Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers.

Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (Tmax) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (Tmax, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [Cmax]) similar to that of the ascending dose study and a median Tmax of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.).

Hollow-fiber liquid-phase microextraction and gas chromatography-mass spectrometry of barbiturates in whole blood samples.

Here, we present a method for measuring barbiturates (butalbital, secobarbital, pentobarbital, and phenobarbital) in whole blood samples. To accomplish these measurements, analytes were extracted by means of hollow-fiber liquid-phase microextraction in the three-phase mode. Hollow-fiber pores were filled with decanol, and a solution of sodium hydroxide (pH 13) was introduced into the lumen of the fiber (acceptor phase). The fiber was submersed in the acidified blood sample, and the system was subjected to an ultrasonic bath. After a 5 min extraction, the acceptor phase was withdrawn from the fiber and dried under a nitrogen stream. The residue was reconstituted with ethyl acetate and trimethylanilinium hydroxide. An aliquot of 1.0 µL of this solution was injected into the gas chromatograph/mass spectrometer, with the derivatization reaction occurring in the hot injector port (flash methylation). The method proved to be simple and rapid, and only a small amount of organic solvent (decanol) was needed for extraction. The detection limit was 0.5 µg/mL for all the analyzed barbiturates. The calibration curves were linear over the specified range (1.0 to 10.0 µg/mL). This method was successfully applied to postmortem samples (heart blood and femoral blood) collected from three deceased persons previously exposed to barbiturates.

Development of a dispersive liquid-liquid microextraction method for spectrophotometric determination of barbituric acid in pharmaceutical formulation and biological samples.

In this paper, a novel and simple method for the determination of trace amounts of barbituric acid in water and biological samples was developed by using dispersive liquid-liquid microextraction (DLLME) techniques combined with spectrophotometric analysis. The procedure is based on color reaction of barbituric acid with p-dimethylaminobenzaldehyde and extraction of the color product using the DLLME technique. Some important parameters such as reaction conditions and the type and volume of extraction and dispersive solvents as well as the extraction time were investigated and optimized in detail. Under the optimum conditions, the calibration graphs were linear over the range of 5.0 to 200 ng ml(-1) with limit of detection of 2.0 ng ml(-1). Relative standard deviation for five replicate determinations of barbituric acid at 50 ng ml(-1) concentration level was calculated to be 1.64%. Average recoveries for spiked samples were determined to be between 94% and 105%. The proposed method was applied for the determination of barbituric acid in pharmaceutical formulation and biological samples.

Barbiturate detection in oral fluid, plasma, and urine.

BACKGROUND: Although current abuse of barbiturates is low compared with other classes of abused drugs, their narrow margin of safety, risk of dependence, and abuse liability remain a health concern. Limited information is available on the disposition of barbiturates in different biologic matrices. OBJECTIVE: The authors conducted a clinical study of the disposition of barbiturates in oral fluid, plasma, and urine after single-dose administration to healthy subjects. METHODS: Three parallel groups of 15 subjects were administered a single oral dose of one barbiturate: butalbital (50 mg), Phenobarbital (30 mg), or sodium secobarbital (100 mg). Subjects remained at the clinic for two confinement periods; the first was -1 to 36 hours postdose and again at 48 to 52 hours. Oral fluid specimens were collected by bilateral collection (Intercept; one on each side of the mouth simultaneously). Blood specimens were obtained by venipuncture and urine specimens were collected through separate collection pools of varying periods. Oral fluid specimens were analyzed for barbiturates by liquid chromatography-tandem mass spectroscopy with a limit of quantitation of 8 ng/mL. Plasma and urine specimens were analyzed by gas chromatography-mass spectroscopy with a limit of quantitation of 100 ng/mL. RESULTS: Barbiturate side effects included dizziness, drowsiness, and somnolence. All effects resolved spontaneously without medical intervention. The three barbiturates were detectable in oral fluid and plasma within 15 to 60 minutes of administration and in the first urine pooled collection at 2 hours. Butalbital and Phenobarbital remained detectable in all specimens through 48 to 52 hours, whereas secobarbital was frequently negative in the last collection. Oral fluid to plasma ratios appeared stable over the 1- to 48-hour collection period. CONCLUSION: This study demonstrated that single, oral therapeutic doses of butalbital, Phenobarbital, and secobarbital were excreted in readily detectable concentrations in oral fluid over a period of approximately 2 days. Oral fluid patterns of appearance and elimination were similar to that observed for plasma and urine.

