Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in healthy Korean subjects.

WHAT IS KNOWN AND OBJECTIVE: Dexmedetomidine is a selective alpha2-adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects. METHODS: A randomized, double-blind, placebo-controlled study with three parallel dosage groups was conducted. Twenty-four subjects were randomly assigned to placebo or one of three dexmedetomidine dosing regimens, 3 µg/kg/h for 10 min followed by 0.17 µg/kg/h for 50 min (low dose), 6 µg/kg/h for 10 min followed by 0.34 µg/kg/h for 50 min (middle dose) and 3.7 µg/kg/h for 35 min followed by 0.7 µg/kg/h for 25 min (high dose). Serial blood samples for PK analysis were taken up to 12 h. PK parameters were determined using non-compartmental methods (WinNonlin(®)), and a population PK model was developed using nonmem(®). The sedative effect of dexmedetomidine was assessed by Ramsay sedation score and visual analogue scales/sedation. Adverse events, clinical laboratory tests, electrocardiograms, physical examinations and vital signs were monitored for tolerability assessment. RESULTS: Six subjects were assigned to each of the three active treatment group or placebo group. The AUC(last) of the low-, middle- and high-dose group were 1096.8 ± 119.9 (mean ± SD) ng*h/L, 2643.0 ± 353.2 ng*h/L and 5600.6 ± 411.0 ng*h/L, respectively. PK of dexmedetomidine was best described using a two-compartment model. The typical value of the population model can be calculated using the following equations: central volume of distribution (L) = 19.9 (age/27)(0.954), peripheral volume of distribution (L) = 59.4, clearance (L/h) = 33.7 (albumin level/4.3)(1.42) and inter-compartment clearance (L/h) = 67.7. Sedative effects were significantly increased by dexmedetomidine compared to placebo. The blood pressure and heart rate were decreased, but oxygen saturation was maintained stable. WHAT IS NEW AND CONCLUSION: Dexmedetomidine shows linear PK characteristics and dose-dependent sedative effects. A two-compartment population PK model was developed for healthy Korean subjects. The PK parameter estimates are similar in Koreans and Caucasians.

An Altered aroA Gene Product Confers Resistance to the Herbicide Glyphosate.

The hypothesis that the herbicide glyphosate (N-phosphonomethylglycine) acts on plants and microorganisms by inhibiting synthesis of 5-enolpyruvyl-3-phosphoshikimate, a precursor to aromatic amino acids, was tested. Salmonella typhimurium was treated with ethyl methanesulfonate, and mutants mapping at the aroA locus, which encodes 5-enolpyruvyl-3-phosphoshikimate synthetase, were isolated by selection for glyphosate resistance. One of the mutants results in the synthesis of a 5-enolpyruvyl-3-phosphoshikimate synthetase that is resistant to inhibition by glyphosate. The mutant aroA gene and the corresponding wild-type allele were cloned. The mutation confers high resistance to glyphosate when introduced in Escherichia coli in the presence or absence of the wild-type aroA allele.

Herbicide resistance in transgenic plants expressing a bacterial detoxification gene.

The herbicide bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) is a photosynthetic (photosystem II) inhibitor in plants. A gene, bxn, encoding a specific nitrilase that converts bromoxynil to its primary metabolite 3,5-dibromo-4-hydroxybenzoic acid, was cloned from the natural soil bacterium Klebsiella ozaenae. For expression in plants, the bxn gene was placed under control of a light-regulated tissue-specific promoter, the ribulose bisphosphate carboxylase small subunit. Transfer of this chimeric gene and expression of a bromoxynil-specific nitrilase in leaves of transgenic tobacco plants conferred resistance to high levels of a commercial formulation of bromoxynil. The results presented indicate a successful approach to obtain herbicide resistance by introducing a novel catabolic detoxification gene in plants.

Single dose pharmacokinetics of linezolid in infants and children.

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Serum inhibitory titers and serum bactericidal titers for human subjects receiving multiple doses of the antibacterial oxazolidinones eperezolid and linezolid.

