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  • 11
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    Online Resource
    A Predominant Oxidative Renal Metabolite of Empagliflozin in Male Mice Is Cytotoxic in Mouse Renal Tubular Cells but not Genotoxic
    SAGE Publications ; 2017
    In:  International Journal of Toxicology Vol. 36, No. 6 ( 2017-11), p. 440-448
    Details
    In: International Journal of Toxicology, SAGE Publications, Vol. 36, No. 6 ( 2017-11), p. 440-448
    Abstract: In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high-dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA). In order to further evaluate potential modes of action for empagliflozin-associated male mouse renal tumors, we report here a series of in vitro investigative toxicology studies conducted to evaluate the cytotoxic and genotoxic potential of empagliflozin and M466/2. To assess the cytotoxic potential of empagliflozin and M466/2, a primary mouse renal tubular epithelial (mRTE) cell model was used. In mRTE cells, M466/2-derived in vitro 4-OH CTA exposure was cytotoxic, while empagliflozin was not cytotoxic or mitogenic. Empagliflozin and M466/2 were not genotoxic, supporting an indirect mode of action for empagliflozin-associated male mouse renal tumorigenesis. In conclusion, these in vitro data show that M466/2-derived 4-OH CTA exposure is associated with cytotoxicity in renal tubule cells and may be involved in promoting compound-related in vivo renal metabolic stress and chronic low-level renal injury, in turn supporting a nongenotoxic mode of tumor pathogenesis specific to the male mouse.
    Type of Medium: Online Resource
    ISSN: 1091-5818 , 1092-874X
    URL: Article
    DOI: 10.1177/1091581817735090
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
    detail.hit.zdb_id: 1500682-7
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  • 12
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    Online Resource
    Rapid and sensitive analysis of reduced and oxidized coenzyme Q10 in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and application to studies in healthy human subjects
    SAGE Publications ; 2016
    In:  Annals of Clinical Biochemistry: International Journal of Laboratory Medicine Vol. 53, No. 2 ( 2016-03), p. 265-273
    Details
    In: Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, SAGE Publications, Vol. 53, No. 2 ( 2016-03), p. 265-273
    Abstract: Coenzyme Q10 is an endogenous antioxidant as well as a popular dietary supplement. In blood circulation, coenzyme Q10 exists predominantly as its reduced ubiquinol-10 form, which readily oxidizes to ubiquinone-10 ex vivo. Plasma concentrations of coenzyme Q10 reflect net overall metabolic demand, and the ratio of ubiquinol-10:ubiquinone-10 has been established as an important biomarker for oxidative stress. However, the lability of ubiquinol-10 makes accurate determination of both forms of coenzyme Q10 difficult. Ex vivo oxidation of ubiquinol-10 to ubiquinone-10 during sample collection, processing and analysis may obfuscate the in vivo ratio. Methods We developed a rapid and sensitive method for the determination of ubiquinol-10 and ubiquinone-10 in human plasma, using coenzyme Q9 analogues as internal standards. Single-step protein precipitation in 1-propanol, a lipophilic and water-soluble alcohol, allowed for rapid extraction. Results Analysis by ultra performance liquid chromatography-tandem mass spectrometry provided rapid run-time and high sensitivity, with lower limits of quantitation for ubiquinol-10 and ubiquinone-10 of 5 μg/L and 10 μg/L, respectively. Conclusions This method is suitable for clinical studies with coenzyme Q10 supplementation in various disease states where this lipid-antioxidant may be beneficial. We have applied this method to 〉 300 plasma samples from coenzyme Q10 research studies in chronic haemodialysis patients and postsurgical patients.
