18 results on '"Tanaka WK"'
Search Results
2. Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin.
- Author
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Schwartz JI, Musser BJ, Tanaka WK, Taggart WV, Mehta A, Gottesdiener KM, and Greenberg HE
- Subjects
- 6-Ketoprostaglandin F1 alpha urine, Acetaminophen adverse effects, Administration, Oral, Adult, Biomarkers urine, Cross-Over Studies, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors adverse effects, Double-Blind Method, Drug Administration Schedule, Female, Healthy Volunteers, Humans, Indomethacin adverse effects, Male, Philadelphia, Prospective Studies, Renal Elimination drug effects, Thromboxane B2 urine, Young Adult, 6-Ketoprostaglandin F1 alpha analogs & derivatives, Acetaminophen administration & dosage, Cyclooxygenase 2 Inhibitors administration & dosage, Indomethacin administration & dosage, Thromboxane B2 analogs & derivatives
- Abstract
This double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI-M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI-M excretion following single and multiple doses (P = .004 vs placebo). PGI-M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx-M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx-M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx-M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX-1 and COX-2 following a single dose, but acetaminophen was a less potent COX-1 inhibitor than indomethacin., (© 2015, The American College of Clinical Pharmacology.)
- Published
- 2015
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3. High-throughput simultaneous analysis of RNA, protein, and lipid biomarkers in heterogeneous tissue samples.
- Author
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Reiser V, Smith RC, Xue J, Kurtz MM, Liu R, Legrand C, He X, Yu X, Wong P, Hinchcliffe JS, Tanen MR, Lazar G, Zieba R, Ichetovkin M, Chen Z, O'Neill EA, Tanaka WK, Marton MJ, Liao J, Morris M, Hailman E, Tokiwa GY, and Plump AS
- Subjects
- Biomarkers analysis, Cryopreservation, Dissection, Humans, Lipids isolation & purification, Proteins isolation & purification, RNA isolation & purification, RNA, Messenger analysis, RNA, Messenger isolation & purification, Tissue Extracts chemistry, Lipids analysis, Plaque, Atherosclerotic chemistry, Proteins analysis, RNA analysis, Specimen Handling methods, Tissue Preservation methods
- Abstract
Background: With expanding biomarker discovery efforts and increasing costs of drug development, it is critical to maximize the value of mass-limited clinical samples. The main limitation of available methods is the inability to isolate and analyze, from a single sample, molecules requiring incompatible extraction methods. Thus, we developed a novel semiautomated method for tissue processing and tissue milling and division (TMAD)., Methods: We used a SilverHawk atherectomy catheter to collect atherosclerotic plaques from patients requiring peripheral atherectomy. Tissue preservation by flash freezing was compared with immersion in RNAlater®, and tissue grinding by traditional mortar and pestle was compared with TMAD. Comparators were protein, RNA, and lipid yield and quality. Reproducibility of analyte yield from aliquots of the same tissue sample processed by TMAD was also measured., Results: The quantity and quality of biomarkers extracted from tissue prepared by TMAD was at least as good as that extracted from tissue stored and prepared by traditional means. TMAD enabled parallel analysis of gene expression (quantitative reverse-transcription PCR, microarray), protein composition (ELISA), and lipid content (biochemical assay) from as little as 20 mg of tissue. The mean correlation was r = 0.97 in molecular composition (RNA, protein, or lipid) between aliquots of individual samples generated by TMAD. We also demonstrated that it is feasible to use TMAD in a large-scale clinical study setting., Conclusions: The TMAD methodology described here enables semiautomated, high-throughput sampling of small amounts of heterogeneous tissue specimens by multiple analytical techniques with generally improved quality of recovered biomolecules.
- Published
- 2011
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4. Quantitative measurement of cysteinyl leukotrienes and leukotriene B₄ in human sputum using ultra high pressure liquid chromatography-tandem mass spectrometry.