[State under the influence of drugs or psychotropic agents--a comparison of toxicological and medical examinations in materials of the Department of Forensic Medicine and Toxicology, Silesian University of Medicine, Katowice]. / Stan "pod wplywem substancji odurzajacych lub psychotropowych" porównanie wyników badan toksykologicznych z ocena lekarska w materialach Katedry i Zakladu Medycyny Sadowej i Toksykologii Sadowo-Lekarskiej Slaskiego Uniwersytetu Medycznego w Katowicach.

In the paper, the authors present the results of toxicological examinations of blood samples taken from drivers during road check procedures or from perpetrators of traffic road accidents, which--taking into consideration the kind of the determined agents and their concentrations--were compared with the results of medical examinations from blood sampling protocols studied in the Department of Forensic Medicine and Toxicology, Silesian University of Medicine. All the blood samples were first analyzed using an immunoenzymatic assay (ELISA). Then, the LC-MS method was used. The positive results of screening for the presence of cannabinols were verified by GC-MS. Out of 329 blood samples, 145 were positive. The presence of cannabinols, amphetamine or MDMA was the most predominant finding. Diazepam was determined in 4 cases and opiates in 1 case. Only in 31% cases did positive results of toxicological examinations correspond to deviations found during the medical examinations constituting the basis for the final diagnosis of state "under the influence". In practice, appraisal of drug influence during medical examination seems to be limited and dependent on variable reactions of the examined individuals to a psychoactive agent, time lapse between the traffic road event and the examination or concomitant symptoms associated with ethylene alcohol activity. The final diagnosis of state "under the influence of drugs" or "under the influence of psychotropic agents" given by the physician does not result from the effect of these substances observed during the medical examination, but is very often formulated based on the medical history or police findings. The analysis of the above mentioned cases where Delta9THC or/and amphetamine was detected showed no correlation between the concentration of the psychoactive agent determined in blood and symptoms triggered by its action as described by the physician.

[The use of enzymatic hydrolysis for isolation of barbituric acid derivatives from blood (as exemplified by phenobarbital and barbamyl)].

Modern isolation techniques by direct extraction with organic solvents or after protein precipitation by various sedimenting or salting-out agents are characterized by low efficiency and do not permit to liberate derivatives of barbituric acid from their complexes with blood proteins. The use of enzymatic hydrolysis makes it possible to break bonds between barbiturates and protein and thereby improve the efficiency of isolation. We performed enzymatic hydrolysis of the model phenobarbital-blood and barbamyl-blood complexes with the use of trypsin, pepsin, chymotrypsin, and papain. The degree of phenobarbital extraction with trypsin and barbamyl was estimated at 62.1 +/- 1.2% and 75.1 +/- 1.6% respectively; in other words, it was 32.7 +/- 1.0% and 51.1 +/- 1.0% higher than that achieved by traditional methods. Certain validation characteristics of the new method are presented.

A Single-Dose, Open-Label, Randomized, Two-Way Crossover Study in Healthy Japanese Participants to Evaluate the Bioequivalence and the Food Effect on the Pharmacokinetics of Daprodustat.

Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition of hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD). This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male participants consisting of 2 parts. The primary objective was to evaluate the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A total of 64 healthy Japanese male participants were enrolled; 52 participants were included in part 1 and 12 in part 2. BE was demonstrated between the daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did not have a large effect on the PK parameters of daprodustat after a single oral dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4 mg was generally well tolerated in the healthy Japanese participants, and no new safety signals were identified without regard to food.

[Determinations of the presence of drugs in traffic users in the material of the Department of Forensic Medicine, Medical University of Bialystok]. / Badania nad obecnoscia srodków odurzajacych i substancji psychotropowych w organizmach uczestników ruchu drogowego w materiale Zakladu Medycyny Sadowej UM w Bialymstoku.

