scholarly journals Capsaicin is a New Gastrointestinal Mucosal Protecting Drug Candidate in Humans — Pharmaceutical Development and Production Based on Clinical Pharmacology

10.5772/58359 ◽  
2014 ◽  
Author(s):  
Gyula Mózsik ◽  
Tibor Past ◽  
Tamás Habon ◽  
Zsuzsanna Keszthelyi ◽  
Pál Perjési ◽  
...  
Keyword(s):  
Clinical Pharmacology ◽  
Drug Candidate ◽  
Pharmaceutical Development

AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats

2019 ◽  
Vol 171 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Chunhua Qin ◽  
Amy G Aslamkhan ◽  
Kara Pearson ◽  
Keith Q Tanis ◽  
Alexei Podtelezhnikov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Carcinogenic Risk ◽  
Drug Candidate ◽  
Short Term ◽  
Pharmaceutical Development ◽  
Aryl Hydrocarbon ◽  
Carcinogenic Potential ◽  
Liver Gene ◽  
Dose Levels

Abstract Aryl hydrocarbon receptor (AhR) activation is associated with carcinogenicity of non-genotoxic AhR-activating carcinogens such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and is often observed with drug candidate molecules in development and raises safety concerns. As downstream effectors of AhR signaling, the expression and activity of Cyp1a1 and Cyp1a2 genes are commonly monitored as evidence of AhR activation to inform carcinogenic risk of compounds in question. However, many marketed drugs and phytochemicals are reported to induce these Cyps modestly and are not associated with dioxin-like toxicity or carcinogenicity. We hypothesized that a threshold of AhR activation needs to be surpassed in a sustained manner in order for the dioxin-like toxicity to manifest, and a simple liver gene expression signature based on Cyp1a1 and Cyp1a2 from a short-term rat study could be used to assess AhR activation strength and differentiate tumorigenic dose levels from non-tumorigenic ones. To test this hypothesis, short-term studies were conducted in Wistar Han rats with 2 AhR-activating carcinogens (TCDD and PCB126) at minimally carcinogenic and noncarcinogenic dose levels, and 3 AhR-activating noncarcinogens (omeprazole, mexiletine, and canagliflozin) at the top doses used in their reported 2-year rat carcinogenicity studies. A threshold of AhR activation was identified in rat liver that separated a meaningful “tumorigenic-strength AhR signal” from a statistically significant AhR activation signal that was not associated with dioxin-like carcinogenicity. These studies also confirmed the importance of the sustainability of AhR activation for carcinogenic potential. A sustained activation of AhR above the threshold could thus be used in early pharmaceutical development to identify dose levels of drug candidates expected to exhibit dioxin-like carcinogenic potential.

scholarly journals Non-alcoholic Steatohepatitis (NASH) Drug Discovery – Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development

2018 ◽  
Vol 21 ◽  
pp. 481-495
Author(s):  
Ranjeet Prasad Dash ◽  
R. Jayachandra Babu ◽  
Nuggehally R Srinivas
Keyword(s):  
Clinical Pharmacology ◽  
Late Phase ◽  
Clinical Development ◽  
Screening Tools ◽  
Drug Candidate ◽  
Dose Selection ◽  
Alcoholic Steatohepatitis ◽  
Unbiased Manner

Number of drugs with different mechanisms of actions is undergoing clinical trials for non-alcoholic steatohepatitis (NASH). Given the complexity of the disease with respect to pathophysiology in the liver and associated changes in the renal function, it becomes apparent that a clear ADME (absorption, distribution, metabolism and excretion) strategy needs to be put in place for a successful nomination of a drug candidate for NASH. This review discusses using in vitro and in vivo ADME screens to understand the properties of drugs and to establish whether or not the chosen drug(s) can overcome the challenges related hepatic and renal transporters covering both uptake and efflux mechanisms imposed by NASH. A complete panel of in vivo preclinical experiments including a 14C-labeled study are proposed in NASH animal models to delineate the problematic areas for early drug development. Furthermore, a framework is provided with respect to the clinical pharmacology studies early in clinical development to characterise in an unbiased manner, the altered pharmacokinetics of drug in NASH patients for optimizing the dose selection for late phase clinical development. Because NASH patients have other co-morbid conditions and are prescribed co-medications for treating blood pressure, type 2 diabetes mellitus, obesity, dyslipidemia and many more disorders, it is also suggested to examine the drug-drug interaction potential by performing a cocktail probe study to cover a broad range of cytochrome P450 (CYP) enzymes and transporters.

Clinical Pharmacology of Local Anaesthetics

Anaesthesia ◽  
2000 ◽  
Vol 55 (9) ◽  
pp. 938-938
Author(s):  
K. R. Milligan
Keyword(s):  
Clinical Pharmacology ◽  
Local Anaesthetics

Rapacuronium: clinical pharmacology

2001 ◽  
Vol 18 (Suppl. 23) ◽  
pp. 77-82 ◽  
Author(s):  
R. K. Mirakhur ◽  
K. C. McCourt
Keyword(s):  
Clinical Pharmacology
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