- Author
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Chappell GP, Xiao X, Pica-Mendez A, Varnell T, Green S, Tanaka WK, and Laterza O
- Subjects
- Asthma, Drug Stability, Hot Temperature, Humans, Hydrogen-Ion Concentration, Leukotrienes chemistry, Linear Models, Pulmonary Disease, Chronic Obstructive, Reproducibility of Results, Sensitivity and Specificity, Chromatography, High Pressure Liquid methods, Leukotrienes analysis, Sputum chemistry, Tandem Mass Spectrometry methods
- Abstract
The role of leukotrienes (LTs) in airway inflammatory diseases, such as asthma, has been extensively reported. The measurement of LTs in sputum supernatants, which is commonly done via enzyme immunoassays (EIAs), may prove to be useful for assessing airway inflammation. Despite the many advantages of EIA, these methods suffer from a lack of selectivity. Therefore, a selective and reliable method for the analysis of LTs in human sputum is needed. In this study we developed and validated a sensitive and specific method using ultra high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), to measure simultaneously cysteinyl leukotrienes (CysLTs) and leukotriene B₄ (LTB₄) in human sputum. Sputum supernatants obtained by ultracentrifugation were stabilized by protease inhibitors, spiked with stable isotopic internal standards, and subjected to solid phase extraction (SPE) and UHPLC separation. Multiple reaction monitoring (MRM) transitions were optimized and measured on a mass spectrometer. The limit of detection (LOD) for LTE₄ and LTB₄ was 9.8 and 19.5 pg/mL, respectively. The lower limit of quantitation (LLOQ) for LTE₄ and LTB₄ was 19.5 and 39.0 pg/mL, respectively. The dynamic range of the LTE₄ assay was from 9.8 to 5000 pg/mL, whereas for the LTB₄ assay was from 19.5 to 10,000 pg/mL. The intra- and inter-day % coefficient of variation (%CV) was <6.5% and <10%, for both LTE₄ and LTB₄, respectively. Spike recovery ranged from 105% to 111% for both analytes. In addition, twenty-two sputum samples were analyzed for cysLTs and LTB₄. Fourteen of these samples were purchased commercially and eight were collected during the course of a clinical trial. LTB₄ was detectable in all samples tested and it ranged from 79 to 7220 pg/mL. LTE₄ was detectable in most of the sputum samples (12.3-891 pg/mL), whereas LTC₄ and LTD₄ were below limit of detection for majority of sputum samples. The in vitro conversion of LTC₄ and LTD₄ into LTE₄ was observed. The measurement of LTB₄ was sensitive to low pH and high temperature. The use of UHPLC-MS/MS method will allow a more accurate and reliable quantitation of LTs in human sputum, which in turn, may lead to a better understanding of the role of LTs in airway disease pathways and the application in associated clinical treatments., (© 2010 Elsevier B.V. All rights reserved.)
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- 2011
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5. Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury.
- Author
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Laterza OF, Lim L, Garrett-Engele PW, Vlasakova K, Muniappa N, Tanaka WK, Johnson JM, Sina JF, Fare TL, Sistare FD, and Glaab WE
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- Animals, Biomarkers blood, Female, Heart Injuries diagnosis, Heart Injuries genetics, Kidney injuries, Kidney pathology, Liver injuries, Liver pathology, Male, Muscle, Skeletal injuries, Muscle, Skeletal pathology, Myocardium pathology, Rats, Rats, Sprague-Dawley, Stroke diagnosis, Stroke genetics, MicroRNAs blood, Wounds and Injuries diagnosis, Wounds and Injuries genetics
- Abstract
Background: MicroRNAs (miRNAs) are endogenous, small noncoding RNAs. Because of their size, abundance, tissue specificity, and relative stability in plasma, miRNAs hold promise as unique accessible biomarkers to monitor tissue injury., Methods: We investigated the use of liver-, muscle- and brain-specific miRNAs as circulating biomarkers of tissue injury. We used a highly sensitive quantitative PCR assay to measure specific miRNAs (miR-122, miR-133a, and miR-124) in plasma samples from rats treated with liver or muscle toxicants and from a rat surgical model of stroke., Results: We observed increases in plasma concentrations of miR-122, miR-133a, and miR-124 corresponding to injuries in liver, muscle, and brain, respectively. miR-122 and miR-133a illustrated specificity for liver and muscle toxicity, respectively, because they were not detectable in the plasma of animals with toxicity to the other organ. This result contrasted with the results for alanine aminotransferase (ALT) and aspartate aminotransferase, which were both increased with either organ toxicity. Furthermore, miR-122 exhibited a diagnostic sensitivity superior to that of ALT when the results were correlated to the liver histopathologic results. The miR-124 concentration increased in the plasma of rats 8 h after surgery to produce brain injury and peaked at 24 h, while the miR-122 and miR-133a concentrations remained at baseline values., Conclusions: These results demonstrate that tissue-specific miRNAs may serve as diagnostically sensitive plasma biomarkers of tissue injury.
