Diphenylhydantoin: Disposition and effects of administration on hepatic function in guinea pigs

1979 ◽  
Vol 57 (5) ◽  
pp. 517-523 ◽  
Author(s):  
E. M. K. Lui ◽  
D. J. Ecobichon
Keyword(s):  
Body Weight ◽  
Transit Time ◽  
Guinea Pigs ◽  
Barium Meal ◽  
Serum Levels ◽  
Hepatic Function ◽  
Pharmacokinetic Studies ◽  
Gas Liquid Chromatography ◽  
Β Phase

Diphenylhydantoin sodium (phenytoin; DPH) was administered per os to fasted and non-fasted male and female albino guinea pigs either as single doses or as daily doses for 3 consecutive days. Pharmacokinetic studies involved measurement of the serum and alimentary DPH residues by gas–liquid chromatography following solvent extraction. The transit time of barium meal in the alimentary tract was studied by fluoroscopy in both fasted and nonfasted animals. Animals were killed 24 h following three consecutive daily doses of DPH (25 mg/kg body weight) and in vitro measurements of hepatic microsomal p-nitroanisole O-demethylase (OD), aniline hydroxylase (AH), NADPH-cytochrome c reductase (NADPH-CcR), nonspecific carboxylesterase, and UDPglucuronosyltransferase activities were made.Severe toxicity and sedation were observed at doses of 100 and 50 mg/kg body weight, respectively. No overt signs were observed at a dose of 25 mg/kg body weight, this dosage being selected for futher study. The apparent β-phase t0.5 of serum DPH following a single oral dose of 25 mg/kg body weight was approximately 6.5 h in nonfasted guinea pigs. Initial peak serum levels of DPH were observed at 2 h in fasted and nonfasted animals and secondary peak levels were observed at 12 h in nonfasted and at 24 h in fasted animals. There was a good correlation between the rate of DPH absorption, fasting state, and alimentary transit time. In animals receiving 25 mg DPH/kg body weight orally for 3 consecutive days, there was marked induction of hepatic OD, AH, and NADPH-CcR. No changes were observed in nonspecific carboxylesterase or UDPglucuronosyltransferase activities. The major metabolite of DPH, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), was not detected in the tissue in sufficient quantities to exert an influence on monooxygenase activities.

Methadone hydrochloride: effects of acute administration on disposition and hepatic function in guinea pigs

1978 ◽  
Vol 56 (4) ◽  
pp. 610-616 ◽  
Author(s):  
R. C. K. Pak ◽  
D. J. Ecobichon
Keyword(s):  
Guinea Pigs ◽  
Peak Plasma ◽  
Residue Analysis ◽  
Hepatic Function ◽  
Gas Liquid Chromatography ◽  
Acute Administration ◽  
Β Phase ◽  
Hepatic Monooxygenase ◽  
Stopping Treatment

d,l-Methadone hydrochloride (10 or 25 mg/kg body weight) was administered to adult female albino guinea pigs as either single doses or as daily doses for 6 consecutive days. A pharmacokinetic study was carried out on the animals receiving single doses, the plasma methadone being quantified by gas–liquid chromatography following solvent extraction. Different subgroups of animals receiving daily doses were killed after successive 24-h intervals for plasma and hepatic methadone residue analysis and for the in vitro measurement of hepatic monooxygenase (p-nitroanisole O-demethylase (OD); aniline hydroxylase (AH)) and glucuronyltransferase (GT) activities.No overt toxicity was observed at either dose administered. The β-phase plasma half-lives of the 10- and 25-mg/kg single doses were 13.2 and 13.8 h, respectively. Animals treated with six consecutive daily doses showed peak plasma and hepatic levels by day 2 of the treatment, followed by a gradual decline in subsequent days. The d,l-methadone did not significantly affect hepatic OD or AH though some reduction in activity was observed with the higher dose up to 7 days after stopping treatment. Significant reduction of GT activity was observed 24 h after the initial doses but, while the activities of animals receiving subsequent 10-mg/kg doses recovered, those of animals receiving 25-mg/kg doses remained significantly reduced even up to 7 days after treatment despite the fact that only traces of methadone could be detected in the livers.

