bluuebunny/crossref_metadata_2025 huggingface dataset:
Febuxostat
Authors: Du Jiangbo
Published: October 2014

Febuxostat is an inhibitor of xanthine oxidase. It reduces uric acid production in the body. It is used to reduce the risk of gout or kidney stone formation. The in vivo metabolism and excretion of [
14
C]‐febuxostat were investigated in six healthy male subjects after a single oral dose of 80 mg. Unchanged febuxostat was the dominant component (85%) in plasma samples 4‐h post dosing. Mean cumulative recovery of administered radioactivity in excreta was 94% (49% urine and 45% feces) over 9 days. Unchanged febuxostat contributed to a combined total in excreta of 10–18% of the dose, indicating its extensive metabolism and well absorption. Major metabolites detected including methyl hydroxylated metabolite
2
(10%), isopropyl hydroxylated metabolite
3
(11%), febuxostat acyl‐glucuronide (30%), dicarboxylic acid (14%), sulfate conjugate of
2
(3%), and dehydrated acyl‐glucuronides of
2
and
2
(totally 0.5%).
Imidafenacin
Authors: Gao Chunying
Published: October 2014

Imidafenacin is a urinary antispasmodic of the anticholinergic class. It is used to control overactive bladder. The in vivo metabolism of [
14
C]‐imidafenacin was assessed in six healthy male subjects after a single oral administration of 0.25 mg. Unchanged parent drug was the main radioactivity component in the 2‐h plasma. The
N
‐glucuronide conjugate of imidafenacin was the major metabolite detected, whereas the oxidized form (keto) of the 2‐methylimidazole moiety, the ring cleavage form, and two diol metabolites (likely generated from an epoxide intermediate) were minor metabolites in the 2‐h plasma samples. A ring cleavage metabolite was the major component in the 12‐h plasma samples. Approximately, 66 and 29% of the administered radioactivity were recovered in urine and feces, respectively, within 192‐h post dosing. Unchanged parent and most metabolites were excreted in urine. Minor urinary metabolites also included imidafenacin
N
‐oxide, an imidazole ring‐opening product, and an unidentified glucuronide conjugate.
Imrecoxib
Authors: Zhou Xin
Published: October 2014

Imrecoxib is a moderately selective COX‐II inhibitor used to treat acute and chronic inflammatory diseases. The metabolism and excretion of imrecoxib were investigated in rats after a single intravenous administration. Extensive metabolism of imrecoxib was observed, with <2% of the dose excreted as parent drug in either urine or feces. The major metabolic pathway observed was the hydroxylation at 4
′
‐methyl group, followed by further oxidation to 4
′
‐carboxylic acid metabolite. Metabolites 4
′
‐hydroxymethyl‐5‐hydroxyl imrecoxib and 4
′
‐hydroxymethyl‐5‐carbonyl imrecoxib along with three glucuronide conjugates were also identified. The majority of the dose was recovered in faces, mainly as the form of 4
′
‐carboxylic acid, while 4
′
‐hydroxymethyl imrecoxib was the main metabolite in urine.
Indacaterol
Authors: Xie Cen
Published: October 2014

Indacaterol is a long‐acting inhaled β
2
‐adreneregic receptor agonist. It is used as an aerosol formulation in dry powder inhaler to treat patients with chronic obstructive pulmonary diseases. Rapid absorption of [
14
C]‐indacaterol was observed in four healthy adult male subjects after a single oral dose of 800 μg free base equivalent. In the serum, the unchanged indacaterol was the major component, accounting for 30% of the total radioactivity. Recoveries of the administered radioactivity in feces and urine were 85 and 10%, respectively. Approximately, 54% of fecal radioactivity and 0.3% of the urinary radioactivity were attributed to the parent drug. The metabolic pathways involved mono‐hydroxylation at 5‐(1‐ethyl) position and the sequential O‐glucuronidation of metabolites at the 8‐hydroxyl moiety, direct O‐glucuronidation at the 8‐hydroxyl moiety of the parent, N‐glucuronidation at the 2‐amino moiety of parent, cleavage of the carbon–carbon bond between the hydroxyquinolinone moiety and the diethyl‐indanylamino‐ethanol moiety, and N‐dealkylation.
Lersivirine
Authors: Gao Chunying
Published: October 2014

Lersivirine is a non‐nucleoside reverse transcriptase inhibitor used for the treatment of HIV‐1 infection. Its development has been terminated. The metabolism and excretion of lersivirine were investigated in four healthy male volunteers. All subjects received a single oral 500‐mg dose of [
14
C]‐lersivirine. About 80% of radioactivity was excreted in urine and the remainder 20% excreted in feces. Lersivirine underwent extensive metabolism. Enzymatic studies showed that UGT2B7 and CYP3A4 were responsible for the majority of its metabolism. The lersivirine
N
‐glucuronide conjugate was the major circulating component (45% of total radioactivity), whereas lersivirine represented 13% of total plasma radioactivity. Other metabolic pathways observed were monohydroxylation, dihydroxylation, oxidation of —OH to the ketone, nitrile hydration/oxidation, primary alcohol oxidation to give the carboxylic acid form, and N‐dealkylation.
Meloxicam
Authors: Zhou Xin
Published: October 2014

Meloxicam is a nonsteroidal anti‐inflammatory drug used to relieve the symptoms of arthritis, primary dysmenorrhea, and fever. The metabolism of [
14
C]‐meloxicam was studied in four male healthy volunteers. There is no difference in the metabolic patterns between oral and intravenous administrations. Four major metabolites were detected in urine; they were 5′‐hydroxymethylmeloxicam, 5′‐carboxymeloxicam, and two metabolites yielded by opening of the thiazine ring. There were differences in the metabolic patterns between feces and urine. For example, 5′‐carboxymeloxicam was the major metabolite detected in feces.
Nilutamide
Authors: Lin Lishan
Published: October 2014

