keyword(s):

Drug Safety ◽

Safety Testing

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Drug safety testing, disposals and dealing in an English field: Exploring the operational and behavioural outcomes of the UK’s first onsite ‘drug checking’ service

International Journal of Drug Policy ◽

10.1016/j.drugpo.2018.11.001 ◽

2019 ◽

Vol 67 ◽

pp. 102-107 ◽

Cited By ~ 38

Author(s):

Fiona Catherine Measham

Keyword(s):

Drug Safety ◽

Safety Testing ◽

Drug Checking

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Optogenetic Stimulation of Primary Cardiomyocytes Expressing ChR2

Journal of lasers in medical sciences ◽

10.34172/jlms.2021.32 ◽

2021 ◽

Vol 12 (1) ◽

pp. e32-e32

Author(s):

Hoda Keshmiri Neghab ◽

Mohammad Hasan Soheilifar ◽

Ali Akbar Saboury ◽

Bahram Goliaei ◽

Jun Hong ◽

...

Keyword(s):

Intracellular Calcium ◽

Drug Safety ◽

Lentiviral Vector ◽

Cell Model ◽

Pharmaceutical Products ◽

Delayed Rectifier ◽

Main Step ◽

Optical Stimulation ◽

Safety Testing ◽

Qt Interval Prolongation

Introduction: Non-clinical cardiovascular drug safety assessment is the main step in the progress of new pharmaceutical products. Cardiac drug safety testing focuses on a delayed rectifier potassium channel block and QT interval prolongation, whereas optogenetics is a powerful technology for modulating the electrophysiological properties of excitable cells. Methods: For this purpose, the blue light-gated ion channel, channelrhodopsin-2 (ChR2), has been introduced into isolated primary neonatal cardiomyocytes via a lentiviral vector. After being subjected to optical stimulation, transmembrane potential and intracellular calcium were assessed. Results: Here, we generated cardiomyocytes expressing ChR2 (light-sensitive protein), that upon optical stimulation, the cardiomyocytes depolarized result from alterations of membrane voltage and intracellular calcium. Conclusion: This cell model was easily adapted to a cell culture system in a laboratory, making this method very attractive for therapeutic research on cardiac optogenetics.

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COCONUT OIL EXTRACT OF GLIRICIDIA SEPIUM LEAVES AS BOTANICAL ACARICIDES FOR SCABIES IN GOATS

jurnal veteriner ◽

10.19087/jveteriner.2020.21.4.617 ◽

2020 ◽

Vol 21 (4) ◽

pp. 617-628

Author(s):

Dyah Haryuningtyas Sawitri ◽

Yuningsih Yuningsih

Keyword(s):

Drug Safety ◽

Skin Disease ◽

Animal Health ◽

Coconut Oil ◽

Gliricidia Sepium ◽

Sarcoptes Scabiei ◽

Stability Test ◽

Safety Testing ◽

Oil Extract

Scabies is a contagious parasitic skin disease caused by Sarcoptes scabiei. In Indonesia, this disease considerably remains a major problem in animal health, particularly in goats. The aim of this study is to investigate the effectivity of gamal leaves coconut oil extract (GLEC) for scabies treatment in goat. This research was divided into 2 parts: 1. Preparing Gamal Leaves Coconut Oil Extract (GLCE) which included 4 stages of study: collection of gamal leaves; measurement coumarin level in gamal leaves; gamal leaves extraction with coconut oil; and extract stability test and 2. Application of GLCE in goats includes 3 stages of study : artificial S. scabiei infestations in goats; GLCE treatment in goats with 3 concentrations (12.5%, 25%, 50%); and drug safety testing. The results showed that the concentration of coumarin in the gamal leaves which was effectively for scabies drugs was > 1000 ppm. The 12.5%, 25%, 50% of GLCE concentrations are safe as botanical acariside and can reduce 100% of S.scabiei mite populations after 4x, 3x and 2x treatment at 1 week intervals, respectively. The 50% concentration of GLCE is safe, most effective, efficient and stable in storage for scabies drug.