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- 2009
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6. Squamous cell carcinoma radiographically resembling a dentigerous cyst: report of a case.
- Author
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Elo JA, Slater LJ, Herford AS, Tanaka WK, King BJ, and Moretta CM
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- Carcinoma, Squamous Cell diagnostic imaging, Carcinoma, Squamous Cell surgery, Diagnosis, Differential, Humans, Male, Mandibular Neoplasms diagnostic imaging, Mandibular Neoplasms surgery, Middle Aged, Molar, Third diagnostic imaging, Radiography, Tooth, Impacted diagnostic imaging, Toothache etiology, Treatment Outcome, Carcinoma, Squamous Cell pathology, Mandibular Neoplasms pathology, Tooth, Impacted pathology
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- 2007
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7. A high-precision fluorogenic cholesteryl ester transfer protein assay compatible with animal serum and 3456-well assay technology.
- Author
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Eveland SS, Milot DP, Guo Q, Chen Y, Hyland SA, Peterson LB, Jezequel-Sur S, O'Donnell GT, Zuck PD, Ferrer M, Strulovici B, Wagner JA, Tanaka WK, Hilliard DA, Laterza O, Wright SD, Sparrow CP, and Anderson MS
- Subjects
- Animals, CHO Cells, Cholesterol Ester Transfer Proteins metabolism, Cholesterol Esters metabolism, Cricetinae, Cricetulus, Fluorescence Resonance Energy Transfer, Humans, Models, Biological, Time Factors, Transfection, Biological Assay methods, Cholesterol Ester Transfer Proteins blood, Fluorescent Dyes chemistry, Spectrometry, Fluorescence methods
- Abstract
Cholesteryl ester transfer protein (CETP) is a serum component responsible for both cholesteryl ester and triglyceride trafficking between high-density lipoprotein (HDL) and the apolipoprotein B (apoB)-containing very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Several fluorescence-based assays that monitor these transfers have been reported, but to date such assays have suffered from a low signal/background (S/B) ratio and have been described for use only in relatively purified in vitro systems. We have modified the more advanced of these assays to incorporate a noninterfering, nondiffusable fluorescence quencher into previously described cosonicate particles, often referred to as microemulsions. This simple improvement resulted in particles that had an average threefold enhanced S/B window over particles without quenchers but that continued to show the essential properties of a catalytic assay, including catalysis to a single endpoint, excellent linearity with protein and particle concentration, and an appropriate sensitivity to inhibition. This reduced assay noise allowed the subsequent development of protocols for the direct measure of cholesteryl ester (CE) transfer activity resident in human and animal serum as well as the development of 384- and 3456-well screening protocols with good precision and accuracy. Thus, by expanding the dynamic response window of the assay, we have created an assay generalizable to many settings.
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- 2007
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8. Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults.
