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Biomedical subjects

R E Hartnagel

Publications and source records attributed to R E Hartnagel.

At least 19 recordsLinked to original sources
PubMed1996

Absorption, distribution, metabolism, and excretion of N,N-diethyl-M-toluamide in the rat.

This study was conducted to evaluate the pharmacokinetic parameters of absorption, distribution, metabolism, and excretion (ADME) of the personal insect repellent N,N-diethyl-m-toluamide (DEET) after oral or dermal administration of [14C]DEET in the rat. Six experiments were conducted using separate groups, each consisting of five male and five female rats. Three experiments involved the determination of ADME patterns after oral administration of [14C]DEET as: 1) a single low dose (100 mg DEET/kg body weight); 2) a single high dose (500 mg DEET/kg body weight); and 3) a repeated low dose (100 mg DEET/kg body weight daily for 14 days). A fourth experiment involved the determination of ADME patterns after dermal administration of [14C]DEET at a single low dose of 100 mg DEET/kg body weight. In these four experiments, urine and feces were collected over a 7-day posttreatment period, after which time the animals were euthanized and selected tissues and organs were harvested. Urine, feces, and tissues were analyzed for total 14C content. The major urinary metabolites were identified, and the urinary metabolic profile for each dosage regimen was determined. The remaining two experiments examined the distribution of radioactivity in tissues of animals euthanized at peak 14C blood levels after receiving a single oral low dose or a dermal low dose. In the three experiments designed to determine the ADME patterns of DEET after oral administration, 85-91% of the administered radioactivity was found in the urine and 3-5% was found in the feces. The overall quantitative pattern of excretion of radioactivity into the urine and feces was similar for males and females in the three groups; however, the rate at which the radioactivity was excreted into the urine differed noticeably between individual oral dosing regimens. The fastest rate was observed in the repeated oral low-dose group, followed by the single oral low-dose and the single oral high-dose groups. In the group of rats that received the dermal low dose, 74-78% of the administered dose was found in the urine and 4-7% was found in the feces. An additional 6.5% was found on the surface of the skin at the application site or in association with the occlusive enclosure. The rate of absorption and subsequent excretion of administered radioactivity into the urine and feces was much slower after dermal administration than after all oral dosing regimens. Total tissue residues of 14C activity at 7 days ranged from 0.15 to 0.67% of the administered dose for all dosage regimens. At peak 14C blood levels, the percentages of administered dose reaching the systemic circulation and total 14C tissue residues were significantly higher in the group of animals administered [14C]DEET orally vs. the animals administered [14C]DEET by the dermal route of administration. In both cases, the only tissues with 14C residues consistently higher than that of plasma were the liver, kidney, and fat. HPLC analysis of urine from rats in the ADME phase of the study showed that DEET was metabolized completely in all treatment groups, with little or no parent compound excreted in the urine. Two major urinary metabolites were identified by mass spectroscopy. In both metabolites, the aromatic methyl substituent in the DEET molecule was oxidized to a carboxylic acid moiety. One of the metabolites also had undergone N-dealkylation of an ethyl substituent on the amide moiety.

Administration, Cutaneous↗
PubMed1995

Absorption, metabolism, and excretion of N,N-diethyl-m-toluamide following dermal application to human volunteers.

The absorption, metabolism, and excretion of N,N-diethyl-m-toluamide (DEET) in male human volunteers following dermal application of [14C]DEET was studied. DEET was applied to two groups of six volunteers either as the undiluted technical grade material or as a 15% solution in ethanol. The material was applied over a 4 x 6-cm area on the volar surface of the forearm and was left in contact with the skin for 8 hr, then rinsed off the skin. Application sites also were tape stripped at 1, 23, and 45 hr after rinsing. Serial blood samples and all urine and feces were collected for 5 days after application. Aliquots of these materials were analyzed for total radioactivity in order to define absorption and excretion patterns. Urine samples also were analyzed by HPLC to characterize the metabolic profile and/or to identify metabolites. Absorption of DEET as evidenced by plasma radioactivity occurred within 2 hr after dose application. Elimination of radioactivity from plasma was rapid and quantifiable levels of radioactivity were observed in plasma for only 4 hr after the end of the 8-hr exposure period. Urine was the principal route of excretion of radioactivity and accounted for an average of 5.61 and 8.33% of the applied dose in the undiluted DEET and 15% DEET in ethanol groups, respectively. Excretion of radioactivity in the feces was less than 0.08% of the applied dose in both groups. DEET did not accumulate in the superficial layers of the skin as evidenced by low amounts of radioactivity in the tape strippings.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1994

Teratologic evaluations of N,N-diethyl-m-toluamide (DEET) in rats and rabbits.

