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C J Portier

Publications and source records attributed to C J Portier.

At least 19 recordsLinked to original sources
PubMed2006

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion.

Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 microg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses).

Algorithms↗
PubMed2004

Pharmacokinetics and pharmacodynamic effects of amiodarone in plasma of ponies after single intravenous administration.

Atrial fibrillation is a well-known heart disease in horses. The common therapy consists of administration of quinidine. More potent antiarrhythmic drugs have become available for human therapy and the use of these as alternatives to quinidine for equine antiarrhythmic therapy is a matter of interest. Amiodarone (AMD) is used in human medicine for treatment of many arrhythmias, including atrial fibrillation. Its disposition in horses has not yet been investigated. The purpose of this study was to measure the effect of single intravenous doses of amiodarone (5 and 7 mg/kg) on the surface electrocardiogram (ECG) of healthy minishetland ponies during the first 2 days after drug administration and to calculate pharmacokinetic parameters with a physiologically based pharmacokinetic model (PBPK) using amiodarone and desethylamiodarone (DAMD) plasma levels that were determined by high-performance liquid chromatography (HPLC). As expected for a K(+)-channel-blocker, the main effect on the measured ECG could be seen on the ventricular complex, as the QT interval and the T wave showed statistically significant alterations. The doses investigated were well tolerated clinically. Results from the pharmacokinetic model were found to compare well with literature data of rats, dogs, and humans. It showed a rapid distribution in the tissue, beginning with the rapidly perfused tissue, like the heart, followed by slowly perfused tissues, and finally an accumulation in fat. The half-life for total elimination was calculated to be 16.3 days with 99% eliminated by 97 days. The model predicts that approximately 96% of amiodarone is eliminated as desethylamiodarone in urine, 2% eliminated as desethylamiodarone in bile, and 2% as other metabolites.

Adrenergic beta-Antagonists↗
PubMed2002

A physiologically based pharmacokinetic model of p,p'-dichlorodiphenylsulfone.

A physiologically based pharmacokinetic model of the absorption, distribution, metabolism, and elimination of p,p'-dichlorodiphenylsulfone (DDS) in male and female rats and mice is presented. Data used in constructing the model come from single-dose intravenous administration of DDS to male Fischer 344 rats (10 mg/kg, with data taken up to 504 h after administration), from single-dose gavage administration to male rats (10, 100, or 1000 mg/kg, with data up to 72 h after administration), and from chronic feed studies in male and female rats and male and female B6C3F(1) mice (studies of duration from 2 weeks up to 18 months, with feed concentrations of DDS up to 300 ppm). The model uses diffusion-limited kinetic for the distribution of the parent compound. Because fewer data are available for the metabolites of DDS (at least five of which are known to exist in the data), the model groups the metabolites into one metabolic pathway and uses simpler flow-limited kinetics for the metabolites. The data show that the kinetics of DDS are nonlinear. Possible sources of nonlinearity considered in the model were nonlinear (Michaelis-Menten) metabolism, nonlinear absorption of DDS from the gut, and induction by DDS of its own metabolism. A model using Michaelis-Menten metabolism was not found to give a significantly better fit than one using first-order linear metabolism, but omitting either of the other nonlinear effects was found to give a significantly poorer fit to the data. Because the data from mice are limited compared to those from rats, there is more confidence in the model's description of DDS kinetics in rats than in its description of kinetics in mice.

Algorithms↗
PubMed2002

Effects of ketanserin and DOI on spontaneous and 5-HT-evoked peristalsis of the pig ureter in vivo.

