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The human metabolism and pharmacokinetics of ethyl N(alpha)-lauroyl-L-arginate hydrochloride (LAE), a new antimicrobial agent for use in foods have been investigated using both in vitro and in vivo techniques with (14)C-LAE and (13)C-LAE respectively. LAE was readily hydrolysed to the corresponding lauroyl arginine (LAS) on incubation with human plasma samples to the extent of about 50% during 4h. LAE was stable in simulated gastric fluid but in simulated intestinal fluid it was rapidly hydrolysed to LAS and arginine with more than 90% conversion to arginine after 1h. Oral doses of (13)C-LAE in propylene glycol were administered to human volunteers at dose levels of 1.5mg/kg (4 subjects) and 2.5mg/kg (2 subjects). LAE was only detected in two plasma samples in one individual at the higher dose level close to the limit of quantification (1 ng/ml). Maximum plasma concentrations of LAS generally occurred at 2h with mean peak levels of 18.2 ng/ml (1.5mg/kg dose) and 23.9 ng/ml (2.5mg/kg dose). Maximum concentrations of (13)C-arginine occurred earlier (0.5 to 1h) and at much higher levels than LAS with mean peak levels of 124 ng/ml (1.5mg/kg dose) and 240 ng/ml (2.5mg/kg dose). The results showed that in humans LAE was rapidly metabolized to the naturally occurring dietary components lauric acid and arginine.

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Although Se is essential for antioxidant and thyroid hormone function, factors influencing its requirement are not well understood. A survey and two experiments were conducted to determine the influence of cattle breed and age on selenoprotein activity and the effect of maternal Se supplementation on cow and calf selenoprotein activity and neonatal thyroid hormone production. In our survey, four cowherds of different ages representing three breeds were bled to determine the influence of breed and age on erythrocyte glutathione peroxidase activity (RBC GPX-1). All females were nonlactating, pregnant, and consumed total mixed diets (Holstein) or grazed pasture (Angus and Hereford). In our survey of beef breeds, yearlings had greater average RBC GPX-1 activity than mature cows. In Exp. 1, neonatal Holstein heifers (n = 8) were bled daily from 0 to 6 d of age to determine thyroid hormone profile. An injection of Se and vitamin E (BO-SE) was given after the initial bleeding. Thyroxine (T4) and triiodothyronine (T3) concentrations were greatest on d 0 and decreased (P < 0.05) continuously until d 5 postpartum (156.13 to 65.88 and 6.69 to 1.95 nmol/L, d 0 to 5 for T4 and T3, respectively). Reverse T3 concentrations were 3.1 nmol/L on d 0 and decreased (P < 0.05) to 0.52 nmol/ L by d 5. In Exp. 2, multiparous Hereford cows were drenched weekly with either a placebo containing 10 mL of double-deionized H2O (n = 14) or 20 mg of Se as sodium selenite (n = 13). After 2 mo of treatment, Se-drenched cows had greater (P < 0.01) plasma concentrations than control cows (84.92 vs. 67.08 ng/mL), and at parturition, they had plasma Se concentrations twofold greater than (P < 0.05) control cows (95.51 vs. 47.14 ng Se/mL). After 4 mo, cows receiving Se had greater (P < 0.05) RBC GPX-1 activity than controls; this trend continued until parturition. Colostrum Se concentration was twofold greater (P < 0.05) in Se-drenched cows than control cows (169.97 vs. 87.00 ng/mL). Calves born to cows drenched with Se had greater (P < 0.05) plasma Se concentration, RBC GPX-1, and plasma glutathione peroxidase activity on d 0 compared with calves born to control cows. By d 7, no differences in plasma glutathione peroxidase activity in calves were observed. Maternal Se supplementation did not influence calf thyroid hormone concentrations. Selenium provided by salt and forages is not adequate for cattle in Se-deficient states.

