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| 2. |
- Denison, H, et al.
(författare)
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Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects : a randomized clinical trial
- 2014
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 16:4, s. 334-343
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Tidskriftsartikel (refereegranskat)abstract
- AIM:Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.METHODS:Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.RESULTS:Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.CONCLUSIONS:Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.
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| 3. |
- Rydholm, H., et al.
(författare)
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Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia
- 2016
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Ingår i: Clinical Therapeutics. - : Elsevier BV. - 0149-2918. ; 38:4, s. 946-960
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Lesogaberan, a gamma-aminobutyric acid (GABA)(B) receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. Methods: This study was a narrative review of the literature and unpublished data. Findings: The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. Implications: The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action. (C) 2016 Elsevier HS Journals, Inc. All rights reserved.
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| 5. |
- Berglund, K. M., et al.
(författare)
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Prevalence of pain and dysfunction in the cervical and thoracic spine in persons with and without lateral elbow pain
- 2008
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Ingår i: Manual Therapy. - : Elsevier BV. - 1356-689X .- 1532-2769. ; 13:4, s. 295-299
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to Survey the prevalence of pain in the cervical and thoracic spine (C2-T7) in persons with and Without lateral elbow pain. Thirty-one subjects with lateral elbow pain and 31 healthy controls participated in the study. The assessment comprised a pain drawing, provocation tests of the cervical and thoracic spine, a neurodynamic test of the radial nerve, and active cervical range of motion. Seventy percent of the subjects with lateral elbow pain indicated pain in the cervical or thoracic spine, as compared to 16% in the control group (p< ;0.001). The frequency of pain responses to the provocation tests of the cervical and thoracic spine was significantly higher (p< ;0.05) in the lateral elbow pain (LEP) group, as was the frequency of pain responses to the neurodynamic test of the radial nerve (p< ;0.001). Cervical flexion and extension range of motion was significantly lower (p< ;0.01) in the LEP group. The results indicate a relation between lateral elbow pain and pain in the vertebral spine (C2-T7). The cervical and thoracic spine should be included in the assessment of patients with lateral elbow pain.
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| 6. |
- Denison, H, et al.
(författare)
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Proof of mechanism for the DGAT1 inhibitor AZD7687 : results from a first-time-in-human single-dose study
- 2013
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 15:2, s. 136-143
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687.METHODS: Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity.RESULTS: AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687.CONCLUSIONS: The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.
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| 7. |
- Doriese, W B, et al.
(författare)
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A practical superconducting-microcalorimeter X-ray spectrometer for beamline and laboratory science
- 2017
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 88:5
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Tidskriftsartikel (refereegranskat)abstract
- We describe a series of microcalorimeter X-ray spectrometers designed for a broad suite of measurement applications. The chief advantage of this type of spectrometer is that it can be orders of magnitude more efficient at collecting X-rays than more traditional high-resolution spectrometers that rely on wavelength-dispersive techniques. This advantage is most useful in applications that are traditionally photon-starved and/or involve radiation-sensitive samples. Each energy-dispersive spectrometer is built around an array of several hundred transition-edge sensors (TESs). TESs are superconducting thin films that are biased into their superconducting-to-normal-metal transitions. The spectrometers share a common readout architecture and many design elements, such as a compact, 65 mK detector package, 8-column time-division-multiplexed superconducting quantum-interference device readout, and a liquid-cryogen-free cryogenic system that is a two-stage adiabatic-demagnetization refrigerator backed by a pulse-tube cryocooler. We have adapted this flexible architecture to mate to a variety of sample chambers and measurement systems that encompass a range of observing geometries. There are two different types of TES pixels employed. The first, designed for X-ray energies below 10 keV, has a best demonstrated energy resolution of 2.1 eV (full-width-at-half-maximum or FWHM) at 5.9 keV. The second, designed for X-ray energies below 2 keV, has a best demonstrated resolution of 1.0 eV (FWHM) at 500 eV. Our team has now deployed seven of these X-ray spectrometers to a variety of light sources, accelerator facilities, and laboratory-scale experiments; these seven spectrometers have already performed measurements related to their applications. Another five of these spectrometers will come online in the near future. We have applied our TES spectrometers to the following measurement applications: synchrotron-based absorption and emission spectroscopy and energy-resolved scattering; accelerator-based spectroscopy of hadronic atoms and particle-induced-emission spectroscopy; laboratory-based time-resolved absorption and emission spectroscopy with a tabletop, broadband source; and laboratory-based metrology of X-ray-emission lines. Here, we discuss the design, construction, and operation of our TES spectrometers and show first-light measurements from the various systems. Finally, because X-ray-TES technology continues to mature, we discuss improvements to array size, energy resolution, and counting speed that we anticipate in our next generation of TES-X-ray spectrometers and beyond.
