Nickel: an essential micronutrient for legumes and possibly all higher plants.

Soybean plants deprived of nickel accumulated toxic concentrations of urea (2.5 percent) in necrotic lesions on their leaflet tips. This occurred regardless of whether the plants were supplied with inorganic nitrogen or were dependent on nitrogen fixation. Nickel deprivation resulted in delayed nodulation and in a reduction of early growth. Addition of nickel (1 microgram per liter) to the nutrient media prevented urea accumulation, necrosis, and growth reductions. This evidence suggests that nickel is essential for soybeans and possibly for higher plants in general.

Cigarette smoking: stimulatory effect on metabolism of 3,4-benzpyrene by enzymes in human placenta.

The enzymatic hydroxylation of 3,4-benzpyrene was not detected in human placentas obtained after childbirth from nonsmokers, whereas this enzyme activity was present in placentas obtained from individuals who smoked cigarettes. The degree of induction of benzpyrene hydroxylase caused by cigarette smoking varied in different individuals. Treatment of pregnant rats with benzpyrene increased the activity of this hydroxylase in the placenta.

Climatic impact of tropical lowland deforestation on nearby montane cloud forests.

Tropical montane cloud forests (TMCFs) depend on predictable, frequent, and prolonged immersion in cloud. Clearing upwind lowland forest alters surface energy budgets in ways that influence dry season cloud fields and thus the TMCF environment. Landsat and Geostationary Operational Environmental Satellite imagery show that deforested areas of Costa Rica's Caribbean lowlands remain relatively cloud-free when forested regions have well-developed dry season cumulus cloud fields. Further, regional atmospheric simulations show that cloud base heights are higher over pasture than over tropical forest areas under reasonable dry season conditions. These results suggest that land use in tropical lowlands has serious impacts on ecosystems in adjacent mountains.

Growth and Nutrient Uptake by Barley (Hordeum vulgare L. cv Herta): Studies Using an N-(2-Hydroxyethyl)ethylenedinitrilotriacetic Acid-Buffered Nutrient Solution Technique (I. Zinc Ion Requirements).

The critical range of Zn2+ activity in nutrient solution required for optimum growth of barley (Hordeum vulgare L. cv Herta) was studied using the synthetic chelating agent N-(2-hydroxyethyl)ethylenedinitrilotriacetic acid to buffer micronutrient metal ions. The activity of Zn2+ was varied over a wide range from approximately 0.1 x 10-11 to 22 x 10-11 M Zn2+. The dry weight of barley shoots reached a maximum at Zn2+ activities above approximately 3 x 10-11 M and was clearly depressed when Zn2+ activities were below about 1 x 10-11 M. The relationship in shoots between dry weight and Zn concentrations supports the view that there is a critical Zn concentration of about 25 [mu]g g-1 dry weight in whole shoots of barley seedlings. When Zn2+ activities in solution were near or below approximately 3 x 10-11 M, barley shoots accumulated higher concentrations of P, Mn, Ca, Mg, and Na, whereas Cu concentrations were reduced. P and Mn began to accumulate in the shoots before differences in dry weights were apparent and provided the earliest index of Zn deficiency. In Zn-deficient roots, concentrations of Ca and Mg increased by 25 to 30%, and those of Fe and Mn more than doubled. Zn appears to play a special role in regulating uptake of several mineral nutrients in barley.

Growth and Nutrient Uptake by Barley (Hordeum vulgare L. cv Herta): Studies Using an N-(2-Hydroxyethyl)ethylenedinitrilotriacetic Acid-Buffered Nutrient Solution Technique (II. Role of Zinc in the Uptake and Root Leakage of Mineral Nutrients).

Barley seedlings (Hordeum vulgare L. cv Herta) were grown in N-(2-hydroxyethyl)ethylenedinitrilotriacetic acid-buffered nutrient solutions with or without adequate Zn supplies. Fifteen-d-old Zn-deficient seedlings contained higher concentrations of Mn, Ca, Mg, and P in their shoots and more Fe, Mn, Cu, K, Ca, and P in their roots than did similar Zn-adequate seedlings, confirming results reported in our companion study (W.A. Norvell and R.M. Welch [1993] Plant Physiol 101: 619-625). Zn-deficient roots leaked greater quantities of K, Mn, Cu, and Cl than did roots supplied adequately with Zn; they also leaked significant amounts of Zn even though the seedlings were not supplied Zn during growth. Calculated uptake rates of P, Mn, and Na were sharply reduced, but uptake rates of K and Mg were stimulated by increasing the Zn2+ activity in nutrient solutions. Intact roots of Zn-deficient seedlings contained lower concentrations of 5,5[prime] -dithio-bis(2-nitrobenzoic acid) reactive sulfhydryl groups in comparison to Zn-adequate roots. Apparently, Zn is required for the uptake and retention of several mineral nutrients by roots, possibly by playing a protective role in preventing the oxidation of sulfhydryl groups to disulfides in root-cell plasma membrane proteins involved in ion channel-gating phenomena.