Nilutamide is an antineoplastic hormonal agent. It is primarily used in the treatment of prostate cancer. After oral administration of [
14
C]‐nilutamide, absorption is essentially complete. The half‐life was about 2 days. In humans, unlike other species, plasma concentration of nilutamide was very low. Urinary excretion was predominant, consisted of mainly metabolic products. Total radioactivity showed a longer plasma half‐life than that of the drug alone, indicating that the clearance of metabolites was slower. Primary urinary metabolites included hydroxylamino‐, amino‐, and nitroso‐nilutamides, metabolites yielded by hydroxylation of the methyl group at the imidazolidinedione ring, and imidazolidinedione ring‐opening products.
Piroxicam
Authors: Du Jiangbo
Published: October 2014

Piroxicam is a nonselective COX inhibitor. It is a nonsteroidal anti‐inflammatory drug used to relieve the symptoms of rheumatoid arthritis and osteoarthritis. The biotransformation of [3H]‐piroxicam was studied in rats, dogs, and monkeys. Major metabolic pathways observed were hydroxylation on the pyridyl ring (5′‐hydroxypiroxicam), cyclodehydration, hydrolysis of amide bond, decarboxylation, ring contraction (
N
‐methyl‐
O
‐benzosulfimide), and N‐demethylation (
O
‐benzosulfimide). Two aryl hydroxylation metabolites were detected only in rats. The metabolism of piroxicam in humans was similar to that observed in animals. In addition, a glucuronide of piroxicam was identified.
Repaglinide
Authors: Ding Juefang
Published: October 2014

Repaglinide is a short‐acting antidiabetic drug. It is used in type II diabetic patients to normalize postprandial hyperglycemia. Metabolism and excretion of [
14
C]‐repaglinide in healthy male volunteers were investigated following multiple oral dosing of 2 mg. Five oxidative metabolites were identified, including an aromatic amine (
2
) and a dicarboxylic acid (
3
), both formed by the opening of the piperidine ring; metabolites yielded by hydroxylation of the piperidine ring, O‐deethylation, and hydroxylation on the isopropyl moiety. Phase II metabolites of acylglucuronide conjugate and tauride conjugate were also detected. The parent compound accounted for 61% of the total radioactivity in plasma, followed by the major metabolite
3
(11%), which was also the major metabolite in feces. Metabolites
2
(24%) and
3
(22%) were the major urinary metabolites.
Rufinamide
Authors: Du Jiangbo
Published: October 2014

Rufinamide is an anticonvulsant medication used in the treatment of various seizure disorders. Metabolism of [
14
C]‐rufinamide in healthy male subjects was investigated after a single oral 600 mg dose. Carboxylic acid derivative from the hydrolysis of the carboxamide group was the major metabolite found in urine (70% of the dose) and feces (9%). Its corresponding acylglucuronide metabolite, accounting for 7% of the dose, was excreted in urine.
Terazosin
Authors: Gao Chunying
Published: October 2014

Terazosin is an α1‐adrenergic blocker used to treat male patients with hypertension and benign prostatic hyperplasia. Following oral administration of [
14
C]‐terazosin to humans, most of the radioactivity in plasma during the first day was attributable to the unchanged parent drug along with two minor, unidentified polar metabolites. Seven days after the administration of [
14
C]‐terazosin, an average of 39% of the radioactivity was excreted in urine. Fecal excretion accounted for 56% of the total radioactivity. The unchanged parent drug accounted for 29% of the radioactive dose, with 11% excreted in urine and 18% eliminated in stools. The primary metabolic pathway in humans involved O‐demethylation, hydrolysis of the amide linkage, piperazine ring opening, and N‐dealkylation. Further phase II conjugation products were also observed.
Tolbutamide
Authors: Du Jiangbo
Published: October 2014

Tolbutamide is an oral hypoglycemic drug used to treat type II diabetes. [
14
C]‐Tolbutamide metabolites were detected in rat microsomes, including hydroxyl‐tolbutamide, carboxy‐tolbutamide, p‐tolylsulfonylurea, p‐tolylsulfonamide, three monohydroxylated metabolites from the butyl side chain, and two GST‐mediated glutathione conjugates. The metabolic profile of [
14
C]‐tolbutamide in rats was studied. Three new metabolites, ω‐carboxyl tolbutamide, O‐glucuronide conjugate of hydroxyl‐tolbutamide, and ortho‐ or meta‐tolbutamide glutathione, were detected in rat biological samples, in addition to the metabolites detected in vitro. After oral administration of [3H]‐tolbutamide to male human subjects, metabolites hydroxyl‐tolbutamide and carboxy‐tolbutamide were the radioactive materials detected in urine.
Bendamustine
Authors: Du Jiangbo
Published: October 2014

Bendamustine is a nitrogen mustard used in the treatment of chronic lymphocytic leukemias and lymphomas. The metabolism of bendamustine in patients with cholangiocarcinoma was studied. Numerous conjugates derived from three major glutathione‐conjugated intermediates were identified. Primary phase I metabolites were resulted from hydroxylation, N‐demethylation, and mono‐ and dioxidative dechlorination reactions.
Cyclobenzaprine
Authors: Yu Jinghua
Published: October 2014

Cyclobenzaprine is a muscle relaxant used in the treatment of skeletal muscle spasms and used to relieve pain associated with acute musculoskeletal conditions and fibromyalgia. The metabolism of [
14
C]‐cyclobenzaprine was investigated in healthy volunteers after either an oral or an intravenous (i.v.) 8.9‐mg dosing. As a result, two
N
‐glucuronides were found as the major metabolites. Minor metabolites detected were an N‐demethylation product, a mono‐dehalogenation product, and a hydroxylation product.
Degarelix
Authors: Jinghua Yu
Published: October 2014