The effects of furosemide and bumetanide on lung liquid production by in vitro lungs from fetal guinea pigs

1990 ◽  
Vol 68 (8) ◽  
pp. 1131-1135 ◽  
Author(s):  
J. Thom ◽  
A. M. Perks
Keyword(s):  
Body Weight ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Loop Diuretics ◽  
Dilution Technique ◽  
Blue Dextran ◽  
Lung Fluid ◽  
Lung Liquid ◽  
Secretion Rates

Lungs from fetal guinea pigs of 61 ± 3 days of gestation were supported in vitro for 3 h, and lung liquid secretion rates were measured by a dye dilution technique based on Blue Dextran 2000. Ten preparations that had received no treatment showed an average secretion rate of 1.12 ± 0.28 mL∙kg−1 body weight∙h−1 during the first hour, and there were no significant changes over the following 2 h. In studies of 54 fetal lungs, furosemide, bumetanide, control ethanol carrier, or saline alone were placed in the supporting medium during the middle hour of the 3-h incubations (ABA design). Furosemide at 10−3 M reduced secretion 83.4 ± 16.8%; at 10−4 and 10−5 M it produced smaller reductions. Bumetanide at 10−3 M usually produced reabsorption (129.9 ± 23.0% reduction), at 10−4 M it reduced secretion 30.9 ± 11.8%, but at 10−5 M it was ineffective. Control carrier and saline were without effect. The ability of the loop diuretics to produce reabsorption of fluid in some preparations suggests the unmasking of an active reabsorptive process. The results also suggest that lung liquid secretion in the fetal guinea pig, as in the sheep, is dependent on a Na+ and Cl− cotransport system.Key words: fetus, lung fluid, bumetanide, furosemide.

Effects of lung expansion on lung liquid production in vitro by lungs from fetal guinea-pigs. II. Evidence for generation of an inhibitory factor

1996 ◽  
Vol 8 (3) ◽  
pp. 347 ◽  
Author(s):  
PG Nelson ◽  
AM Perks
Keyword(s):  
Body Weight ◽  
Guinea Pigs ◽  
Inhibitory Factor ◽  
Dilution Method ◽  
Lung Fluid ◽  
Lung Expansion ◽  
Fluid Production ◽  
Near Term ◽  
Lung Liquid

Lungs from near-term fetal guinea-pigs were supported in vitro for 3 h; lung liquid production was measured by a dye-dilution method using Blue Dextran 2000 [fetuses 63 +/- 2 days of gestation, 97.6 +/- 19.8 (SD) g body weight]. Preparations were incubated in pairs taken from the same mother. Twenty lungs incubated in pairs without treatment (controls) showed no significant changes in fluid production throughout incubation (analysis of variance; regression analysis); rates in successive hours were: first lung, 1.36 +/- 0.39, 1.09 +/- 0.34 and 1.27 +/- 0.42 ml/kg body weight per h; second lung, 1.46 +/- 0.52, 1.09 +/- 0.41 and 1.18 +/- 0.43 ml/kg body weight per h. Twenty lungs were incubated similarly in pairs, but after one hour one lung from each pair was expanded with Krebs-Henseleit saline in volumes approximating those of the first breath (68 +/- 10% of lung volume). The expanded lungs began to reabsorb fluid immediately after expansion; the untreated lungs also stopped production or reached reabsorption by the final hour. Rates in successive hours were: expanded lungs; before expansion, 1.00 +/- 0.21, after expansion, -0.23 +/- 0.17 and 0.14 +/- 0.09 ml/kg body weight per h; unexpanded lungs, 1.27 +/- 0.49, 0.02 +/- 0.01 and -0.01 +/- 0.004 ml/kg body weight per h. The decrease in production was significant for each type of lung. The effects persisted in both expanded and unexpanded lungs in the presence of 1.78 x 10(-5) M phentolamine (n = 12; 70 +/- 2% expansion). The results suggest that expansion of the lungs at birth may release an unknown inhibitory factor, provisionally termed Expansion Factor (EF), within the lungs; this agent, probably not a catecholamine, can change lung fluid production into reabsorption and may partly account for the failure of beta-antagonists to prevent fluid reabsorption at delivery.