1. The influence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the ureter motility was investigated in vivo on intact ureters of anaesthetized pigs. Drugs were administered intravenously or topically. 2. 5-HT induced a dose-dependent increase in the frequency of ureter contractions in anaesthetized pigs when given intravenously (0.0001-1 mg kg(-1); ED(50) 0.066 mg kg(-1)) or topically (0.001-1 mg ml(-1); EC(50) 0.043 mg ml(-1)). Significant increases in heart rate and blood pressure were observed when the drug was given intravenously but not topically. 3. The 5-HT(2A) agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) increased the frequency of ureteral contractions in a dose-dependent manner (1-300 microg kg(-1) i.v.). Calculation of ED(50) indicated this compound to be about 1.5 times more potent with an efficacy of 23% compared to 5-HT. 4. The 5-HT(2A/2C) antagonist, ketanserin (0.5 mg kg(-1)) and the 5-HT(2C) antagonist, methysergide (1 mg kg(-1)) antagonized the 5-HT-induced ureter peristalsis when given intravenously. Contraction amplitude, blood pressure and heart rate were not affected by the antagonists. 5. Intravenous (0.0001-1 mg kg(-1)) and topical (0.0001-1 microg ml(-1)) ketanserin significantly decreased the frequency of spontaneous ureteral contractions to about 30% of controls, which could be partly reversed by 5-HT (0.3 mg kg(-1) i.v.). The contraction amplitude, contractions of the contralateral, saline perfused ureter, heart rate and mean arterial blood pressure were not affected. 6. Thus, contractility of porcine ureter is mediated by 5-HT(2) receptors. Their antagonists ketanserin and methysergide seem to be promising drugs for treatment of acute ureteric colic or in preparing the ureter for ureteroscopy.

Animals↗
PubMed2001

A physiologically based pharmacokinetic model for inhalation and intravenous administration of naphthalene in rats and mice.

A diffusion limited physiologically based pharmacokinetic model for rats and mice was developed to characterize the absorption, distribution, metabolism, and elimination of naphthalene after inhalation exposure. This model includes compartments for arterial and venous blood, lung, liver, kidney, fat, and other organs. Primary sites for naphthalene metabolism to naphthalene oxide are the lung and the liver. The data used to create this model were generated from National Toxicology Program inhalation and iv studies on naphthalene and consisted of blood time-course data of the parent compound in both rats and mice. To examine the basis for possible interspecies differences in response to naphthalene, the model was extended to describe the distribution and metabolism of naphthalene oxide and the depletion and resynthesis of glutathione. After testing several alternative models, the one presented in this paper shows the best fit to the data with the fewest assumptions possible. The model indicates that tissue dosimetry of the parent compound alone does not explain why this chemical was carcinogenic to the female mouse lung but not to the rat lung. The species difference may be due to a combination of higher levels of naphthalene oxide in the mouse lung and a greater susceptibility of the mouse lung to epoxide-induced carcinogenesis. However, conclusions regarding which metabolite(s) may be responsible for the lung toxicity could not be reached.

Administration, Inhalation↗
PubMed2001

Physiological modeling of a proposed mechanism of enzyme induction by TCDD.

A physiological model was previously constructed to facilitate extrapolation of surrogates for the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver to doses comparable to human environmental exposures. The model included induction of P450 isozymes and suggested the presence of multiple binding sites with different affinities for the TCDD-liganded Ah receptor at CYP1A1 dioxin responsive elements. The model also indicated that protein synthesis on the mRNA template exhibited saturation kinetics with respect to message levels. In the present work the earlier model was revised to include the increased proteolysis of the Ah receptor on binding TCDD, more realistic representations of gene transcription and mRNA translation, and different stability for each mRNA. The revised model includes multiple TCDD-liganded Ah receptor binding sites for CYP1A1 and CYP1B1 genes, a lag of 0.2 day for production of mRNA and induced proteins, and stabilization of mRNA by a poly(A) tail. The model reproduced the transient depletion of the Ah receptor subsequent to binding ligand and the dose-response of the receptor in rats treated with biweekly oral doses of TCDD in corn oil. The model reproduced tissue TCDD concentrations observed for several dosing scenarios. Such robustness indicates the utility of the model in estimating internal dose. The model also reproduced the observed dose-response patterns for mRNA and protein for CYP1A1, CYP1A2, and CYP1B1 after repeated dosing. Neither of the two dissociation constants for the Ah receptor bound to the CYP1B1 gene is negligible, supporting the assumption of multiple response elements for this gene. The poorer induction of CYP1B1 was predicted to be due to lower affinity of the dioxin responsive elements for binding the liganded Ah receptor, suggesting the involvement of other regulatory factors, and a shorter poly(A) tail on CYP1B1 mRNA, leading to a shorter lifetime. Saturation in the kinetics of protein synthesis was linked to the limited number of ribosomes that could bind to each message molecule, resulting in fewer ribosomes bound per message at higher doses. Predicted induction at low doses was found to vary widely with the assumptions used in the construction of a model. More detailed descriptions of biological processes might provide more reliable predictions of enzyme induction.

Adipose Tissue↗
PubMed2001

Identification of a cardiac sodium channel insensitive to synthetic modulators.