- Author
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Gantz I, Erondu N, Mallick M, Musser B, Krishna R, Tanaka WK, Snyder K, Stevens C, Stroh MA, Zhu H, Wagner JA, Macneil DJ, Heymsfield SB, and Amatruda JM
- Subjects
- Administration, Intranasal, Adolescent, Adult, Aged, Body Mass Index, Body Weight drug effects, Diet, Reducing, Dose-Response Relationship, Drug, Double-Blind Method, Exercise Therapy, Female, Humans, Male, Middle Aged, Peptide Fragments, Peptide YY administration & dosage, Peptide YY adverse effects, Treatment Outcome, Weight Loss drug effects, Obesity drug therapy, Peptide YY therapeutic use
- Abstract
Context: The gastrointestinal peptide hormone, peptide YY(3-36) (PYY(3-36)), is implicated to be a postprandial satiety factor., Objective: The aim of this study is to assess the safety, tolerability, and efficacy of intranasal PYY(3-36) to induce weight loss in obese patients., Design: The study was designed as a randomized, 2-wk, single-blind placebo run-in followed by a 12-wk double-blind, placebo-controlled treatment period., Setting: The study was set within a private and institutional practice., Patients: A total of 133 obese patients (body mass index, 30-43 kg/m(2); age, 18-65 yr) participated in the study., Intervention: Placebo or 200- or 600-microg PYY(3-36) was administered as an intranasal spray 20 min before breakfast, lunch, and dinner in conjunction with a hypocaloric diet and exercise., Main Outcome Measure: Body weight was the main outcome measure., Results: The number of patients completing 12 wk on the drug was 38 of 43 (88%), 31 of 44 (70%), and 12 of 46 (26%) for placebo, 200 microg three times a day (t.i.d.) and 600 microg t.i.d., respectively. In the 600 microg t.i.d. group, 27 of 46 (59%) patients discontinued due to nausea and vomiting. Among all randomized patients who took at least one drug dose and had a postbaseline measurement, the mean body weight change from baseline was -2.8, -3.7, and -1.4 kg for placebo, 200 and 600 microg, respectively. The least squares mean difference (95% confidence interval) between placebo and 200 microg was -0.9 (-2.6, 0.7) kg (P = 0.251). A difference of 2.11 kg was sought. No meaningful inference can be drawn from the few patients who completed the study on 600 microg., Conclusions: Intranasal PYY(3-36) as administered at these intervention doses and preprandial timing is not efficacious in inducing weight loss in obese patients after 12 wk of treatment.
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- 2007
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9. A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.
- Author
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Martin NE, Brunner TB, Kiel KD, DeLaney TF, Regine WF, Mohiuddin M, Rosato EF, Haller DG, Stevenson JP, Smith D, Pramanik B, Tepper J, Tanaka WK, Morrison B, Deutsch P, Gupta AK, Muschel RJ, McKenna WG, Bernhard EJ, and Hahn SM
- Subjects
- Adult, Aged, Cell Line, Tumor, Combined Modality Therapy, Dose-Response Relationship, Drug, Farnesyltranstransferase, Female, Humans, Imidazoles administration & dosage, Infusions, Intravenous, Male, Middle Aged, Survival Analysis, Time Factors, Alkyl and Aryl Transferases antagonists & inhibitors, Imidazoles toxicity, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer., Experimental Design: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2., Results: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated., Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.
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- 2004
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10. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist.
- Author
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Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, Bronsky E, Guerreiro D, and Hendeles L
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- Acetates blood, Adolescent, Adult, Asthma, Exercise-Induced blood, Asthma, Exercise-Induced urine, Cross-Over Studies, Cyclopropanes, Double-Blind Method, Exercise Test, Forced Expiratory Volume drug effects, Humans, Male, Middle Aged, Quinolines blood, Sulfides, Acetates therapeutic use, Asthma, Exercise-Induced drug therapy, Exercise physiology, Leukotriene Antagonists, Leukotriene E4 urine, Quinolines therapeutic use
- Abstract
Background: A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated., Methods: Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis., Results: The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction., Conclusions: Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.
- Published
- 1997
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11. MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen.
