| 1. |
- Rein-Hedin, Erik, et al.
(författare)
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Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist
- 2024
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Ingår i: Clinical and Translational Science. - : WILEY. - 1752-8054 .- 1752-8062. ; 17:2
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Tidskriftsartikel (refereegranskat)abstract
- Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open-label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra-arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 mu g/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8-3.2 mu g/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra-arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3-200 mu g/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230-320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra-arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects.
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| 2. |
- Tornling, Göran, et al.
(författare)
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Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial
- 2021
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 41
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Tidskriftsartikel (refereegranskat)abstract
- Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines.Methods: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP > 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020.Findings: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated.Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway.
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| 3. |
- Fuhlbrigge, Anne L., et al.
(författare)
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A novel endpoint for exacerbations in asthma to accelerate clinical development : A post-hoc analysis of randomised controlled trials
- 2017
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Ingår i: The Lancet Respiratory Medicine. - 2213-2600. ; 5:7, s. 577-590
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Tidskriftsartikel (refereegranskat)abstract
- Background: Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. Methods: Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35-53 years, 59-69% were female, and had a mean FEV1 percentage of predicted normal of 63-84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations. Findings: CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2·8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1·01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed. Interpretation: CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations. Funding: AstraZeneca.
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| 4. |
- Fosså, Sophie D., et al.
(författare)
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Reduction of quality of life in prostate cancer patients : experience among 6200 men in the Nordic countries
- 2016
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 50:5, s. 330-337
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Although many studies have dealt with adverse effects (AEs) and quality of life (QoL) in prostate cancer (PCa) patients, the quantification of the patients’ perspective on AE-related reduction in QoL has been less studied. This study describes the impact of self-reported local (erectile, bowel, urinary dysfunction) or systemic (mental distress, fatigue, virility loss) AEs on QoL reduction. Materials and methods: Nordic PCa patients completed a questionnaire containing 84 multiple-choice questions. The main outcome variable of the survey was patient-reported PCa-induced QoL reduction, assessed by descriptive and regression analyses. The level of significance was p
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| 7. |
- Greiff, Lennart, et al.
(författare)
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Effects of a dual CCR3 and H-1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis
- 2010
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation. Objective: To examine whether a dual CCR3 and H-1-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis. Methods: Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and alpha(2)-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation. Results: Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine. Conclusions: AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.
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| 8. |
- Bondesson, Eva, et al.
(författare)
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Exhaled breath condensate-site and mechanisms of formation
- 2009
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Ingår i: Journal of Breath Research. - : IOP Publishing. - 1752-7163 .- 1752-7155. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Exhaled breath condensate (EBC) analysis is a promising tool for diagnosis and management of pulmonary diseases. Its clinical usefulness is still limited however due to unresolved issues around e. g. reproducibility, anatomical site of origin of EBC solutes and mechanisms of EBC formation. To gain some knowledge on these issues, three different airway deposition patterns of an aqueous aerosol containing technetium-99m were studied in eight healthy non-smoking subjects. EBC was collected 20 min after each radioaerosol administration and analyzed for gamma radiation and electrolytes. Radioaerosol deposition in preferentially central lung compared with preferentially peripheral lung resulted in 3.8 times higher EBC radioactivity. EBC concentrations of Na+ and K+ correlated significantly indicating dilution by water vapor to be a major source of variability. Since Na+/K+- and Na+/S2--concentration ratios, but not Na+/Cl--or Na+/Ca2+-, were comparable to those previously reported for alveolar lining fluid (ALF), some mechanisms other than dilution are likely also to be involved. In conclusion, our findings indicate that EBC derives mainly from the central airways, that the electrolyte composition of EBC does not consistently reflect that of ALF, and that EBC concentrations of electrolytes are determined not only by ALF dilution with water vapor but also by other mechanisms.
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| 9. |
- Persson, Gunnar, et al.
(författare)
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Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers
- 2008
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Ingår i: Current Medical Research and Opinion. - 1473-4877. ; 24:5, s. 1511-1517
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Tidskriftsartikel (refereegranskat)abstract
- Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI-A* 200 mu g) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI-B dagger). Budesonide CPI-B is available in two strengths (90 mu g, 180 mu g). Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI-A and DPI-B and test for systemic absorption bioequivalence. Methods: Adults (n = 37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI-A 200 mu g x 4 inhalations, budesonide DPI-B 180 mu g x 4 inhalations, or budesonide DPI-B 90 mu g x 8 inhalations, on 3 days, each separated by a washout period of >= 5 days. Plasma samples were collected immediately before and up to 12 h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration-time curve from 0 to infinity (AUC(0-infinity)) and maximum plasma concentration (C-max); plasma concentration at 12 h (C-12h) and time to maximum plasma concentration (T-max) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (Cls) for their AUC(0-infinity) and C-max ratios fell between 80 and 125%. Adverse events were collected. Results: The 90% Cls for the ratios of AUC(0-infinity) and C-max for budesonide DPI-A 200 mu g and DPI-B 180 mu g and for both budesonide DPI-B strengths fell between 80% and 125% (AUC(0-infinity): budesonide DPI-B 180 mu g x 4/DPI-A 200 mu g x 4: 96.3% [90% Cl: 90.9,102,1]; budesonide DPI-B 180 mu g x 4/DPI-B 90 mu g x 8: 92.2% [90% Cl: 87.0, 97.7]; C-max: (budesonide DPI-B 180 mu g x 4/DPI-A 200 mu g x 4:100.4% [95% Cl: 92.1, 109.4]; budesonide DPI-B 180 mu g x 4/DPI-B 90 mu g x 8: 94.4% [90% Cl: 86.6,102.9]). No differences in C-12h and T-max were found between treatments. All treatments were well tolerated. Conclusions: Budesonide DPI-A 200 mu g and CPI-B 180 mu g have systemic absorption bioequivalence, and DPI-B 90 mu g and 180 mu g are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged >= 19 years.
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| 10. |
- Pettersson, Jonas, et al.
(författare)
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Muscular exercise can cause highly pathological liver function tests in healthy men.
- 2008
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 65:2, s. 253-259
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Tidskriftsartikel (refereegranskat)abstract
- What is already known about this subject • The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. • Physical exercise can result in transient elevations of liver function tests. • There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds • Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. • Liver function tests are significantly increased for at least 7 days after weightlifting. • It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.
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