BACKGROUND: DPI 201-106 (DPI) was the first synthetic compound showing cardioselective modulation of voltage-gated sodium channels (VGSCs) resulting in a positive inotropic effect. Currently, the exact mode of action for this class of compounds is not known. METHODS: Effects of different natural and synthetic sodium channel modulators were investigated in cardiac tissue of several species with conventional electrophysiologic methods. RESULTS: In electrically driven cardiac tissues, all compounds investigated increased force of contraction (FC) and action potential duration (APD) with increasing concentrations except for DPI in cattle trabecular muscle, which demonstrated no effect. Interestingly, calculation of EC50 levels at 30% repolarization demonstrates that natural VGSC-ligands were highly potent in prolonging the APD in cattle whereas no positive trends could be obtained for DPI and SDZ 211-939 (SDZ) in cattle. CONCLUSIONS: These results demonstrate that the binding site for DPI and SDZ is distinct from sites 2 or 3 of the VGSC alpha-subunit. Moreover, this is the first time that these compounds show no effect or even shortening of APD. This finding will enable the characterization of the mode of action and probably the binding site for synthetic VGSC-modulators.

Action Potentials↗
PubMed2001

Effects of temperature and air pollutants on cardiovascular and respiratory diseases for males and females older than 65 years of age in Tokyo, July and August 1980-1995.

We studied exposures to higher daily maximum temperatures and concentrations of air pollutants in Tokyo during the summer months of July and August from 1980 to 1995 and their effects on hospital emergency transports for cardiovascular and respiratory diseases for males and females > 65 years of age. Cardiovascular diseases were angina, cardiac insufficiency, hypertension, and myocardial infarction. Respiratory diseases were asthma, acute and chronic bronchitis, and pneumonia. Except for pneumonia, daily maximum temperatures were not associated with hospital emergency transports. Increasing daily maximum temperatures, however, were associated with decreased hospital emergency transports for hypertension. Concentrations of nitrogen dioxide or particulate matter < or = 10 microm, however, were associated with daily hospital emergency transports for angina, cardiac insufficiency, myocardial infarction, asthma, acute and chronic bronchitis, and pneumonia. For cardiac insufficiency, hypertension, myocardial infarction, asthma, chronic bronchitis, and pneumonia, the expected daily number of emergency transports per million were greater for males than for females. For angina and acute bronchitis, there were no differences for the expected daily numbers of emergency transports per million between males and females.

Aged↗
PubMed2000

Calculation of the cumulative distribution function of the time to a small observable tumor.

Multistage mathematical models of carcinogenesis (when applied to tumor incidence data) have historically assumed that the growth kinetics of cells in the malignant state are disregarded and the formation of a single malignant cell is equated with the emergence of a detectable tumor. The justification of this simplification is, from a mathematical point of view, to make the estimation of tumor incidence rates tractable. However, analytical forms are not mandatory in the estimation of tumor incidence rates. Portier et al.(1996b, Math. Biosci. 135, 129-146) have demonstrated the utility of the Kolmogorov backward equations in numerically calculating tumor incidence. By extending their results, the cumulative distribution function of the time to a small observable tumor may be numerically obtained.

Adenoma, Liver Cell↗
PubMed2000

Incorporating observability thresholds of tumors into the two-stage carcinogenesis model.

This paper discusses a general way of incorporating the growth kinetics of malignant tumors with the two-stage carcinogenesis model. The model is presented using time-homogeneous rate parameters. In that case, the differential equations comprising the model are straightforward to solve using standard numerical techniques and software. An extension of the method to time-dependent rate parameters is included in Appendix A. Allowing the rate parameters to be time-dependent does incur computational cost. An expression is given for the expected time without visible tumor, a generalization of the expected time to an observable tumor that includes the possibility of tumor regression. The model is illustrated using incidental liver tumor data in control rats from NTP rodent carcinogenicity studies, using linear birth-death kinetics of tumors combined with a non-absorbing detection limit. The approach is also shown to be potentially useful with tumor observability thresholds having more complicated features.