    Type of Medium: Online Resource
    ISSN: 0004-5632 , 1758-1001
    URL: Article
    DOI: 10.1177/0004563215593097
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
    detail.hit.zdb_id: 2041298-8
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  • 13
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    Spontaneous Findings in the Reproductive System of Sexually Mature Male Cynomolgus Macaques
    SAGE Publications ; 2022
    In:  Toxicologic Pathology Vol. 50, No. 5 ( 2022-07), p. 660-678
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 50, No. 5 ( 2022-07), p. 660-678
    Abstract: Sexually mature nonhuman primates are often used in nonclinical safety testing when evaluating biopharmaceuticals; however, there is limited information in historical control databases or in the published literature on the spontaneous findings in the male reproductive system. This review evaluated digital slides from the male reproductive tract (testes, epididymides, prostate, and seminal vesicles) in sexually mature cynomolgus macaques ( Macaca fascicularis; n = 255) from vehicle control groups in nonclinical toxicology studies and compared the observations with body weight, organ weight, and geographical origin. The most common microscopic findings were hypospermatogenesis and tubular dilatation in the testes; inflammatory cell infiltrate, cellular debris, and decreased sperm in the epididymides; inflammatory cell infiltrate and acinar dilatation in the prostate; and corpora amylacea and atrophy in the seminal vesicles. There were a few correlative observations in animals when grouped by weight or geographical origin: animals with lower terminal body weights ( 〈 5 kg) often displayed features of late puberty despite having sperm in the epididymis, while animals originating from Mauritius had a lower incidence of inflammatory cell infiltrates than those from Southeast Asia/China. This review provides incidence, descriptions, and photomicrographs of the common spontaneous microscopic findings in the reproductive system of mature male cynomolgus macaques.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/01926233221082302
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2056753-4
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  • 14
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    Online Resource
    Integrative Toxicopathological Evaluation of Aflatoxin B 1 Exposure in F344 Rats
    SAGE Publications ; 2013
    In:  Toxicologic Pathology Vol. 41, No. 8 ( 2013-12), p. 1093-1105
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 41, No. 8 ( 2013-12), p. 1093-1105
    Abstract: In this study, male F344 rats were orally exposed to a single dose of aflatoxin B 1 (AFB 1 ) at 0, 50, 250, or 1,000 µg/kg body weight (BW) or repeated dose of 0, 5, 10, 25, or 75 µg/kg BW for up to 5 weeks. Biochemical and histological changes were assessed together with the formation of AFB 1 -lysine adduct (AFB-Lys) and liver foci positive for placental form glutathione S transferase (GST-P + ). In single-dose protocol, serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) showed dose-related elevation, with maximal changes observed ( 〉 100-fold) at day 3 after treatment. Animals that received 250 µg/kg AFB 1 showed concurrent bile duct proliferation, necrosis, and GST-P + hepatocytes at 3 day, followed by liver GST-P + foci appearance at 1 week. In repeated-dose protocol, bile duct proliferation and liver GST-P + foci co-occurred after 3-week exposure to 75 µg/kg AFB 1 , followed by proliferation foci formation after 4 week and dramatic ALT, AST, and CK elevations after 5 weeks. Liver GST-P + foci were induced temporally and in a dose-related manner. Serum AFB-Lys increased temporally at low doses (5–25 µg/kg), and reached the maximum after 2-week exposure at 75 µg/kg. This integrative study demonstrated that liver GST-P + cells and foci are sensitive biomarkers for AFB 1 toxic effect and correlated with bile duct proliferation and biochemical alterations in F344 rats.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/0192623313477256
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2013
    detail.hit.zdb_id: 2056753-4
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  • 15
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    Changes in Viral Load in People with Virological Failure who Remain on the Same Haart Regimen
    SAGE Publications ; 2003
    In:  Antiviral Therapy Vol. 8, No. 2 ( 2003-02), p. 127-136
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 8, No. 2 ( 2003-02), p. 127-136
    Abstract: To assess the rate of change in viral load and CD4 count over time in HIV-infected patients experiencing virological failure on a HAART regimen. Design Study population included patients from EuroSIDA, a large, multicentre, observational study enrolling HIV-infected patients across Europe. Methods Median change in viral load and CD4 count per month were estimated using the viral load and CD4 measurements obtained over a 12-month period after confirmed virological failure between 3 and 4 log 10 copies/ml in a population of 488 HIV-infected patients who were left on a failing HAART regimen. Results The estimated median viral load change in our study population was 0.024 log 10 copies/ml per month, statistically different from 0 (P=0.0001). In 20.9% of the patients studied viral load showed a tendency to decrease, in 47.8% showed a tendency to increase by a positive rate no higher than 0.04 log 10 copies/ml per month and in the remaining 31.3% showed a tendency to increase by a rate greater than 0.04 log 10 copies/ml per month. On average, CD4 counts were estimated to remain stable (decrease at a slow rate of about –0.53 cells/μl per month). Conclusions In patients that remained on a stable, but virologically failing HAART regimen (with viral load ranging 1000–10000 copies/ml), the viral load over the ensuing 12-month period increased at a relatively slow rate. In contrast, the CD4 count remained stable, possibly because of partial but sustained viral suppression below the viral load natural set-point. The time-course of selecting more replication-competent virus in patients with virological failure remains to be fully clarified.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350300800207
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2003
    detail.hit.zdb_id: 2118396-X
    SSG: 15,3
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  • 16
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    Online Resource
    The characterisation of unexplained pain after knee replacement
    SAGE Publications ; 2017
    In:  British Journal of Pain Vol. 11, No. 4 ( 2017-11), p. 203-209
    Details
    In: British Journal of Pain, SAGE Publications, Vol. 11, No. 4 ( 2017-11), p. 203-209
    Abstract: The aims of this study were to characterise the pain experienced by patients with chronic pain after knee replacement (KR), in whom no apparent ‘orthopaedic’ problem could be identified, and to establish how many have pain sensitisation problems (including neuropathic pain). Methods: A total of 44 patients were prospectively evaluated at a multidisciplinary tertiary referral clinic by an orthopaedic surgeon, pain specialist, rheumatologist and physiotherapist. These patients had been pre-screened by an orthopaedic surgeon to remove cases where there was an obvious cause of pain that could be treated with revision surgery. They were then followed up to find out whether any subsequent interventions had occurred. Results: The mean time since surgery was 29 months (range: 3–108 months), and 18% were revision KR. Patients were evaluated for symptoms of nociceptive pain, allodynia, pains elsewhere and psychosocial factors. The patients were categorised into nociceptive pain 43% (n = 19), pain sensitisation 25% (n = 11) and mixed pain 32% (n = 14). Mean Visual Analogue Score (VAS) pain scores were 6.7/10 with high scores for both constant (66%) and intermittent (70%) pain elements, and pain caused high levels of interference with life. Fifty percent suffered depression and 25% suffered widespread pains (more than three pains elsewhere in the body). Patients with widespread pains suffered more pain (p = 0.01) and higher rates of both pain sensitisation (p = 0.07) and thermal allodynia (p  〈  0.04). Conclusion: Patients after KR can experience severe pain that interferes with their lives, depression and many have pain sensitisation problems rather than any local, nociceptive cause. We advocate screening patients with unexplained pain after KR for pain sensitisation problems, pains at other sites and depression. Appropriate further treatment and multidisciplinary interventions can then be arranged.