- Author
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Schwartz JI, Tanaka WK, Wang DZ, Ebel DL, Geissler LA, Dallob A, Hafkin B, and Gertz BJ
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- Adolescent, Adult, Androstane-3,17-diol analogs & derivatives, Androstane-3,17-diol blood, Finasteride pharmacology, Humans, Luteinizing Hormone blood, Male, Middle Aged, Testosterone blood, 5-alpha Reductase Inhibitors, Azasteroids pharmacology, Dihydrotestosterone blood, Dihydrotestosterone metabolism, Enzyme Inhibitors pharmacology, Sebum metabolism, Semen metabolism
- Abstract
Two isozymes (types 1 and 2) of 5alpha-reductase (5alphaR; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one), an azasteroid that specifically inhibits the human 5alphaR1 isozyme in vitro. Finasteride, a selective inhibitor of 5alphaR2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment. The mean changes from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5, 20, and 50 mg MK-386 were 6.9%, 4.6%, -2.7%, -1.2%, -14.1% (P < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1% (P < 0.05 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (- 14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in semen DHT was noted with 20 or 50 mg MK-386. Serum 3alpha-androstanediol glucuronide values were also reduced after the 20- and 50-mg MK-386 treatments in parallel with the changes in serum DHT. No meaningful changes were observed in serum LH after MK-386 treatment. MK-386 was generally well tolerated by all subjects; reversible aspartate aminotransferase/alanine aminotransferase elevations were observed in two subjects at the 50-mg dose. The differential responses in serum, sebum, and semen DHT concentrations associated with MK-386 and finasteride treatments are consistent with those changes anticipated for selective inhibitors of the human 5alphaR isozymes. Dose-dependent suppression of sebum DHT by a 5alphaR1 inhibitor suggests the potential utility of such compounds in the treatment of acne.
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- 1997
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12. Comparison of the effects of new specific azasteroid inhibitors of steroid 5 alpha-reductase on canine hyperplastic prostate: suppression of prostatic DHT correlated with prostate regression.
- Author
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Cohen SM, Werrmann JG, Rasmusson GH, Tanaka WK, Malatesta PF, Prahalada S, Jacobs JG, Harris G, and Nett TM
- Subjects
- Animals, DNA metabolism, Dihydrotestosterone blood, Dogs, Finasteride therapeutic use, Magnetic Resonance Imaging, Male, Molecular Structure, Organ Size drug effects, Prostate drug effects, Prostate metabolism, Prostatic Hyperplasia metabolism, Prostatic Hyperplasia pathology, Proteins metabolism, Structure-Activity Relationship, Time Factors, 5-alpha Reductase Inhibitors, Dihydrotestosterone metabolism, Finasteride analogs & derivatives, Finasteride pharmacology, Prostate pathology, Prostatic Hyperplasia drug therapy
- Abstract
Four new azasteroid inhibitors of steroid 5 alpha-reductase were compared to the benchmark compound finasteride, each at a dose level of 1 mg/kg/day, as well to placebo and to castration, in seven groups of mature male beagle dogs with enlarged prostates. Prostate volumes were measured repetitively by a volume MRI method over 15 weeks of treatment. The study probed the obverse of the familiar relation between DHT and prostate growth, and provides the first documentation of a tight negative correlation between prostate regression and the prostatic concentration of DHT across a range of treatment regimens (r = -0.982). In this first direct comparison study of structure vs. in vivo activity for several azasteroids in the dog model of BPH, relative efficacy for induction of shrinkage of the dog prostate did not correlate at all with the inhibitor's relative activity against the dog 5 alpha-reductase in vitro. On the basis of the relative IC50 values it would not have been predicted that, at the dose tested, the analogue MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1-en-3-one) was distinguished from the other inhibitors with respect to the induction of faster and more complete regression (69%) as well as greater reduction in prostatic DHT (95%), both of which approached the castrated dog levels of 75% prostatic shrinkage and > 98% reduction in DHT. Treatment with any one of the five azasteroids induced two- to five-fold increases in prostatic testosterone. However, total androgen was conserved at the placebo control level. Despite the differences noted, each azasteroid tested induced a highly significant decrease in prostatic volume that correlated tightly with a decreased prostatic DHT level in canine spontaneous BPH.
- Published
- 1995
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13. Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients.
- Author
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Goldberg MR, Bradstreet TE, McWilliams EJ, Tanaka WK, Lipert S, Bjornsson TD, Waldman SA, Osborne B, Pivadori L, and Lewis G
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- Adult, Aged, Angiotensin II blood, Biphenyl Compounds therapeutic use, Double-Blind Method, Enalapril pharmacology, Female, Humans, Hypertension physiopathology, Imidazoles therapeutic use, Losartan, Male, Middle Aged, Norepinephrine blood, Renin blood, Tetrazoles therapeutic use, Angiotensin II antagonists & inhibitors, Angiotensin Receptor Antagonists, Biphenyl Compounds pharmacology, Hypertension drug therapy, Imidazoles pharmacology, Renin-Angiotensin System drug effects, Tetrazoles pharmacology
- Abstract
We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.