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Drug use, harm-reduction practices and attitudes toward the utilisation of drug safety testing services in an Irish cohort of festival-goers

Irish Journal of Medical Science (1971 -) ◽

10.1007/s11845-021-02765-2 ◽

2021 ◽

Author(s):

Jo-Hanna Ivers ◽

Nicki Killeen ◽

Eamon Keenan

Keyword(s):

Public Health ◽

Social Media ◽

Drug Use ◽

Harm Reduction ◽

Drug Safety ◽

Online Survey ◽

Health Concern ◽

Safety Testing ◽

Significant Difference ◽

Drug Checking

Abstract Background Festival drug-related deaths are a growing public health concern. Aim To examine drug use and related harm-reduction practices and attitudes towards utilisation of drug safety testing services. Methods Data collection took place over the 2019 festival season (June–October). The questionnaire was self-reported. Data was gathered via the online survey, which was promoted through online and social media platforms and outlets. Social media communication methods were used to reach the targeted population more effectively. Results A total of 1193 Irish festival attendees over the age of 18 completed an anonymous online survey. Alcohol, MDMA powder/crystals, ecstasy pills and cocaine were the highest reported drugs used by Irish festival attendees. The vast majority of participants reported polysubstance use (86.8%/n = 1036). Forty percent of participants (39.98%/n = 477) reported having had sex following the use of a drug at a festival; of these, 66% (n = 316) said that the sex was unprotected. Most participants (84.0%/n = 1003) engaged in some form of harm reduction when taking drugs at festivals. Overwhelmingly, participants reported a willingness to engage with drug-checking services. The vast majority (96.3%; n = 1149) and would use drug checking services more than three-quarters (75.1%/n = 897) reported that they would use an ‘amnesty bin’ for drugs if it were part of an alert system to notify if dangerous drugs are in circulation. A chi-square test of Independence was conducted to examine whether age and utilisation of drug safety testing service a festival were independent. Moreover, when all cases are taken together, the difference between testing modalities (onsite, offsite and amnesty bin) shows a significant difference p < 001 between those who would use onsite and offsite drug testing facilities. Conclusion The evidence from this survey indicates that those young people who use drugs at festivals would be prepared to utilise drug checking services and amnesty bins should help inform the public health response to this important area.

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Characterization of Renal Papillary Antigen 1 (RPA-1), a Biomarker of Renal Papillary Necrosis

Toxicologic Pathology ◽

10.1177/0192623310362246 ◽

2010 ◽

Vol 38 (3) ◽

pp. 346-358 ◽

Cited By ~ 19

Author(s):

Sally A. Price ◽

Dai Davies ◽

Rachel Rowlinson ◽

Clive G. Copley ◽

Andrew Roche ◽

...

Keyword(s):

Drug Safety ◽

Collecting Duct ◽

Rat Kidney ◽

Biochemical Properties ◽

Papillary Necrosis ◽

Safety Testing ◽

Renal Papillary Necrosis ◽

Early Stages ◽

Noninvasive Biomarker ◽

Early Biomarker

Renal papillary necrosis (RPN) is a relatively common toxicity observed in preclinical drug safety testing. It is also observed in a variety of human diseases. RPN is difficult to diagnose without expensive scanning methods or histopathology. A noninvasive biomarker that could be detected at early stages of kidney damage would be of great value both to preclinical drug safety testing and in the clinic. An antibody raised to an unknown epitope of an antigen in rat kidney papilla was found to be specific for collecting duct cells in the kidney; this was termed renal papillary antigen 1 (RPA-1). In this study, the authors show that RPA-1 is an early biomarker of RPN in two different rat models of toxicity: 2-bromoethanamine (BEA) and N-phenylanthranilic acid (NPAA). RPA-1 can be detected in urine at early stages of toxicity and correlates well with the histopathology observed. We also characterized the biochemical properties of RPA-1 and found that the antigen is a high molecular weight membrane bound glycoprotein, with the epitope likely to be carried on an N-linked carbohydrate structure. This study demonstrates that RPA-1 is an excellent marker of RPN that can be used to detect this toxicity in preclinical safety testing.

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