Animals↗
PubMed2000

Hepatocarcinogenesis in female Sprague-Dawley rats following discontinuous treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In this study, we investigated the time course of promotion of tumors and putatively preneoplastic altered hepatic foci in the livers of diethylnitrosamine (DEN)-initiated female Sprague-Dawley rats. These rats had been treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) under different dosing regimens, but we used the same administered biweekly dose of 1.75 microg/kg of body weight. Animals were treated continuously for up to 60 weeks, or continuously for 30 weeks, followed by cessation of treatment for up to 30 weeks. In addition, TCDD treatment in these groups was begun either 2 or 18 weeks after initiation with DEN. Liver tumors were only observed in animals after 60 weeks on the study and were increased by continuous TCDD treatment, relative to controls. The incidence of hepatocellular adenoma and carcinoma combined, in animals treated with TCDD for 30 weeks followed by no TCDD treatment for 30 weeks (17%), was lower than in animals receiving either TCDD (79%) or vehicle control (corn oil) alone (55%) for 60 weeks. The lower liver-tumor incidence after cessation of TCDD treatment paralleled time-dependent decreases in the volume fraction occupied by placental glutathione S-transferase-positive altered hepatic foci and the number of foci per unit volume, but not the mean focus volume that exhibited a time-dependent increase after cessation of TCDD treatment. Cessation of TCDD treatment led to reductions in liver TCDD levels, and these changes were reflected in a cessation of reduced body weight because of TCDD treatment. These data indicate that liver-tumor promotion by TCDD in female rats is dependent upon continuous exposure to TCDD, and that alterations in patterns of TCDD exposure can have significant effects on tumor incidence not reflected by standard measures of dioxin exposure.

Adenoma↗
PubMed2000

Reevaluating cancer risk estimates for short-term exposure scenarios.

Estimates of cancer risk from short-term exposure to carcinogens generally rely on cancer potency values derived from chronic, lifetime-exposure studies and assume that exposures of limited duration are associated with a proportional reduction in cancer risk. The validity of this approach was tested empirically using data from both chronic lifetime and stop-exposure studies of carcinogens conducted by the National Toxicology Program. Eleven compounds were identified as having data sufficient for comparison of relative cancer potencies from short-term versus lifetime exposure. The data were modeled using the chronic data alone, and also using the chronic and the stop-exposure data combined, where stop-exposure doses were adjusted to average lifetime exposure. Maximum likelihood estimates of the dose corresponding to a 1% added cancer risk (ED(01)) were calculated along with their associated 95% upper and lower confidence bounds. Statistical methods were used to evaluate the degree to which adjusted stop-exposures produced risks equal to those estimated from the chronic exposures. For most chemical/cancer endpoint combinations, inclusion of stop-exposure data reduced the ED(01), indicating that the chemical had greater apparent potency under stop-exposure conditions. For most chemicals and endpoints, consistency in potency between continuous and stop-exposure studies was achieved when the stop-exposure doses were averaged over periods of less than a lifetime-in some cases as short as the exposure duration itself. While the typical linear adjustments for less-than-lifetime exposure in cancer risk assessment can theoretically result in under- or overestimation of risks, empirical observations in this analysis suggest that an underestimation of cancer risk from short-term exposures is more likely.

Animals↗
PubMed1999

Effects of glutathione transferase theta polymorphism on the risk estimates of dichloromethane to humans.

The carcinogenic potential of dichloromethane (DCM) has been linked to its metabolism to formaldehyde by glutathione-S-transferase theta 1 (GSTT1). GSTT1 is polymorphic in humans. The frequency of the GSTT1 homozygous null genotype ranges from 10 to 60% in different ethnic and racial populations around the world. We investigated how varying GSTT1 genotype frequencies would impact cancer risk estimates for DCM by the application of Monte Carlo simulation methods in combination with physiologically based pharmacokinetic (PBPK) models. The PBPK model was used to estimate the DNA-protein cross links (DPX) caused by metabolism of DCM based on an earlier model. Cancer potency of DCM was obtained by the application of the estimated DPX amounts to the results of a carcinogenicity study by National Toxicology Program in B6C3F(1) mice. Human risks were estimated based on the carcinogenic potency of DCM to mice and PBPK-predicted amounts of DPX formed in humans. The Monte Carlo simulations were used to provide distributions of risk estimates for a sample of 1000 PBPK runs, each run representing a collection of biochemical and physiological parameters for a single person (with and without polymorphism included in the model). Our results show that average and median risk estimates were 23-30% higher when GSTT1 polymorphism was not included at inhalation DCM doses of 1000, 100, 10, and 1 ppm. This increase in risk was significantly reduced when it was based on the 95th percentile measure for all the doses. The specific effect of this polymorphism on population risk was further investigated by varying the probability that an individual may have a nonfunctional form of the enzyme at a constant dose level of 10 ppm of DCM. Higher values of this probability resulted in a corresponding decrease in risk. Again, this drop in population risk was not as significant when the 95th percentile measure was used.

