scholarly journals Safety reassessment of cinobufotalin injection: new findings into cardiotoxicity

2020 ◽  
Vol 9 (4) ◽  
pp. 390-398
Author(s):  
Min Li ◽  
Xijie Wang ◽  
Yunliang Qiu ◽  
Yizhe Zhang ◽  
Xueying Pan ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Troponin I ◽  
Latin Square ◽  
Treatment Phase ◽  
Clinical Practices ◽  
Clinical Observations ◽  
New Findings ◽  
Traditional Chinese Medicine Preparation ◽  
Dose Levels

Abstract Cinobufotalin injection, a traditional Chinese medicine preparation, successfully used for several years, might induce cardiotoxicity. The aim of the study was to evaluate the cardiotoxicity of cinobufotalin injection and the cardiotoxicity-preventive effect of sodium phenytoin in vivo. According to the 4 × 4 Latin square design, four Beagle dogs were allocated into four dose levels of 0, 0.3, 1, and 3 g/kg in treatment phases I–IV (cinobufotalin injection) and 3 g/kg in treatment phase V (cardiotoxicity antidote). The following parameters and endpoints were assessed: clinical observations, body weight, indicators of myocardial injury, and electrocardiogram (ECG) parameters. The cinobufotalin injection-related changes were observed in clinical observations (rapid breathing pattern), indicators of myocardial injury (increased cardiac troponin I, creatine kinase isoenzymes, and aspartate aminotransferase), and ECG graphics (arrhythmia) at 3 g/kg concentration in treatment phases I–IV. The cardiotoxicity of cinobufotalin injection was attenuated by sodium phenytoin in treatment phase V. The results confirmed the cardiotoxicity of cinobufotalin injection, and they might bring information about the appropriate monitoring time points and cardiotoxicity parameters in clinical practices and shed light on the treatment of cardiovascular adverse reactions.

VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15167-e15167 ◽  
Author(s):  
Joel Robert Eisner ◽  
David H Abbott ◽  
Ian M Bird ◽  
Stephen W Rafferty ◽  
William R Moore ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Castrate Male ◽  
Plasma Progesterone ◽  
Clinical Observations ◽  
Treatment Paradigm ◽  
Androgen Suppression ◽  
Dose Levels ◽  
Peak Increase

e15167 Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extra-gonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995-2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.

VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 198-198 ◽  
Author(s):  
Joel Robert Eisner ◽  
David H Abbott ◽  
Ian M Bird ◽  
Stephen W Rafferty ◽  
William R Moore ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Castrate Male ◽  
Plasma Progesterone ◽  
Clinical Observations ◽  
Treatment Paradigm ◽  
Androgen Suppression ◽  
Dose Levels ◽  
Peak Increase

198 Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extragonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995–2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.

In vivo apparent digestibility in ponies given rolled, micronised or extruded barley

1999 ◽  
Vol 1999 ◽  
pp. 133-133 ◽  
Author(s):  
B M L McLean ◽  
J J Hyslop ◽  
A C Longland ◽  
D Cuddeford ◽  
T Hollands
Keyword(s):  
Dry Matter ◽  
Latin Square ◽  
Design Experiment ◽  
Apparent Digestibility ◽  
Processing Methods ◽  
Physical Processing ◽  
Adaptation Phase

Processed cereals are used routinely in diets for equines but little information is available on how physical processing affects the digestibility of cereals in equines. This study examines the effects of three physical processing methods (rolling, micronisation and extrusion) on the in vivo apparent digestibility of barley fed to ponies.Three mature caecally-fistulated Welsh-cross pony geldings, (LW 284kg ± 3.8kg) were used in a 3 x 4 incomplete latin square changeover design experiment consisting of four 21 day periods. Each period comprised a sixteen day adaptation phase and a five day recording phase when apparent digestibility in vivo was determined. Ponies were offered 4kg dry matter (DM) per day of either 100% hay cubes (HC) or one of three diets consisting of a 50:50 barley:hay cubes mix. The barley in the mixed diets was either rolled barley (RB), micronised barley (MB) or extruded barley (EB). Diets were offered in 2 equal meals per day fed at 09:00 and 17:00 hours respectively.