In Phase I trials subjects received multiple doses of eperezolid (PNU-100592; formerly U-100592) and linezolid (PNU-100766; formerly U-100766), and steady-state samples were drawn at the projected peak and trough timepoints. Serum inhibitory titer and serum bactericidal titer values were determined using single strains of Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Serum inhibitory titer values generally correlated with drug concentration in serum and inherent organism susceptibility. Against S. aureus and E. faecalis sera from patients dosed with either drug were generally inhibitory at the peak timepoint, but at trough only linezolid exhibited a persistent effect. No bactericidal activity was seen for either drug against S. aureus or E. faecalis. The sera from patients dosed with either drug exhibited inhibition of S. pneumoniae at peak and trough. Bactericidal activity was seen against S. pneumoniae for both drugs at peak time and at trough for many of the sera for patients on the higher dose regimens. The results demonstrated that the sera from most human subjects dosed with eperezolid or linezolid were inhibitory to S. aureus and E. faecalis and S. pneumoniae and that many of the samples exhibited bactericidal activity for S. pneumoniae.

Bioavailability of medroxyprogesterone acetate from three oral dosage formulations.

The bioavailability of three formulations of medroxyprogesterone acetate (MPA) was assessed in 30 healthy male volunteers in a three-way, open-label, cross-over-designed trial. Each subject received one Provera 500-mg tablet, one Farlutal 500-mg tablet, and one Provera 500-mg granule packet according to a randomized schedule, with each treatment separated by a 21-day washout period. Serum MPA levels were determined using both radioimmunoassay (RIA) and high-performance liquid chromatography techniques. Based on the results of RIA analysis, Farlutal tablets produced significantly lower serum MPA concentrations compared with Provera tablets at most sampling times, resulting in statistically lower AUC0-144 for the Farlutal tablet (544 vs 768 ng.hr/ml; -29.2%). The Farlutal tablet also had a significantly lower maximum concentration than the Provera tablet (27.8 vs 47.4 ng/ml; -41.4%). However, there was no significant difference in time of maximum concentration between the tablet formulations (3.71 vs 3.41 hr), indicating that the rates of absorption of the two tablet formulations were comparable. Provera granules provided significantly higher serum MPA levels than Provera tablets at 0.5, 1, 1.5, 2, and 6 hours, and the AUC0-144 for Provera granules was higher by 5.47% (810 vs 768 ng.hr/ml). There were no differences in terminal elimination rate constants among the dosage forms. No significant adverse events were noted during the trial. The relative bioavailabilities of Provera granules and Farlutal tablets were 105% and 71.2%, respectively, compared with Provera tablets.

Population pharmacokinetics of glyburide in patients with well-controlled diabetes.

STUDY OBJECTIVES: To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics. METHODS: Prospective, open-label study. SETTING: University-affiliated, internal medicine outpatient clinic. PATIENTS: Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below. INTERVENTION: After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs). CONCLUSION: Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.

Ibuprofen piconol hydrolysis in vitro in plasma, whole blood, and serum using different anticoagulants.

Hydrolysis kinetics of ibuprofen piconol to ibuprofen were determined in vitro in plasma, whole blood, and serum. Varying initial concentrations of ibuprofen piconol with different anticoagulants (EDTA, heparin, citrate, or no anticoagulant) were used in determining the effects each had on the rate of ibuprofen piconol hydrolysis. Varying the initial concentration of ibuprofen piconol did not alter the hydrolysis half-life (concentration range from 50 to 200 micrograms/mL). The anticoagulant used altered the hydrolysis half-life. For plasma, the half-life was shortest when no anticoagulant was present (t 1/2 = 2.5 h) and longer with the presence of anticoagulants; for citrate, t 1/2 = 8.0 h, for heparin; t 1/2 = 15.5 h; and for EDTA, t 1/2 = 161.8 h. Red blood cell uptake of ibuprofen piconol was minimal and ranged from 0.4 to 4.1% over the ibuprofen piconol concentrations used in the study.

Solubility enhancement of phenol and phenol derivatives in perfluorooctyl bromide.