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| 8. |
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| 9. |
- Nilsagård, Ylva, 1964-
(författare)
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Walking ability, balance and accidental falls in persons with Multiple Sclerosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- By using a pragmatic paradigm, different research methodologies were employed in this thesis. MS-related symptoms may be exaggerated due to heatsensitivity and it is supposed that cooling garments relieve the symptoms. The effects of wearing a Rehband® vest were evaluated in a sample of 42 persons with MS in a randomised controlled crossover study. Both objective and subjective statistically significant improvements were found when a cooled Rehband® vest was worn compared to the wearing of a room-tempered vest. Using a repeated-measures design, 10m and 30m timed walks and Timed Up and Go were studied in 42 persons with MS. Reproducibility was investigated within and between test points. High reproducibility was found both within (r=0.97–0.98) and between measure points (r=0.91–0.93). The correlation between the three tests was high (r=0.85). Differences at –23% to +40% were established as being needed to detect genuine changes. Severity of MS infl uenced the size of the differences, especially for the 30m timed walk test. The 12-item MS Walking Scale was translated and used in a cross-sectional study. Out of 81 persons with MS, 89–96% perceived limitations in standing or walking. The internal consistency of the scale was acceptable for nine items (0.69–0.84). The concurrent validity between the 12-item MS Walking Scale and the investigated objective tests was low: Berg Balance Scale (r=–0.368**), Four Square Step Test (r=0.338**) and Timed Up and Gocognitive (r=0.319*). A prevalence of falling was found at 63% in a longitudinal cohort study with prospectively registered falls including 76 persons with MS. The odds of falling were fi ve fold when there was a reported need of using a walking aid indoors and outdoors and by 2.5 to 15.6 times while there was disturbed proprioception, depending on severity. The highest sensitivity was found for the Berg Balance Scale (94%) and the highest specifi city was found for the 12-item MS Walking Scale (82%). Positive predictive values at 70–83% were found for the Berg Balance Scale, Timed Up and Gocognitive, the Four Square Step Test and the 12-item MS Walking Scale. Finally, we explored and described factors that persons with MS perceive as related to accidental falls. A content analysis with a deductive approach was chosen. By conducting interviews, we found previously untargeted factors: divided attention, reduced muscular endurance, fatigue and heat-sensitivity. The content of the interviews also gave support to previously reported risk factors such as changes in gait pattern, walking disability, impaired proprioception and vision, and spasticity.
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| 10. |
- Robb, A O, et al.
(författare)
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Influence of menstrual cycle on circulating endothelial progenitor cells
- 2009
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Ingår i: Human Reproduction. - Oxford, England : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 24:3, s. 619-625
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Endothelial progenitor cells (EPCs) are circulating mononuclear cells that participate in angiogenesis. The aim of this study was to determine the influence of the menstrual cycle on the number and function of EPCs, and to investigate their relationship with circulating concentrations of sex steroids and inflammatory mediators. METHODS: Ten healthy nulliparous, premenopausal, non-smoking women with regular menses were studied over a single menstrual cycle. Venepuncture was performed in the menstrual, follicular, peri-ovulatory and luteal phases. EPCs were quantified by flow cytometry (CD133(+)CD34(+)KDR(+) phenotype) and the colony-forming unit (CFU-EPC) functional assay. Circulating concentrations of estradiol, progesterone and inflammatory mediators (TNF-alpha, IL-6, sICAM-1 and VEGF) were measured by immunoassays. RESULTS: The numbers of CD133(+)CD34(+)KDR(+) cells were higher in the follicular phase (0.99 +/- 0.3 x 10(6) cells/l) compared with the peri-ovulatory phase (0.29 +/- 0.1 x 10(6) cells/l; P < 0.05). In contrast, the numbers of CFU-EPCs did not vary over the menstrual cycle. There were no correlations between EPCs and concentrations of either circulating sex steroids or inflammatory mediators. CONCLUSIONS: CD133(+)CD34(+)KDR(+) cells but not CFU-EPCs vary during the menstrual cycle. Our findings suggest a potential role for circulating EPCs in the normal cycle of physiological angiogenesis and repair of the uterine endometrium that is independent of circulating sex steroids or inflammatory mediators.
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