Respective Half-lives Research Articles

Pediatric Patients Have Shorter Lansoprazole Half-Life Than Previously Reported

Purpose: Traditional pharmacokinetic teaching suggests that the elimination rate (half-life) of drugs is related to patient age. However, the package insert for lansoprazole, a common proton-pump inhibitor (PPI) drug, reports that its “pharmacokinetics in pediatric patients aged 1 to 17 years [are] similar to those observed in healthy adult subjects.” Numerous recent articles, in contrast, suggest that higher dosages are needed for children, although these articles establish no definite pharmacokinetic relationship between patient age and drug half-life. Establishing the correct half-life is important for appropriate dosage regimen development for PPI drugs. Methods: Evaluation of previously published literature reveals an unusually large degree of variability in most studies. This variation can be caused by: (1) rapid versus slow metabolizer status based on genetic variation in Cytochrome P450, (2) immature hepatic function, (3) hepatic dysfunction, and (4) errors related to timing of blood draws with enteric-coated products. Meanwhile, when the ages of the patients in the same studies are plotted against the respective half-lives of lansoprazole, an increase in half-life with age is observable. After removing data involving patients with immature hepatic function and eliminating outlying points by using statistically acceptable methods, the relationship between age and half-life becomes even more evident.TableTo further investigate this relationship between age and half-life, a single dose of buffered lansoprazole suspension was administered to six children and pharmacokinetics were evaluated by standard methods. The drug was delivered in caracream, a flavored suspension that is buffered with sodium bicarbonate (which causes immediate release of lansoprazole into the bloodstream and, therefore, the elimination phase is discrete from the absorption phase and timing of blood draws is much simpler). Results: The half-life of the drug in each of the six patients was much lower than in other studies involving adults; furthermore, almost no variability was evident. When this data is compared with previously published data in pediatrics, it becomes clear that lansoprazole half-life increases with age. Conclusion: These results explain why many clinicians find a need for larger daily doses of PPIs in children and the consideration of such factors is critical in the effort to control Gastroesophageal Reflux Disease in children.

Down-Regulation of the Monocarboxylate Transporter 1 Is Involved in Butyrate Deficiency During Intestinal Inflammation

Butyrate oxidation is impaired in intestinal mucosa of patients with inflammatory bowel diseases (IBD). Butyrate uptake by colonocytes involves the monocarboxylate transporter (MCT) 1. We aimed to investigate the role of MCT1 in butyrate oxidation deficiency during colonic inflammation. Colonic tissues were collected from patients with IBD or healthy controls and from rats with dextran sulfate sodium (DSS)-induced colitis. The intestinal epithelial cell line HT-29 was treated with interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). MCT1 expression was analyzed by real-time reverse-transcription polymerase chain reaction, Western blot, and immunofluorescence. Butyrate uptake and oxidation in HT-29 cells was assessed using [(14)C]-butyrate. The mechanism of MCT1 gene regulation was analyzed by nuclear run-on and reporter gene assays. MCT1 messenger RNA (mRNA) and protein levels were markedly decreased in inflamed colonic mucosa of IBD patients and rats. In HT-29 cells, down-regulation of MCT1 mRNA and protein abundance by IFN-gamma and TNF-alpha correlated with a decrease in butyrate uptake and subsequent oxidation. IFN-gamma and TNF-alpha did not affect MCT1 mRNA stability but rather down-regulated gene transcription. We demonstrate that the cytokine response element is located in the proximal -111/+213 core region of the MCT1 promoter. The data suggest that butyrate oxidation deficiency in intestinal inflammation is a consequence of reduction in MCT1-mediated butyrate uptake. This reinforces the proposition that butyrate oxidation deficiency in IBD is not a primary defect.

Nuclear Data Sheets for A = 232

The evaluator presents in this publication spectroscopic data and level schemes from radioactive decay and nuclear reactions for all nuclei with mass number A = 232. Highlights from this evaluation include the discovery of a new isotope of francium, 232Fr, and the study of its β − decay to levels in 232Ra (2004Pe17,1990Me13). Also, it includes the first observation of spontaneous fission in 232Th and 232U, as well as the measurement of their respective partial half-lives of 1.2 (4) × 10 21y (1995Bo18) and 2.6 (5) × 10 15y (2000Bo46) for this type of decay.