Perfluorinated solvents are gaining popularity as pulmonary ventilation fluids, but they suffer from poor solvent quality in concurrent drug delivery applications. The present study examines the use of a hydrophobic solubilizing agent capable of interacting with model drug solutes by hydrogen bonding with the purpose of enhancing solubility in perfluorooctyl bromide (PFOB). A series of solubilizing agents containing a ketone carbonyl to act as a hydrogen bond acceptor and a perfluoroalkyl chain to maintain the solubility of the putative complex in PFOB are investigated. The solubility of phenol in PFOB is enhanced to the greatest extent by 1-(4-perfluorobutyl phenyl)-1-hexanone (III) where the ketone carbonyl is protected from the electron withdrawing effects of the perfluorobutyl chain by a phenyl ring. Experiments with solubilizers lacking the ketone group suggest that pi-pi bond interactions of III with phenol do not significantly enhance solubility. For a series of phenol derivatives, a rank-order correlation exists between the magnitude of solubility enhancement by III, as reflected by the calculated association constants, and the Hammett sigma parameter of the phenols. Because the O-methyl-substituted phenols do not have the ability to hydrogen bond, their solubility is not enhanced by the presence of III. The results of the present study indicate that solubility of model drug hydrogen bond donating compounds can be enhanced in PFOB by the presence of fluorocarbon-soluble hydrogen bond acceptors.

Evidence and alternative medicine.

The most important thing we have to decide about alternative therapies is whether to test them in a clinical trial format. In order to decide this, we need to compare the prior probabilities of alternative therapy hypotheses with the prior probabilities of conventional therapy hypotheses that end up in clinical trials. If the prior probabilities of the alternative therapy hypotheses are lower than the prior probabilities for their competing conventional hypotheses, we do not have a good reason to test them. There are basic science reasons, source reasons, and methodologic reasons for assigning low prior probabilities to typical alternative therapy hypotheses--indeed, hypotheses that the NIH Office of Alternative Medicine supports. Basic science reasons are of two types: whether the hypothesis agrees with a piece of basic science that does not have a good deal of support, and whether the hypothesis is logically incompatible with a well-supported piece of basic science. The source reasons are about the educational and other characteristics of the people who discover, pursue, and promote a therapy hypothesis. The methodologic reasons are about how well a therapy hypothesis satisfies methodologic criteria such as simplicity and modesty. Other things being equal, a hypothesis that is simpler and more modest than other is more plausible as well. Problems arise also about using positive cases in assigning a prior probability to an alternative-therapy hypothesis because virtually every alternative therapy has positive cases, but not every hypothesis is true. The NCI and OTA "best-case" review approach does not solve this problem because it does not include a rule for distinguishing (in a reliable way) between positive cases that show something about a therapy hypothesis being true and positive cases that show nothing of the kind. This paper (as long as it is) is no more than an introductory discussion of some basic points involved in making sensible estimates of the prior probabilities of hypotheses.(ABSTRACT TRUNCATED AT 400 WORDS)

Carnitine supplementation of parenterally fed neonates.

BACKGROUND: Carnitine, a quaternary amino acid, plays an important role in the oxidation of long chain fatty acids. Both breast milk and infant formulas contain carnitine. However, it is not routinely provided in parenteral nutrition solutions. Non supplemented parenterally fed infants have very low tissue carnitine levels. The clinical significance of this is uncertain. Carnitine deficiency may be an etiological factor in the limited ability of premature babies to utilize parenteral lipid. In vitro studies have suggested that fatty acid oxidation is impaired when the tissue carnitine levels fall below 10% of normal. Therefore relative carnitine deficiency may impair fatty acid oxidation, thus reducing the available energy and impairing growth. OBJECTIVES: The primary aim of this review is to determine whether carnitine supplementation of parenterally fed neonates will improve weight gain. The secondary aims are to determine the effect on lipid tolerance and ketogenesis. SEARCH STRATEGY: Computerised searches were carried out by both reviewers. Searches were made of Medline, Embase, The National Research Register (UK), the Cochrane Controlled Trials Register and expert informants. The MeSH headings used were carnitine and parenteral nutrition. SELECTION CRITERIA: Only randomised trials were considered. Trials were included if they involved carnitine supplementation alone, parenterally fed newborn infants, and measured at least one outcome of interest (weight gain, plasma fatty acids, plasma triglycerides, quantity of lipid tolerated, respiratory quotient or beta hydroxybutyrate levels). DATA COLLECTION AND ANALYSIS: The two reviewers searched the literature separately and reached a consensus for inclusion of trials. Data were extracted and evaluated by the two reviewers independently of each other. Authors were contacted if possible to clarify or provide missing data. MAIN RESULTS: Fourteen studies were identified, six met the selection criteria. The results of the review are limited by the fact that the studies were generally short term and studied different outcomes. One study examined short term and long term weight gain, three reported only short term weight gain, three reported biochemical results in response to a short lipid challenge, and two reported results obtained during normal parenteral nutrition. Among infants supplemented with carnitine, there was no evidence of effect on weight gain, lipid utilization or ketogenesis. REVIEWER'S CONCLUSIONS: We found no evidence to support the routine supplementation of parenterally fed neonates with carnitine.