- Published
- 1995
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14. The effect of finasteride, a 5 alpha-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness.
- Author
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Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, Nguyen HH, Moore EC, and Tanaka WK
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- Adult, Alopecia metabolism, Dihydrotestosterone blood, Double-Blind Method, Finasteride pharmacology, Humans, Male, Middle Aged, Scalp drug effects, Testosterone blood, 5-alpha Reductase Inhibitors, Alopecia drug therapy, Dihydrotestosterone metabolism, Finasteride therapeutic use, Scalp metabolism, Testosterone metabolism
- Abstract
The effects of the 5 alpha-reductase inhibitor, finasteride, on scalp skin testosterone (T) and dihydrotestosterone (DHT) levels were studied in patients with male pattern baldness. In a double blind study, male patients undergoing hair transplantation were treated with oral finasteride (5 mg/day) or placebo for 28 days. Scalp skin biopsies were obtained before and after treatment for measurement of T and DHT by high pressure liquid chromatography-RIA. In 10 male subjects studied at baseline, mean (+/- SEM) DHT levels were significantly higher in bald (7.37 +/- 1.24 pmol/g) compared to hair-containing (4.20 +/- 0.65 pmol/g) scalp, whereas there was no difference in mean T levels at baseline. In bald scalp from 8 patients treated with finasteride, the mean DHT concentration decreased from 6.40 +/- 1.07 pmol/g at baseline to 3.62 +/- 0.38 pmol/g on day 28. Scalp T levels increased in 6 of 8 subjects treated with finasteride. Finasteride decreased the mean serum DHT concentration from 1.36 +/- 0.18 nmol/L (n = 8) at baseline to 0.46 +/- 0.10 nmol/L on day 28 and had no effect on serum T. There were no significant changes in scalp or serum T or DHT in placebo-treated patients. In this study, male subjects treated with 5 mg/day finasteride for 4 weeks had significantly decreased concentrations of DHT in bald scalp, resulting in a mean level similar to the baseline levels found in hair-containing scalp.
- Published
- 1994
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15. Measurement of plasma angiotensin II: purification by cation-exchange chromatography.
- Author
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Ledwith BJ, Cahill MK, Losse LS, Satiritz SM, Eydelloth RS, Dallob AL, Tanaka WK, Galloway SM, and Nichols WW
- Subjects
- Amino Acid Sequence, Angiotensins blood, Animals, Cations, Chemistry, Physical methods, Chromatography, High Pressure Liquid methods, Chromatography, Ion Exchange methods, Molecular Sequence Data, Radioimmunoassay methods, Rats, Reproducibility of Results, Angiotensin II blood, Angiotensin II isolation & purification
- Abstract
Measurement of plasma angiotensin II (AII) by radioimmunoassay (RIA) usually requires prior purification of the plasma to remove substances that cross-react in the RIA, most notably angiotensin III (AIII). Purification of AII is generally accomplished by solid-phase extraction (SPE) followed by reverse-phase HPLC, with tedious evaporation and resuspension steps in between, and requires collection of many HPLC fractions per sample for RIA. In this report, we describe a rapid two-step SPE procedure for the purification of plasma AII, including an improved protease inhibitor cocktail for preventing the formation or degradation of AII in vitro. Plasma is first extracted on an S-Sepharose cation-exchange column, in which AII is separated from AIII by virtue of their difference in net charge, and then extracted on a C8 SPE column, without need for intermediate sample handling. The two-step SPE method is fast, results in only a single fraction for RIA per sample, and yields consistently high recoveries (77-86%) of AII, reducing the volume of plasma needed from 2 to 0.5 ml. Rat plasma was used in the present study, but the complete conservation of angiotensin peptide sequences (except angiotensinogen) in mammals suggests that this method will be applicable for other species including humans. In summary, the two-step SPE method offers the speed and simplicity of solid phase extraction while achieving a purity in AII (i.e., free of AIII) previously only obtained by laborious procedures involving HPLC.