Animals↗
PubMed1999

Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

One of the current knowledge gaps in the evaluation of risk for human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the relationship between gene expression induced by TCDDmore complex biological responses such as altered growth, differentiation, and neoplasia. This study investigates the dose-dependent expression of CYP1A1, CYP1A2,CYP1B1 in the livers of female Sprague-Dawley rats chronically exposed to TCDD. Animals were treated biweekly for 30 weeks with daily averaged doses of 0 to 125 ng TCDD/kg/day. Immunoblot analysis showed that protein levels for CYP1B1, CYP1A1, CYP1A2 exhibited a dose-dependent induction by TCDD. However, CYP1A1 and CYP1A2 protein levels were approximately 100-fold higher than CYP1B1, which could not be detected by either immunoblot analysis or immunohistochemistry in the livers of rats treated with TCDD for 30 weeks at a dose-equivalent less than 35.7 ng/kg/day. In control animals, CYP1A1CYP1A2 RNA levels, measured by quantitative RT-PCR, were 1100-15,000-fold higher than that of CYP1B1, respectively. TCDD induced CYP1B1 RNA levels at all doses, although absolute TCDD-induced levels of CYP1A1CYP1A2 at the highest dose (125 ng/kg/day) were more than 40-fold higher than that of CYP1B1. While the liver concentration of TCDD required for half-maximal induction of CYP1A1, CYP1A2,CYP1B1 RNA levels was similar, the shaping parameter (Hill coefficient) of the dose-response curve for CYP1B1 was significantly higher than that for CYP1A1 or CYP1A2. The low level of TCDD-induced CYP1B1 expression in the liver relative to that of the CYP1A1CYP1A2 suggest that, if CYP1B1 is involved in TCDD-induced hepatocarcinogenesis, its endogenous function is likely to be uniquenot overlapping with that of CYP1A1 or CYP1A2.

Animals↗
PubMed1999

Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice.

Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to 1,3-butadiene, a trans-species carcinogen, inhalation studies were performed with chloroprene to evaluate its carcinogenic potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male and female B6C3F1 mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6 h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas), Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a Weibull model for estimation of the shape of the dose-response curves, estimation of ED10 values (the estimated exposure concentration associated with an increased cancer risk of 10%) and comparison of these parameters with those for 1,3-butadiene. Butadiene has been identified as a potent carcinogen in mice and has been associated with increased risk of lymphatic and hematopoietic cancer in exposed workers. Shape parameter values for most of the neoplastic effects of chloroprene and 1,3-butadiene were consistent with linear or supralinear responses in the area near the lowest tested exposures. The most potent carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the rat lung, but greater in the rat kidney than in the mouse kidney and nearly equivalent in the mammary gland of each species.

Administration, Inhalation↗
PubMed1999

Temperature and air pollution as risk factors for heat stroke in Tokyo, July and August 1980-1995.

Heat stroke is associated with prolonged exposures to high air temperatures that usually occur in the summer months of July and August in Tokyo, Japan. Also during July and August, residents of Tokyo are often exposed simultaneously to high concentrations of air pollutants. To assess the impacts of these combined exposures, daily numbers of heat stroke emergency transport cases/million residents for Tokyo were stratified by gender and three groups: 0-14, 15-64; and > 65 years of age, for the months of July and August in 1980-1995. A regression model was constructed using daily maximum temperature (Tmax) and daily average concentrations of NO2 and O3 as model covariates. Classification indices were added to make it possible to compare the expected number of heat stroke cases by age and gender. Lag times of 1-4 days in Tmax and air quality covariates and terms to account for interactions between pairs of model covariates were also included as additional risk factors. Generalized linear models (GLMs), assuming a Poisson error structure for heat stroke emergency transport cases, were used to determine which covariates were significant risk factors for heat stroke for the three age groups of males and females. Same-day Tmax and concentrations of NO2 were the most significant risk factors for heat stroke in all age groups of males and females. The number of heat stroke emergency transport cases/million residents was greater in males than in females in the same age groups. The smallest number of heat stroke emergency transport cases/million residents occurred for females 0-14 years of age and the greatest number of heat stroke emergency transport cases/million residents occurred for males > 65 years of age.

Adolescent↗