Population pharmacokinetics of amikacin in a Korean clinical population.

OBJECTIVE: This study aimed at investigating the influence of demographic and clinical covariates on the population pharmacokinetics of amikacin in Korean patients from routinely collected therapeutic drug monitoring data. MATERIALS AND METHODS: Pharmacokinetics was studied in 305 adult Korean patients who received amikacin 125 - 1,000 mg once-daily or every-other- day. Peak and trough plasma levels of steady state were measured. Patients were randomized into an index dataset (n = 197) and a validation dataset (n = 108). Covariates were selected in a step-wise approach using NONMEM 7 software. The predictive performance of the model was evaluated by the percent prediction error and the percent coverage of 95% population prediction interval. RESULTS: The covariates significantly influencing amikacin pharmacokinetics were creatinine clearance (p < 0.0001) and ward setting (p = 0.0017) for clearance, and body weight (p < 0.0001) and presence of cholecystitis (p = 0.0135) for volume of distribution. The estimates of pharmacokinetic parameters for a typical individual were 2.82 l/h for clearance, and 18.04 l for volume of distribution. Inter-individual variability (CV%) was 31% for clearance. The mean (SD) of percent prediction errors was 2.1 (26.4)% for peak and -121.5 (460.3)% for trough concentrations. Percent coverage of 95% PPIs for peak and trough concentrations were above 80%. CONCLUSIONS: The population pharmacokinetic model developed in this study may be used as a basis for finding optimal amikacin dosing in a Korean patient population without a significant bias. Further studies will be needed to validate these results.

Effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Korean subjects.

OBJECTIVE: This study aimed to evaluate the effect of genetic polymorphisms of SLCO1B1 and ABCB1 on the pharmacokinetics of atorvastatin and its metabolites. METHODS: 290 Koreans were genotyped for SLCO1B1, ABCB1 and CYP3A5, and 28 subjects were selected for the pharmacokinetic study. Each subject received a single oral dose of 20 mg atorvastatin and blood samples were collected up to 48 hr after dosing. The relationship between the genotypes and atorvastatin pharmacokinetics was examined. RESULTS: For SLCO1B1 genotypes, the mean area under the concentration-time curve from time 0 to infinity (AUC0-infinity) of atorvastatin was 148.2 ng x hr/ml for *15/*15 subjects (n = 3), which was significantly larger than for 1a/*15 and *1b/*15 (n = 8) (80.7 ng x hr/ml, p = 0.0121) and also larger than for *1a/*1a, *1a/*1b and *1b/*1b (n = 17) (66.3 ng x hr/ml, p = 0.0018). The mean AUC0-infinity of 2-hydroxyatorvastatin for *15/*15 was also larger than in *1a/*1a, *1a/*1b and *1b/*1b (p = 0.012). In lactone forms, no significant pharmacokinetic difference was found among the genotypes. For ABCB1 genotypes, the half-lives of atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin and 2-hydroxyatorvastatin lactone were significantly longer in c.2677TT-c.3435TT (n = 3) vs. c.2677GG-c.3435CC and c.2677GT-c.3435CT (n = 10), yielding p = 0.049, 0.007, 0.007 and 0.007, respectively. CONCLUSION: This study shows that the SLCO1B1*15 allele may be associated with the individual difference in the AUC0-infinity of atorvastatin whereas the ABCB1 TT-TT diplotype may affect the elimination half-life of the drug in the Korean population.

A novel K+ competitive acid blocker, YH4808, sustains inhibition of gastric acid secretion with a faster onset than esomeprazole: randomised clinical study in healthy volunteers.

BACKGROUND: YH4808, a K+ -competitive acid blocker, is under clinical development for the treatment of acid-related disorders, such as gastroesophageal reflux disease. AIMS: To determine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH4808, compared to placebo and esomeprazole. METHODS: This double-blind, randomised, placebo- and active comparator (esomeprazole)-controlled study was conducted with 123 healthy male volunteers. We evaluated YH4808 (30-800 mg) properties, administered in single (N=55) and multiple (N=24) oral doses, and recorded the effects on 24-hour intragastric acidity. Results were compared to placebo (N=20) and esomeprazole 40 mg (N=24). RESULTS: Plasma YH4808 exposure increased dose-proportionally and declined in a multi-phasic manner. YH4808 ≥200 mg/d maintained intragastric acidity at pH >4 for longer times than esomeprazole during both day and night (%Time at pH >4: >70% vs 58% of a 24-hour period, respectively; and >50% vs 33% of a 9-hour night respectively). A twice-daily regimen of YH4808 more effectively controlled intragastric pH at night than a once-daily regimen. In evaluating the mean areas under the intragastric pH-time curves in 15-minute intervals for 2 hours after dosing, we found that YH4808 had a faster onset than esomeprazole. Moreover, unlike esomeprazole, YH4808 PK and PD were not significantly affected by the CYP2C19 genotype of the subjects. YH4808 was well-tolerated at all doses administered. CONCLUSION: This study showed that YH4808 produced a rapid, sustained suppression of gastric secretion with good tolerability. The results at YH4808 ≥200 mg/d provide a rationale for further clinical investigations in populations with acid-related diseases.