- Published
- 1993
- Full Text
- View/download PDF
16. Subcellular distribution of aminoacyl-tRNA synthetases in various eukaryotic cells.
- Author
-
Ussery MA, Tanaka WK, and Hardesty B
- Subjects
- Animals, Centrifugation, Density Gradient, Chick Embryo, Embryo, Mammalian, Mice, Rabbits, Species Specificity, Subcellular Fractions enzymology, Amino Acyl-tRNA Synthetases metabolism, Friend murine leukemia virus enzymology, HeLa Cells enzymology, Liver enzymology, Reticulocytes enzymology, Ribosomes enzymology
- Abstract
The total amount, size distribution and binding of aminoacyl-tRNA synthetases to ribosomes in a variety of mammalian and avian cells was studied under standard conditions of sample preparation and assay. Aminoacyl-tRNA synthetases appear to exist in three general forms; 'free' enzyme of about 4-9 S, one or more 'enzyme complexes' of about 18-25 S, and in association with ribosomes. The aminoacyl-tRNA synthetase activity for many individual amino acids was surprisingly similar in cell types chosen to be diverse with respect to differentiation state, transformation, and growth rate. Total activity for all amino acids varied about 4-fold, based on a constant volume of cells. Embryonic tissues had a comparatively high proportion of total synthetase activity associated with ribosomes, whereas this value was relatively low for mouse liver. Distinctive distribution patterns with common and variable features were observed for individual enzymes. The only aminoacyl-tRNA synthetases found not to be associated in significant amounts with either 18-25 S enzyme complexes or ribosomes in any of the cell types examined were the enzymes for alanine, histidine, and serine. All cell types evidenced 18-25-S synthetase activity for arginine, aspartic acid, glutamine, glutamic acid, isoleucine, leucine, lysine, methionine, proline, and valine, although in quite variable porportions of the total activity observed for these amino acids. For example, of the valyl-tRNA synthetase activity not associated with ribosomes, 35% and 100% were found to sediment at 18-25 S in Friend leukemia cells and mouse liver respectively. All cells had two easily distinguishable peaks of arginyl tRNA synthetase activity at 4-9S and 18-25S respectively; however, the relative proportion of enzyme activity in the peaks differed between cell types. Phenylalanyl-tRNA synthetase was not observed to occur in an 18-25-S complex in any of the cell types examined but was bound to ribosomes in variable but generally relatively high proportions. Numerous other specific differences are described. No underlying physiological or biochemical principle has been recognized to account for the specific distribution patterns observed. However, they may reflect variations in cellular architecture that may be related to regulation of protein synthesis.
- Published
- 1977
- Full Text
- View/download PDF
17. Comparison of free and ribosome-bound phenylalanyl-tRNA synthetase from rabbit reticulocytes.
- Author
-
Tanaka WK, Som K, and Hardesty BA
- Subjects
- Animals, Cytosol enzymology, Drug Stability, Kinetics, Molecular Weight, Phenylalanine-tRNA Ligase isolation & purification, Rabbits, Amino Acyl-tRNA Synthetases blood, Phenylalanine-tRNA Ligase blood, Reticulocytes enzymology, Ribosomes enzymology
- Published
- 1976
- Full Text
- View/download PDF
18. Labeling patterns in prodigiosin biosynthesis.
- Author
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Tanaka WK, Bascur de Medina L, and Hearn WR
- Subjects
- Carbon Isotopes, Chemical Phenomena, Chemistry, Genetics, Microbial, Glycine metabolism, Maleimides chemical synthesis, Methionine metabolism, Mutation, Oxidation-Reduction, Prodigiosin biosynthesis, Proline metabolism, Serratia marcescens growth & development, Anti-Bacterial Agents biosynthesis, Pigments, Biological biosynthesis, Pyrroles biosynthesis, Serratia marcescens metabolism
- Published
- 1972
- Full Text
- View/download PDF
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