In recent years, there has been observed an increasing number of traffic users being under influence of psychoactive substances that affect the central nervous system. A total of 198 blood samples and 23 urine samples collected from traffic users (drivers, passengers and pedestrians) suspected of having ingested psychoactive substances were examined. The analysis included blood samples collected from living individuals and blood or urine from the deceased. Ethyl alcohol levels were determined by gas chromatography, while body fluids were examined by Elisa tests for determination of cannabinoids, amphetamines, opium narcotics, cocaine (benzoiloecgonine), benzodiazepines, barbiturates and tricyclic antidepressants. The confirmation of positive results was carried out by gas chromatography with mass detector. Twenty-nine blood samples were positive, what constituted 14.6% of the total number of investigated cases, including 12 (7.8%) of samples originating from living individuals and 17 (37.8)--from the fatalities. In both groups, the most commonly detected substances were cannabinoids (THC and its metabolite carboxy-THC) and amphetamines and its analogues.

Identification of phenobarbital and other barbiturates in forensic drug screening using positive electrospray ionization liquid chromatography-high resolution mass spectrometry.

Comprehensive drug-screening performed by liquid chromatography-high resolution mass spectrometry (LC-HRMS) enables identification of hundreds to thousands of drug compounds in a single analysis. Forensic drug screening is generally performed with positive electrospray ionization (ESI+ ), targeting basic drugs; however, a few toxicologically important drugs such as barbiturates, may require analysis by negative ESI. In this work, screening targets for barbiturates were determined using our LC-HRMS screening with ESI+ . For several years, our forensic whole blood samples have been analyzed using the LC-HRMS-ESI+ screening in parallel with a multi-target LC-MS/MS-ESI- method. From 2014 to 2018, 23 samples were positive for phenobarbital (0.5-81 mg/kg). Retrospective data analysis of 4816 blood samples (15 positive) revealed several potential screening targets for phenobarbital. The targets were tentatively identified by exact mass and isotopic pattern as uncommon adducts of phenobarbital and as a decomposition product of phenobarbital N-glucoside (C17 H24 N2 O7 ). Analysis of a test set containing eight positive (0.5-65 mg/kg phenobarbital) and 31 negative samples supported the use of the observed target m/z 323.0614 at 5.14 minutes, corresponding to the [M + HCOONa+Na]+ adduct of phenobarbital. The [M + HCOONa+Na]+ adduct was confirmed as a screening target for common barbiturates, by analysis of barbiturate reference standards in ESI+ /ESI- . The [M + HCOONa+Na]+ adduct allowed retrospective analysis with 91% sensitivity (n = 23) and 100% specificity (n = 4855) for phenobarbital in our existing LC-HRMS-ESI+ screening. The two negative results were the two whole-blood samples with the lowest phenobarbital concentration (<1.8 mg/kg). Thus, a specialized screening is not necessary and use of this adduct likely enables screening for other barbiturates.

Triage DOA® versus INSTANT-VIEW M-1® in Urinary Drug Screening for Acute Drug Poisoning: A Prospective Cross-sectional Study.

Objective In the management of patients with suspected acute drug poisoning, a screening test using the patient's urine is usually performed. The Triage DOA® and INSTANT-VIEW M-1® kits are two commonly used point-of-care screening kits in Japan. However, the relationship between the results of these screening kits and the blood concentration of the poisoning drug is not clear. In this study, we evaluated which kit is more useful for acute drug poisoning screening based on a comparison of their results with the results of a serum drug analysis. Methods This prospective cross-sectional study investigated all patients with acute drug poisoning admitted to a general hospital in Tokyo, Japan, over a nine-month period. The Triage DOA® and INSTANT-VIEW M-1® screening kits were used, and a qualitative serum analysis was conducted simultaneously in all cases. We compared the kits for use in screening patients with acute drug poisoning and evaluated the utility of the kits. Results For the 117 patients enrolled in this study, the 2 kits showed different sensitivities to benzodiazepines (Triage®, 78.6%; INSTANT-VIEW®, 90.5%). Both kits showed high sensitivity to barbiturates (Triage®, 87.0%; INSTANT-VIEW®, 91.3%) but low sensitivity to tricyclic antidepressants (Triage®, 25.0%; INSTANT-VIEW®, 45.8%). Conclusion Because the sensitivity varies depending on the kind of drug, it is difficult to discuss the superiority of these kits. However, this study compared the results of two types of urinary drug screening kits with the results of qualitative analysis of drugs in serum as a gold standard, providing important reference data.