Degarelix is a competitive gonadotropin‐releasing hormone receptor antagonist that is used to treat advanced prostate cancer. The in vitro metabolism of degarelix was investigated in rat, dog, and monkey liver microsomes and rat and dog hepatocytes. Degarelix is stable to cytochrome P450 mediated metabolism. After [
3
H]‐degarelix was incubated with rat and dog hepatocytes, no degradation of degarelix was observed. The in vivo metabolism of [
3
H]‐degarelix in rats, dogs, and monkeys was investigated following either a single subcutaneous or an intravenous (i.v.) dosing. Significant species difference in the metabolic profile of degarelix was not observed. Unchanged parent was the major compound found in rat plasma and urine. Hydrolysis of various amide bonds was the primary metabolic pathway.
Ertugliflozin
Authors: Zhong Kan
Published: October 2014

The metabolism of [
14
C]‐ertugliflozin was studied in six healthy human subjects after a single oral dose of 25 mg. The major circulating radioactivity was attributed to ertugliflozin (50%). Hydroxylation products and glucuronide conjugates of the parent accounted for 3 and 46% of the circulating radioactivity, respectively. The total administered radioactivity recovered in urine and feces was 50 and 41%, respectively. Unchanged ertugliflozin was a minor component in urine accounting for only 1.5% of the administered dose. The primary urinary metabolites in urine were three ertugliflozin glucuronides. In feces, the unchanged drug was the most abundant component (accounting for about 34% of the dose), hydroxylation and oxidation metabolites were minor.
Felodipine
Authors: Gao Ruina
Published: October 2014

Felodipine is a calcium channel blocker used to treat hypertension. The biotransformation of felodipine was investigated in liver microsomes from rats, dogs, and humans. Felodipine was extensively metabolized. Two distinct parallel metabolic pathways were observed. One involved with the initial oxidation/aromatization of the dihydropyridine ring to the pyridine ring and the other proceeded directly with the dihydropyridine ring. Primary metabolic reactions after the initial transformation to the pyridine analog of felodipine (
2
) were ester hydrolysis, which yielded two monocarboxylic acid metabolites (
3
and
4
), two lactones and their corresponding open hydroxy acid forms, and a lactone compound with a carboxylic acid group. The presence of two decarboxylated products was also detected. The metabolism of [
14
C]‐felodipine was studied after oral administration to humans. Urinary excretion accounted for 70% of the administered radioactive dose in humans 72‐h postdosing. Metabolites
3
and
4
and the dicarboxylic acid yielded from
2
were identified.
Iloperidone
Authors: Li Xiuli
Published: October 2014

Iloperidone is a dopamine‐D
2
/serotonin‐5‐HT
2
antagonist used for the treatment of schizophrenia. The in vitro metabolism of iloperidone was conducted in human liver microsomes. With the addition of NADPH, methyl hydroxylation metabolite was the most abundant product and keto‐reduction metabolite and
O
‐demethylated metabolite were the major products. CYP2D6 and 3A4 were responsible for the hydroxylation and O‐demethylation, respectively. The reduction metabolite was mainly produced by cytosolic enzymes. Urine and plasma samples were collected after an oral administration of 4‐mg iloperidone in a clinical study. Two parallel metabolic processes were observed; one was carried out with the intact benzisoxazole and the other proceeded after the initial opening of the benzisoxazole ring. The reduction metabolite was the major component found in both plasma and urine of humans. The O‐demethylation metabolite was also found in plasma and urine and mainly existed in the form of glucuronide conjugate in urine.
Isoxicam
Authors: Lin Lishan
Published: October 2014

Isoxicam is a nonsteroidal anti‐inflammatory agent, primarily used in the treatment of rheumatoid arthritis and degenerative joint disease. Metabolism of [
14
C]‐isoxicam in normal healthy adult male volunteers was investigated following a single oral 300‐mg dose. Methyl hydroxylation to yield hydroxymethylisoxicam followed by glucuronide conjugation was the major metabolic pathway observed in the human study.
Linagliptin
Authors: Du Jiangbo
Published: October 2014

Linagliptin is a DPP‐4 inhibitor used as an antidiabetic to treat type II diabetes. The metabolism and disposition of [
14
C]‐linagliptin were investigated in 12 healthy male volunteers after either an oral or an intravenous (i.v.) administration. Fecal excretion was the dominant elimination pathway with 85% per os (p.o.) and 58% i.v. doses. Renal excretion accounted for 5% p.o. and 31% i.v. doses. Unchanged parent was the most abundant radioactive material in all biological matrices investigated. Primary metabolic reactions included hydroxylation at the methyl group of the butinyl side chain, oxidative deamination of the piperidine moiety followed by oxidation, opening of the piperidine moiety and decarboxylation, N‐acetylation, oxidation of the methyl group at position 4 of the quinazoline moiety to a carboxylic acid metabolite, and combinations of these reactions, yielding numerous secondary metabolic products. Direct N‐glucuronidation of linagliptin was also observed.
Pirprofen
Authors: Lin Lishan
Published: October 2014

Pirprofen is an orally nonsteroidal anti‐inflammatory drug used to treat chronic arthritic conditions and certain soft tissue disorders associated with pain and inflammation. Metabolism of pirprofen was studied in healthy male volunteers after either 200 mg oral doses of nonlabeled pirprofen or a single oral dose of 200 mg of [
14
C]‐pirprofen. Renal excretion was the major elimination pathway in humans. About 83% of the administered radioactivity was recovered in urine within 96 h. Dehydrogenation and epoxidation of the dihydropyrrole moiety, hydration of the epoxide, cleavage of the pyrroline ring, and acyl glucuronidation metabolites were identified.
Tafluprost
Authors: Du Jiangbo
Published: October 2014

