| 1. |
- Berg, K, et al.
(författare)
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Iodinated radiographic contrast media possess antioxidant properties in vitro
- 2005
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Ingår i: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 46:8, s. 815-822
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study potential properties of iodinated radiographic contrast media (IRCM) for intravascular use in in vitro free radical generating reactions. Material and Methods: Superoxide (center dot O-2(-)) and hydroxyl ((OH)-O-center dot) radicals were generated in xanthine oxidase and Fenton reactions. center dot O-2(-) was assayed by the nitroblue tetrazolium (NBT) method, whereas (OH)-O-center dot was assayed by an aromatic hydroxylation (2-hydroxybenzoic acid) method. Total antioxidant status (TAS) of test substances was determined by a colorimetric assay. Finally, acetyl-cholinesterase (AChE) activity was measured in the absence and presence of IRCM. Results: High concentrations (greater than50 mM) of IRCM inhibited center dot O-2(-) production, ionic more than non-ionic IRCM. Medium concentrations (25-50 mM) of IRCM reduced (OH)-O-center dot production, and both types of IRCM were equally potent. Low concentrations (less than25 mM) of non-ionic IRCM displayed higher antioxidant capacity than their ionic counterparts when tested in the TAS assay. Visipaque 320 (iodixanol) was found to have the highest TAS value, followed by Omnipaque 350(R) (iohexol), Hexabrix 320(R) (ioxaglate), and Urografin 370(R) (diatrizoate). Conclusion: IRCM have in vitro antioxidant properties in concentrations relevant for their clinical application. These properties may therefore be of potential importance when evaluating IRCM effects in vivo, particularly those concerning cardiovascular and renal function.
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| 2. |
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| 3. |
- Blomlie, V., et al.
(författare)
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Manganese Uptake and Accumulation in the Human Brain
- 2020
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Ingår i: American Journal of Neuroradiology. - Oak Brook, IL, United States : American Society of Neuroradiology. - 0195-6108 .- 1936-959X. ; 41:1, s. E3-E3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
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| 4. |
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| 5. |
- Jynge, Per, et al.
(författare)
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MnDPDP: Contrast Agent for Imaging and Protection of Viable Tissue
- 2020
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Ingår i: Contrast Media & Molecular Imaging. - : WILEY-HINDAWI. - 1555-4309 .- 1555-4317. ; 2020
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Forskningsöversikt (refereegranskat)abstract
- The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan (TM), GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn2+ for cellular uptake in competition with calcium (Ca2+), and intracellular (IC) macromolecular Mn2+ adducts lower myocardial T-1 to midway between native values and values obtained with gadolinium (Gd3+). What is essential is that T-1 mapping and, to a lesser degree,T-1 weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn2+ retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca2+ channel activity, capabilities beyond the scope of Gd3+ based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.
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| 6. |
- Karlsson, Jan-Erik, et al.
(författare)
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Mangafodipir as a cardioprotective adjunct to reperfusion therapy: a feasibility study in patients with ST-segment elevation myocardial infarction
- 2015
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Ingår i: European Heart Journal - Cardiovascular Pharmacotherapy. - : European Society of Cardiology. - 2055-6837 .- 2055-6845. ; 1:1, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- Aims The aim of the present study was to examine the feasibility of applying the catalytic antioxidant mangafodipir [MnDPDP, manganese (Mn) dipyridoxyl diphosphate] as a cardioprotective adjunct to primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation (STE) myocardial infarction (STEMI). Both MnDPDP and a metabolite (Mn dipyridoxyl ethyldiamine) possess properties as mitochondrial superoxide dismutase mimetics and iron chelators, and combat oxidative stress in various tissues and conditions.Methods and resultsThe study tested MnDPDP (n ¼ 10) vs. saline placebo (n ¼ 10), given as a brief intravenous (i.v.) infusion prior to balloon inflation during pPCI in patients with STEMI. Mangafodipir waswell tolerated and did not affect heart rate or blood pressure. Despite longer ischaemic time (205 vs. 144 min, P ¼ 0.019) in theMnDPDPgroup, plasma biomarker releaseswere identical for the two groups. With placebo vs.MnDPDP, mean STE resolutions were 69.8 vs. 81.9% (P ¼ 0.224) at 6 h and 73.1 vs. 84.3% (P ¼ 0.077) at 48 h. Cardiac magnetic resonance revealed mean infarct sizes of 32.5 vs. 26.2% (P ¼ 0.406) andmeanleft ventricular (LV) ejection fractions of 41.8 vs. 47.7% (P ¼ 0.617) with placebovs.MnDPDP.More LVthrombi were detected in placebo hearts (5 of 8) than MnDPDP-treated hearts (1 of 10; P ¼ 0.011).Conclusions Mangafodipir is a safe drug for use as an adjunct to reperfusion therapy. A tendency to benefit of MnDPDP needs confirmation in a larger population. The study revealed important information for the design of a Phase II trial.
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| 7. |
- Karlsson, Jan Olof, et al.