scholarly journals Frequency- and Afterload-Dependent Cardiac Modulation In Vivo by Troponin I With Constitutively Active Protein Kinase A Phosphorylation Sites

2004 ◽  
Vol 94 (4) ◽  
pp. 496-504 ◽  
Author(s):  
Eiki Takimoto ◽  
David G. Soergel ◽  
Paul M.L. Janssen ◽  
Linda B. Stull ◽  
David A. Kass ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Troponin I ◽  
Phosphorylation Sites ◽  
Active Protein ◽  
Cardiac Modulation ◽  
Kinase A ◽  
Constitutively Active

scholarly journals PSII-13 Effect of corn stover silages inoculated with effective microorganisms (EM®) on digestibility of sheeps

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 408-410
Author(s):  
Manuel Pérez- ◽  
Claudia C Márquez-Mota ◽  
Atmir Romero-Pérez ◽  
Jonathan Avilés-Nieto ◽  
Luis Corona
Keyword(s):  
Corn Stover ◽  
Latin Square ◽  
Ruminal Fermentation ◽  
Effective Microorganisms ◽  
Cane Molasses ◽  
Milk Whey ◽  
Corn Stover Silage ◽  
Silage Process ◽  
Male Sheep

Abstract The objective of the study was to evaluate the effect of corn stover silages with two sources of energy (cane molasses or milk whey) and EM (effective microorganisms, 1 mL/kg DM) on the digestibility of nutrients and rumen fermentation. We hypothesized that inoculation with EM (lactobacillus spp and Rhodopseudomona palustris and Saccharomyces cerevisiae) in the silage process of corn stover coud improve the in vivo digestibility and ruminal fermentation in sheep. Six male sheep with cannula in the rumen were used in a 6 x 6 Latin square design. Experimental periods consisted of 11 d for diet adjustment followed by 5 d for collection. The animals were housed in metabolic cages, with a harness to collect faeces individually. Diets consisted of concentrate (corn grain, soybean meal, mineral salt) 55% and corn stover 45% dry basis. The treatments were: CS-AMW= Corn stover with acid milk whey, CS-CM= corn stover with sugar cane molasses, SIL-AMW= corn stover silage with acid milk whey, SIL-CM= corn stover silage with cane molasses, SIL-AMW-EM= corn stover silage with acid milk whey and EMand SIL-CM-EM= Corn stover silage with cane molasses and EM. The results were analyzed with PROC MIXED procedures of SAS. The inoculation of corn stover with EM increased (P < 0.05) the content of CP in SIL-AMW-EM and SIL-CM-EM respect CS-CM (Table 1). SIL-CM-EM increase (P < 0.05) the ruminal N-NH3 and pH (Table 2) but no effect was observed for digestibility (Table 3). However, the SIL-AMW improved (5.8%, P < 0.05) the OM digestion compared with CS-AMW. A diet with 45% corn stover silage with EM was not sufficient to improve in vivo digestibility of nutrients in sheep. This project was supported by UNAM,DGAPA, PAPIIT (IT202120)

scholarly journals Misclassification of Myocardial Injury by a High-Sensitivity Cardiac Troponin I Assay

2021 ◽  
Author(s):  
Peter A. Kavsak ◽  
Shawn Mondoux ◽  
Andrew Worster ◽  
Janet Martin ◽  
Vikas Tandon ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Myocardial Injury ◽  
Troponin I ◽  
High Sensitivity ◽  
Cardiac Troponin I

scholarly journals The role of neurohormonal blockers in the primary prevention of acute-, early-, and late-onset anthracycline-induced cardiotoxicity

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Ahmed Ayuna ◽  
Nik Abidin
Keyword(s):  
Primary Prevention ◽  
Myocardial Injury ◽  
Troponin I ◽  
Late Onset ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Main Body ◽  
Converting Enzyme Inhibitors ◽  
Ventricular Ejection Fraction