Tafluprost is a prostaglandin analog used as eye drops to control the progression of glaucoma and ocular hypertension. The metabolism of [
3
H]‐tafluprost in hepatocytes from rats, dogs, monkeys, and humans was investigated. Three primary phase I metabolic reactions were observed. The initial reaction was the hydrolysis of the isopropyl ester to the corresponding tafluprost acid. Sequential β‐oxidation of the metabolite yielded 1,2‐dinor‐tafluprost acid and 1,2,3,4‐tetranor‐tafluprost acid. Aryl hydroxylation yielded hydroxylated metabolites. Phase II conjugation products were also identified as glucuronide conjugates and a sulfate conjugate. The disposition and metabolism of tafluprost were studied in rats after ocular administration. The in vivo and in vitro metabolic pathways are consistent.
Tolcapone
Authors: Zhou Xin
Published: October 2014

Tolcapone is a catechol‐O‐methyl transferase inhibitor. It is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication. The excretion and metabolism of [
14
C]‐tolcapone were examined in six healthy male volunteers after an oral administration. Results showed that tolcapone was completely metabolized and excreted in urine (57% of the administered radioactivity) and feces (41%). Only 0.5% of the administered tolcapone was excreted unchanged. Glucuronide conjugation was the major metabolic reaction observed to form
2
as the major metabolite in plasma within 2 h after dosing, whereas 3‐O‐methyl tolcapone was the major terminal metabolite in plasma. Metabolite
2
was also the most abundant metabolite in urine and feces, accounting for 27 and 33%, respectively, of the total radioactivity excreted by these routes.
Vilanterol
Authors: Zhong Kan
Published: October 2014

Vilanterol is a novel long‐acting β
2
‐adrenoceptor agonist used for the treatment of chronic obstructive pulmonary disease and asthma. The metabolism of [
14
C]‐vilanterol was investigated in human subjects after an oral administration of 200 μg. Unchanged vilanterol and its metabolites were excreted in urine and feces, accounting for 50% and 21% of the administered radioactivity, respectively. Vilanterol was metabolized extensively and no unchanged vilanterol was observed in urine. In feces, the unchanged drug was <5% of the recovered radioactivity. Primary phase I metabolic reactions were the initial O‐dealkylation to yield two metabolites. Further oxidation of the —OH moiety yielded the corresponding acid and ketone. Oxidation of the hydroxymethylphenol moiety yielded carboxylic acids. Minor metabolic reactions were N‐dealkylation and C‐dealkylation. Glucuronide conjugates of the phenol group were also observed.
Triamcinolone
Authors: Li Xiuli
Published: October 2014

Triamcinolone is a synthetic corticosteroid used to prevent inflammation, such as allergies, arthritis, eczema, psoriasis, and asthma attacks. After a single oral dose of 10 mg triamcinolone to healthy male volunteers, urine samples were collected and analyzed. The most abundant component was the unchanged parent drug. Oxidation of the parent to the corresponding 11‐ketotriamcinolone and the formation of a diol metabolite roxytriamcinolone were observed as the primary metabolic pathways of triamcinolone in humans.
Amantadine
Authors: Zhou Xin
Published: October 2014

Amantadine is used to treat and to prevent influenza A and tremor in Parkinson's disease. Metabolism of amantadine in male volunteers was investigated after an oral dose of 200 mg.
N
‐Acetylamantadine was the major metabolite detected accounting for 5–15% of the administered dose. N‐Methylation, formation of Schiff bases and
N
‐formiates, and deamination reactions yielded
N
‐methylamantadine,
N
,
N
‐dimethylamantadine,
N
‐methyleneamantadine,
N
‐formylamantadine,
N
‐methyl‐
N
‐hydroxymethyl amantadine,
N
‐methyl‐
N
‐formyl amantadine,
N
‐ethylideneamantadine, and amantadine acetate. No metabolite with a hydroxylated adamantane ring system was detected.
Aprepitant
Authors: Ding Juefang
Published: October 2014

Aprepitant is a potent and selective human substance P neurokinin 1 receptor antagonist to prevent or delay chemotherapy‐induced nausea and vomiting. Following a single per os (p.o.) dose of 300 mg [
14
C]‐aprepitant to eight healthy subjects, about 92% of the radioactivity was recovered in 10 days after dosing, of which 5% was excreted in urine and 86% excreted in feces. Parent drug was major component in plasma. Primary metabolic reaction was N‐dealkylation yielded des‐triazolone aprepitant. Further dehydrogenation yielded the imine derivative of the morpholine ring and hydroxylation/oxidation yielded a lactam and a hydroxylactam derivative. Opening of the morpholine ring yielded keto acid and the corresponding hydroxyacid. Additional metabolites resulted from the O‐dealkylation and phase II conjugations were also observed in urine.
Arbidol
Authors: Deng Pan
Published: October 2014

Arbidol is an antiviral agent used for the treatment of influenza infection. It is commonly used to prevent and treat flu including H5N1 bird flu and pandemic H1N1 swine flu. The metabolism and excretion of arbidol were investigated in healthy male Chinese volunteers after a single oral administration of 200 mg arbidol hydrochloride. A total of 33 metabolites were identified in human plasma, urine, and feces. Major biotransformation pathways were S‐oxidation, S‐dealkylation, N‐demethylation, and direct glucuronidation of the parent –OH moiety. The major drug‐related component in human plasma was sulfinylarbidol, followed by unmetabolized arbidol,
N
‐demethylsulfinylarbidol, and sulfonylarbidol. The unchanged arbidol, accounting for 32% of the dose, was the major fecal product.
Doxorubicin
Authors: Fan Yaxin
Published: October 2014

