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Biomedical subjects

J E Riviere

Publications and source records attributed to J E Riviere.

At least 19 recordsLinked to original sources
PubMed1998

Percutaneous absorption of salicylic acid, theophylline, 2, 4-dimethylamine, diethyl hexyl phthalic acid, and p-aminobenzoic acid in the isolated perfused porcine skin flap compared to man in vivo.

Human risk assessment for topical exposure requires percutaneous absorption data to link environmental contamination to potential systemic dose. Human absorption data are not readily available, so absorption models are used. In vitro diffusion systems are easy to use but have proved to be somewhat unreliable and are not validated to man. This study compares percutaneous absorption in the isolated perfused porcine skin flap (IPPSF) system with that in man in vivo. The study design utilized the same compounds and the same dose concentration and vehicle in both systems. Methodology for each system was that which is routinely used ineach system. The skin surface was not protected during the absorption dosing period. Percutaneous absorption values were, for man and the IPPSF system, respectively: salicylic acid (6.5 +/- 5.0%; 7.5 +/- 2.6%), theophylline (16.9 +/- 11.3%; 11.8 +/- 3.8%), 2,4-dimethylamine (1.1 +/- 0.3%; 3.8 +/- 0.6%), diethyl hexyl phthalic acid (1.8 +/- 0.5%; 3.9 +/- 2.4%), and p-aminobenzoic acid (11.5 +/- 6.3%; 5.9 +/- 3.7%) (correlation coefficient was 0.78; p < 0.04). The skin surface wash recovery postapplication was similar for salicylic acid in man (53.4 +/- 6.3%) and the IPPSF system (48.2 +/- 4.9%). With the other compounds the majority of surface chemical was recovered in the surface wash and skin tape strip in the IPPSF system. With man, other than salicylic acid, only a few percent applied dose was recovered with surface washing and tape stripping. Since the wash procedure was effective with pig skin, we can assume that these chemicals in man were lost to adsorption to any clothing or bedding with the volunteers. The absorption in man was not less than that in the IPPSF. Assuming the dose was lost in man, it seems plausible that whatever compound was to penetrate human skin in solvent vehicle did so in the period of time before the chemical was removed. The IPPSF system appears to be a good model for predicting percutaneous absorption relative to man. This study design should be used to validate other systems to humans in vivo.

4-Aminobenzoic Acid↗
PubMed1998

Population pharmacokinetics in veterinary medicine: potential use for therapeutic drug monitoring and prediction of tissue residues.

Population pharmacokinetics can be defined as a study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability. It is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number of samples were obtained per individual, such as those in late stage human clinical trials. This is the situation commonly encountered in all aspects of veterinary medicine. The exploratory nature of this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc.) and drug disposition and/or effect. Similarly, the utilization of these techniques in the clinical research phases of drug development optimize the determination of efficacy and safety of drugs. Given the observational nature of most studies published so far, statistical methods to validate the population models are necessary. Simulation studies may be conducted to explore data collection designs that maximize information yield with a minimum expenditure of resources. The breadth of this approach has allowed population studies to be more commonly employed in all areas of drug therapy and clinical research. Finally, in veterinary medicine, there is an additional field in which population studies are potentially ideally suited: the application of this methodology to the study of tissue drug depletion and drug residues in production animals, and the establishment of withdrawal times tailored to the clinical or production conditions of populations or individuals. Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off-label clinical uses. Population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labelling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530).

Animals↗
PubMed1998

Influence of inert ingredients in pesticide formulations on dermal absorption of carbaryl.