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Coumarin, a well recognized rat hepatotoxicant, also causes acute, selective necrosis of terminal bronchiolar Clara cells in the mouse lung. Further, chronic oral gavage administration of coumarin at 200 mg/kg, a dose that causes Clara cell death, resulted in a statistically significant increased incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. In contrast, mouse lung tumors were not observed at the 100 and 50 mg/kg dose levels in the oral gavage study, or in CD-1 mice following chronic intake of coumarin at levels equivalent to 276 mg/kg in diet. The current studies were designed to determine the impact of oral gavage vs dietary administration on the pharmacokinetics and metabolism of coumarin in CD-1 and B6C3F1 mice and F344 rats. Following the administration of 200 mg/kg 14C-coumarin via oral gavage, lung C(max) values (total 14C-associated radioactivity) were five- and 37-fold greater than those resulting from a 50 mg/kg oral gavage dose or 1000 ppm in diet, respectively. Coumarin (200 mg/kg) pharmacokinetics and metabolism was also examined in F344 rats following oral gavage dosing. Total 14C-coumarin associated radioactivity in plasma was 3.5-fold lower than in the mouse, and the plasma half-life in rats was five-times longer than in mice. Using non-radiolabeled compound (200 mg/kg), coumarin and products of the coumarin 3,4-epoxidation pathway were quantitated in plasma and urine after oral gavage administration to mice and rats. 7-Hydroxycoumarin (7-HC) was quantitated in mouse plasma and urine. o-Hydroxyphenylacetic acid (o-HPAA) reached a concentration of 37 microg/ml in plasma, and accounted for 41% of the dose in the urine, whereas the C(max) for 7-hydroxycoumarin was 3 microg/ml, and represented 7% of the administered dose. In the rat, the plasma C(max) for o-HPAA was 6 microg/ml, and accounted for 12% of the dose. The coumarin C(max) in rat plasma was comparable to that in mouse. Coumarin 3,4-epoxide (CE) and its rearrangement product o-hydroxyphenylacetaldehyde (o-HPA) and o-hydroxyphenylethanol (o-HPE), were not detected at any time point in plasma or urine. This analysis of coumarin and CE pharmacokinetics in rodents suggests that the differential tumor response in the mouse oral gavage and dietary bioassays is a function of the route of exposure, whereas species differences in lung toxicity between mice and rats result from heightened local bioactivation in the mouse lung.

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The disposition and metabolic fate of [4-14C]coumarin in a 70% aqueous ethanol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simulate that which may be encountered when using an alcohol-based perfumed product. In both cases, the 6-h exposure was 0.02 mg/cm(2) (rats 0.023 mg/kg and humans 0.77 mg/kg). In both, coumarin was quickly absorbed, distributed and excreted in urine and feces, although fecal excretion of coumarin in humans was only 1% of the applied dose as opposed to 21% in rats. Total absorption was 72% of the applied dose with rats and 60% with humans. Peak plasma radioactivity in both was at 1 h. The mean plasma half-life of coumarin and metabolites was approximately 1.7 h for humans and 5 h for rats. In humans, coumarin was primarily metabolized to and excreted in urine as 7-hydroxycoumarin glucuronide and 7-hydroxycoumarin sulfate. Small amounts of unconjugated 7-hydroxycoumarin and o-hydroxyphenylacetic acid (o-HPAA) were also excreted. In rats, about twenty metabolites were present, but only o-HPAA was identified. These studies show the rat is a very poor model for humans and toxicity in the rat cannot be extrapolated to humans.

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Absorption through the skin is a route of exposure to a wide variety of therapeutic and/or environmental compounds. In vivo assays are advantageous in that they retain intact epidermal and dermal structures and thus reflect a more normal situation. The test compound is applied to the skin in a protected area for a specified period of time. At the end of the incubation, skin, tissues, and excreta are assessed for the presence of the test compound. The assay can also be performed with volatile compounds. When performed using laboratory animals, it is possible to assess the distribution of the compound throughout the body. If human volunteers are studied such analysis is limited to the skin, blood, and excreta.

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The pharmacokinetics and metabolism of sucralose were investigated in dogs following intravenous or oral administration. Oral doses of (14)C-sucralose were rapidly absorbed, although there was some variation in the extent of absorption (range 18-48% of the dose). After intravenous or oral administration, radioactivity excreted in the urine was associated mainly with unchanged sucralose. One urinary metabolite was detected after both intravenous and oral doses and was identified by mass spectrometry as a glucuronic acid conjugate of sucralose. This metabolite accounted for about 15-20% of the intravenous dose but for only about 2-8% of the oral dose.

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The excretion and metabolism of (14)C-sucralose has been investigated in mice following intravenous and oral administration. A 20mg/kg intravenous dose was rapidly excreted mainly in the urine (80% in 5 days). After 100, 1500 and 3000mg/kg oral doses of (14)C-sucralose, means of 23%, 15% and 16% of the dose, respectively, were excreted in the urine during 5 days. Comparison with the intravenous dose indicated that 20-30% of the oral doses was absorbed. Sucralose was excreted almost entirely unchanged and represented more than 80-90% of the radioactivity in all urine and faeces samples. Only two minor metabolites were detected, representing 2-8% of urine radioactivity.