Doxorubicin is an anthracycline topoisomerase inhibitor commonly used in the treatment of a wide range of cancers. The metabolic profile of doxorubicin in tumor patients was investigated following single intravenous (i.v.) dose. Primary metabolic reactions observed were reductive glycosidic cleavage, carbonyl reduction, O‐demethylation, hydrolytic glycosidic cleavage, O‐sulfation, and O‐β‐glucuronidation. Metabolites doxorubicinol, doxorubicin aglycone, 7‐deoxydoxorubicinol aglycone, 7‐deoxydoxorubicin aglycone, demethyl deoxydoxorubicinol aglycone, doxorubicinol aglycone, demethyl deoxydoxorubicinol aglycone 4‐
O
‐sulfate, and demethyl deoxydoxorubicinol aglycone 4‐
O
‐β‐glucuronide were identified.
Lorazepam
Authors: Ding Juefang
Published: October 2014

Lorazepam is used for the short‐term treatment of anxiety, insomnia, acute seizures, including status epilepticus and sedation of hospitalized and aggressive patients. Metabolism of lorazepam was studied in eight healthy male subjects receiving a single oral dose of 2 mg [
14
C]‐lorazepam. A mean of 88% and 7% of the administered radioactivity was recovered in urine and feces, respectively. Major metabolite was lorazepam glucuronide, which comprised 86% of the urinary reactivity. Quinazoline carboxylic acid product was also identified. Following oral administration of 2 mg lorazepam to six volunteers, further metabolites detected in urine were a quinazoline derivative, glucuronide conjugate of the phenylhydroxylated lorazepam, and a chlorobenzodiazepine ring hydroxylated product.
Nilotinib
Authors: Ding Juefang
Published: October 2014

Nilotinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia. The in vivo metabolism of [
14
C]‐nilotinib was studied in human subjects, following a single oral dosing. The major circulating component detected was the parent drug. Extensive metabolism of nilotinib was observed. Following primary in vivo metabolic reactions were observed: hydroxylation/oxidation of the methyl‐imidazole group, N‐oxidation, amide hydrolysis, opening of the imidazole ring, and O‐ or N‐glucuronide conjugations of the parent compound and its metabolites. Additional hydroxylated and conjugated products were detected. The more interesting result was the identification of different imidazole ring‐opening products. The hydroxylation, oxidation, and deamination reactions yielded amine and its N‐acetyl conjugate as terminal products.
Pioglitazone
Authors: Ding Juefang
Published: October 2014

Pioglitazone selectively stimulates nuclear receptor peroxisome proliferator‐activated receptor gamma. It has hypoglycemic activity and is used to treat diabetes mellitus type 2. After an oral administration of 30 mg pioglitazone to human volunteers, about 28% of the administered dose was excreted in urine in 48 h, and the drug was primarily excreted as metabolites and their conjugates. Unchanged parent and three unconjugated metabolites were observed in human serum. Aliphatic hydroxylation products were the major metabolites excreted in urine. Metabolic activation of pioglitazone was evaluated in rat and human liver microsomes and suspensions of freshly isolated hepatocytes using glutathione as the trapping agent. Two novel 1,3‐thiazolidine‐2,4‐dione ring‐opened glutathione conjugates were identified.
Tolvaptan
Authors: Chen Meixia
Published: October 2014

Tolvaptan is a selective vasopressin receptor 2 antagonist used for the treatment of low blood sodium level. Metabolism of [
14
C]‐tolvaptan was investigated in humans following oral administration. Metabolic reactions observed were hydroxylation and the opening of benzazepine ring via N‐dealkylation, and oxidation of the formed hydroxyl group. Amide bond hydrolysis products were also detected. A ring‐opened metabolite was the major circulating metabolite. In humans, 40% and 59% of the dose were excreted in urine and feces, respectively.
Warfarin
Authors: Diao Xingxing
Published: October 2014

Warfarin is an anticoagulant that inhibits the synthesis of vitamin K‐dependent coagulation factors. It is used to treat venous thrombosis, pulmonary embolism, and atrial fibrillation. Metabolic fate of racemic warfarin in normal healthy human subjects was studied after oral administration. In human urine extracts, besides parent drug warfarin, the major metabolites identified were 6‐hydroxywarfarin, 7‐hydroxywarfarin, and warfarin alcohols. S‐Warfarin and R‐warfarin were differentially metabolized by recombinant human CYPs. S‐Warfarin was predominantly metabolized by CYP2C9 to 7‐hydroxywarfarin. Using R‐warfarin as the substrate, formation of 10‐hydroxywarfarin was catalyzed by CYP3A4, and primarily CYP1A2 mediated the formation of 6‐hydroxywarfarin and 8‐hydroxywarfarin.
Systemic chemotherapy decreases brain glucose metabolism
Authors: Horky Laura L. , Gerbaudo Victor H. , Zaitsev Alexander , Plesniak Wen , Hainer Jon , Govindarajulu Usha , Kikinis Ron , Dietrich Jörg
Published: October 2014

Objective

Cancer patients may experience neurologic adverse effects, such as alterations in neurocognitive function, as a consequence of chemotherapy. The mechanisms underlying such neurotoxic syndromes remain poorly understood. We here describe the temporal and regional effects of systemically administered platinum‐based chemotherapy on glucose metabolism in the brain of cancer patients.

Methods

Using sequential FDG‐PET/CT imaging prior to and after administration of chemotherapy, we retrospectively characterized the effects of intravenously administered chemotherapy on brain glucose metabolism in a total of 24 brain regions in a homogenous cohort of 10 patients with newly diagnosed non‐small‐cell lung cancer.

Results

Significant alterations of glucose metabolism were found in response to chemotherapy in all gray matter structures, including cortical structures, deep nuclei, hippocampi, and cerebellum. Metabolic changes were also notable in frontotemporal white matter (WM) network systems, including the corpus callosum, subcortical, and periventricular WM tracts.