Structure and bonding in the metal complexes of ethylenediaminetetra-acetic acid.

The metal-ion complexes of ethylenediaminetetra-acetic acid (EDTA) find widespread use not only in analysis, but also in foodstuffs, pharmacy, and medicine. A review of the structures of the solid complexes illustrates the considerable variation in co-ordination number of the metal-ion, and the possible denticities of EDTA. These data are relevant to the solid-state properties and also to the structures of the complexes in solution, which cannot be directly determined.

Spectroscopic studies of the metal complexes of ethylenediaminetetra-acetic acid in aqueous solution.

Aqueous solutions of the metal complexes of ethylenediaminetetra-acetic acid (EDTA) are widely used in analysis; though X-ray diffraction methods cannot be directly used for structural determination in solution, ultraviolet-visible region, vibrational and NMR spectroscopy studies demonstrate that the species in solution adopt a similar range of stereochemistries to those determined for the solid state. Thus a review of the spectroscopic properties of the solutions suggests that chelates are formed in which the denticity of EDTA varies from one to six and the co-ordination number about the metal from four to nine.

Production of cyclodextrins, a novel carbohydrate, in the tubers of transgenic potato plants.

Cyclodextrins (CDs) are cyclic oligosaccharides containing six (alpha), seven (beta), or eight (gamma) glucose molecules, respectively. The cyclodextrin glycosyltransferases (CGT), which produce CDs from starch, are found only in bacteria and are used in batch fermentors with hydrolyzed starch to produce CDs commercially. Using a CGT gene from Klebsiella, we attempted to engineer the tubers of developing potatoes to produce these novel, high-value carbohydrates. A chimeric gene, consisting of (1) the patatin promoter for tuber-specific expression, (2) the small subunit of ribulose bisphosphate carboxylase (SSU) transit peptide for plastid targeting, (3) the CGT structural gene from Klebsiella and (4) the nopaline synthase 3' region, was introduced into potatoes. Both alpha and beta CDs were produced in tubers of transgenic potatoes at levels corresponding to 0.001-0.01% of the starch being converted to CDs.

Amplification of a chimeric Bacillus gene in chloroplasts leads to an extraordinary level of an insecticidal protein in tobacco.

The Bacillus thuringiensis (Bt) crystal toxins are safe biological insecticides, but have short persistance and are poorly effective against pests that feed inside plant tissues. Production of effective levels of these proteins in plants has required resynthesis of the genes encoding them. We report that amplification of an unmodified crylA(c) coding sequence in chloroplasts up to approximately 10,000 copies per cell resulted in the accumulation of an unprecedented 3-5% of the soluble protein in tobacco leaves as protoxin. The plants were extremely toxic to larvae of Heliothis virescens, Helicoverpa zea, and Spodoptera exigua. Since the plastid transgenes are not transmitted by pollen, this report has implications for containment of Bt genes in crop plants. Furthermore, accumulation of insecticidal protein at a high level will facilitate improvement in the management of Bt resistant insect populations.