Reabsorption of lung liquid produced by 2,4-dinitrophenol in in vitro lungs from fetal guinea pigs

1993 ◽  
Vol 71 (1) ◽  
pp. 1-11 ◽  
Author(s):  
A. M. Perks ◽  
T. Ruiz ◽  
B. Chua ◽  
I. Vonder Muhll ◽  
P. M. Kindler ◽  
...  
Keyword(s):  
Body Weight ◽  
Regression Analysis ◽  
Guinea Pigs ◽  
Dilution Technique ◽  
Dye Dilution ◽  
Fluid Production ◽  
Oxidative Processes ◽  
Near Term ◽  
Lung Liquid

Lungs from near-term fetal guinea pigs (62 ± 2 days of gestation) were supported in vitro for 3 h, and lung liquid production was measured by a dye dilution technique. Twelve untreated preparations produced fluid at 1.54 ± 0.29 mL∙kg−1 body weight∙h−1 during the 1st h, with no significant changes in later hours. Twelve preparations treated with 2 × 10−4 M 2,4-dinitrophenol (DNP) showed strong reabsorptions (significant, ANOVA and regression analysis); total loss of lactate from the preparations doubled (significant, same tests). In 12 additional preparations, increasing DNP fivefold did not abolish reabsorption; results resembled those at the lower concentration. Amiloride at 10−6 M abolished reabsorptions after 2 × 10−4 M DNP, although fluid production still halted (n = 6; reductions significant, same tests). Amiloride alone had no effect (n = 6); untreated controls showed no change (n = 6). Similarly, 10−4 M sodium iodoacetate virtually abolished reabsorptions after 2 × 10−4 M DNP, although fluid production still stopped (n = 6; reductions significant, same tests). Iodoacetate alone only reduced fluid production (n = 6; significant, same tests); untreated controls showed no change (n = 6). The results suggest that reabsorptions seen after inhibition of oxidative processes depend on amiloride-sensitive Na+ channels and glycolytic metabolism.Key words: fetus, lung liquid, 2,4-dinitrophenol, amiloride, iodoacetate.

Effects of lung expansion on lung liquid production in vitro by lungs from fetal guinea-pigs. I. Basic studies and the effects of amiloride and propranolol

1996 ◽  
Vol 8 (3) ◽  
pp. 335 ◽  
Author(s):  
PG Nelson ◽  
AM Perks
Keyword(s):  
Body Weight ◽  
Guinea Pigs ◽  
Receptor Activation ◽  
Lung Damage ◽  
Dilution Method ◽  
Exponential Relationship ◽  
Excessive Pressure ◽  
Lung Expansion ◽  
Lung Liquid

Lungs from near-term fetal guinea-pigs were supported in vitro for 3 h; lung liquid production was measured by a dye-dilution method using Blue Dextran 2000 (fetuses 62 +/- 2 days of gestation, 97.6 +/- 19.0 (SD) g body weight; n = 134). Untreated control preparations produced fluid at 1.30 +/- 0.22 ml/kg body weight per h, and showed no significant changes during incubation (n = 30). After 1 h of incubation, experimental lungs were expanded with Krebs-Henseleit saline in volumes estimated to be below or approximating those of the first breath (n = 30; first breath, 0.6-1.2 ml). Expansions were graded at 18 +/- 4%, 31 +/- 4%, 43 +/- 3%, 50 +/- 3% and 72 +/- 2% of lung volume (volumes used for expansion at the maximal level, 0.64 +/- 0.25 ml). All expansions of 31% or above produced reductions in fluid production significant by analysis of variance (P < 0.01-0.001); production halted at 50% expansion, and there was strong reabsorption at 72% expansion (-0.87 +/- 0.45 ml/kg body weight per h by the final hour). There was an exponential relationship between percentage expansion and percentage fall in production (r = 1.00). There was no evidence for excessive pressure, and no evidence for lung damage as judged by electron microscopy or entry of intracellular materials into the fluid (lactic dehydrogenase, protein, K+). In studies based on 36 preparations, 10(-6) M amiloride present in the lung lumen (apically) abolished the reabsorptions seen at 70 +/- 3% expansion, but not the arrest of production; it had no effect on control preparations. Studies based on 24 preparations showed that responses to 72 +/- 2% expansion were not affected by 10(-7) M propranolol placed in the outer saline. In studies of 14 fetuses of widely different body weights (68.3-124.9 g), responses to 74 +/- 2% expansion showed an exponential increase with increasing body weight (r = 0.96). Although caution is needed, the results suggest that expansion of the lungs at birth may induce fluid reabsorption by an action independent of tissues outside the lungs, probably involving both activation of a Na(+)-based reabsorptive system and arrest of production, but not requiring beta-receptor activation. The probability that the responses are maximal at birth is discussed, and it is suggested that the effect of expansion may be a specialization of the perinatal lung.

