Dosing in the dark—effect of time of dosing on preclinical safety profiles

AbstractImpairment of Eustachian tube function with nonsufficient ventilation of the middle ear is a main cause for chronic otitis media. To provide an effective and safe therapy, the innovative concept of Eustachian tube stenting was established. Biodegradable polymeric stents are developed to restore impaired tube function and dissolve after fulfilling their supportive purpose. To evaluate the applicability of the stents in the Eustachian tube, prototypes in conjunction with corresponding implantation instruments were tested in human cadaver studies. Radiopaque markers and a diaphanoscopic approach were tested as additional features to prove correct positioning of catheter and stent in the tube. In the current study biodegradable polymeric stents were implanted in the Eustachian tube of human cadavers without difficulty. Correct positioning of the stents in the tube was proved by diaphanoscopy during intervention and postoperative tomographic and histological analyses. Once designs are optimized on the basis of cadaver studies, preclinical safety and efficacy studies using animal models will be initiated.

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Preclinical safety evaluation of nafithromycin (WCK 4873) with emphasis on liver safety in rat and dog

Regulatory Toxicology and Pharmacology ◽

10.1016/j.yrtph.2021.104889 ◽

2021 ◽

Vol 122 ◽

pp. 104889

Author(s):

Manohar Nandanwar ◽

Rajesh Chavan ◽

Atul Kansagara ◽

Muftedar Ahmed Patel ◽

Anasuya Patel ◽

...

Keyword(s):

Safety Evaluation ◽

Liver Safety ◽

Preclinical Safety

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Self-preserving gelatin emulgel containing whole cell probiotic for topical use: preclinical safety, efficacy and germination studies

Expert Opinion on Drug Delivery ◽

10.1080/17425247.2021.1947239 ◽

2021 ◽

Author(s):

Garima Sharma ◽

Manuhaar Sharma ◽

Rishav Sood ◽

Jayanthi Neelamraju ◽

Suvarna G. Lakshmi ◽

...

Keyword(s):

Whole Cell ◽

Preclinical Safety

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The Role of Microscopy in Preclinical Safety Assessment

Microscopy and Microanalysis ◽

10.1017/s143192760003748x ◽

2000 ◽

Vol 6 (S2) ◽

pp. 998-999

Author(s):

Barbara J. Dovey-Hartman

Keyword(s):

Electron Microscopy ◽

Vital Role ◽

Pathology Report ◽

Clinical Phase ◽

Transmission Electron ◽

New Chemical Entities ◽

Regulatory Submissions ◽

Hematoxylin And Eosin ◽

Preclinical Safety

Microscopy plays a vital role in assessing the safety of New Chemical Entities (NCE) in the pre-clinical phase of drug development. Light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM) are used at the Schering-Plough Research Institute (SPRI) for evaluation of NCE. To support regulatory submissions, NCE are routinely tested in rodents in short-term studies such as one-month toxicity studies, and in longterm studies such as oncogenicity studies that may last 24 months. At the completion of a study, the animals are necropsied and the required tissues collected and stored in fixative. The tissues for LM are processed to slides and stained with Hematoxylin and Eosin (H&E). The information derived from the examination of these tissues by LM becomes an essential part of the pathology report. The LM examination of these tissues usually yields the information needed to either progress a NCE or otherwise deter or halt development.

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Placental Mesenchymal Stromal Cells: Preclinical Safety Evaluation for Fetal Myelomeningocele Repair

Journal of Surgical Research ◽

10.1016/j.jss.2021.06.011 ◽

2021 ◽

Vol 267 ◽

pp. 660-668

Author(s):

Jordan E Jackson ◽

Christopher Pivetti ◽

Sarah C Stokes ◽

Christina M Theodorou ◽

Priyadarsini Kumar ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Safety Evaluation ◽

Myelomeningocele Repair ◽

Preclinical Safety

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A sensitive HPLC-FLD method for the quantification of 6-O-demethylmenisporphine isolated from Menispermi Rhizoma in rat plasma

Journal of Analytical Science & Technology ◽

10.1186/s40543-020-00255-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jinxia Wei ◽

Jia Shao ◽

Yanan Li ◽

Yubo Li

Keyword(s):