OBJECTIVES: To assess the influence of solvent plus various mixtures on percutaneous absorption and disposition of the carbamate insecticide, carbaryl (CA). ANIMALS: Skin was obtained from the dorsum of 14 female weanling specific-pathogen-free Yorkshire pigs. PROCEDURE: In this 8-hour in vitro flow-through diffusion study, porcine skin sections were dosed with 40 micrograms of CA/cm2 of surface area, different amounts of solvents (40 or 80% acetone or dimethyl sulfoxide [DMSO]), different amounts of a surfactant (0, 1, or 5% sodium lauryl sulfate [SLS]), an insect repellent (0 or 15% diethyl-m-toluamide [DEET]), an insecticide synergist (0 or 2% piperonyl butoxide [PB]), and a CA metabolite (40 micrograms/cm2 1-naphthol [1-NA]). RESULTS: In general, CA absorption was greater from acetone than from DMSO mixtures, and CA penetration into skin and stratum corneum was greater from DMSO at 8 hours. This is consistent with the flux-time profiles, which depicted initial peak flux within 2 to 3 hours for most acetone mixtures, but a slow increase in flux for DMSO mixtures. Irrespective of the solvent, increasing water content in pesticide dosing mixtures significantly increased CA absorption from SLS mixtures only. The SLS also enhanced CA absorption, especially at low solvent concentrations. The DEET significantly reduced CA absorption from acetone, but not from DMSO mixtures, and 1-NA enhanced CA absorption from acetone, but not from DMSO mixtures. Piperonyl butoxide significantly enhanced CA absorption from acetone and DMSO mixtures. However, addition of PB or PB plus SLS did not significantly increase CA flux above that observed from solvent plus surfactant mixtures. CONCLUSIONS: Inert ingredients can modulate percutaneous absorption of toxicologically important pesticides and their effect or activity on CA disposition is dependent on solvent specificity and solvent concentration. Whereas SLS, PB, and 1-NA can enhance pesticide absorption, DEET can reduce absorption.

Acetone↗
PubMed1997

Residue avoidance after topical application of veterinary drugs and parasiticides.

Deriving adequate withdrawal intervals for extralabel use of veterinary topical products is difficult because there are limited published data, and data for approved drugs and pesticides are usually proprietary. Where possible, approved products and doses labeled for the specific indication at hand should be used and label withdrawal times should be adhered to. When determining whether topical application of these chemicals may violate tolerance levels in meat and milk, the veterinarian often is limited to empirical data. In the decision-making process, factors, such as type of drug and pesticide formulations used, method of topical application, presence of hair or wool, environmental conditions, and animal species treated, should be considered. In many cases a conservative estimate for the slaughter withdrawal interval can be derived, despite the data gaps. Such recommendations should not be used for routine extralabel use, but are meant to apply to situations in which the drug or pesticide has been used, and human food safety concerns must be addressed.

Administration, Topical↗
PubMed1997

The influence of diethyl-m-toluamide (DEET) on the percutaneous absorption of permethrin and carbaryl.

Simultaneous exposure to DEET and permethrin was recently proposed to be associated with the "Gulf War Syndrome." However, no studies have reported the percutaneous absorption of DEET and permethrin when applied simultaneously to the skin as a mixture, the relevant route of exposure in the Persian Gulf. The present study quantitates percutaneous absorption of DEET and permethrin after coadministration to rodent and pig skin in vitro. Dosing solutions were also prepared with either acetone, dimethyl sulfoxide (DMSO), or ethanol to compare vehicle effects on percutaneous absorption of permethrin and DEET. The influence of DEET on carbaryl absorption and dermal disposition was also assessed in pig studies to statistically demonstrate DEET effects in acetone or DMSO and different solvent concentrations. Topical application of permethrin + DEET resulted in absorption of DEET (1-20% dose), but no permethrin. Permethrin (1.2-1.7% dose) was detected only when mouse skin was dosed solely with permethrin, a finding suggesting that DEET decreased permethrin absorption. DEET also inhibited carbaryl absorption in acetone mixtures, but had no effect on DMSO mixtures. Irrespective of solvent, DEET did not enhance carbaryl penetration into skin. For DEET, absorption was greater in mouse skin (10.7-20.6% dose) than in rat skin (1.1-5.2% dose) and pig skin (2.8% dose). The extent of DEET absorption was greater with DMSO and acetone than with ethanol in rat and mouse skin. These studies support DEET, but not permethrin or carbaryl, as having sufficient systemic exposure to potentially cause signs of toxicity when simultaneously applied with pesticides. Furthermore, these studies demonstrated that DEET does not necessarily enhance dermal absorption of all toxicants as was originally hypothesized.