The potential for DEET to produce developmental toxicity was evaluated in Charles River CD rats and New Zealand White rabbits. Rats were administered undiluted DEET by gavage on Gestational Days (gd) 6-15 at dosage levels of 0, 125, 250, and 750 mg/kg/day. Rabbits were administered undiluted DEET by gavage on gd 6-18 at dosage levels of 0, 30, 100, and 325 mg/kg/day. Group sizes were 25 females per group for rats and 16 females per group for rabbits. Control rats and rabbits were administered corn oil at the same dosage volumes administered in the high-dose DEET groups. In rats, maternal toxicity in the form of clinical signs including two deaths and depressed body weight and food consumption was observed at the high-dose level of 750 mg/kg/day. Rat fetal body weights per litter also were reduced at 750 mg/kg/day. In rabbits, maternal toxicity in the form of depressed body weight and food consumption was observed at the high-dose level of 325 mg/kg/day. No maternal toxicity was observed at the low- or mid-dose groups for rats or rabbits. With the exception of the reduced fetal weights in rats at 750 mg/kg, there was no evidence of fetal toxicity, no effects on any of the gestational parameters, nor were there any treatment-related increases in external, visceral, or skeletal variations or malformations in the offspring from the rats and rabbits from these studies.

Animals↗
PubMed1993

Neurotoxicity evaluation of N,N-diethyl-m-toluamide (DEET) in rats.

The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) was evaluated following acute oral administration or following multigeneration plus chronic dietary administration to the rat. For the acute study, rats were administered undiluted DEET at dose levels of 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kg was considered to be the highest practical dose that could be evaluated in this study based upon observations of overt toxicity at 500 mg/kg and mortality at 1000 mg/kg in a dose range-finding study. The two measures of neurotoxicity evaluated in the acute study were functional observational battery (FOB) and motor activity measurements. An apparent treatment-related effect in thermal response time (increased) was noted for both sexes 1 hr after dosing at the 500 mg/kg dose level. A questionable effect on rearing activity (decreased) also was noted at the same dose level. For the multigeneration plus chronic dietary administration study, rats were administered DEET at dietary concentrations of 0, 500, 2000, or 5000 ppm continuously over two generations and then chronically for 9 months. A dietary concentration of 5000 ppm meets the criteria for a maximum tolerated dose (MTD) based on traditional chronic toxicology assessments. Evaluations included FOB, motor activity, discriminative acquisition and reversal in an M-maze, acoustic startle habituation, passive avoidance acquisition and retention, and microscopic examination of central and peripheral nervous tissue. The only effect that was considered to be possibly treatment-related was a slight increase in exploratory locomotor activity at the 5000 ppm dose level. Based on the results of these studies, the nervous system does not appear to be a selective target when DEET is administered to rats either as a single oral dose at high dose levels or chronically at the MTD.

Acoustic Stimulation↗
PubMed1991

Safety evaluation of Protaminobacter rubrum: intravenous pathogenicity and toxigenicity study in rabbits and mice.

The iv pathogenicity and toxigenicity of Protaminobacter rubrum was studied in New Zealand White rabbits and CF1 BR mice. Following a probe study, nine groups of six rabbits each were injected iv with; 1 ml of viable-cell suspension (VCS) at concentrations of 2.23 x 10(8), 10(6), 10(4) and 10(2) organisms/ml; the cell-free supernatant (CFS; in which the test organism had been cultured to a concentration of approximately 3 x 10(10) cells/ml) at dilutions of 1:100, 1:10,000 and 1:1,000,000 in phosphate buffered saline (PBS); uninoculated culture medium; or uninoculated PBS. Rabbits were observed daily for 14 days and body weights were recorded on days 0, 7 and 14. Body temperatures were recorded in two rabbits per group until 18 hr after dosing. On day 14, each rabbit was killed. Blood samples, sections of liver and spleen, and any tissues presenting lesions possibly indicating an infection were excised and cultured for P. rubrum. Deaths occurred in the probe study following 1 ml iv injection of VCS at a concentration of 2.5 x 10(10) organisms/ml or of undiluted CFS in which P. rubrum had been grown to a concentration of approximately 2.5 x 10(10) organisms/ml. Blood and tissue samples obtained less than 24 hr after treatment from rabbits in the VCS group tested positive for P. rubrum, which would be expected after iv administration of such a high concentration of cells. No deaths occurred, no adverse effects on body-weight gain were seen, and in no instance was P. rubrum recovered from blood or tissue cultures in the definitive study. Overt signs of infection or toxinosis were limited to transient reduced activity in the highest two VCS concentration groups, and the highest CFS group. Modestly elevated body temperatures were also recorded for rabbits that received the highest two concentrations of either VCS or CFS. A similar 14-day study was carried out in mice. Four groups of 20 Crl: COBS CF1 BR mice received a single iv injection of 0.1 ml of VCS (2.5 x 10(10) organisms/ml), CFS in which the test organism was cultured to approximately 2.5 x 10(10) cells/ml, uninoculated culture medium or uninoculated PBS. The mice were observed daily and body weights were recorded on days 0, 7 and 14. On day 14, each mouse was killed and blood samples as well as liver and spleen sections were obtained and cultured. In this study no deaths occurred, and signs of infection or toxinosis were limited to reduced activity and ptosis for all mice in the VCS and CFS groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Teratological, neurochemical, and postnatal neurobehavioral assessment of METASYSTOX-R, an organophosphate pesticide in the rat.

The purpose of this study was to assess the embryotoxic, fetotoxic, and teratogenic potential of METASYSTOX-R (MSR) in the rat. Furthermore, the study was designed to determine if maternally toxic doses of MSR altered fetal brain acetylcholinesterase (AChE), compromised neonatal survival, growth, and development, or affected neurobehavioral development. Inseminated female rats (45/dose group) received single daily oral doses of 0, 0.5, 1.5, or 4.5 mg/kg of MSR from Days 6 to 15. Dose groups were subdivided into three termination phases: Phase I, 5 females terminated on Day 16 of gestation; Phase II, 28 females terminated on Day 20 of gestation; Phase III, 12 females terminated on Day 21 postpartum. MSR produced a dose-related reduction in maternal plasma (30-72%), red blood cell (18-56%), and brain (21-68%) cholinesterase (ChE) activity, when measured on Day 16 of gestation. The high dose of MSR significantly (p less than or equal to 0.05) reduced food consumption, suppressed body weight gain, and produced tremors in 98% of the dams. MSR administered at maternally toxic doses as high as 4.5 mg/kg was devoid of embryotoxic, fetotoxic, and teratogenic effects. Fetal brain AChE was not substantially different from control for any dose level in Day 20 fetuses. Furthermore, neonatal survival, growth, and development were unaffected and an extensive neurobehavioral testing scheme demonstrated no alteration of sensory or reflex functions, maze learning ability, or open field activity for neonates.

Abnormalities, Drug-Induced↗
PubMed1989

A review of the toxicology profile of rioprostil.

The toxicity of rioprostil was extensively investigated. Studies in rodents, dogs and monkeys indicate a low order of acute toxicity. Oral subchronic and chronic toxicity studies in rats and dogs produce effects that would be expected based on the pharmacological activity of the compound. In reproduction studies with rioprostil, male and female fertility is unaffected in rats at doses up to 2.0 mg/kg/day and there is no evidence of embryotoxicity, fetotoxicity, or teratogenicity in rats at doses up to 1.7 mg/kg/day. In rabbits a maternally toxic dose (1.5 mg/kg) also increases resorptions, reduces fetal weight, and increases the incidence of malformations. Evaluation of 24-month carcinogenicity studies in mice and rats at oral doses up to 2.0 and 1.5 mg/kg/day, respectively, are in progress. Mutagenicity studies are negative.

Animals↗
PubMed1986

Rioprostil prevents gastric bleeding induced by nonsteroidal antiinflammatory drugs in dogs and arthritic rats.

Gastrointestinal irritation is the most significant side effect in patients chronically taking nonsteroidal antiinflammatory drugs (NSAID) for treatment of arthritic conditions. Rioprostil, a primary alcohol prostaglandin E1 analog, prevents gastric bleeding induced by several NSAID in a rat model of arthritis that is similar in many aspects to human rheumatoid arthritis. Daily oral dosing of rioprostil (50 micrograms/kg BID for 15 days) did not influence the course of the adjuvant disease in rats or alter the antiinflammatory or analgesic effect of the NSAID. In a 13 week efficacy study in dogs, rioprostil (40-60 micrograms/kg, PO) completely prevented gastric hemorrhagic lesions induced by daily administration of aspirin.

Animals↗
PubMed1986

Spontaneous lesions in the sternums of growing rats.

Pathologic examination of sternums from young growing rats revealed a number of skeletal lesions involving both cartilage and bone elements. Degeneration or aseptic necrosis of the intersternebral cartilage was a frequent finding in most rats that were examined either at 130 or 180 days of age. Thickening of the sternal cortices and trabeculae containing prominent cement lines were less frequently occurring lesions in these sternums. These changes were absent in rats of 70 days of age. The etiology of the lesions is not understood, although several factors may be incriminated.

Animals↗
PubMed1984

An unusual case of generalized ceroid-lipofuscinosis in a cynomolgus monkey.

Histologic, histochemical, and electron microscopic studies of generalized ceroid-lipofuscinosis in a cynomolgus monkey are presented. Histologically, a wide variety of tissue cells contained numerous bright eosinophilic intracytoplasmic granules that varied in size from 0.5 micron to 4.0 microns in diameter. Histochemically, the granules gave a weakly positive reaction with periodic acid-Schiff and for lipids. They were weakly acid fast and capable of emitting autofluorescence. Ultrastructurally, the granules were single unit membrane-bound, and contained dense osmiophilic material with frequent concentric or fingerprint-type lamellar formation. The granules were different than hemofuscin, iron, and bilirubin. Tinctorially the granules were unique--they were bright red with hematoxylin and eosin and, thus, differed from typical age-related lipofuscin pigment.

Aging↗
PubMed1984

Three types of cytoplasmic granules in cardiac muscle cells of cynomolgus monkeys (Macaca fascicularis).

Ceroid, lipofuscin, and hyaline-type intracytoplasmic granules found in cardiac muscle cells of cynomolgus monkeys were studied using histologic, histochemical, and fluorescent microscopic techniques. The studies indicated that the ceroid granules contained an insoluble lipid as well as a component that was stainable with Luxol fast blue and Mallory's phloxine stain for hyaline. Lipofuscin granules had staining reactions characteristic of the classical age-related pigment. Hyaline granules were devoid of lipid component and were distinctly different from either ceroid or lipofuscin. All three types of granules were located at the poles of cardiac muscle cell nuclei.

Animals↗
PubMed1976

The influence of aspirin on gastrointestinal microbleeding in dogs with gastric ulcers.

Fecal blood volume was determined daily in 11 dogs with single gastric ulcers. Beginning 11 days after production of the ulcers and dogs received, in crossover fashion, 2 placebo or ordinary 325-mg aspirin tablets orally twice daily during two 7-day treatment periods separated and followed by 5-day periods of no treatment. Mean daily fecal blood volumes of 0.52 and 3.25 ml were observed during periods of treatment with placebo and aspirin, respectively. However, in 7 previous studies in this laboratory a total of 24 normal dogs have received 7-day courses of treatment with 650 mg ordinary aspirin twice daily on 105 occasions; during these 105 treatment periods fecal blood volume averaged 2.90 ml/day. Thus, it is concluded that the effect of ordinary aspirin in dogs with gastric ulcers is essentially the same as the effect in normal dogs, and that there is no tendency for dogs with gastric ulcers to bleed massively in response to aspirin.

Administration, Oral↗
PubMed1976

The acute and target organ toxicity of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) and guanethidine in the rat and dog.

The effects of acute and repeated increasing oral doses of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) and guanethidine in the rat and dog have been described. On repeated oral administration guanethidine produced histopathological changes in cervical ganglia of rats and dogs which were clearly dose-dependent and reproduced lesions reported in the literature. Repeated oral administration of MA540 resulted in no histopathological changes in either species. The maximum tolerated oral dose for guanethidine was estimated to be 515 mg/kg in the rat and 26 mg/kg in the dog compared with an estimated maximum tolerated oral dose for MA540 of 1750 mg/kg in the rat and 460 mg/kg in the dog. On the basis of these findings it is suggested that subchronic studies with MA540 in the rat and dog should provide evidence which would justify the use of MA540 in man at daily oral doses as high as 9 mg/kg.

Animals↗
PubMed1976

Does aspirin play a role in analgesic nephropathy?

Using a compound analgesic mixture, it was found that renal pathology could be produced in rats if the analgesic mixture was administered as a concentrated aqueous suspension, but that development of renal pathology was not favored by hot, dry environmental conditions. Determination of whole body total salicylate concentrations in rats and humans receiving various doses of aspirin revealed that twice daily doses of 24, 60 and 125 mg/kg aspirin in the rat were equivalent to human doses of 8, 20 and (approximately) 40 ordinary 325 mg aspirin tablets daily. These doses of aspirin were then employed in a subchronic study of the nephrotoxicity of aspirin in the rat using the experimental design which maximized the nephrotoxic effects of the compound analgesic mixture. Six groups of ten male and ten female rats received aspirin orally at doses of 24,60 or 125 mg/kg twice a day five days a week for 12 weeks. Two additional groups of ten male and ten female rats received only the vehicle, at a volume equivalent to that received by the high dose group, and served as controls. Four groups (one each, control, low, mid-, and high dose) were denied access to water for 16 hours daily overnight. No pathologic renal changes were observed in any of the rats. These findings are consistent with a growing body of evidence, from both animal and human studies, that aspirin alone does not produce analgesic nephropathy.

Animals↗
PubMed1975

A subchronic study of the toxicity of an orally administered benzoquinolizinyl derivative in the rat and dog.

The subchronic toxicity of the trans isomer of N-(1,3,4,6,7-hexahydro-11bH-benzo[a] quinolizin-2-yl) propionanilide hydrochloride (TR2379), a new antihypertensive agent, was studied in rats and dogs. TR2379 was well tolerated for 13 weeks at daily p.o. doses up to 200 mg/kg in the rat and 70 mg/kg in the dog. However, severe toxic manifestations, including death, were elicited in the rat at 820 mg/kg and in the dog at 160 mg/kg. Toxicity in both species was characterized by a reduction in body weight gain and an increase in the weight of several organs, (liver, heart, kidneys, adrenals, and thyroids). Serum alkaline phosphatase, which was not assayed in the rat, was markedly increased in the dog. Microscopic examination of the various tissues revealed no evidence of organ pathology in either species.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1975

Influence of a benzoquinolizinyl derivative on serum and hepatic alkaline phosphatase activity in the dog and rat.

Oral administration of 100 mg/kg of TR2379, N-(1,3,4,6,7-hexahydro-11bH-benzo[a]quinolizin-2-yl) propionanilide hydrochloride, for 20--29 days to 6 dogs resulted in significant elevations of alkaline phosphatase (AP) activity in serum and in liver microsomes. Results of biochemical and histochemical experiments revealed that the liver was the sole source of the increased AP activity but there was no evidence of liver damage. The subchronic (7-35 day) p.o. administration of TR2379 at 820 mg/kg to 20 rats did not produce elevation of AP activity in serum or liver. Relative liver weights (g/100 g body wt) of rats receiving TR2379 were significantly increased during the 2nd week and thereafter. The results of these studies suggest that high doses of TR2379 induce protein synthesis in dog and rat liver and induce AP activity in the dog but not in the rat. The elevation of AP in the dog is not considered to have toxicologic implications.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