Mobile Phase ◽

Internal Standard ◽

Rat Plasma ◽

Hplc Assay ◽

Isocratic Elution ◽

Fluorescence Detector ◽

Limit Of Quantification ◽

The Mean ◽

Preclinical Safety ◽

Concentration Levels

Abstract Background To investigate the pharmacokinetics of 6-O-demethylmenisporphine, an oxoisoaporphine alkaloid with significant anti-tumor activities and isolated from Menispermi Rhizoma, a novel and sensitive HPLC assay was established for 6-O-demethylmenisporphine quantification in rat plasma. Methods Peak responses were detected by a highly selective and sensitive fluorescence detector with 426-nm excitation and 514-nm emission wavelengths. Curcumin was employed as the internal standard (IS). A Capcell Pak C18 column (150 mm × 4.6 mm i.d., 5 μm) and an isocratic elution procedure with a flow rate of 1.0 mL/min were used to exclude the endogenous interfering substance. Acetonitrile-water (68:32, v/v) containing 1% formic acid was employed as mobile phase. A 7-point calibration curve that covered the concentration range of 10–2500 ng/mL was constructed. Results A good linearity was observed with a correlation coefficient (r) of 0.9993. The lower limit of quantification for 6-O-demethylmenisporphine was 10 ng/mL. The mean recoveries of analyte in rat plasma exceeded 80.5%. The precision at four concentration levels was within 11.3% and the accuracy ranged from − 7.6 to 6.7%. Conclusion Using this new HPLC-FLD method, the investigation of plasma samples from rats following oral dosing of neat compound and Menispermi Rhizoma extract was successfully conducted. The results will provide a reference for the evaluation of preclinical safety of 6-O-demethylmenisporphine.

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Preclinical safety assessment of a combined vaccine against Hepatitis a virus and enterovirus 71

Vaccine ◽

10.1016/j.vaccine.2021.05.058 ◽

2021 ◽

Author(s):

Ting Yang ◽

Baofeng Liu ◽

Lei Yue ◽

Tianhong Xie ◽

Hua Li ◽

...

Keyword(s):

Safety Assessment ◽

Hepatitis A ◽

Hepatitis A Virus ◽

Enterovirus 71 ◽

Combined Vaccine ◽

Preclinical Safety

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Lessons learned from the porcine CARPA model: constant and variable responses to different nanomedicines and administration protocols

European Journal of Nanomedicine ◽

10.1515/ejnm-2015-0011 ◽

2015 ◽

Vol 7 (3) ◽

Cited By ~ 17

Author(s):

Rudolf Urbanics ◽

Péter Bedőcs ◽

János Szebeni

Keyword(s):

Inflammatory Mediator ◽

Lessons Learned ◽

Bolus Administration ◽

Variable Parameters ◽

Skin Changes ◽

Wide Range ◽

Slow Infusion ◽

Technical Details ◽

Drug Nanocarriers ◽

Preclinical Safety

AbstractPigs provide a sensitive and quantitative animal model of complement (C) activation-related pseudoallergy (CARPA) caused by liposomes and a wide range of nanoparticulate drugs or drug nanocarriers (nanomedicines). The tetrad of symptoms (hemodynamic, hematological, laboratory and skin changes) that arise within minutes after i.v. injection of reactogenic nanomedicines (RNMs) are highly reproducible among different pigs but the presence, direction and relative severity of symptoms are very different with different RNMs and their administration schedule. Bolus administration of RNMs usually trigger pulmonary hypertension with or without various degrees of systemic hyper- or hypotension, tachy-or bradycardia, arrhythmia, blood cell and inflammatory mediator changes and skin rash. These reactions can be rapid or protracted, and fully tachyphylactic, semi-tachyphylactic or non-tachyphylactic. Slow infusion usually diminishes the reactions and/or entail delayed, protracted and less severe hemodynamic and other changes. The goal of this review is to present some technical details of the porcine CARPA model, point out its constant and variable parameters, show examples of different reactions, highlight the unique features and capabilities of the model and evaluate its utility in preclinical safety assessment. The information obtained in this model enables the understanding of the complex pathomechanism of CARPA involving simultaneous anaphylatoxin and inflammatory mediator actions at multiple sites in different organs.

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