MODIFICATION OF HEXOBARBITAL METABOLISM BY MORRIS HEPATOMA 5123tc

1967 ◽  
Vol 45 (6) ◽  
pp. 975-983 ◽  
Author(s):  
R. A. Hickie ◽  
H. Kalant
Keyword(s):  
Tumor Necrosis ◽  
Surgical Removal ◽  
Host Liver ◽  
Sleeping Time ◽  
Tumor Bearing ◽  
Hexobarbital Sleeping Time ◽  
Morris Hepatoma ◽  
Hexobarbital Metabolism

Slices of the Morris 5123tc "minimum-deviation" hepatoma fail to metabolize hexobarbital in vitro; slices of non-tumorous liver from the host rats metabolize it at a lower rate than liver slices from normal animals. A corresponding in vivo difference is indicated by a prolonged hexobarbital sleeping time in tumor-bearing rats. The prolongation begins only when the hepatoma becomes large enough to show areas of necrosis or ulceration, and increases steadily with further tumor growth. Surgical removal of the tumor restores the sleeping time to normal. Since the tumor is implanted subcutaneously and does not invade the liver, it is suggested that a diffusible product of tumor necrosis is responsible for the impairment of hexobarbital metabolism in the host liver.

Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice

1995 ◽  
Vol 14 (8) ◽  
pp. 623-629 ◽  
Author(s):  
DH Kim ◽  
EJ Kim ◽  
SS Han ◽  
JK Roh ◽  
TC Jeong ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Receptor Antagonists ◽  
Sleeping Time ◽  
Icr Mice ◽  
In Vitro Effects ◽  
Hexobarbital Metabolism ◽  
Dose Dependent

1 The present study was undertaken to examine the effects of H2-receptor antagonists including newly developed mifentidine derivatives, IY-80843 and IY-80845, on cytochrome P450(P450) in vitro and in vivo. 2 Initially, 3-methylcholanthrene-, phenobarbital-, ethanol- and dexamethasone-induced liver microsomes were prepared from male ICR mice to study in vitro effects of above chemicals on ethoxyresorufin O- deethylase(EROD), pentoxyresorufin O-dealkylase(PROD), p-nitrophenol hydroxylase and erythromycin N-demethy lase(ERDM) activities, respectively. It was found that hist amine, cimetidine and famotidine were not inhibitory to four enzyme activities. Meanwhile, mifentidine slightly inhibited EROD and PROD activities and its derivatives IY-80843 and IY-80845 strongly inhibited PROD, EROD and ERDM activities. 3 Prolongation of hexobarbital-induced sleeping time was determined in male ICR mice to confirm in vitro inhibito ry effects of mifentidine and its derivatives in vivo. It was observed that cimetidine, mifentidine, IY-80843 and IY- 80845 caused dose-dependent increases in the sleeping time, indicating the inhibition of P450 responsible for hexobarbital metabolism. 4 It was concluded that mifentidine and its derivatives are P450 inhibitors and that our newly synthesized IY-80843 is most inhibitory. 5 The present results indicate that mifentidine and its derivatives not only antagonise the H 2-receptor but also inhibit P450 enzymes.

A Study of the Effect of Ovex on Parathion Toxicity in Rats

1973 ◽  
Vol 51 (9) ◽  
pp. 682-685 ◽  
Author(s):  
W. D. Black ◽  
A. E. Wade ◽  
R. B. Talbot
Keyword(s):  
Oral Administration ◽  
Liver Size ◽  
Sleeping Time ◽  
Hexobarbital Sleeping Time ◽  
Organophosphate Toxicity ◽  
Naphthyl Acetate

Oral administration (100 mg/kg) of the miticide ovex (p-chlorophenyl p-chlorobenzene-sulfonate) caused a decrease in the hexobarbital sleeping time of rats. Administration of this same dosage of ovex resulted in a significant decrease in the toxicity of orally administered parathion (100 mg/kg) to rats.The changes in rats noted in conjunction with the increased resistance to organophosphate toxicity in vivo were an increased liver size, an increased rate of in vitro α-naphthyl acetate hydrolysis by the 9000 × g liver supernatant.The hexane-extractable organophosphate detected in the liver of the ovex-pretreated rats was significantly lower than the hexane extractable organophosphate found in the liver of the control rats.

scholarly journals EXTH-71. CYTOSTATIC HYPOTHERMIA FOR GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii102-ii103
Author(s):  
Syed Faaiz Enam ◽  
Jianxi Huang ◽  
Cem Kilic ◽  
Connor Tribble ◽  
Martha Betancur ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
Progression Free Survival ◽  
Rodent Model ◽  
Behavioral Alterations ◽  
Free Survival ◽  
Tumor Bearing ◽  
Car T ◽  
The Brain