Opiate Concentrations in Hair from Subjects in a Controlled Heroin-Maintenance Program and from Opiate-Associated Fatalities

One month before (T-1) and 12 months after (T12) controlled intravenous administration of pharmaceutical heroin-HCl (10-1000 mg/d) in the context of a heroin-maintenance program, concentrations of opiates in head hair were determined (n = 46), using a validated gas chromatography-mass spectrometry method with limits of detection (LOD) between 0.02 and 0.04 ng/mg. In addition, a collective of opiate-associated fatalities was examined (n = 24). The obtained concentrations in the proximal segment (1 cm) of the patients were between 0.04 and 1.16 ng/mg (mean 0.13 ng/mg) for heroin (HER), between 0.02 and 32.41 ng/mg (mean 1.48 ng/mg) for 6-monoacetylmorphine (MAM) and between 0.03 and 11.79 ng/mg (mean 1.19 ng/mg) for morphine (MOR). With the exception of the analyte HER, there was no other statistically significant difference in the concentrations in comparison to the opiate fatalities [HER 1.55-5.20 ng/mg mean 3.38 ng/mg), MAM 0.04-30.01 ng/mg (mean 2.14 ng/mg), and MOR 0.03-11.87 ng/mg (mean 1.15 ng/mg) in the proximal segments]. After controlled HER administration, a correlation between the dose and the total opiate concentration in the hair was found (r = 0.66). These results disagree with the observations of authors who found only limited dose-concentration relationships after heroin abuse in hair. When considering a single analyte, the coefficient of correlation increased in correspondence to the respective plasma half-life (r = 0.42, r = 0.58, and r = 0.69 for HER, MAM, and MOR). The latter findings are in agreement with the report that states that this correlation is influenced by the plasma half-lifes of analytes. Codeine and acetylcodeine (AC) were detected in 50% and 43.5% (T-1) and 13% and 10.9% (T12) of the samples of the HER-maintenance program, as well as in 33.3% and 16.7% in opiate-associated fatalities, respectively. The lack of differences between obtained opiate concentrations in the hair of participants in a controlled heroin maintenance program and of opiate-associated fatalities does not support the hypothesis that an absence of tolerance can be regarded as a potential cause of death. In addition, the lack of AC, which was also observed in the majority of the deaths, questions its applicability as a characteristic marker of the consumption of illicit heroin.

KINETICS OF PAHS LOSSES AND RELATIONSHIPS BETWEEN PAHS PROPERTIES AND PROPERTIES OF SOIL IN SEWAGE SLUDGE-AMENDED SOIL

The properties of soil determine the activity of its microflora which is responsible for the degradation of polycyclic aromatic hydrocarbons (PAHs). Moreover, soil properties influence the strength of the interactions between the PAHs and individual soil components. The introduction of sewage sludge into the soil changes these properties which, in turn, changes environmental conditions. In the present studies, relationships between the PAH content and changes in selected soil properties (pH, CEC, TEB, BS, N t ) have been evaluated. The present experiment was carried out in two blocks of experimental plots divided according to the type of plants grown. In the first block, the following field plants were grown in specific sequence, (maize, spring barley, winter rape, potatoes and cereal mixture) while in the other block a perennial, i.e. willow, was grown. Plant cultivation was carried out for 54 months, whereas the cultivation of the willow was conducted over 42 months. Each block consisted of 6 plots with a surface area of 15 m2 into which sewage sludge had been introduced in the following doses: soil without fertilization – control, sludge 30, 75, 150, 300, 600 t/ha. Both the disappearance rate and the scope of the individual polycyclic aromatic hydrocarbons as determined by their respective half-lives showed that losses of these compounds depended on the sewage sludge properties (among other things, the pollutant content) as well as the sludge dose and the type of area used. The correlation coefficients determined depended on the sludge dose and the experimental variant. The highest frequency of their occurrence was found in the case of the total sum of nitrogen and cation exchange capacity for the highest sludge doses (in the experimental with willow).