    Type of Medium: Online Resource
    ISSN: 2049-4637 , 2049-4645
    URL: Article
    DOI: 10.1177/2049463717719774
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
    detail.hit.zdb_id: 2670872-3
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  • 17
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    Online Resource
    Pathogenesis of Renal Injury and Gene Expression Changes in the Male CD-1 Mouse Associated with Exposure to Empagliflozin
    SAGE Publications ; 2018
    In:  Toxicologic Pathology Vol. 46, No. 6 ( 2018-08), p. 671-682
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 46, No. 6 ( 2018-08), p. 671-682
    Abstract: An increased incidence of renal tubular adenomas and carcinomas was identified in the 2-year CD-1 mouse carcinogenicity study with empagliflozin (sodium-glucose transporter 2 inhibitor) in high dose (1,000 mg/kg/day) male mice. A 13-week mouse renal investigative pathogenesis study was conducted with empagliflozin to evaluate dose dependency and temporal onset of nonneoplastic degenerative/regenerative renal tubular and molecular (genes, pathways) changes which precede neoplasia. Male and female CD-1 mice were given daily oral doses of 0, 100, 300, or 1,000 mg/kg/day (corresponding carcinogenicity study dose levels) for 1, 2, 4, 8, or 13 weeks. The maximum expected pharmacology with secondary osmotic diuresis was observed by week 1 at ≥100 mg/kg/day in both genders. Histopathologic kidney changes were first detected after 4 weeks of dosing in the male 1,000 mg/kg/day dose group, with progressive increases in the incidence and/or number of findings in this dose group so that they were more readily detected during weeks 8 and 13. Changes detected starting on week 4 consisted of minimal single-cell necrosis and minimal increases in mitotic figures. These changes persisted at an increased incidence at weeks 8 and 13 and were accompanied by minimal to mild tubular epithelial karyomegaly, minimal proximal convoluted tubular epithelial cell hyperplasia, and a corresponding increase in Ki-67-positive nuclei in epithelial cells of the proximal convoluted tubules. There were no corresponding changes in serum chemistry or urinalysis parameters indicative of any physiologically meaningful effect on renal function and thus these findings were not considered to be adverse. Similar changes were not identified in lower-dose groups in males nor were they present in females of any dose group. RNA-sequencing analysis revealed male mouse-specific changes in kidney over 13 weeks of dosing at 1,000 mg/kg/day. Treatment-related changes included genes and pathways related to p53-regulated cell cycle and proliferation, transforming growth factor β, oxidative stress, and renal injury and the number of genes with significant expression change dramatically increased at week 13. These treatment-related changes in genes and pathways were predominant in high-dose males and complemented the observed temporal renal tubular changes. Overall, these mouse investigative study results support the role of early empagliflozin-related degenerative/regenerative changes only observed in high-dose male CD-1 mice as a key contributing feature to a nongenotoxic mode of renal tumor pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/0192623318784514
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
    detail.hit.zdb_id: 2056753-4
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  • 18
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    Online Resource
    Mindfulness Training Improves Working Memory Capacity and GRE Performance While Reducing Mind Wandering
    SAGE Publications ; 2013
    In:  Psychological Science Vol. 24, No. 5 ( 2013-05), p. 776-781
    Details
    In: Psychological Science, SAGE Publications, Vol. 24, No. 5 ( 2013-05), p. 776-781
    Abstract: Given that the ability to attend to a task without distraction underlies performance in a wide variety of contexts, training one’s ability to stay on task should result in a similarly broad enhancement of performance. In a randomized controlled investigation, we examined whether a 2-week mindfulness-training course would decrease mind wandering and improve cognitive performance. Mindfulness training improved both GRE reading-comprehension scores and working memory capacity while simultaneously reducing the occurrence of distracting thoughts during completion of the GRE and the measure of working memory. Improvements in performance following mindfulness training were mediated by reduced mind wandering among participants who were prone to distraction at pretesting. Our results suggest that cultivating mindfulness is an effective and efficient technique for improving cognitive function, with wide-reaching consequences.
    Type of Medium: Online Resource
    ISSN: 0956-7976 , 1467-9280
    URL: Article
    DOI: 10.1177/0956797612459659
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2013
    detail.hit.zdb_id: 2022256-7
    SSG: 5,2
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