Interpretation

Our data demonstrate a decrease in glucose metabolism in both gray and white matter structures associated with chemotherapy. Among the affected regions are those relevant to the maintenance of brain plasticity and global neurologic function. This study potentially offers novel insights into the spatial and temporal effects of systemic chemotherapy on brain metabolism in cancer patients.
Reversed‐Polarity Synthesis of Diaryl Ketones through Palladium‐Catalyzed Direct Arylation of 2‐Aryl‐1,3‐dithianes
Authors: Yucel Baris , Walsh Patrick J.
Published: October 2014

An umpolung approach to the synthesis of diaryl ketones has been developed based on in situ generation of acyl anion equivalents and their catalytic arylation. This method entails the base‐promoted, palladium‐catalyzed direct C‐H arylation of 2‐aryl‐1,3‐dithianes with aryl bromides. Use of MN(SiMe3)2 (M=Li, Na) base results in reversible deprotonation of the weakly acidic dithiane. In the presence of a Pd(NiXantphos)‐based catalyst and aryl bromide, cross‐coupling of the metallated 2‐aryl‐1,3‐dithiane takes place under mild conditions (2 h at rt) with yields as high as 96 %. The resulting 2,2‐diaryl‐1,3‐dithianes were converted into diaryl ketones by either molecular iodine, N‐bromo succinimide (NBS) or Selectfluor in the presence of water. The dithiane arylation/hydrolysis can be performed in a one‐pot procedure to yield a variety of diaryl ketones in good to excellent yields. This method is suitable for rapid and large‐scale synthesis of diaryl ketones. A one‐pot preparation of anti‐cholesterol drug fenofibrate (TriCor®) has been achieved on 10.0 mmol scale in 86 % yield.

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Leptin, adiponectin, and heart rate variability among police officers
Authors: Charles Luenda E. , Burchfiel Cecil M. , Sarkisian Khachatur , Li Shengqiao , Miller Diane B. , Gu Ja K. , Fekedulegn Desta , Violanti John M. , Andrew Michael E.
Published: October 2014

Objectives

Police officers have a high prevalence of cardiovascular disease (CVD). Reduced heart rate variability (HRV) is known to increase CVD risk. Leptin and adiponectin may be related to CVD health. Therefore, our objective was to investigate the relationship between these variables and HRV.

Methods

Leptin and adiponectin levels were measured in 388 officers from the Buffalo Cardio‐Metabolic Occupational Police Stress study. HRV was assessed according to methods published by the Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology for measurement and analysis of HRV. Mean values of high‐frequency (HF) and low‐frequency (LF) HRV were compared across tertiles of leptin and adiponectin using analysis of variance and analysis of covariance; trends were assessed using linear regression models.

Results

Leptin, but not adiponectin, was significantly and inversely associated with HRV. Body mass index (BMI) and percent body fat significantly modified the association between leptin and LF (but not HF) HRV. Among officers with BMI < 25 kg/m2, leptin was not significantly associated with HRV. However, among officers with BMI ≥ 25 kg/m2, leptin was inversely associated with HRV, after adjustment for age, gender, and race/ethnicity; HF HRV, P = 0.019 and LF HRV, P < 0.0001. Similarly, among officers with percent body fat ≥ 25.5%, leptin and LF HRV showed significant, inverse associations (adjusted P = 0.001).

Conclusions

Leptin levels were inversely associated with LF HRV, especially among officers with increased adiposity. Increased leptin levels may be associated with CVD‐related health problems. Am. J. Hum. Biol. 27:184–191, 2015. © 2014 Wiley Periodicals, Inc.
School day and weekend patterns of physical activity in urban 11‐year‐olds: A cross‐cultural comparison
Authors: Jurak Gregor , Sorić Maroje , Starc Gregor , Kovač Marjeta , Mišigoj‐Duraković Marjeta , Borer Katarina , Strel Janko
Published: October 2014

Objectives

This multi‐center study was conducted to objectively evaluate energy expenditure and physical activity (PA) patterns on school days and weekends in urban 11‐year‐olds.

Methods

The sample consisted of 241 children from three cities: Zagreb, Ljubljana (both in Central Europe) and Ann Arbor (United States). Energy expenditure and PA were assessed during two school days and two weekend days using a multiple‐sensor body monitor.

Results

Differences between the cities were observed for all PA variables. The highest level of moderate to vigorous PA (MVPA) was noted in Ljubljana boys [284 (98) min/day] and the lowest in Zagreb girls [179 (95) min/day]. In Zagreb and Ljubljana, boys were more physically active than girls, while in Ann Arbor the opposite was observed. In contrast, no gender difference in sedentary behavior was observed in any of the cities. A decline in PA from school days to weekends was noted in all city groups in both genders. However, the magnitude of the reduction in daily energy expenditure differed between the cities, with the largest differences being observed in Ljubljana and the smallest in Ann Arbor. In all three city groups, the great majority of boys and girls achieved current recommendations of 60 min of MVPA either during school days or weekends.

Conclusions

Weekends seem to be an appropriate target when promoting PA in 11‐year‐olds in all the cities included in the study. Increasing vigorous activity on weekends seems to be of particular importance in Zagreb and Ljubljana. Am. J. Hum. Biol. 27:192–200, 2015. © 2014 Wiley Periodicals, Inc.
Cousins, siblings, or copies: the genomics of recurrent Staphylococcus aureus infections in chronic rhinosinusitis
Authors: Drilling Amanda , Coombs Geoffrey W. , Tan Hui‐leen , Pearson Julie C. , Boase Samuel , Psaltis Alkis , Speck Peter , Vreugde Sarah , Wormald Peter‐John
Published: October 2014

Background

Staphylococcus aureus infection is known to play a role in recalcitrant chronic rhinosinusitis (CRS). However, it is unknown if recurrent S. aureus infections are caused by the same strain or are due to independent acquisitions of different strains.

Methods

Samples were collected from patients with CRS from July 2011 to August 2012. S. aureus was isolated from mucosal swabs and tissue specimens from patients who underwent surgery during the study period, or from swabs of areas of purulence taken in the postoperative period under endoscopic guidance. Pulsed‐field gel electrophoresis was used to characterize S. aureus isolates.