Anaerobic degradation of diethyl phthalate, di- n-butyl phthalate, and di-(2-ethylhexyl) phthalate from river sediment in Taiwan

We investigated anaerobic degradation rates for three phthalate esters (PAEs), diethyl phthalate (DEP), di- n-butyl phthalate (DBP), and di-(2-ethylhexyl) phthalate (DEHP), from river sediment in Taiwan. The respective anaerobic degradation rate constants for DEP, DBP, and DEHP were observed as 0.045, 0.074, and 0.027 1/day, with respective half-lives of 15.4, 9.4, and 25.7 days under optimal conditions of 30 °C and pH 7.0. Anaerobic degradation rates were enhanced by the addition of the surfactants brij 35 and triton N101 at a concentration of 1 critical micelle concentration (CMC), and by the addition of yeast extract. Degradation rates were inhibited by the addition of acetate, pyruvate, lactate, FeCl 3, MnO 2, NaCl, heavy metals, and nonylphenol. Our results indicate that methanogen, sulfate-reducing bacteria, and eubacteria are involved in the degradation of PAEs.

Dynamic structure–function relationships in enzyme stabilization by ionic liquids

The stability of α-chymotrypsin and Candida antarctica lipase B (CALB) in two ionic liquids (i.e. 1-ethyl-3-methyl-imidazolium, bis[(trifluoromethyl)sulfonyl]imide [emim] [NTf2], and butyl-trimethylamonium bis[(trifluoromethyl)sulfonyl]imide [btma] [NTf2]) has been studied. Both enzymes were strongly stabilized by the ionic liquids, the respective half-life times increasing 96 and 1660 times, with respect to those obtained in classical organic solvents such as 1-propanol and hexane, respectively. The stabilization of both enzymes by ionic liquids may be related to the associated structural changes of proteins that they can be observed by both fluorescence and circular dichroism spectroscopic studies.

Stability-Indicating HPLC Method for the Determination of Metadoxine as Bulk Drug and in Pharmaceutical Dosage Form

A sensitive and reproducible method is described for the quantitative determination of metadoxine in the presence of its degradation products. The method was based on high performance liquid chromatographic separation of the drug from its degradation products on the reversed phase, kromasil column [C18 (5-micron, 25 cm × 4.6 mm, i.d.)] at ambient temperature using a mobile phase consisting of methanol and water (50: 50, v/v). Flow rate was 1.0 mL min−1 with an average operating pressure of 180 kg cm−2 and tR was found to be 2.85 ± 0.05 min. Quantitation was achieved with UV detection at 286 nm based on peak area with linear calibration curves at concentration range 10–100 μg mL−1. This method has been successively applied to pharmaceutical formulation. No chromatographic interference from the tablet excipients was found. The method was validated in terms of precision, robustness, recovery and limits of detection and quantitation. Drug was subjected to acid, alkali and neutral hydrolysis, oxidation, dry heat, wet heat treatment and photo and UV degradation. As the proposed method could effectively separate the drug from its degradation products, it can be employed as stability indicating one. Moreover, the proposed HPLC method was utilized to investigate the kinetics of the acidic, alkaline and oxidative degradation processes at different temperatures and their respective apparent pseudo first order rare constant, half-life and activation energy was calculated with the help of Arrhenius plot. In addition the pH-rate profile of degradation of metadoxine in constant ionic strength buffer solutions with in the pH range 2–11 was studied.

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the rat.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.

Atrazine and metolachlor in surface runoff under typical rainfall conditions in southern Louisiana.

Atrazine and metolachlor are commonly detected in surface water bodies in southern Louisiana. These herbicides are frequently applied in combination to corn, and atrazine to sugarcane, in this region. A study was conducted on the runoff of atrazine and metolachlor from 0.21 ha plots planted to corn on Commerce silt loam, a Mississippi River alluvial soil. The study, carried out over a three-year period characterized by rainfall close to the 30-year average, provided data on persistence in the surface soil (top 2.5 cm layer) and in the runoff active zone of the soil, as measured by decrease in runoff concentrations with time after application. Regression equations were developed that allow an estimate of the runoff extraction coefficients for each herbicide. Atrazine showed soil half-lives in the range 10.5-17.3 days, and metolachlor exhibited half-lives from 15.8-28.0 days. Concentrations in successive runoff events declined much faster than those in the surface soil layer: Atrazine runoff concentrations decreased over successive runoff events with a half-life from 0.6 to 5.7 days, and metolachlor in runoff was characterized by half-lives of 0.6-6.4 days. That is, half-lives of the two herbicides in the runoff-active zone were one-tenth to one-half as long as the respective half-lives in the surface soil layer. Within years, the half-lives of these herbicides in the runoff active zone varied from two-thirds longer for metolachlor in 1996 to one-fifth longer for atrazine in 1995. The equations relating runoff concentrations of atrazine and metolachlor to soil concentrations contain extraction coefficients of 0.009. Losses in runoff for atrazine were 5.2-10.8% of applied, and for metolachlor they were 3.7-8.0%; atrazine losses in runoff were 20-40% higher than those for metolachlor. These relatively high percent of application losses indicate the importance of practices that reduce runoff of these chemicals from alluvial soils of southern Louisiana.