Abstract As a cancer therapy, hypothermia has been used at sub-zero temperatures to cryosurgically ablate tumors. However, these temperatures can indiscriminately damage both tumorous and healthy cells. Additionally, strategies designed to kill tumor typically accelerate their evolution and recurrence can be inevitable in cancers such as glioblastoma (GBM). To bypass these limitations, here we studied the use of hypothermia as a cytostatic tool against cancer and deployed it against an aggressive rodent model of GBM. To identify the minimal dosage of ‘cytostatic hypothermia’, we cultured at least 4 GBM lines at 4 continuous or intermittent degrees of hypothermia and evaluated their growth rates through a custom imaging-based assay. This revealed cell-specific sensitivities to hypothermia. Subsequently, we examined the effects of cytostatic hypothermia on these cells by a cursory study of their cell-cycle, energy metabolism, and protein synthesis. Next, we investigated the use of cytostatic hypothermia as an adjuvant to chemotherapy and CAR T immunotherapy. Our studies demonstrated that cytostatic hypothermia did not interfere with Temozolomide in vitro and may have been synergistic against at least 1 GBM line. Interestingly, we also demonstrated that CAR T immunotherapy can function under cytostatic hypothermia. To assess the efficacy of hypothermia in vivo, we report the design of an implantable device to focally administer cytostatic hypothermia in an aggressive rodent model of F98 GBM. Cytostatic hypothermia significantly doubled the median survival of tumor-bearing rats with no obvious signs of distress. The absence of gross behavioral alterations is in concurrence with literature suggesting the brain is naturally resilient to focal hypothermia. Based on these findings, we anticipate that focally administered cytostatic hypothermia alone has the potential to delay tumor recurrence or increase progression-free survival in patients. Additionally, it could also provide more time to evaluate concomitant, curative cytotoxic treatments.

Abstract 354: Lower Circulating Levels of Tumor Necrosis Factor Related Apoptosis-inducing Ligand (TRAIL) are Associated with Increased Sub-clinical Coronary Atherosclerosis among Smokers

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Aman Gupta ◽  
Divay Chandra ◽  
Yingze Zhang ◽  
Steven Reis ◽  
Frank Sciurba
Keyword(s):  
Tumor Necrosis Factor ◽  
Coronary Atherosclerosis ◽  
Tumor Necrosis ◽  
Smoking Status ◽  
Calcium Score ◽  
Meso Scale Discovery ◽  
The Mean ◽  
Necrosis Factor

Rationale: There is significant in vitro evidence demonstrating anti-atherogenic effect of circulating Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Also, decreased circulating TRAIL levels have been reported in patients with acute myocardial infarction and in those undergoing coronary catheterization due to suspected coronary atherosclerosis. However, it remains unknown if TRAIL levels are associated with sub-clinical coronary atherosclerosis. Methods: The study included 460 current and former smokers enrolled in the Pittsburgh COPD SCCOR study. Serum TRAIL levels were measured by electrochemiluminescence immunoassay, according to the manufacture’s protocol (Meso Scale Discovery, Gaithersburg, Maryland). Coronary atherosclerosis was assessed by a validated visual coronary artery calcium scoring system using non-EKG gated chest CT scans (Weston score). Ordinal logistic regression models were used to identify significant associations between categories of CAC score (0, 1-3, 4-8, and 9-12) and TRAIL level, and to adjust for cardiovascular risk factors. Results: The mean age of the 460 participants was 65.7 ± 6.3 years, 52.2% were male, and the mean pack years of smoking was 55.0 ± 30.8 years. In univariate analyses, each standard deviation decrease in TRAIL levels was associated with 1.42-fold increase in the odds of having calcium scores in one higher category (p<0.001). This association persisted despite adjustment for age, gender, race, body mass index, hypertension, diabetes, hyperlipidemia, pack years of smoking, and current smoking status (adjusted OR for higher category of calcium score per SD decrease in TRAIL level 1.22, p=0.04). Conclusions: Our results expand on the in vitro and in vivo data linking decreased TRAIL levels with increased atherosclerosis by demonstrating a novel association between lower circulating TRAIL and increased subclinical coronary atherosclerosis.

scholarly journals Preclinical Pharmacokinetics of C118P, a Novel Prodrug of Microtubules Inhibitor and Its Metabolite C118 in Mice, Rats, and Dogs