Codeine kinetics as determined by radioimmunoassay.

Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 ng/ml) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 ng/ml) appeared within 0.75 to 1 hr. The mean plasma t1/2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5.1 L/kg, respectively. Oral, relative to intramuscular, bioavailability of codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).

The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium, in human and rat plasma.

OBJECTIVE: To assess the mechanism and rate of in vitro degradation of cisatracurium in aqueous buffer and in human and rat plasma. METHODS: Cisatracurium was incubated in aqueous buffer at various pH values or in human and rat plasma maintained at pH 7.4 with HEPES buffer. Cisatracurium and the degradation products, laudanosine and the monoquaternary alcohol, were quantitated by HPLC with use of fluorescence detection. RESULTS: In Sørenson's phosphate buffer, cisatracurium degraded spontaneously by a chemical process commonly referred to as "Hofmann elimination." The rate of degradation increased with increasing pH. From pH 6.4 to 7.8 there was a 6.5-fold increase in the rate of degradation of cisatracurium and, on a molar basis, the final decomposition product laudanosine accounted for all of the drug. At a pH of 7.4, cisatracurium degraded with a half-life of about 34.1 +/- 2.1 minutes. Cisatracurium incubated in human plasma degraded with a mean (+/- SD) half-life of 29.2 +/- 3.8 minutes, which is consistent with Hofmann elimination. Besides laudanosine, and unlike that observed in Sørenson's phosphate buffer, significant amounts of the monoquaternary alcohol were formed that slowly degraded to laudanosine. The micromoles of laudanosine formed eventually accounted for the total amount of cisatracurium incubated with human plasma. The monoquaternary alcohol appears to be a product of ester hydrolysis of a monoquaternary acrylate formed during the first step in Hofmann elimination. Evidence for esterase involvement at this step in the degradation of cisatracurium was based on inhibition studies with O-cresyl benzodioxaphosphorin oxide (CBDP), a specific carboxylesterase inhibitor. The addition of CBDP to human plasma completely blocked the formation of monoquaternary alcohol and converted the degradation of cisatracurium to total Hofmann elimination. In rat plasma cisatracurium was hydrolyzed, with a half-life of only 3 1/2 minutes, by carboxylesterases. The addition of CBDP increased the half-life to 25 minutes, which is consistent with Hofmann elimination. CONCLUSION: In human plasma the rate-limiting step in the degradation of cisatracurium is Hofmann elimination, with the initial formation of a monoquaternary acrylate. The observation that the monoquaternary alcohol results from ester hydrolysis of the monoquaternary acrylate by plasma esterase(s) explains the presence of the monoquaternary alcohol metabolite in human plasma during clinical studies with cisatracurium. The rapid hydrolysis of cisatracurium by rat plasma relative to human indicates a major species difference in plasma esterase(s).

Elimination of antipyrine from saliva as a measure of metabolism in man.

The salivary half-life of antipyrine was used as a convenient procedure for estimating the relative rates of drug metabolism in man. The concentration ratio of antipyrine in plasma and saliva was one over a 24-hr period following the oral or parenteral administration of the drug to man and rat. Phenobarbital, a known stimulator of drug metabolism in animals and man, increased markedly the elimination of antipyrine from saliva of rats, while SKF-525A, a potent inhibitor of drug metabolism, prolonged the elimination of antipyrine from rat saliva. In addition, the known sex difference in the metabolism of drugs in the rat was detected by measuring the elimination rate of antipyrine from saliva of male and female rats. The clinical application of the procedure indicated that a group of epileptic patients treated with anticonvulsants for more than 2 mo had a mean antipyrine salivary half-life of 4 hr, whereas a mean half-life of 13 hr was found in a group of normal volunteers. The results show that the elimination rate of antipyrine from saliva is a useful index of drug metabolism in animals and man.

Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and beta-phase elimination half-lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 ng/ml (aspirin-codeine phosphate administration) and 7.4 ng/ml (acetaminophen-codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration-time curves for morphine and codeine was 0.095 for the aspirin-codeine phosphate study and 0.12 for the acetaminophen-codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Analgesic drugs in breast milk and plasma.

The disposition of salicylic acid, phenacetin, caffeine, and codeine, and two metabolites, acetaminophen and morphine, was studied in breast milk and plasma of two lactating mothers after single oral doses of a compound analgesic. Salicylic acid penetrated poorly into milk, with peak levels of only 1.12 to 1.60 micrograms/ml, whereas peak plasma levels were 33 to 43.4 micrograms/ml. The drug was also eliminated more slowly from milk than plasma. In contrast, caffeine and phenacetin kinetics in breast milk and plasma were similar, but milk levels were somewhat lower than plasma levels in both subjects. Metabolically produced acetaminophen levels in both fluids were much higher than those of the parent drug, phenacetin, in one subject, but early plasma and milk phenacetin levels exceeded those of acetaminophen in the other subject, thereafter dropping sharply to assume the pattern of the first subject. Elimination of the metabolite, acetaminophen, from milk was slower than from plasma (subject 1, half-life (t1/2) of drug in milk, 4.7 hr; t1/2 in plasma, 2.9 hr). In both subjects codeine concentrations in milk were 1.5 to 2.4 times as high as in plasma at the same times after drug. Metabolically produced morphine levels in milk from both mothers were low but exceeded those in plasma after 1 hr. Calculations based on average milk concentrations over the 12 hr after drug in subject 1 revealed milk excretion of 0.7% or less of the ingested dose of each drug. Similar calculations based on predicted steady-state milk drug concentrations in subject 2 indicated maximum milk excretion of 2.7% of the dose. In each case caffeine was excreted in the milk in the greatest amount.

Acetaminophen metabolism in subjects fed charcoal-broiled beef.

The effects of consumption of charcoal-broiled beef on the metabolism of acetaminophen by conjugation were determined in nine normal subjects. We had reported that beef prepared in this manner accelerates the oxidative metabolism of drugs, including the oxidation of phenacetin to N-acetyl-p-aminophenol (acetaminophen). In nine normal subjects, a control diet was followed by a charcoal-broiled beef diet, which was followed by the control diet. The charcoal-broiled beef had little or no effect on the plasma-level profile of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate, or on the urinary excretion of acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, 3-methoxy-acetaminophen, or the cysteine and mercapturic acid conjugates of acetaminophen. Results indicate that the enzyme systems that conjugate acetaminophen in man are subject to little or no influence by charcoal-broiled beef. Therefore dietary factors that increase drug oxidations cannot be assumed to have a similar effect on drug conjugation.

Codeine disposition in smokers and nonsmokers.

The bioavailability of codeine and extent of its transformation to morphine were stated in 12 smoking and 11 nonsmoking subjects after single doses 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12-hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half-life (t1/2), or areas under plasma concentration-time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 +/- 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 +/- 2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 +/- 4.9%) and in nonsmokers (50.2 +/- 2.1%) did not offer. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first-pass O-demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O-demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.

Physiologic processes affecting the content and distribution of phytonutrients in plants.

Plant physiologists and biochemists are unraveling the transport mechanisms and biosynthetic pathways that determine each plant's unique phytonutrient composition so that crop plants can be modified to improve their nutrition quality. However, before this goal can be achieved, more information is needed on various plant and human phytonutrient-related processes, and some new technical capabilities are required. The current status of our knowledge base and recommendations for technical improvements and research priorities will be discussed.

Agronomic problems related to provitamin A carotenoid-rich plants.