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The excretion and metabolism of (14)C-sucralose has been investigated in non-pregnant and pregnant rabbits after administration of single 10mg/kg oral doses. Means of 22% and 55% of the dose were excreted in urine and faeces, respectively, by non-pregnant animals during 5 days. Excretion was similar in pregnant animals with means of 22% and 65% of the dose in urine and faeces, respectively, during the same time. Following a single oral dose, a mean of approximately 7% of the dose was still being excreted during the 96-120-hr collection period. Only one major radioactive component was detected in urine samples which corresponded to unchanged sucralose.

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Dermal doses of carbon-14 labelled musk ambrette (MA), musk ketone (MK) or musk xylene (MX) to male Sprague-Dawley CD rats were applied at a nominal dose level of 0.5 mg/kg (11 microg/cm2 of skin) and excess material removed at 6 h. Means of about 40, 31 and 19% of the applied doses of MA, MK and MX, respectively, were absorbed. Most of the absorbed material was excreted within 5 days with only 1-2% of the applied dose remaining in the animal at this time. Tissue concentrations of radiolabel were similar for all three compounds with peak concentrations occurring at 6-8 h. In general, fat and liver contained the highest concentrations at around 0.2 microg nitromusk equivalents/g but concentrations in fat declined fairly rapidly to around 0.005 microg equiv./g at 120 h. Most of the absorbed dose was eliminated in bile mainly in the form of polar conjugated metabolites. Structural characterisation of the major aglycones for MA and MX indicated that they were hydroxylated analogues formed by oxidation of the ring methyl. Repeated daily dosing for 14 days resulted in little bioaccumulation for musk xylene and accumulation of about three-fold for musk ketone.

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7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexa-methylcyclopenta-gamma-2-be nzopyran (HHCB) are two large volume fragrance ingredients widely used in consumer products. As part of the risk evaluation, the systemic exposures to these materials was determined in rats under occlusion and in humans under simulated conditions of exposure. Ring 14C-labeled AHTN or HHCB were applied dermally in alcoholic solutions to rats at doses of 4.5 mg/kg and occluded for 6 h. Urine, feces and air were collected for up to 120 h and analyzed for radioactivity. Pairs of rats were sacrificed periodically for analysis of tissues and organs. The total amount absorbed was approximately 19% for AHTN and 14% for HHCB. In both cases, significant amounts diffused into the skin, most of which was further absorbed but a significant amount of which was lost to surface dressing by reverse diffusion and/or desquamation. Ring 14C-labeled AHTN or HHCB were applied in alcoholic solutions without occlusion to three male volunteers at concentrations approximating that which might be encountered in a typical cologne type product. After a 6-h period, all material was removed from the surface of the skin. Blood, feces and urine were collected over a 5-day period. For both materials, levels in blood and plasma were below limits of detection at all times. Based on excretion, primarily in the urine, the total absorbed dose was approximately 1 and 0.1% for AHTN and HHCB, respectively. However, over the 5-day period, 14.5% of AHTN and 19.5% of HHCB was recovered from the skin in dressings over the site of application indicating that a 'reservoir' had formed in the skin but the material in the reservoir was lost, by desquamation and/or by reverse absorption, and not available systemically. A mean of 24% (AHTN) and 22% (HHCB) was shown to evaporate under the conditions of exposure.

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OBJECTIVES: This study examined the availability of state funding for comprehensive primary care programs and the need for primary care subsidies for medically underserved communities. METHODS: A brief questionnaire was used to ask health agencies in all 50 states whether their state funded a program that met our definition of comprehensive primary medical care practice programs. An in-depth written survey instrument was then administered to the states with programs. RESULTS: Almost half of all states provide some funds for the development and/or operation of comprehensive primary medical care practices. Expenditures in most states were found to be relatively modest in comparison with both federal funding and the total level of unmet need for primary care. States that subsidize primary care practices tend to follow the model established under the federal health centers program. CONCLUSIONS: The findings suggest the continued viability of the health center model of care, as well as the presence of some state support for such a program. However, in light of limited state resources for the development and operation of comprehensive practices, a continued and significant federal effort is imperative.

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While a national health insurance plan is needed, this alone will not provide access for approximately 30 million persons who face geographic, cultural, language, or health care system barriers, or who live in areas with provider shortages. These barriers often coexist with lack of insurance coverage, but they also affect millions who have public, or even private, coverage. Moreover, large segments of this population suffer from health problems not adequately addressed by the traditional medical model: teenage pregnancy, AIDS, injury, substance abuse, and the like. To provide appropriate care for these underserved persons, we propose to expand the existing network of community health centers over the next 10 years to a total of approximately 3,000. Such an expansion would provide a cost-effective approach to improving provider distribution, increasing consumer input, combining personal health services with health promotion, and removing both financial and nonfinancial barriers to care. This model can be implemented either independent of or in conjunction with other health care system reform efforts.

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Two previously unknown metabolites of halofantrine, a candidate anti-malarial drug, have been isolated by thin-layer chromatography from the plasma of dogs administered a single oral dose of 60 mg/kg. Their identifies were investigated after trimethylsilylation by gas chromatography-mass spectrometry under electron-impact and negative-ion chemical ionization conditions. The structural assignment was further confirmed by using a combination of elemental composition analysis of all the isotope peaks at low mass resolution and isotope pattern matching. These two metabolites were formed by modification of the dibutylaminopropyl side-chain of the parent compound involving deamination and oxidation or reduction.

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The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h +/- 2.1 SD), low systemic clearance (13 mL/min/kg +/- 1 SD) and high volumes of distribution (Vd lambda z, 8.7 L/kg +/- 1.9 SD and Vdss, 3.9 L/kg +/- 0.9 SD). The ratio of mean residence times in tissues and plasma was greater than 4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% +/- 4.3 SD from the syrup and 33.6% +/- 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.

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The pharmacokinetics of the anti-leishmanial agent WR 6026 (8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride) has been studied after single intravenous infusion and oral doses of 5 mg (base)/kg to 6 Beagle dogs. After single intravenous infusions of 15 min, plasma concentrations of unchanged drug declined bi-exponentially from a mean maximum of 1203 ng/ml +/- 277 SD at the end of infusion to the limit of quantitation during 16 hours. After single oral doses, the mean Cmax of 23 ng/ml +/- 14 SD occurred at a mean Tmax of 2.2 hours +/- 1.3 SD. During 72 hours after the intravenous and oral doses, 0.6% and less than 0.2% of the dose respectively was excreted unchanged in the urine. The mean terminal-life of WR 6026 after the infusion doses was +/- 0.3 SD, but after the oral doses, plasma concentrations of drug were too low to allow estimation of the terminal half-life. The systemic clearance of WR 6026 (43.5 ml/min/kg) greatly exceeded the nomina, plasma flow (ca. 22 ml/min/kg) and indicated considerable extra-hepatic and extra-renal elimination of WR 6026 in dogs. The mean systemic availability of WR 6026 after the oral doses was ca.4%. The mean volumes of distribution of WR 6026 in dogs were 3.3 litres/kg +/- 1.1 SD (V(ss)) and 7.7 litres/kg +/- 2.4 SD (V(area)). These data characterise WR 6026 as a drug of relatively high systemic clearance, large volume of distribution, relatively short half-life and low systemic availability, probably due to presystematic elimination in the liver.

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1. The metabolic fate of 14C-ximoprofen was compared in rat (2 mg/kg), baboon (2 mg/kg) and human (approx. 0.4 mg/kg). An oral dose was well absorbed in all three species as indicated by urinary excretion of 80%, 86% and 94% dose respectively in 5 days: excreted in the faeces were 14%, 2% and 2% dose respectively. 2. Total 14C in plasma reached peak concentrations at 1-1.5 h in humans and earlier in animals. In humans, plasma 14C was initially associated mainly with unchanged drug which declined with a half-life of about 2 h (plasma 14C t1/2 about 8 h; cf. about 6 h in animals). 3. Tissue 14C concentrations in rats were generally similar to those in baboons at 1 h after dosing, decreasing substantially at later times. The distribution of 14C was consistent with that of a compound readily eliminated. 4. The major biotransformation products of ximoprofen were formed by hydrolysis to the keto-analogue followed by reduction to the hydroxy-analogue and conjugation of these two compounds. The same major metabolites were detected in urine of rat, baboon and humans but there was (a) complete biotransformation of ximoprofen in the rat, (b) an apparent difference in the nature of the conjugated component(s) in rat urine and those in baboon and human urine, (c) only one hydroxy-analogue detected in human urine but two such compounds in animal urine as indicated by mass spectrometry. 5. In human plasma at peak concentrations, the relative importance of circulating components was ximoprofen greater than keto-analogue greater than hydroxy-analogue, whereas in the plasma of the animal species this order was reversed, consistent with the more extensive biotransformation of ximoprofen observed in rat or baboon.

