Determination of LD50 and assessment of drug induced developmental toxicity in zebrafish

2008 ◽  
Vol 58 (2) ◽  
pp. 150
Author(s):  
Patricia McGrath ◽  
Wen Lin Seng ◽  
Catherine Willett ◽  
Karen A. Augustine
Keyword(s):  
Developmental Toxicity ◽  
Drug Induced

scholarly journals Mechanisms of amphipath-induced stomatocytosis in human erythrocytes

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 782-786 ◽  
Author(s):  
SL Schrier ◽  
A Zachowski ◽  
PF Devaux
Keyword(s):  
Blood Cells ◽  
Shape Change ◽  
Drug Induced ◽  
Inhibiting Effect ◽  
Outer Leaflet ◽  
Human Red Blood Cells ◽  
Spin Resonance ◽  
Vanadate Inhibition

Abstract We studied stomatocytosis induced in human red blood cells (RBC) by vinblastine and chlorpromazine, monitoring the movements of spin- labeled phosphatidylcholine (PC*) and sphingomyelin (SM*) by electron spin resonance (ESR) spectroscopy. This technique allows determination of the fraction of labeled lipids, respectively, on the external leaflet, on the cytosol face, or trapped in endocytic vacuoles. Both vinblastine and chlorpromazine produce a time- and concentration- dependent stomatocytic shape change, which is paralleled by a shift of approximately 10% to 33% of outer leaflet SM* and PC* inward. Of this amount, 8% to 12% was trapped in endocytic vacuoles and 8% to 19% had flipped to the inner leaflet. Vanadate, while inhibiting the stomatocytosis, did not block the flip of either SM* or PC* to the inner leaflet. To explain the inhibiting effect of vanadate, as well as the adenosine triphosphate (ATP) requirement for drug-induced stomatocytosis, we propose the following model: (1) addition of amphipath partially scrambles the bilayer; and (2) the flop of phosphatidylserine (PS) and phosphatidylethanolamine (PE) to the outer leaflet provides substrate for the aminophospholipid translocase (APLT), which flips back PS and PE inward faster than PC or SM can diffuse outward--thereby producing inner layer expansion or stomatocytosis. This role of APLT accounts for the vanadate inhibition of amphipath stomatocytosis. However, the vanadate effect can be overcome by increasing the amphipath concentration, which at such levels probably passively expands the inner leaflet.

Two automated procedures for N-acetyl-beta-D-glucosaminidase determination evaluated for detection of drug-induced tubular nephrotoxicity.

1986 ◽  
Vol 32 (11) ◽  
pp. 2052-2055 ◽  
Author(s):  
M P Goren ◽  
R K Wright ◽  
S Osborne
Keyword(s):  
Enzymatic Activity ◽  
Methotrexate Therapy ◽  
Tubular Damage ◽  
Sample Treatment ◽  
Urine Ph ◽  
Drug Induced ◽  
Alkaline Urine ◽  
Automated Procedures ◽  
Drugs And Metabolites

Abstract We automated two procedures for determination of urinary N-acetyl-beta-D-glucosaminidase (NAG; EC 3.2.1.30) concentrations and evaluated their reliability for detecting drug-induced tubular damage in children receiving cisplatin, methotrexate, or ifosfamide. Results for 174 patient specimens correlated well (r = 0.98), but NAG concentrations determined by the m-cresolsulfonphthaleinyl (MCP) procedure were about 40% lower than those obtained with p-nitrophenyl-N-acetyl-beta-D-glucosaminide substrate. Dialysis and assay of 50 specimens disclosed no evidence of activators or inhibitors of enzymatic activity. Drugs and metabolites added to urine had negligible effect on NAG determinations; however, NAG was unstable in alkaline urine (pH greater than 8) associated with methotrexate therapy. Both procedures detect tubular damage equally well and neither requires laborious sample treatment. The MCP procedure, being more sensitive and not requiring a sample blank, is better suited for rapid automated assays. Comparisons of clinical data obtained by the two procedures require standardization against human NAG.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo

2013 ◽  
Vol 304 (6) ◽  
pp. H895-H902 ◽  
Author(s):  
Radka Kockova ◽  
Jarmila Svatunkova ◽  
Jiri Novotny ◽  
Lucie Hejnova ◽  
Bohuslav Ostadal ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Heart Rate ◽  
Cardiac Output ◽  
Adrenergic Receptors ◽  
Developmental Toxicity ◽  
Premature Death ◽  
Chick Embryos ◽  
In Ovo ◽  
Drug Induced ◽  
Β Adrenergic Receptors

A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of β-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of β-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate.