Results

Thirty‐four patients were included in the study; 79% showed persistence of the same S. aureus strain in their paranasal sinuses (p = 0.001; H1 ≠ 50%). Furthermore, a significantly high frequency of patients with known biofilm status were positive for S. aureus biofilm (p = 0.002; H1 ≠ 50%). When patients were stratified according to disease evolution postsurgery, certain strains appeared to be more commonly associated with symptom persistence.

Conclusion

The same S. aureus strain appears to persist in the paranasal sinuses of CRS patients despite multiple courses of culture‐directed antibiotics. This suggests that conventional antimicrobial therapies in patients with CRS may not eliminate the organism. This may be partly explained by the formation of biofilms in the paranasal sinus region.
A new muscle glycogen storage disease associated with glycogenin‐1 deficiency
Authors: Malfatti Edoardo , Nilsson Johanna , Hedberg‐Oldfors Carola , Hernandez‐Lain Aurelio , Michel Fabrice , Dominguez‐Gonzalez Cristina , Viennet Gabriel , Akman H. Orhan , Kornblum Cornelia , Van den Bergh Peter , Romero Norma B. , Engel Andrew G. , DiMauro Salvatore , Oldfors Anders
Published: October 2014

We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin‐1 gene (GYG1). Most patients showed depletion of glycogenin‐1 in skeletal muscle, whereas 1 showed presence of glycogenin‐1 lacking the C‐terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin‐1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin‐1. Ann Neurol 2014;76:891–898
Experimental and Computational Studies on the Reactivity of a Terminal Thorium Imidometallocene towards Organic Azides and Diazoalkanes
Authors: Ren Wenshan , Zhou Enwei , Fang Bo , Hou Guohua , Zi Guofu , Fang De‐Cai , Walter Marc D.
Published: October 2014

The reaction of the base‐free terminal thorium imido complex [{η5‐1,2,4‐(Me3C)3C5H2}2ThN(p‐tolyl)] (1) with p‐azidotoluene yielded irreversibly the tetraazametallacyclopentene [{η5‐1,2,4‐(Me3C)3C5H2}2Th{N(p‐tolyl)NNN(p‐tolyl)}] (2), whereas the bridging imido complex [{[η5‐1,2,4‐(Me3C)3C5H2]Th(N3)2}2{μ‐N(p‐tolyl)}2][(n‐C4H9)4N]2 (3) was isolated from the reaction of 1 with [(n‐C4H9)4N]N3. Unexpectedly, upon the treatment of 1 with 9‐diazofluorene, the NN bond was cleaved, an N atom was transferred, and the η2‐diazenido iminato complex [{η5‐1,2,4‐(Me3C)3C5H2}2Th{η2‐[NN(p‐tolyl)]}{N(9‐C13H8)}] (4) was formed. In contrast, the reaction of 1 with Me3SiCHN2 gave the nitrilimido complex [{η5‐1,2,4‐(Me3C)3C5H2}2Th{NH(p‐tolyl)}{N2CSiMe3}] (5), which slowly converted into [{η5‐1,2,4‐(Me3C)3C5H2}{η5:κ‐N‐1,2‐(Me3C)2‐4‐CMe2(CH2NNCHSiMe3)C5H2}Th{NH(p‐tolyl)}] (6) by intramolecular CH bond activation. The experimental results are complemented by density functional theory (DFT) studies.
Self‐healing Ag/epoxy electrically conductive adhesive using encapsulated epoxy‐amine healing chemistry
Authors: Tao Yu , Chang Yu , Tao Yuxiao , Wu Haiping , Yang Zhenguo
Published: October 2014

In this study, a dual‐microcapsule epoxy‐amine self‐healing concept is used for electrically conductive adhesives (ECAs). It provides the ECA samples with the ability to recover mechanical and electrical properties automatically. Epoxy and amine microcapsules were prepared and incorporated into silver/epoxy ECAs. The healing efficiency and bulk resistivity of the undamaged, damaged, and healed specimens were measured, respectively. The optimal loading of the epoxy and amine microcapsules is 6 wt % (weight ratio 1.05), and the bulk resistivity of the healed specimens is 3.4 × 10−3 Ω cm. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41483.
Mixed templates molecularly imprinted solid‐phase extraction for the detection of sulfonamides in fish farming water
Authors: Qin Shili , Su Liqiang , Wang Peng , Deng Sheng
Published: October 2014

Highly selective molecularly imprinted polymers (MIPs) that absorb sulfonamides (SAs) are prepared using two types of SAs as mixed templates, 2‐vinylpyridine as the functional monomer and ethylene glycol dimethacrylate as the crosslinker. The optimum combination of the mixed templates, their adsorption effect and the imprinting mechanism are evaluated based on SPE recoveries of a family of analytes, equilibrium binding, BET surface area analysis and UV. The results indicate that the mixed templates not only optimize the cavities of the MIPs but also improve the MIPs selectivity and adsorption capacity for the target analytes in aqueous solution. Therefore, MIPs are used for the quantitative analysis of SAs in fish farming water using off‐line SPE coupled to HPLC/DAD. The recovery and RSD were 84.16–101.19 and 1.98–7.10%, respectively. Four SAs analytes were detected in four types of water samples in the range of 8.49–74.60 ng L−1. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41491.
Characterization of cross‐linking depth for thin polymeric films using atomic force microscopy
Authors: Guo Qiuquan , Paliy Maxim , Kobe Brad , Trebicky Tomas , Suhan Natalie , Arsenault Gilles , Ferrari Lorenzo , Yang Jun
Published: October 2014