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2883 ◽  
Author(s):  
Cang Zhang ◽  
Xiaolan Zhang ◽  
Guangji Wang ◽  
Ying Peng ◽  
Xueyuan Zhang ◽  
...  
Keyword(s):  
Clinical Development ◽  
High Dose ◽  
Protein Inhibitor ◽  
Promising Candidate ◽  
Preclinical Pharmacokinetics ◽  
Tumor Bearing ◽  
Microtubule Protein ◽  
Further Development

C118P, a phosphate prodrug of C118, which is a novel microtubule protein inhibitor, is currently under Phase I clinical development in China for treating ovarian cancer and lung cancer. The preclinical pharmacokinetics of prodrug C118P and its metabolite C118 were extensively characterized in vivo in mice, rats, and dogs and in vitro to support the further development of C118P. The preclinical tissue distribution and excretion were investigated in rats. Plasma protein binding in mice, rat, and human, and hepatic microsomal metabolic stability in mice, rat, dog, monkey, and human, were also evaluated. The (AUC0-inf) and C30s of C118P at 50 mg/kg in rats and 6 mg/kg in dogs, and the C2min of C118 at 6 mg/kg in dogs increased less than the dosage increase, suggested nonlinear pharmacokinetic occurred at high dose. As a prodrug, C118P can be quickly hydrolyzed into C118 after an intravenous administration. The unbound C118 in plasma is slightly higher than C118P. C118P can hardly penetrate the tissue, while C118 can distribute widely into tissues. In tumor-bearing nude mice, the concentration of C118 is high in lung, ovary, and tumor, with an extended half-life in tumor. C118P is a promising candidate prodrug for further clinical development.

scholarly journals pH-Sensitive Hydrazone-Linked Doxorubicin Nanogels via Polymeric-Activated Ester Scaffolds: Synthesis, Assembly, and In Vitro and In Vivo Evaluation in Tumor-Bearing Zebrafish

2018 ◽  
Vol 30 (23) ◽  
pp. 8587-8596 ◽  
Author(s):  
Alexandra Van Driessche ◽  
Agnese Kocere ◽  
Hannelien Everaert ◽  
Lutz Nuhn ◽  
Simon Van Herck ◽  
...  
Keyword(s):  
Ph Sensitive ◽  
In Vivo Evaluation ◽  
Tumor Bearing

scholarly journals In Vivo and in Vitro Evidence for the Involvement of Tumor Necrosis Factor-α in the Induction of Leptin by Lipopolysaccharide*

Endocrinology ◽  
1998 ◽  
Vol 139 (5) ◽  
pp. 2278-2283 ◽  
Author(s):  
Brian N. Finck ◽  
Keith W. Kelley ◽  
Robert Dantzer ◽  
Rodney W. Johnson
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation

1994 ◽  
Vol 266 (6) ◽  
pp. H2535-H2541 ◽  
Author(s):  
P. Wang ◽  
Z. F. Ba ◽  
I. H. Chaudry
Keyword(s):  
Mean Arterial Pressure ◽  
Tumor Necrosis Factor ◽  
Arterial Pressure ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Vascular Relaxation ◽  
Endothelium Dependent Relaxation ◽  
Necrosis Factor

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.

scholarly journals Biodistribution Study of Niosomes in Tumor-Implanted BALB/C Mice Using Scintigraphic Imaging

2022 ◽  
Vol 12 ◽  
Author(s):  
Leanne De Silva ◽  
Ju-Yen Fu ◽  
Thet Thet Htar ◽  
Wan Hamirul Bahrin Wan Kamal ◽  
Azahari Kasbollah ◽  
...  
Keyword(s):  
Intravenous Injection ◽  
Gamma Scintigraphy ◽  
Biodistribution Study ◽  
Scintigraphic Imaging ◽  
Tumor Bearing ◽  
Tumor Accumulation ◽  
Tumor Area

The purpose of this work was to study the biodistribution of niosomes in tumor-implanted BALB/c mice using gamma scintigraphy. Niosomes were first formulated and characterized, then radiolabeled with Technetium-99 m (99mTc). The biodistribution of 99mTc-labeled niosomes was evaluated in tumor-bearing mice through intravenous injection and imaged with gamma scintigraphy. The labeled complexes possessed high radiolabeling efficiency (98.08%) and were stable in vitro (&gt;80% after 8 h). Scintigraphic imaging showed negligible accumulation in the stomach and thyroid, indicating minimal leaching of the radiolabel in vivo. Radioactivity was found mainly in the liver, spleen and kidneys. Tumor-to-muscle ratio indicated a higher specificity of the formulation for the tumor area. Overall, the formulated niosomes are stable both in vitro and in vivo, and show preferential tumor accumulation.

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