OBJECTIVES: Review how agricultural systems might be changed to increase the vitamin A density of diets in developing countries to provide sustainable solutions to vitamin A deficiency globally. DESIGN: Develop agricultural systems that not only assure calorie adequacy for people, but also address vitamin A density in diets. SETTINGS: Agricultural systems could be modified in some developing nations in ways that would provide adequate dietary amounts of provitamin A carotenoids from plant food sources. SUBJECTS: Infants and children of low-income families are most at risk of developing vitamin A deficiency in developing countries. INTERVENTIONS: Cropping systems could be modified to include more vegetable and fruit crops containing higher bioavailable amounts of provitamin A carotenoids in some countries. Additionally, cultural practices could be modified through education, agricultural extension and/or social marketing to insure that the bioavailable provitamin A carotenoid levels in food crops are optimized. Staple food crops could be improved as sources of provitamin A carotenoids by traditional plant breeding and/or by genetic engineering efforts. RESULTS: Currently, many techniques are available to increase the vitamin A content of diets through sustainable food-based approaches. Agricultural approaches should be examined closely to finding sustainable food-based system solutions to vitamin A deficiency globally. CONCLUSIONS: The world community should strive to find food-based system approaches to eliminating vitamin A deficiency. Modifying agricultural systems in ways that will not only maximizing food production, but also insure nutritional adequacy of vitamin A is a desirable goal for many developing countries.

Food systems for improved health: linking agricultural production and human nutrition.

OBJECTIVES: Link traditional agricultural production disciplines to the food sciences and the various disciplines concerned with human nutrition and health in order to find sustainable solutions to malnutrition. DESIGN: Develop a new integrated program area within a university by forging explicit linkages within a wide array of disciplines concerned with food systems and human health. SETTING: The College of Agriculture and Life Sciences, the College of Human Ecology, the Division of Nutrition, and the Cornell International Institute for Food, Agriculture, and Development at Cornell University, Ithaca, New York, USA. INTERVENTIONS: Use food-based, system approaches to meet human nutrition goals. Current focus is on the provision of micronutrients (especially iron, vitamin A and iodine) for people globally. RESULTS: A new program area 'Food Systems for Health' has been developed at Cornell University. The program fosters effective interdisciplinary research, teaching and extension activities directed towards sustainable improvements in human nutrition and health. CONCLUSIONS: The old paradigms of agriculture, human nutrition, and public health must be shifted from current linear approaches to integrated and interactive approaches if effective long-term, food-based solutions to micronutrient malnutrition are to be found.

Determination of triprolidine in human plasma by quantitative TLC.

A chromatographic thin-layer fluorescence procedure, with a sensitivity limit of 0.8 ng/ml, is described for the quantitative analysis of triprolidine in human and rat plasma. Following the intravenous administration of 1 mg/kg of triprolidine to rats, the drug distributed rapidly into tissues and was eliminated from plasma with a half-life of 53 min. The method was used to determine the plasma triprolidine levels in 16 normal human volunteers following oral administration of 3.75 mg of triprolidine hydrochloride in 15 ml of a syrup. The drug obtained a mean peak plasma level of 8.2 ng/ml in 2 hr and was eliminated from the plasma with a half-life of 5 hr. Considerable individual variation was observed in the area under the plasma triprolidine level-time curve; values ranged from 19 to 163 ng hr/ml with a mean value of 75 ng hr/ml.

Triprolidine radioimmunoassay: disposition in animals and humans.

A hapten derivative of triprolidine, bearing an acrylic acid side chain ortho to the pyridine ring nitrogen atom, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with the resulting drug-protein conjugate resulted in the production of antisera capable of binding a radioiodinated tyramine conjugate of the triprolidine hapten derivative at high antiserum dilutions (1:70,000-1:150,000). These antisera were used to develop a radioimmunoassay (RIA) for triprolidine in human plasma with a sensitivity limit of 0.1 ng/mL (0.01 ng of actual mass). The known hydroxymethyl and carboxyl metabolites of triprolidine cross-reacted weakly (less than 2 and less than 0.05%, respectively) with this antiserum. The RIA could be used for the direct analysis of triprolidine in human and rabbit plasma, but not for rat or dog plasma, presumably due to the presence of other interfering substances (possibly metabolites). The validity of the RIA procedure in human plasma was demonstrated by comparative analysis of a number of samples by quantitative TLC (r = 0.985, slope = 1.076). The assay was employed to describe the pharmacokinetics of triprolidine in the rabbit (t 1/2, beta = 1.7 h). The assay had adequate sensitivity to detect low circulating drug concentrations in humans after therapeutic oral doses and also substantiated previous disposition experiments with triprolidine in humans (t 1/2, beta = 2.27 h). TLC analysis demonstrated that the absolute oral bioavailability of triprolidine (1-mg/kg dose) in the dog was low (4%). A comparison of triprolidine pharmacokinetic parameters in dogs, rabbits, rats, and humans revealed considerable similarity in elimination characteristics in these species.