Purification and characterization of an extracellular laccase of a fungus (family Chaetomiaceae) isolated from soil

A laccase-producing fungus was newly isolated from soil and shown to belong to family Chaetomiaceae. The extracellular laccase was purified to electrophoretic homogeneity from coffeic acid-induced culture medium by ammonium sulfate precipitation and anion exchange column chromatography. The enzyme was determined to be a monomeric protein with an apparent molecular mass of approximately 73–80 kDa and an isoelectric point (p I) of 3.5. One of its peptide fragments derived by endopeptidase digestion had a 68.75% amino acid sequence homologous to that of laccase I of Botryotinia fuckeliana. Spectroscopic analysis revealed that the enzyme has four bound copper atoms, a type I Cu(II), a type II Cu(II), and a type III binuclear Cu(II). The optimum pH for the oxidation of syringaldazine was 7.0 and the optimum temperature was 42 °C. The laccase was stable for up to 288 h at 4 °C and its respective half-life times at 25 and 40 °C were estimated to be 150 and 20 h. The enzyme reaction was inhibited by l-cysteine, dithiothreitol (DTT), p-coumaric acid, kojic acid, and thioglycolic acid. The enzyme oxidized various known laccase substrates, its lowest K m value being for syringaldazine, highest k cat value for 4-hydroxyindole, and highest k cat/ K m for 2,6-dimethoxy-phenol. In addition to these substrates, this laccase was effective for the biodegradation of endocrine-disrupting chemicals such as bisphenol A and nonylphenol (NP).

Simulated in vitro Quinolone Pharmacodynamics at Clinically Achievable AUC/MIC Ratios: Advantage of IE over Other Integral Parameters

To compare the antimicrobial effects of clinically achievable ratios of area under the curve (AUC) to MIC, a clinical isolate of Moraxella catarrhalis was selected with MICs corresponding to the MIC₅₀s of four quinolones. Monoexponentially declining concentrations observed in human plasma after oral administration of 1,000 mg of ciprofloxacin (as two 500-mg doses at a 12-hour interval), 320 mg gemifloxacin, 500 mg levofloxacin or 400 mg moxifloxacin (each as a single dose) and were simulated in an in vitro dynamic model. The respective half-lives were 4, 7.4, 6.8 and 12.1 h, and the AUC/MICs were 730, 1,130, 920 and 690 h. The time-kill/regrowth curves yielded similar patterns with the four quinolones: a rapid reduction in bacterial numbers followed by bacterial regrowth that occurred later with moxifloxacin than with ciprofloxacin, gemifloxacin, and levofloxacin. The total antimicrobial effect of moxifloxacin as expressed by the I_E parameter (area between the control growth and time- kill curves from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of antimicrobial) was 30, 55, and 120% greater than gemifloxacin, levofloxacin and ciprofloxacin, respectively. Unlike I_E, the other integral indices determined over a fixed time (24 h) – the area between the control growth and time-kill curves, area above the time-kill curve and area under the time-kill curve were similar for the four fluoroquinolones, thus precluding their differentiation.

American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.