Administration, Cutaneous↗
PubMed1997

Pentachlorophenol dermal absorption and disposition from soil in swine: effects of occlusion and skin microorganism inhibition.

Residue of the environmentally relevant biocide pentachlorophenol (PCP) is found mainly in soil, making dermal contact one of the primary routes for PCP exposure. To quantify exposure effects on dermal absorption and systemic disposition, [14C-UL]PCP was dosed nonocclusively or occlusively at 40 micrograms/cm2 in a soil-based mixture in an in vivo swine model. Additionally, antibiotics were also codosed with occlusive PCP in soil to examine the impacts of skin microbial PCP biodegradation on total dermal absorption. Under nonocclusive, occlusive, and occlusive-antibiotic conditions, total radiolabel absorption by 408 hr was 29.08, 100.72, and 86.21% dose, respectively. Tissue accumulation of PCP and its labeled metabolite(s) was very significant in swine since one-half to two-thirds of the absorbed dose was still present in tissues by 17 days after PCP dermal exposure. High 14C concentrations were found in liver, kidney, lung, ovary, and uterus. Urine and fecal routes were equally important for label excretion from the body. Occlusion enhanced total dermal absorption and changed the shape of the absorption profiles in the blood and plasma. Skin microorganism inhibition retarded 14C dermal absorption, altered local and systemic tissue distribution, and increased plasma/blood concentration ratios, suggesting skin microbial PCP degradation might play an important role in the altered absorption and disposition by occlusion. This study demonstrated significant dermal absorption and extensive tissue persistence of PCP after soil exposure. Occlusion and skin microflora growth may greatly impact dermal absorption, cutaneous disposition, and systemic toxic input. Therefore, exposure-specific PCP absorption and disposition profiles must be taken into consideration in risk analysis.

Animals↗
PubMed1997

Cutaneous toxicity of the benzidine dye direct red 28 applied as mechanistically-defined chemical mixtures (MDCM) in perfused porcine skin.

Complex chemical mixtures at hazardous waste sites can potentially consist of a marker chemical and several other chemicals, each of which can have different modulating actions on the dermatotoxicity of the marker chemical and/or other components in the mixture. A total of 16 mixtures, consisting of a marker chemical direct red 28 (DR28), a solvent (80% acetone or DMSO in water), a surfactant (0 or 10% sodium lauryl sulfate, SLS), a vasodilator (0 or 180 microg methyl nicotinate, MN) and a reducing agent (0 or 2% stannous chloride, SnCl2) were selected. Isolated perfused porcine skin flaps (IPPSFs), which have been proven to be an in vitro model for assessing absorption and toxicity, were utilized. These mixtures did not cause severe dermatotoxicity. However, light microscopic observations depicted minor alterations (intracellular and intercellular epidermal edema) with DMSO mixtures than with acetone mixtures. The presence of SLS caused an alteration in the stratum corneum. Enzyme histochemical staining for alkaline phosphatase (ALP) and nonspecific esterase (NSE) revealed no significant treatment effects, but increased staining for acid phosphatase (ACP) in the stratum basale was significant when associated with SLS or SLS + MN in DMSO mixtures. At 8 h post-dose, only DMSO mixtures containing SL + MN, SL + SnCl2, or SLS + MN + SnCl2 significantly increased transepidermal water loss. In conclusion, this study demonstrated that various mixtures, especially those containing SLS alter the epidermal barrier differently with complex interactions occurring simultaneously.

Animals↗
PubMed1997

Electrically-assisted transdermal drug delivery.

Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.

Administration, Cutaneous↗
PubMed1997

Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species.

The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vdss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (51/2 beta) were determined for this selected group of drugs by using the empirically determined function Y = a Wb. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally 'well behaved.'

Animals↗
PubMed1997

Pharmacokinetics and ovarian-stimulatory effects of equine and human chorionic gonadotropins administered singly and in combination in the domestic cat.

Pregnancy success and embryo survival are low with the use of assisted reproduction in felids treated with exogenous gonadotropins. In this study, the pharmacokinetics and ovarian-stimulatory effects of eCG and hCG were evaluated in the domestic cat. Catheterized anestrual queens (n = 4 per treatment [Trt] group) were given 100 IU eCG i.v. (Trt 1), 100 IU eCG i.m. (Trt 2), 75 IU hCG i.v. (Trt 3), 75 IU hCG i.m. (Trt 4), or 100 IU eCG i.m. followed 80 h later by 75 IU hCG i.m. (Trt 5). Blood samples were collected at 0, 5, 30, and 60 min and 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 h postinjection, and serum samples were analyzed for estradiol-17beta, progesterone, eCG, and hCG. Pharmacokinetic traits (volume of distribution, Vd; elimination half-life, t1/2beta; clearance rate, Clr) were calculated for eCG and hCG. When i.v. and i.m. administration were compared, no differences (p > 0.05) were observed in follicle or corpus luteum (CL) number or hormone concentrations for queens receiving eCG or hCG alone. Number of mature ovarian follicles (> or = 2 mm diameter) observed at 168 h postinjection did not differ (p > 0.05) for eCG (mean +/- SEM, 10.5 +/- 2.0) vs. hCG (11.1 +/- 3.0), indicating that these were equally effective in inducing follicular growth. In most queens (> 90%) given single gonadotropins (i.m. or i.v.), eCG and hCG persisted in circulation for at least 120 h and 96 h after injection, respectively, reflecting similar (p > 0.05) pharmacokinetic (i.v.) values for Vd (eCG, 91.4 +/- 24.8 ml/kg; hCG, 59.1 +/- 7.9 ml/kg), t1/2beta (eCG, 23.0 +/- 2.4 h; hCG, 22.9 +/- 4.1 h), and Clr (eCG, 2.7 +/- 0.5 ml/h per kg; hCG, 1.8 +/- 0.1 ml/h per kg). Sequential treatment with eCG+hCG did not affect (p > 0.05) the t1/2beta of individual gonadotropins. In summary, eCG and hCG have comparable pharmacokinetics and ovarian-stimulatory activity when administered alone to the domestic cat. These findings suggest that hCG promotes the ancillary follicle formation that is frequently observed after ovulation in cats treated with eCG+hCG regimens, possibly disrupting the maternal environment and decreasing fecundity following assisted reproductive procedures.

Animals↗
PubMed1997

Fluconazole in cats: pharmacokinetics following intravenous and oral administration and penetration into cerebrospinal fluid, aqueous humour and pulmonary epithelial lining fluid.

The pharmacokinetics of fluconazole following intravenous (i.v.) and oral (p.o.) administration and the penetration of fluconazole into cerebrospinal fluid, aqueous humour and epithelial lining fluid (ELF) of the lungs were evaluated in adult male cats. Pharmacokinetic parameters were calculated from serum concentration-time data obtained following i.v. and p.o. administration of 50 mg per cat using a cross-over study design. Fluconazole concentrations were measured using a high-performance liquid chromatography assay. Mean total body clearance of fluconazole was 37.7 mL/h.kg, mean volume of distribution at steady state was 1.14 L/kg, mean residence time was 31.0 h and mean half-life of elimination was 25 h as derived by non-compartmental analysis of data. Absorption was complete. Mean ratios of fluid:serum fluconazole concentrations following administration of 50 mg fluconazole per day for 8 days were as follows: cerebrospinal fluid, 0.88; aqueous humour 0.79; ELF, 1.20. Fluconazole concentrations in cerebrospinal fluid, aqueous humour and ELF exceeded reported minimum inhibitory concentrations of fluconazole for pathogenic fungi. Results of this study suggest fluconazole can effectively be administered to cats at 50 mg per cat per day.

Administration, Oral↗