Thin polymeric films made with various elastomers, like polyisoprene, and elastomer composites were prepared for characterization of cross‐linking depth in this study. Various cross‐linking methods have been applied to get mechanically stronger, more thermally stable and chemically resistant polymer coatings. However, there is no existing approach that could effectively characterize the degree or depth of cross‐linking for thin polymer films. The objective of this work is to use atomic force microscopy to characterize cross‐linking depth in a precise way. Hyperthermal hydrogen bombardment‐induced cross‐linking was employed as a cross‐linking method and the depth of cross‐linking was estimated via local change of the elastic modulus along the sample cross‐section with precise force measurement and high spatial resolution. It is found that the cross‐linking depth is closely related to the chemical composition of thin films. Understanding the depth of cross‐linking is vital for a broad range of applications. It is believed that the developed technique is also applicable for studying other cross‐linkable materials. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41493.
Spectroscopic analysis and catalytic application of biopolymer capped silver nanoparticle, an effective antimicrobial agent
Authors: Pramanik Nilkamal , Bhattacharyya Aditi , Kundu Patit Paban
Published: October 2014

Microbial reduction of silver ion (conc. 1 mM AgNO3) was performed by Alkaliphilus oremlandii strain ohILAs in an alkaline pH 10. The synthesized silver nanoparticle was stabilized by poly(3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) biopolymer which was also synthesized by the microbial culture of Alkaliphilus oremlandii strain ohILAs at pH8. The particle size and shape of the silver nanoparticles was studied by dynamic light scattering and under a transmission electron microscope and it was found that the particle size of polymer stabilized colloidal silver was comparatively lower (22–43nm) than that for the unstabilized one (63–93 nm). The stabilization of nanoparticles in polymer dispersed medium after around 60 days was confirmed from analysis of UV‐visible spectroscopy and scanning electron microscopy. The crystalline peaks as recorded with X‐ray's diffraction were observed at 2θ values of 38° and 43°, indicating the fcc crystalline structure of the silver nanoparticle. The antimicrobial activity of silver nanoparticles on gram‐negative bacteria strain (Escherichia coli XL1B) and gram‐positive strain (Lysinibacillus fusiformis) showed better performance by the solution of polymer stabilized nanoparticle than that for the non polymer stabilized one. The reduction of nitro group in p‐nitrophenol to p‐aminophenol was observed from the analysis of UV‐Visible spectroscopy in which, the shifting of absorption peak at 400 to 295 nm and the simultaneous regeneration of light brown color (λmax 410 nm) of silver nanoparticles confirmed the catalytic activity of silver nanomaterials. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41495.
Influence of BaTiO3 submicrometric particles on the structure, morphology, and crystallization behavior of poly(vinylidene fluoride)
Authors: Sánchez Freddy A. , Redondo Marta , González‐Benito Javier
Published: October 2014

Real uniform dispersion of barium titanate, BaTiO3, submicrometric particles within Poly(vinylidene fluoride), PVDF, was achieved to understand induced structure, morphology, and crystallization process of the polymer. Composites with uniform dispersions of BaTiO3 particles within PVDF were accomplished for the first time, blending the polymer with particles by high energy ball milling, HEBM. Different compositions in PVDF/BaTiO3 composite were considered (0, 1, 5, and 10 weight percent of particles). Morphology and structure were studied by scanning electron microscopy, SEM, and X‐ray diffraction, XRD, respectively. From dynamic experiments by differential scanning calorimetry, DSC, thermal transitions were determined and melting and crystallization processes were studied. To understand the main mechanism by which specific morphologies can be obtained a deep kinetic analysis of the PVDF crystallization process was carried out. Cooling rate and BaTiO3 content did not provide important variations in the PVDF crystalline structure and morphology; however, the presence of BaTiO3 particles seemed to favor an athermal nucleation, leading to higher fraction of crystals in shorter times. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41497.
Photoluminescent enhancement of polyesters via photocrosslinking
Authors: Lim Wan Leng , Oo Chuan Wei , Kobayashi Takaomi
Published: October 2014

A homologous series of soluble photoluminescent polyesters, namely poly{bis(4‐hydroxybenzylidene)acetone‐5‐(m‐alkyloxyisophthalate)}, PAI1‐PAI5 were designed and synthesized via polycondensation reaction. The branches of these polyesters consisted of flexible alkyloxy chains with different chain lengths in order to investigate their influence toward thermal stability as well as the photocrosslinking property. It was found that increasing length of the flexible chain would reduce the thermal stability of the polyesters. Irradiation of these polyesters under UV light induced photocrosslinking and showed fascinate enhancement in their photoluminescence property with greater emission intensity. This was evidenced visually from the transformation of a weak greenish blue emission to highly intense cloudy blue emission. The photocrosslinking system was further confirmed using spectroscopic methods. Morphology analysis using SEM showed that the photocrosslinked polyesters have a fiber‐like or thread‐like texture with more voids as compared to the virgin polyesters. This was because of the formation of cyclobutanes through photodimerization involving 2π + 2π cycloaddition. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41504.
Optical, electrochemical, and photovoltaic properties of conjugated polymers with dithiafulvalene as side chains
Authors: Gu Chuantao , Du Zhengkun , Shen Wenfei , Bao Xichang , Wen Shuguang , Zhu Dangqiang , Wang Ting , Wang Ning , Yang Renqiang
Published: October 2014

Three conjugated polymers, P1–P3, with dithiafulvalene (DTF) as side chains have been synthesized. All polymers have good thermal stabilities. The DTF unit could be oxidized to DTF•+ which was observed from cyclic voltammetry and ultraviolet–visible (UV–vis) spectra, and the oxidation process was independent of the conjugated backbone of the polymer. The strong π–π* transition absorbing band of the three polymers decreases gradually as increasing oxidation, and the resulting DTF•+ species give rise to an additional band at 750–1100 nm, which can be assigned to a distinguishing feature of the cation radical species. Photovoltaic device based on the blend of P2 and [6,6]‐phenyl‐C61‐butyric acid methyl ester (PC61BM) showed the power conversion efficiency of 1.05% with a fill factor of 42.8%. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41508.