### Mechanism of Action of Coumarin Anticoagulant Drugs Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K–dependent proteins (Figure 1).1–6 These proteins, which include the coagulation factors II, VII, IX, and X, require γ-carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity.7,8 Figure 1. The vitamin K cycle and its link to carboxylation of glutamic acid residues on vitamin K–dependent coagulation proteins. Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders the coagulation factors II, VII, IX, and X and the anticoagulant factors protein C and protein S functionally active. Vit KO is then reduced to Vit K1 in a reaction catalyzed by vitamin KO reductase. By inhibiting vitamin KO reductase, warfarin blocks the formation of vitamin K1 and vitamin KH2, thereby removing the substrate (vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1, either given therapeutically or derived from food sources, can overcome the effect of warfarin by bypassing the warfarin-sensitive vitamin KO reductase step in the formation of vitamin KH2. Carboxylation promotes binding of the vitamin K–dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation.9–11 γ-Carboxylation requires the reduced form of vitamin K (vitamin KH2). Coumarins block the formation of vitamin KH2 by inhibiting the …

Biodegradation of soil-derived dissolved organic matter as related to its properties

Abstract Quantifying the contribution of dissolved organic matter (DOM) to C sequestration in soils requires knowledge about extent and rate of its biodegradation. Since degradation experiments are time consuming, estimating the biodegradability of DOM by more easily measurable properties seems valuable. Our goal was therefore to investigate the biodegradation of DOM of different origin and to relate its extent and rate to properties such as UV absorbance, synchronous and emission scan fluorescence, XAD-8 sorption chromatography and 1 H-NMR spectroscopy. We extracted DOM from 13 different samples (maize straw, forest floors, peats, agricultural soils) and carried out a 90-day liquid incubation experiment. DOM biodegradation was quantified by CO 2 evolution. Rapidly and slowly mineralizable portions of dissolved organic carbon (DOC) as a measure of labile and stable DOC and the respective mineralization rate constants and half-lives were calculated by a double exponential model. The extent and rate of DOM biodegradation from less humified organic material (straw, litter and fermentation layers of forest floors) were high resulting in 61–93% of DOC being mineralized. The labile fraction comprised 59–88% of total DOC. DOM extracted from agricultural soils was of an intermediate biodegradability with a CO 2 evolution comprising 17–32% of total DOC. Labile DOC represented 14–25% of total DOC. DOM extracted from peats and Oa forest floor layers was relatively stable (mineralization of 4–9% of total DOC, labile DOC: 3–6%). The half-life of the labile DOC pool was short (2–5 days), whereas that of the stable DOC pool ranged from 0.2 years (DOM from less humified material) to 8.6 years (DOM from the Oa layer under spruce). Extent and rate of DOM biodegradation were closely but nonlinearly related to DOM properties. Solutions exceeding a threshold value of UV absorbance, aromaticity, XAD-8 adsorbable C or of humification indices derived from fluorescence spectra or having carbohydrate contents below a certain level were stable against biodegradation. Relatively simple methods like UV spectroscopy, XAD-8 fractionation and fluorescence emission spectroscopy were suitable to estimate the biodegradation of DOM.

Occurrence and microbial degradation of phthalate esters in Taiwan river sediments.

Concentrations and microbial degradation rates were measured for eight phthalate esters (PAEs) found in 14 surface water and six sediment samples taken from rivers in Taiwan. The tested PAEs were diethyl phthalate (DEP), dipropyl phthalate (DPP), di-n-butyl phthalate (DBP), diphenyl phthalate (DPhP), benzylbutyl phthalate (BBP), dihexyl phthalate (DHP), dicyclohexyl phthalate (DCP), and di-(2-ethylhexyl) phthalate (DEHP). In all samples, concentrations of DEHP and DBP were found to be higher than the other six PAEs. DEHP concentrations in the water and sediment samples ranged from ND to 18.5 microg/l and 0.5 to 23.9 microg/g, respectively; for DBP the concentration ranges were 1.0-13.5 microg/l and 0.3-30.3 microg/g, respectively. Concentrations of DHP, BBP, DCP and DPhP were below detection limits. Under aerobic conditions, average degradation half-lives for DEP, DPP, DBP, DPhP, BBP, DHP, DCP and DEHP were measured as 2.5, 2.8, 2.9, 2.6, 3.1, 9.7, 11.1 and 14.8 days, respectively; under anaerobic conditions, respective average half-lives were measured as 33.6, 25.7, 14.4, 14.6, 19.3, 24.1, 26.4 and 34.7 days. In other words, under aerobic conditions we found that DEP, DPP, DBP, DPhP and BBP were easily degraded, but DEHP was difficult to degrade; under anaerobic conditions, DBP, DPhP and BBP were easily degraded, but DEP and DEHP were difficult to degrade. Aerobic degradation rates were up to 10 times faster than anaerobic degradation rates.