scholarly journals A Role for Galanin-Like Peptide in the Integration of Feeding, Body Weight Regulation, and Reproduction in the Mouse

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 813-822 ◽  
Author(s):  
Stephanie M. Krasnow ◽  
Gregory S. Fraley ◽  
Sonya M. Schuh ◽  
James W. Baumgartner ◽  
Donald K. Clifton ◽  
...  
Keyword(s):  
Body Weight ◽  
Serum Levels ◽  
Term Treatment ◽  
Leptin Receptors ◽  
Downstream Effector ◽  
Reproductive Axis ◽  
Nonspecific Effects ◽  
Long Term Treatment ◽  
The Central Nervous System

Galanin-like peptide (GALP) shares sequence homology with galanin and binds to galanin receptors in vitro. GALP neurons in the arcuate nucleus coexpress leptin receptors, and GALP mRNA expression is up-regulated by leptin. Based on these observations, we postulated that GALP plays a role in mediating leptin’s inhibitory effects on food intake (FI) and body weight (BW), as well as its stimulatory effect on the reproductive axis. To test these hypotheses, we performed several studies in which mice received intracerebroventricular injections of either GALP or vehicle. Acute GALP treatment elicited a dose-dependent suppression of FI and BW. Long-term treatment with GALP caused only transient reductions in FI and BW, demonstrating that the mice became refractory to continued exposure to GALP. GALP inhibited FI as early as 1 h post injection. Central injection of GALP suppressed locomotor activity and elicited the formation of a conditioned taste aversion. In male mice, serum levels of LH and testosterone were increased by GALP administration. Although we cannot rule out possible nonspecific effects of GALP on FI, the present observations are consistent with the argument that GALP is a downstream effector of leptin’s actions within the central nervous system.

scholarly journals Altered Cytokine Production and Impaired Antimycobacterial Immunity in Protein-Malnourished Guinea Pigs

1998 ◽  
Vol 66 (8) ◽  
pp. 3562-3568 ◽  
Author(s):  
Guixiang Dai ◽  
David N. McMurray
Keyword(s):  
Transforming Growth Factor Beta ◽  
Guinea Pigs ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Peritoneal Macrophages ◽  
Protein Malnutrition ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cd4 Lymphocytes

ABSTRACT Protein malnutrition leads to multiple detrimental alterations of host immune responses to mycobacterial infection. In this study, we demonstrated that splenocytes from low-protein (LP) guinea pigs vaccinated 6 weeks previously with attenuated Mycobacterium tuberculosis H37Ra failed to control the accumulation of virulentM. tuberculosis H37Rv in cocultured autologous peritoneal macrophages, despite the fact that they were able to control the accumulation of virulent tubercle bacilli in cocultured syngeneic peritoneal macrophages from normally nourished guinea pigs as successfully as did those from high-protein (HP) counterparts. Vaccine-induced growth control of virulent M. tuberculosisH37Rv in these cocultures appeared to be mediated by CD4 lymphocytes but not CD8 cells. Tuberculin (purified protein derivative [PPD])-induced lymphoproliferation was markedly impaired in vaccinated LP guinea pigs, and the depletion of CD4 lymphocytes significantly decreased lymphocyte proliferation whereas CD8 cell depletion did not. Protein malnutrition also impaired the abilities of cells from vaccinated LP guinea pigs to produce cytokines, including interferon, tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), in response to PPD, despite the demonstration of higher serum levels of TNF-α and TGF-β after an intravenous injection of PPD into LP guinea pigs. In contrast, peritoneal macrophages from protein-malnourished guinea pigs produced a higher level of TGF-β 4 days after infection in vitro with M. tuberculosis H37Rv than did those from protein adequate controls. These results suggest that dietary protein malnutrition impairs vaccine-induced resistance to M. tuberculosis, in part, by altering the cytokine profile to favor macrophage deactivation.

scholarly journals Distribution and Excretion of BisGMA in Guinea Pigs

2008 ◽  
Vol 87 (4) ◽  
pp. 378-380 ◽  
Author(s):  
F.X. Reichl ◽  
M. Seiss ◽  
N. Kleinsasser ◽  
K. Kehe ◽  
K.H. Kunzelmann ◽  
...  
Keyword(s):  
Body Weight ◽  
Guinea Pigs ◽  
Dental Materials ◽  
The Body ◽  
Urine Level ◽  
Mammalian Tissues ◽  
Dose Levels ◽  
Adjusted Dose

Bisphenol-A-glycidyldimethacrylate (BisGMA) is used in many resin-based dental materials. It was shown in vitro that BisGMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of [14C]BisGMA applied via gastric and intravenous administration (at dose levels well above those encountered in dental care) were examined in vivo in guinea pigs to test the hypothesis that BisGMA reaches cytotoxic levels in mammalian tissues. [14C]BisGMA was taken up rapidly from the stomach and intestine after gastric administration and was widely distributed in the body following administration by each route. Most [14C] was excreted within one day as 14CO2. The peak equivalent BisGMA levels in guinea pig tissues examined were at least 1000-fold less than known toxic levels. The peak urine level in guinea pigs that received well in excess of the body-weight-adjusted dose expected in humans was also below known toxic levels. The study therefore did not support the hypothesis.

scholarly journals Activity of trovafloxacin (CP-99,219) against Legionella isolates: in vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pigs with L. pneumophila pneumonia.

1996 ◽  
Vol 40 (2) ◽  
pp. 314-319 ◽  
Author(s):  
P H Edelstein ◽  
M A Edelstein ◽  
J Ren ◽  
R Polzer ◽  
R P Gladue
Keyword(s):  
Guinea Pig ◽  
Alveolar Macrophages ◽  
Guinea Pigs ◽  
Susceptibility Testing ◽  
Pharmacokinetic Studies ◽  
Intracellular Accumulation ◽  
Once Daily ◽  
Drug Free

The activity of trovafloxacin against 22 clinical Legionella isolates was determined by broth microdilution susceptibility testing. The trovafloxacin concentration required to inhibit 90% of strains tested was < or = 0.004 micrograms/ml, in contrast to 0.032 micrograms/ml for ofloxacin. In guinea pig alveolar macrophages, trovafloxacin achieved intracellular levels up to 28-fold over the extracellular concentration, which was similar to the levels obtained with erythromycin. Trovafloxacin (0.25 micrograms/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by > 2 log10 CFU/ml, without regrowth, under drug-free conditions over a 3-day period; trovafloxacin was significantly more active than ofloxacin or erythromycin (0.25 to 1 microgram/ml) in this assay. Single-dose (10 mg of prodrug CP-116,517-27 per kg of body weight given intraperitoneally [i.p.], equivalent to 7.5 mg of trovafloxacin per kg) pharmacokinetic studies performed in guinea pigs with L. pneumophila pneumonia revealed peak serum and lung trovafloxacin levels to be 3.8 micrograms/ml and 5.0 micrograms/g, respectively, at 0.5 h and 4.2 micrograms/ml and 2.9 micrograms/g, respectively, at 1 h. Administration of a lower prodrug dose (1.4 mg of trovafloxacin equivalent per kg i.p.) gave levels in lung and serum of 0.4 microgram/g and 0.4 microgram/ml, respectively, 1 h after drug administration. The terminal half-lives of elimination from serum and lung were 0.8 and 1.1 h, respectively. All 15 infected guinea pigs treated for 5 days with CP-116,517-27 once daily (10 mg/kg/day i.p., equivalent to 7.5 mg of trovafloxacin per kg/day) survived for 10 days after antimicrobial therapy, as did all 15 guinea pigs treated with ofloxacin once daily (10 mg/kg/day i.p.) for 5 days. None of 13 animals treated with saline survived. In a second experiment with animals, trovafloxacin (1.4 mg/kg/day i.p. for 5 days) protected all 16 guinea pigs from death, whereas all 15 animals treated with saline died. Trovafloxacin is an effective antimicrobial agent against Legionella in vitro and in vivo, with the ability to concentrate in macrophages and kill intracellular organisms.

scholarly journals Adult mice are unresponsive to AAV8-Gremlin1 gene therapy targeting the liver

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247300
Author(s):  
Roxana Khatib Shahidi ◽  
Jenny M. Hoffmann ◽  
Shahram Hedjazifar ◽  
Laurianne Bonnet ◽  
Ritesh K. Baboota ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Signalling ◽  
Serum Levels ◽  
Inhibitory Effect ◽  
Liver Cells ◽  
Adult Mice ◽  
Gremlin 1

Objective Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects. Methods Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time. Results Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation. Conclusion GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered.

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