scholarly journals Zebrafish on a Chip: A Novel Platform for Real-Time Monitoring of Drug-Induced Developmental Toxicity

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94792 ◽  
Author(s):  
Yinbao Li ◽  
Fan Yang ◽  
Zuanguang Chen ◽  
Lijuan Shi ◽  
Beibei Zhang ◽  
...  
Keyword(s):  
Real Time ◽  
Developmental Toxicity ◽  
Real Time Monitoring ◽  
Drug Induced

scholarly journals Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

2021 ◽  
Vol 9 (4) ◽  
pp. 173-184
Author(s):  
O. V. Muslimova ◽  
V. A. Evteev ◽  
I. A. Mazerkina ◽  
E. A. Sokova ◽  
A. B. Prokofiev ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Experimental Models ◽  
Injury Incidence ◽  
Drug Induced ◽  
Blood Concentrations ◽  
Incidence And Mortality ◽  
Hospital Patients

Drug-induced kidney injury (DIKI) accounts for 8 to 60% of episodes of acute kidney injury (AKI) among hospital patients. Early DIKI detection and timely adjustment of therapy will help reduce the kidney injury incidence and mortality. The aim of the study was to analyse scientific literature on the biomarkers used in DIKI diagnosis. The study revealed that the use of such kidney damage markers as serum creatinine, urinary output, urea nitrogen, sodium excretion, urinary sediment microscopy is limited because they do not give a full picture of the kidney injury degree and progression and do not allow for early AKI diagnosis. It was demonstrated that some of the most promising biomarkers are KIM-1, L-FABP, NAG, NGAL, cystatin C, clusterin, β2-microglobulin, МСР-1, IGFBP7, and TIMP-2. However, recommendations for determination of these biomarkers’ urine or blood concentrations for AKI diagnosis are somewhat preliminary, because there have been insufficient clinical and preclinical studies to establish validity of such tests. No precise algorithms based on determination of the biomarkers levels in urea and/or blood serum have been developed for AKI risk assessment, diagnosis, monitoring, and treatment. Thus, further research is necessary to investigate different AKI biomarkers and improve experimental models (both in vivo and in vitro), which will support assessment of potential nephrotoxic properties of existing and new medicinal products.

scholarly journals Determination of drug-induced changes in functional MRI signal using a pharmacokinetic model

1999 ◽  
Vol 8 (4) ◽  
pp. 235-244 ◽  
Author(s):  
Alan S. Bloom ◽  
Raymond G. Hoffmann ◽  
Scott A. Fuller ◽  
John Pankiewicz ◽  
Harold H. Harsch ◽  
...  
Keyword(s):  
Functional Mri ◽  
Pharmacokinetic Model ◽  
Drug Induced ◽  
Induced Changes

Determination of serum cholestatic factor level by ELISA in drug-induced allergic hepatitis

1988 ◽  
Vol 23 (6) ◽  
pp. 624-628
Author(s):  
Kiyohide Kioka ◽  
Yasuhiro Mizoguchi ◽  
Chie Kodama ◽  
Yoshihide Sakagami ◽  
Shuichi Seki ◽  
...  
Keyword(s):  
Factor Level ◽  
Drug Induced ◽  
Cholestatic Factor

Dynamic Changes of Nasal Resistance

1979 ◽  
Vol 88 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Makoto Hasegawa ◽  
Eugene B. Kern ◽  
Peter C. O'Brien
Keyword(s):  
Dynamic Range ◽  
Normal Individual ◽  
Human Subjects ◽  
Nasal Resistance ◽  
Dynamic Changes ◽  
Drug Induced ◽  
Physiologic Change ◽  
Average Change ◽  
Minute Interval

Fifty human subjects were studied and evaluated utilizing posterior rhinomanometry techniques. The main purpose of the investigation was to study the physiologic dynamic range of nasal resistance so that the data might serve as a baseline, not only for evaluation and diagnosis of pathologic states but also for the assessment of nasal responses to various physiologic, drug-induced, or pathologic challenges. Analysis was divided into two parts: first, the evaluation of the average resistance and average change in resistance for each patient, and, second, determination of the maximal amount of change to be expected over 15-minute periods in a healthy subject. These studies give the investigator an idea of the magnitude of change that one might expect in normal physiologic situations, based on the 50 subjects that allowed 1,272 observations for justification of the concept of percent change in nasal resistance and not the value of nasal resistance alone. We concluded that the physiologic change in nasal resistance in a normal individual during a 15-minute interval should be less than 53% of the previous observation of nasal resistance. A change greater than 53% suggests a significant change that cannot be attributed to physiologic variability.

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