Extracorporeal elimination of butalbital in acute aspirin-butalbital-caffeine-codeine (Fiorinal with Codeine) poisoning.

BACKGROUND: Butalbital is a small molecule (approximately 220 Da), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325 mg-butalbital 50 mg-caffeine 40 mg with codeine 30 mg (Fiorinal with Codeine). METHODS: This is a case report of a single patient. RESULTS: A 67-year-old female was admitted to the medical intensive care unit approximately 3 h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4 mg/dL (3.4 mmol/L). Approximately 8 h after ingestion of 2000 mg of butalbital, our patient's serum concentration was 26.9 mg/L (normal <10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233-300 mL/min. CONCLUSIONS: The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose.

The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects.

This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. This was a two-part study: Part A assessed the effect of coadministration of daprodustat on the pharmacokinetics of pioglitazone and rosuvastatin in 20 subjects; Part B assessed the coadministration of trimethoprim on the pharmacokinetics of daprodustat in 20 subjects. Coadministration of 100 mg of daprodustat with pioglitazone or rosuvastatin had no effect on the plasma exposures of either probe substrate. When trimethoprim was coadministered with 25-mg daprodustat plasma daprodustat AUC and Cmax increased by 48% and 28%, respectively. Additionally, AUC and Cmax for the metabolite GSK2531401 were decreased by 32% and 40%, respectively. Cmax for the other metabolites was slightly decreased (~8-15%) but no changes in AUC were observed. As 100-mg daprodustat exceeds the planned top therapeutic dose, interaction potential of daprodustat as a perpetrator with substrates of the CYP2C8 enzyme and OATP1B1 transporters is very low. Conversely, daprodustat exposure (AUC and Cmax) is likely to increase moderately with coadministration of weak CYP2C8 inhibitors.

Continuous noninvasive monitoring of barbiturate coma in critically ill children using the Bispectral index monitor.

INTRODUCTION: Traumatic brain injury and generalized convulsive status epilepticus (GCSE) are conditions that require aggressive management. Barbiturates are used to lower intracranial pressure or to stop epileptiform activity, with the aim being to improve neurological outcome. Dosing of barbiturates is usually guided by the extent of induced burst-suppression pattern on the electroencephalogram (EEG). Dosing beyond the point of burst suppression may increase the risk for complications without offering further therapeutic benefit. For this reason, careful monitoring of EEG parameters is mandatory. A prospective study was conducted to evaluate the usefulness of the bispectral index suppression ratio for monitoring barbiturate coma. METHODS: A prospective observational pilot study was performed at a paediatric (surgical) intensive care unit, including all children with barbiturate-induced coma after traumatic brain injury or GCSE. The BIS (Bispectral index) monitor expresses a suppression ratio, which represents the percentage of epochs per minute in which the EEG was suppressed. Suppression ratios from the BIS monitor were compared with suppression ratios of full-channel EEG as assessed by quantitative visual analysis. RESULTS: Five patients with GCSE and three patients after traumatic brain injury (median age 11.6 years, range 4 months to 15 years) were included. In four patients the correlation between the suppression ratios of the BIS and EEG could be determined; the average correlation was 0.68. In two patients, suppression ratios were either high or low, with no intermediate values. This precluded determination of correlation values, as did the isoelectric EEG in a further two patients. In the latter patients, the mean +/- standard error BIS suppression ratio was 95 +/- 1.6. CONCLUSION: Correlations between suppression ratios of the BIS and EEG were found to be only moderate. In particular, asymmetrical EEGs and EEGs with short bursts (less than 1 second) may result in aberrant BIS suppression ratios. The BIS monitor potentially aids monitoring of barbiturate-induced coma because it provides continuous data on EEG suppression between full EEG registrations, but it should be used with caution.

Validated LC-MS-MS Method for Simultaneous Analysis of 17 Barbiturates in Horse Plasma for Doping Control.