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Twenty-one Simmental crossbred bulls (311 +/- 11 kg, 9 mo of age) were used to determine the effect of feeding 10, 12 or 14% CP on concentration of hormones in blood and the relationship of these hormones to composition of gain. Six bulls were slaughtered on d 0 to provide an estimate of initial carcass composition (9-11 rib section). Remaining bulls were assigned to dietary treatments. Blood samples were collected every 30 min from 0800 to 2000 on d 0, 66, 136 and 202 of treatment; bulls were slaughtered on d 203. Across all treatments, growth hormone (GH) declined (P less than .05) from d 0 to d 202. Free insulin-like growth factor I (IGF-I) was lowest (P less than .05) on d 0. In four randomly selected bulls, IGF-I fluctuated during the 12-h sampling periods. Within each treatment group, insulin was greatest on d 202 (P less than .05). Testosterone (T) increased from d 0 to d 66, then declined. Cortisol (C) was lowest on d 66. Thyroid hormones increased (P less than .05) after d 0. Growth hormone and IGF-I were correlated negatively with carcass fat percentage, fat accretion rate and fat thickness. IGF-I concentrations were correlated positively with percentage of carcass protein. Testosterone:cortisol ratio was not related to composition, but high T coupled with low C may be related to carcass leanness (mean carcass fat = 24.4%). These data suggest that GH and IGF-I are the hormones most related to composition of gain in growing beef bulls.

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Two experiments were conducted to evaluate the effects of dietary CP level on rate, efficiency and composition of gain of growing beef bulls. In Exp. 1, 59 bulls (333 +/- 15.8 kg) were used. Eleven bulls were slaughtered on d 0 to provide an estimate of initial carcass composition (9-10-11 rib section chemical analyses), and remaining bulls were assigned to treatment diets containing 10, 12 or 14% dietary CP. Bulls fed the 10% CP diet grew slower (P less than .05) than bulls fed the 12 or 14% CP diets, although dry matter intake and feed-to-gain ratio did not differ. Bulls fed the 12% CP diet had fatter carcasses (P less than .05) than bulls fed the 10 or 14% CP diets and had greater daily fat accretion than bulls fed the 10% CP diet. In Exp. 2, 60 bulls (318 +/- 9.0 kg) were used. Bulls were assigned to initial slaughter (n = 6) or to one of three dietary treatments, 10, 12 or 14% CP, and were slaughtered after feeding for 66, 136 or 202 d (n = 6 . treatment -1 . slaughter time -1). Bulls fed 10% CP diets had lower (P less than .05) rates of carcass protein accretion during d 0 to 136 and d 0 to 202. Carcass fat gain was similar among treatments over the entire experiment, although bulls fed the 14% CP diet gained more fat during d 0 to 136 than bulls fed the other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

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The effects of tallow supplementation [0% (NT) vs 7.5% (T)] and crude protein level [8.5% (LP) vs 12.0% (HP)] on ruminal fermentation, microbial protein (MCP) synthesis, digesta passage and site of digestion were estimated using yearling Angus X Simmental steers (390 kg) fitted with ruminal and T-type duodenal cannulae. Chromium-EDTA and ytterbium (Yb) chloride were used as markers of the liquid and solid phases. Passage and site of digestion data were estimated from the concentrations of Yb in the duodenal digesta and feces. Dry matter (DM) intakes were 6.8, 6.5, 6.3 and 6.6 kg/d for the NT-LP, NT-HP and T-HP diets, respectively. Ruminal ammonia concentrations (mg/100 ml) for the NT-LP, NT-HP, T-LP and T-HP diets were 1.22, 4.75, 1.05 and 3.41, respectively. Tallow decreased (P less than .05) acetate (mol/100 mol), increased (P less than .01) propionate (mol/100 mol) and decreased the total volatile fatty acid concentration. Tallow depressed apparent ruminal DM and organic matter (OM) digestibilities only on the HP diet. High protein increased ruminal DM, OM and fiber digestibilities. Tallow and LP tended to shift the site of OM digestion to the lower tract. The liquid and solid dilution rates for the NT-LP, NT-HP, T-LP and T-HP diets were 9.53, 3.37; 5.63, 3.28; 6.66, 5.10 and 6.79, 5.34%/h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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