Abstract Background Anthracycline-induced cardiotoxicity has been classified based on its onset into acute, early, and late. It may have a significant burden on the quality and quantity of life of those exposed to this class of medication. Currently, there are several ongoing debates on the role of different measures in the primary prevention of cardiotoxicity in cancer survivors. Our article aims to focus on the role of neurohormonal blockers in the primary prevention of anthracycline-induced cardiotoxicity, whether it is acute, early, or late onset. Main body of the abstract PubMed and Google Scholar database were searched for the relevant articles; we reviewed and appraised 15 RCTs, and we found that angiotensin-converting enzyme inhibitors (ACEI) and B-blockers were the most commonly used agents. Angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs) were used in a few other trials. The follow-up period was on the range of 1–156 weeks (mode 26 weeks). Left ventricular ejection fraction (LVEF), left ventricular diameters, and diastolic function were assessed by either echocardiogram or occasionally by cardiac magnetic resonance imaging (MRI). The occurrence of myocardial injury was assessed by troponin I. It was obvious that neurohormonal blockers reduced the occurrence of LVEF and myocardial injury in 14/15 RCTs. Short conclusion Beta-blockers, especially carvedilol and ACEI, especially enalapril, should be considered for the primary prevention of acute- and early-onset cardiotoxicity. ARB and MRA are suitable alternatives when patients are intolerant to ACE-I and B-blockers. We recommend further studies to explore and establish the role of neurohormonal blockers in the primary prevention of the acute-, early-, and late-onset cardiotoxicity.

scholarly journals Longitudinal obesity exposure over two decades is associated with subclinical myocardial injury: the Nord-Trondelag Health Study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.N Lyngbakken ◽  
H Rosjo ◽  
K Hveem ◽  
T Omland
Keyword(s):  
Cardiac Troponin ◽  
Myocardial Injury ◽  
Troponin I ◽  
Linear Increase ◽  
Normal Weight ◽  
Public Institution ◽  
Health Study ◽  
Funding Source ◽  
Study Visit ◽  
Increased Risk

Abstract Background Obesity is associated with subclinical myocardial injury as quantified by concentrations of cardiac troponin, but whether excess weight history is associated with increased cardiac troponin I (cTnI) remains unclear. We aimed to explore the association of obesity with cTnI using different indices of cumulative obesity exposure. Methods We analyzed cTnI with a high-sensitivity assay in 14,157 participants with follow-up over two decades in the prospective observational Nord-Trøndelag Health (HUNT) Study at study visit 4 (2017–2019). All subjects were free from known cardiovascular disease at baseline, and we excluded subjects with BMI <18.5 kg/m2. BMI was assessed at study visit 2 (1995–1997), 3 (2006–2008) and 4, and we categorized participants as normal weight (BMI <25), overweight (BMI ≥25 to <30) and obesity (BMI ≥30). At each study visit, BMI was designated a score of 0 (normal weight), 1 (overweight) or 2 (obesity), totaling a score from 0 to 6. Cumulative obesity exposure was calculated as average BMI above 25 kg/m2 between visits multiplied by the time between visits (excess BMI years, kg/m2 × years). Results Median age at visit 4 was 64.1 (range 40.9 to 101.5) years and 60% were women. Concentrations of cTnI were detectable in 77.2% of study participants, and were median 2.2 (1.3 to 3.9) ng/L. There was a linear increase in cTnI with increasing BMI score (p for trend <0.001) and increasing BMI score was associated with increased risk of high cTnI (p for trend <0.001; Table 1). For every 100 excess BMI years, there was a 15.6 (95% CI, 13.0 to 18.2) % increase in cTnI at study visit 4 (Figure 1). Conclusion Cumulative obesity exposure is associated with a linear increase in cTnI, a highly sensitive index of subclinical myocardial injury, reflecting the detrimental effect of long standing obesity on cardiovascular health. Figure 1. BMI years and cTnI Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority

Elevations of Troponin I after interventional cardiac catheterization

2001 ◽  
Vol 11 (4) ◽  
pp. 375-378 ◽  
Author(s):  
Prince J. Kannankeril ◽  
David F. Wax ◽  
Elfriede Pahl
Keyword(s):  
Cardiac Catheterization ◽  
Cardiac Troponin ◽  
Baseline Level ◽  
Myocardial Injury ◽  
Troponin I ◽  
Cardiac Troponin I ◽  
Specific Marker ◽  
Before And After ◽  
Baseline Sample

Background: Elevation of cardiac troponin I in the serum is a specific marker for myocardial injury. We measured levels of troponin I in the serum in children before and after cardiac catheterization to determine if this procedure was associated with an increase in levels of troponin. Methods: We enrolled patients under 21 years of age undergoing cardiac catheterization at our institution. A baseline sample of serum was drawn at the start of the procedure. Repeat samples were obtained immediately after, and six hours subsequent to the procedure. All samples were analyzed for cardiac troponin I using the Abbott AxSYM microparticle immunoassay system. Levels were considered normal (0–0.4 ng/ml) or elevated (>0.4ng/ml). Patients were excluded if the baseline level was elevated. Results: Levels of cardiac troponin I were elevated in the serum from 11 of 14 (79%) cases immediately after the procedure (p < 0.0001), and in 12 of 14 (86%) six hours later (p < 0.0001). Only 2 patients had recognized complications potentially causing myocardial injury. Conclusion: Levels of cardiac troponin I increase in the serum in a high proportion of children after cardiac catheterization. These elevations can be observed immediately, and are maintained for at least six hours. Our study suggests that cardiac catheterization, predominantly intervention, is associated with myocardial injury, even in the absence of complications.

scholarly journals Evidence that lamprey GnRH-III does not release FSH selectively in cattle

Reproduction ◽  
2004 ◽  
Vol 127 (1) ◽  
pp. 35-43 ◽  
Author(s):  
M Amstalden ◽  
D A Zieba ◽  
M R Garcia ◽  
R L Stanko ◽  
T H Welsh ◽  
...  
Keyword(s):  
Body Weight ◽  
Luteal Phase ◽  
Primary Cultures ◽  
Latin Square ◽  
Weak Competitor ◽  
Hormonal Milieu ◽  
Selective Effects

Experiments were performed to test the hypothesis that lamprey GnRH-III (lGnRH-III) selectively releases FSH. Primary cultures of bovine adenohypophyseal cells were treated with mammalian GnRH (mGnRH) and lGnRH-III (10−9, 10−8, 10−7 and 10−6 M) or control media in Experiment 1. All doses of mGnRH and the two highest doses of lGnRH-III stimulated (P < 0.001) a non-selective release of LH and FSH. In Experiments 2–4, Latin Square designs were utilized in vivo to examine whether physiological and hormonal milieu regulate putative selective effects of lGnRH-III. In Experiments 2 and 3, ovariectomized cows with basal levels of estradiol only (Experiment 2) or in combination with luteal phase levels of progester-one (Experiment 3) were injected with mGnRH and lGnRH-III (0.055, 0.11, 0.165 and 1.1 μg/kg body weight (BW) and saline. All doses of mGnRH released (P < 0.001) LH and FSH, but only the highest dose of lGnRH-III stimulated (P < 0.001) a non-selective release of both LH and FSH (Experiment 3). For Experiments 4A and 4B, intact, mid-luteal phase cows were injected with mGnRH and lGnRH-III (1.1 μg/kg BW; Experiment 4A), lGnRH-III (1.1 and 4.4 μg/kg BW; Experiment 4B) and saline. As before, mGnRH released (P < 0.001) both LH and FSH at all doses. In contrast, lGnRH-III at the highest dose released (P < 0.001) LH but not FSH. These findings suggest that lGnRH-III may act as a weak competitor for the mGnRH receptor and do not support the hypothesis that it selectively releases FSH in cattle.

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