A rapid and sensitive method for simultaneous screening, quantification and confirmation of 17 barbiturates in horse plasma using liquid chromatography-tandem mass spectrometry is described. Analytes were recovered from plasma by liquid-liquid extraction using methyl tert-butyl ether, separated on a C18 column, and analyzed in negative electrospray ionization mode. Multiple-reaction monitoring was employed for screening and quantification. Confirmation for the presence of the analytes was achieved by comparing ion intensity ratio. The ranges for limits of detection, quantification and confirmation were 0.003-1 ng/mL (S/N ≥ 3), 0.01-2.5 ng/mL and 0.02-5 ng/mL, respectively. The linear dynamic range of the method was 0.1-100 ng/mL. The precision and accuracy at 0.5, 5 and 50 ng/mL of all 17 barbiturates during intra-day assay were 1.6-8.6% and 96-106%, respectively. For inter-day assay, precision and accuracy at the same three concentrations were 2.6-8.9% and 96-106%, respectively. Analysis of all 17 analytes was completed within 7 min. Thus, the present method is fast, simple, sensitive and reproducibly reliable.

Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose.

A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ∼280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.74 µmol/L). The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination. The patient's elevated serum lactate level with a high mixed venous saturation suggested possible mitochondrial dysfunction, prompting treatment with barbiturate coma to reduce cerebral metabolic demand. The serum carbamazepine concentration declined steadily, with resolution of lactic acidosis, no long-term end-organ damage, and return to baseline neurologic function. The patient was eventually discharged in her usual state of health. In the laboratory, we demonstrated in vitro that the active metabolite of carbamazepine hyperpolarized the mitochondrial membrane potential, supporting the hypothesis that the drug caused mitochondrial dysfunction. We thus successfully treated a life-threatening carbamazepine overdose with a combination of modalities. Future studies are required to validate this aggressive approach. The occurrence of mitochondrial dysfunction must be confirmed in patients with carbamazepine toxicity and the need to treat it validated.

Rapid determination of nine barbiturates in human whole blood by liquid chromatography-tandem mass spectrometry.

A rapid, simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the qualitative and quantitative analysis of nine barbiturates (barbital, phenobarbital, pentobarbital, amobarbital, secobarbital, thiopental, butalbital, butabarbital, and hexobarbital) in human whole blood. Barbiturates were extracted from 100 µL of human whole blood samples using a simple liquid-liquid extraction (LLE) procedure, and detected by LC-MS/MS. An UPLC C18 (2.1 mm × 100 mm, 1.7 µm) column was used at 40 °C for the separation and acetonitrile/water system was used as the mobile phase with gradient elution. This method showed excellent accuracy (86-111%) and precision (relative standard deviation <15%). The limits of detection (LODs) were 0.2 ng/mL for barbital and secobarbital and 0.5 ng/mL for the other barbiturates. The linearity ranged from 2 ng/mL to 2000 ng/mL, with r2 > 0.99 over the range. This method achieved the separation and detection of pentobarbital and amobarbital at the same time in a convenient way. Moreover, it was both simple and sensitive for the determination of nine most commonly used barbiturate drugs, which was meaningful in the field of clinical and forensic toxicology. Copyright © 2016 John Wiley & Sons, Ltd.

Overcoming bioanalytical challenges associated with the separation and quantitation of GSK1278863, a HIF-prolyl hydroxylase inhibitor, and its 14 stereoisomeric metabolites.

GSK1278863 is an investigative drug under investigation for treatment of anemia associated with chronic kidney disease. Its metabolism is primarily metabolized by P450 enzymes where 19 unique metabolic species have been identified. These include multiple products of mono-, di-, and tri-oxygenation. Initially, two separate and complex ultra high performance liquid chromatography (UHPLC) reverse phase methodologies were developed, validated and applied to measure parent and various predominant and circulating metabolites in numerous clinical studies. However, 5 of the 6 oxidative metabolites may exist in different stereoisomeric forms, resulting in 14 separate species; therefore a chiral methodology was required to determine which stereoisomeric forms circulated in human. A variety of conventional approaches were explored, where in the end a supercritical fluid chromatography (SFC) method was required to separate this complex mixture of 14 stereoisomeric metabolites; data from these experiments provided important information on which species circulate in human. The details of these methodologies will be discussed herein.

[Detection of reladorm and donormil in forensic-medical examination of cadavers].

A method was suggested for identifying reladorm and donormil in pharmaceutical drugs and biological objects. The above substances are isolated by 96% ethanol or by mixture of chloroform and isopropanol. 7 color reactions, 3 microcrystalloscopic reactions and chromatography in thin sorbent layer are suggested for identification.

Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.

This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3-1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD.