Predictive systems ecology.

Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.

Value of radiologic skeletal survey in assessment of abused children.

The usefulness of the radiologic skeletal survey in the assessment of children who were suspected of being abused or neglected was studied. During a 2 1/2-year period at one pediatric hospital, 331 skeletal surveys were performed to aid in the evaluation of possible child maltreatment. Of the 331 surveys, 38 (11.5%) showed evidence of trauma. But, in 30 of the 38 skeletal surveys, trauma was either previously known or suspected by the examiner. Therefore, in only eight cases did the skeletal survey provide new information that was helpful in the investigation of possible abuse or neglect which would have remained undiscovered without the skeletal survey. The age, sex, and clinical signs of the subjects were analyzed in an attempt to identify factors that might predict skeletal surveys with positive radiologic findings. Consideration is given to the costs and risks of skeletal surveys v potential benefits.

Pharmacokinetics and metabolism of benzene in Zymbal gland and other key target tissues after oral administration in rats.

Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with 14C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from those studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and (c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic.

Isolation and analysis of N-oxide metabolites of tertiary amines: quantitation of nicotine-1'-N-oxide formation in mice.

To investigate the formation and elimination of nicotine-1'-N-oxide (NNO) in mice treated with a single injection of nicotine, sensitive and selective methods were developed to quantitate this polar and heat-labile metabolite. The compound was isolated from tissue homogenates as a dodecyl sulfate ion pair with C18 extraction cartridges and analyzed on an amino bonded-phase high-performance liquid chromatographic column with a mobile phase consisting of isopropanol-water. Overall recoveries of NNO were 64-76% from biological media. Several methods of detection were evaluated; radiolabeling was necessary to achieve the sensitivity required for pharmacokinetic studies in mice. The cis and trans isomers of NNO were separated on a Partisil PAC column and enzymatic selectivity was evaluated for the formation of these isomers in mice.

Glucuronidation of propranolol and 4'-hydroxypropranolol. Substrate specificity and stereoselectivity of rat liver microsomal glucuronyltransferases.

Liquid-chromatographic procedures were developed to assay the formation of diastereomeric glucuronides of propranolol (PG) and 4'-hydroxypropranolol (HPG) by rat liver microsomes, with identifications performed by GC/MS techniques. Propranolol was conjugated at a rate 10% of that determined for 4'-hydroxypropranolol. Glucuronyltransferase activity increased slightly (10-17%) in the presence of MgCl2. Inclusion of 0.04% Triton X-100 produced a 55% inhibition of PG formation, but increased HPG formation greater than 2-fold. Pretreatment of animals with phenobarbital resulted in a 4-fold increase in PG formation, but did not affect HPG formation unless MgCl2 was also present. Under these conditions, a 50-60% increase in HPG formation occurred. Pretreatment with 3-methylcholanthrene did not affect the formation of either glucuronide. (R)-(+)-Propranolol was glucuronidated 2-fold faster than the (S)-(-) enantiomer at substrate concentrations below 0.1 mM, and 1.3-fold faster at substrate concentrations above 2.0 mM. The estimated Vmax, 0.67 nmol/mg/min, was identical for both enantiomers. The dissociation constants were significantly different, however, being 0.57 mM for (R)-(+)-propranolol and 0.87 mM for (S)-(-)-propranolol. No stereoselectivity was observed in the formation of HPG when 4'-hydroxypropranolol was used as substrate, or when propranolol was incubated in the presence of an NADPH-generating system. Propranolol and 4'-hydroxypropranolol were used as substrate, or when propranolol was incubated in the presence of an NADPH-generating system. Propranolol and 4-hydroxypropranolol are apparently glucuronidated by different forms of rat liver glucuronyltransferase. Furthermore, propranolol glucuronidation occurs stereoselectively in vitro because of the different enzyme affinities for the enantiomers of the drug.

A comparative study of the disposition of nicotine and its metabolites in three inbred strains of mice.

The disposition of nicotine, cotinine, and nicotine N-oxide was investigated in male C57BL, DBA, and C3H mice following an ip injection of nicotine (1.0 mg/ml). The half-lives (t1/2) of nicotine in blood were 5.9 to 6.9 min. The rapid elimination of nicotine was accompanied by a rapid accumulation of metabolites; maximal concentrations of cotinine in blood (204 to 364 ng/ml) were achieved in 10 min and nicotine N-oxide (23 ng/ml in C3H mice) in 15 min. The t1/2 in blood was 20.1 to 39.8 min for cotinine and 18.4 min for nicotine N-oxide. The t1/2 values for nicotine in brain were similar to those in blood, but the values for liver were slightly larger (6.3 to 9.2 min) and interstrain differences were significant. A large strain-related difference in the t1/2 for cotinine was found; the metabolite was eliminated from the blood of DBA mice at only about one-half the rate determined for the other strains. The t1/2 for nicotine N-oxide in liver ranged from 12.7 to 27.3 min; the values were significantly different with C57BL greater than DBA greater than C3H. Strain-related differences were also observed in response to chronic exposure to cigarette smoke. The t1/2 of injected nicotine appeared to be slightly decreased in C57BL and DBA mice but was increased by 60% in livers of C3H mice compared to a control group.

Quantification of (+)-calanolide A, a novel and naturally occurring anti-HIV agent, by high-performance liquid chromatography in plasma from rat, dog and human.

A HPLC method was validated for quantification of (+)-calanolide A (1), a novel anti-HIV agent, in rat, dog and human plasma. The synthetic intermediate (+/-)-12-oxocalanolide A (2) was found to be a suitable internal standard. Compounds were extracted from plasma using a solid-phase C(18) cartridge and quantified over the assay range of 12.5 to 800 ng/ml. The method was utilized to determine (+)-calanolide A pharmacokinetics in rats, dogs and humans. This is the first report of a validated HPLC assay for determination of (+)-calanolide A concentrations in rat and dog plasma as well as human plasma obtained from clinical trials. There was no evidence of in vivo epimerization of (+)-calanolide A to its inactive epimer (+)-calanolide B (3).