Estimation and implications of random errors in whole-body dosimetry for targeted radionuclide therapy

For targeted radionuclide therapy, the level of activity to be administered is often determined from whole-body dosimetry performed on a pre-therapy tracer study. The largest potential source of error in this method is due to inconsistent or inaccurate activity retention measurements. The main aim of this study was to develop a simple method to quantify the uncertainty in the absorbed dose due to these inaccuracies. A secondary aim was to assess the effect of error propagation from the results of the tracer study to predictive absorbed dose estimates for the therapy as a result of using different radionuclides for each. Standard error analysis was applied to the MIRD schema for absorbed dose calculations. An equation was derived to describe the uncertainty in the absorbed dose estimate due solely to random errors in activity–time data, requiring only these data as input. Two illustrative examples are given. It is also shown that any errors present in the dosimetry calculations following the tracer study will propagate to errors in predictions made for the therapy study according to the ratio of the respective effective half-lives. If the therapy isotope has a much longer physical half-life than the tracer isotope (as is the case, for example, when using 123I as a tracer for 131I therapy) the propagation of errors can be significant. The equations derived provide a simple means to estimate two potentially large sources of error in whole-body absorbed dose calculations.

Single-dose pharmacokinetics of porcine factor VIII (Hyate C).

The objective was to establish the pharmacokinetic properties of porcine factor VIII (pFVIII) at three different doses in a single patient. The patient, born in 1952, had severe haemophilia A and developed an inhibitor to human FVIII (hFVIII) in 1966 aged 14 years. He was first treated with pFVIII in 1980. Apart from a short period of treatment with hFVIII in 1998 which resulted in the reappearance of the inhibitor, pFVIII has been constantly used since 1984. No inhibitor against human or porcine FVIII had been recordable over the 2-year period prior to the study. Three separate pharmacokinetic studies were performed using a washout period of 72 h and doses of 10 U kg (-1), 25 U kg (-1), or 50 U kg (-1), respectively, with sampling at preinfusion, then at 15 and 30 min and 1, 3, 6, 9, 12 and 24 h postinfusion. The FVIII levels were measured using both plasma derived one stage APTT based assay and chromogenic assay. The results were computed using a model-independent analysis and a model-dependent analysis. The respective clearances (mL h(-1)kg(-1)) at doses 50 U, 25 U or 10 U kg (-1) were 1.32, 1.33 1.8 (bioassay) and 2.54, 2.93, 9.43 (chromogenic). The respective half-lives (h) at doses 50 U, 25 U, and 10 U kg (-1) were 23.71, 16.54, 25.17 (bioassay) and 15.71, 17.39, and 10.66 (chromogenic). The respective recoveries (u dL(-1)/u kg(-1)) at doses 50 U, 25 U, and 10 U kg (-1) were 2.32, 2.44, 2.7 (bioassay) and 1.42, 1.16 and 0.9 (chromogenic). It was found that the two compartment model best fitted the curves of the bioassay and a one compartmental model best fitted the curves of the chromogenic assay. The pharmacokinetic studies are the first to be performed at different dose levels and using different assay methods for pFVIII. Using the bioassay, they show a long half-life and high recovery compared to hFVIII. The differences between the bioassay and the chromogenic assay reflect their different biological basis and are of relevance when potency labelling is performed using chromogenic assay (European Pharmacopeia).

Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection

Intravenous glycyrrhizin has been used in Japan for the treatment of chronic hepatitis for >20 years, although only a few reports of its pharmacokinetic profile after multiple intravenous doses in small numbers of Japanese patients have been published. The present study compared these Japanese data against the pharmacokinetic characteristics of glycyrrhizin after single and multiple intravenous doses in 35 European patients with chronic hepatitis C infection. We administered 80, 160, or 240 mg glycyrrhizin 3 times/wk or 200 mg glycyrrhizin 6 times/wk for 4 weeks. Twenty-four-hour pharmacokinetic assessments were performed on day 1 and on or around day 14. Glycyrrhizin levels were determined by high-performance liquid chromatography. The mean (± SD) volume of distribution at steady state on day 1 in the 80-, 160-, 200-, and 240-mg groups were 67 ± 11, 62 ± 13, 54 ± 7, and 66 ± 8 mL/kg, respectively. The respective terminal elimination half-lives on day 1 were 7.7 ± 2.8, 10.1 ± 1.4, 9.0 ± 2.3, and 8.6 ±2.1 hours. The area under the curve (AUC) increased linearly with doses <-200 mg ( r = 0.67; P < 0.001). No significant differences between day 1 and day 14 were found in any dose group, with the exception of AUC in the 200-mg group, which was significantly higher on day 14 compared with day 1 ( P = 0.03). Comparing the European and Japanese data, the mean (± SD) AUC was 289 ± 244 μg/h per mL for the former and 402 ± 372 μg/h per mL for the latter; the half-life was 8.2 ± 2.6 versus 8.8 ± 9.0 hours; and the total clearance was 7.6 ± 3.6 versus 8.5 ± 5.7 mL/h per kg. Thus our pharmacokinetic data are comparable to those from Japan. Glycyrrhizin's pharmacokinetics are linear up to 200 mg. Drug accumulation is seen after 2 weeks of treatment with 200 mg administered 6 times/wk.

Pharmacokinetics of NS-49, a phenethylamine class α 1A-adrenoceptor agonist, at therapeutic doses in several animal species and interspecies scaling of its pharmacokinetic parameters

The pharmacokinetics of NS-49, a newly developed phenethylamine class α 1A-adrenoceptor agonist, was investigated in rats, rabbits, and dogs given intravenous and oral doses that have little effect on the renal blood flow rate (approximating the range of clinical doses). A three-compartment open model adequately described the plasma NS-49 profiles with respective elimination half-lives of 18, 19, and 13 h after intravenous administration of NS-49 to rats, rabbits and dogs. After oral administration, the NS-49 plasma concentrations reached their maximums within 1.5 h in all the species tested, then decreased as in intravenous administration. The systemic availability was 80% for the rats, 70% for the rabbits, and 101% for the dogs. From the pharmacokinetic parameter values for these three species, we predicted human pharmacokinetics of NS-49 after oral administration with an animal scale-up approach. The area under the plasma concentration-time curve (AUC) after oral administration, as well as the total body clearance showed an excellent allometric relationship to body weight across the three species. The oral AUC value for humans therefore could be predicted from this correlation. The predicted value agreed well with the observed value in the clinical phase I study. It was difficult to predict the plasma concentration profile of NS-49 for humans after oral administration because the absorption rate constant ( k a) that is essential for estimation of the maximum concentration exhibited no correlation across the species tested. But we approximately could simulate the plasma concentration profile of NS-49 for humans by using the k a value for the rats or rabbits.

Kinetics of thermal inactivation of pea seed lipoxygenases and the effect of additives on their thermostability

Mature pea seeds contain two major lipoxygenases (LOX) isoenzymes designated LOX-2 and LOX-3. The thermal inactivation of crude pea LOX and the recombinant LOX (rLOX) were studied. Heat-inactivation plots for crude extracts of pea LOX were linear from which thermodynamic activation parameters, ΔH #, ΔS # sand ΔG # have been estimated. The enzymatic activity was relatively stable with a respective half-life ( t 1/2) at 60 °C of 54.2 min for LOX from pea ( Pisum sativum L. cv. Birte) or 18.4 min for a mutant line lacking LOX-2. At 50°C the thermostability of LOX-3 present in crude extracts of the mutant strain ( t 1/2=66.8 min) was 90% greater than purified recombinant LOX-3 (rLOX-3; t 1/2=34.6 min). However, rLOX-3 was more heat-stable than rLOX-2. Both rLOX-3 and pea mutant line lacking LOX-2 possessed considerable thermostability at 60°C ( t 1/2=16.5 min and 18.4 min, respectively). Even at the higher temperatures of 70°C the t 1/2 values were 84 and 51, respectively. It is suggested that LOX in crude enzyme extracts was stabilised at 50°C due to protection by other constituents, possibly including starch and proteins. Separate tests at 70°C in the presence of additives (polyols, detergents and small ions) showed that sucrose was the most effective stabiliser and increased the stability of pea LOX by 400–600%.