Effects of three-dimensional assessment on surgical correction and on hook strategies in multi-hook instrumentation for adolescent idiopathic scoliosis.

STUDY DESIGN: A prospective study using intraoperative stereophotogrammetry to analyze change during the correction of scoliosis. OBJECTIVE: To examine the relation between the number of hooks used during segmental instrumentation and the amount of correction achieved. SUMMARY OF BACKGROUND DATA: An intraoperative stereophotogrammetric technique was developed at our center. Vertebral translations and rotations can be measured at several stages during scoliosis surgery. METHODS: Thirty-two patients with right thoracic adolescent idiopathic scoliosis were studied using our stereophotogrammetry technique during surgical correction. Correlations were determined between apical vertebral movements and the hook ratio (number of vertebrae/number of hooks used). RESULTS: Mean curve Cobb angle correction was 66%. Correction occurred in all three planes but primarily along the x and y axes. Scoliotic deformity was corrected by translation of the vertebra along the y axis and rotation about the x; physiologic kyphosis was restored by translation along the x axis and rotation about the y. The plane of maximum deformity as compared with the sagittal plane of the patient corrected from 57 degrees to 25 degrees as an indication of detorsion of the scoliotic deformity. CONCLUSIONS: Increasing the number of hooks per vertebral segment significantly enhances the correction of the coronal scoliotic deformity and enhances the z axis derotation, but does not significantly change the reestablishment of the kyphosis, nor does it result in significant elongation of the spine.

Modulating the midpoint potential of the [4Fe-4S] cluster of the nitrogenase Fe protein.

Protein-bound [FeS] clusters function widely in biological electron-transfer reactions, where their midpoint potentials control both the kinetics and thermodynamics of these reactions. The polarity of the protein environment around [FeS] clusters appears to contribute largely to modulating their midpoint potentials, with local protein dipoles and water dipoles largely defining the polarity. The function of the [4Fe-4S] cluster containing Fe protein in nitrogenase catalysis is, at least in part, to serve as the nucleotide-dependent electron donor to the MoFe protein which contains the sites for substrate binding and reduction. The ability of the Fe protein to function in this manner is dependent on its ability to adopt the appropriate conformation for productive interaction with the MoFe protein and on its ability to change redox potentials to provide the driving force required for electron transfer. Phenylalanine at position 135 is located near the [4Fe-4S] cluster of nitrogenase Fe protein and has been suggested by amino acid substitution studies to participate in defining both the midpoint potential and the nucleotide-induced changes in the [4Fe-4S] cluster. In the present study, the crystal structure of the Azotobacter vinelandii nitrogenase Fe protein variant having phenylalanine at position 135 substituted by tryptophan has been determined by X-ray diffraction methods and refined to 2.4 A resolution. A comparison of available Fe protein structures not only provides a structural basis for the more positive midpoint potential observed in the tryptophan substituted variant but also suggests a possible general mechanism by which the midpoint potential could be controlled by nucleotide interactions and nitrogenase complex formation.

Insights into nucleotide signal transduction in nitrogenase: structure of an iron protein with MgADP bound.

Coupling the energy of nucleoside triphosphate binding and hydrolysis to conformational changes is a common mechanism for a number of proteins with disparate cellular functions, including those involved in DNA replication, protein synthesis, and cell differentiation. Unique to this class of proteins is the dimeric Fe protein component of nitrogenase in which the binding and hydrolysis of MgATP controls intermolecular electron transfer and reduction of nitrogen to ammonia. In the work presented here, the MgADP-bound (or "off") conformational state of the nitrogenase Fe protein has been captured and a 2.15 A resolution X-ray crystal structure is presented. The structure described herein reveals likely mechanisms for long-range communication from the nucleotide-binding sites for controlling the affinity of association with the MoFe protein component. Two pathways, termed switches I and II, appear to be integral to this nucleotide signal transduction mechanism. In addition, the structure provides the basis for the changes in the biophysical properties of the [4Fe-4S] cluster observed when Fe protein binds nucleotides. The structure of the MgADP-bound Fe protein provides important insights into the respective contributions of nucleotide interaction and complex formation in defining the conformational states that are the keys to nitrogenase catalysis.

Structure of an RNA internal loop consisting of tandem C-A+ base pairs.

The crystal structure of the RNA octamer 5'-CGC(CA)GCG-3' has been determined from X-ray diffraction data to 2.3 A resolution. In the crystal, this oligomer forms a self-complementary double helix in the asymmetric unit. Tandem non-Watson-Crick C-A and A-C base pairs comprise an internal loop in the middle of the duplex, which is incorporated with little distortion of the A-form double helix. From the geometry of the C-A base pairs, it is inferred that the adenosine imino group is protonated and donates a hydrogen bond to the carbonyl group of the cytosine. The wobble geometry of the C-A+ base pairs is very similar to that of the common U-G non-Watson-Crick pair.