(författare)
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First Clinical Experience with the Magnetic Resonance Imaging Contrast Agent and Superoxide Dismutase Mimetic Mangafodipir as an Adjunct in Cancer Chemotherapy-A Translational Study
- 2012
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Ingår i: Translational Oncology. - : NEOPLASIA PRESS, 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA. - 1944-7124 .- 1936-5233. ; 5:1, s. 32-38
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical research suggests that the clinically approved magnetic resonance imaging contrast agent mangafodipir may protect against adverse events (AEs) caused by chemotherapy, without interfering negatively with the anticancer efficacy. The present translational study tested if pretreatment with mangafodipir lowers AEs during curative (adjuvant) FOLFOX6 chemotherapy in stage III colon cancer (Dukes C). The study was originally scheduled to include 20 patients, but because of the unforeseen withdrawal of mangafodipir from the market, the study had to be closed after 14 patients had been included. The withdrawal of mangafodipir was purely based on commercial considerations from the producer and not on any safety concerns. The patients were treated throughout the first 3 of 12 scheduled cycles. Patients were randomized to a 5-minute infusion of either mangafodipir or placebo (7 in each group). AEs were evaluated according to the National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events and the Sanofi-NCI criteria. The primary end points were neutropenia and neurosensory toxicity. There were four AEs of grade 3 (severe) and one AE of grade 4 (life threatening) in four patients in the placebo group, whereas there were none in the mangafodipir group (P andlt; .05). Of the grade 3 and 4 events, two were neutropenia and one was neurosensory toxicity. Furthermore, white blood cell count was statistically, significantly higher in the mangafodipir group than in the placebo group (P andlt; .01) after treatment with FOLFOX. This small feasibility study seems to confirm what has been demonstrated preclinically, namely, that pretreatment with mangafodipir lowers AEs during adjuvant 5-fluorouracil plus oxaliplatin-based chemotherapy in colon cancer patients.
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| 8. |
- Karlsson, Jan Olof G, et al.
(författare)
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Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties.
- 2015
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Ingår i: Drug Discovery Today. - : Elsevier BV. - 1878-5832 .- 1359-6446. ; 20:4, s. 411-421
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Forskningsöversikt (refereegranskat)abstract
- Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in pathological tissue damage. Mitochondrial manganese superoxide dismutase (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir (MnDPDP) as a magnetic resonance imaging (MRI) contrast agent, it was discovered that MnDPDP and its metabolite manganese pyridoxyl ethyldiamine (MnPLED) possessed SOD mimetic activity. MnDPDP has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. Whereas MRI contrast depends on release of Mn(2+), the SOD mimetic activity depends on Mn(2+) that remains bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn(2+) and has superior therapeutic activity. Ca4Mn(DPDP)5 is presently being explored as a chemotherapy adjunct in a clinical multicenter Phase II study in patients with metastatic colorectal cancer.
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| 9. |
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| 10. |
- Karlsson, Jan Olof G., et al.
(författare)
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Exacerbated Neuropathy in POLAR A and M Trials Due to Redox Interaction of PledOx-Associated Mn2+ and Oxaliplatin-Associated Pt2
- 2023
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Ingår i: Antioxidants. - : MDPI. - 2076-3921. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Disappointing results from the POLAR A and M phase III trials involving colorectal cancer patients on chemotherapy with FOLFOX6 in curative (A) and palliative (M) settings have been reported by the principal investigators and the sponsor (PledPharma AB/Egetis Therapeutics AB). FOLFOX6, oxaliplatin in combination with 5-fluorouracil (5-FU), possesses superior tumoricidal activity in comparison to 5-FU alone, but suffers seriously from dose-limiting platinum-associated Chemotherapy-Induced Peripheral Neuropathy (CIPN). The aim of the POLAR trials was to demonstrate that PledOx [calmangafodipir; Ca4Mn(DPDP)(5)] reduced the incidence of persistent CIPN from 40% to 20%. However, this assumption was based on "explorative" data in the preceding PLIANT phase II trial, which did not mirror the expected incidence of unwanted toxicity in placebo patients. In POLAR A and M, the assessment of PledOx efficacy was conducted in patients that received at least six cycles of FOLFOX6, enabling analyses of efficacy in 239 A and 88 M patients. Instead of a hypothesized improvement from 40% to 20% incidence of persistent CIPN in the PledOx group, i.e., a 50% improvement, the real outcome was the opposite, i.e., an about 50% worsening in this bothersome toxicity. Mechanisms that may explain the disastrous outcome, with a statistically significant number of patients being seriously injured after having received PledOx, indicate interactions between two redox active metal cations, Pt2+ (oxaliplatin) and Mn2+ (PledOx). A far from surprising causal relationship that escaped prior detection by the study group and the sponsor. Most importantly, recently published data (ref 1) unequivocally indicate that the PLIANT study was not suited to base clinical phase III studies on. In conclusion, the POLAR and PLIANT trials show that PledOx and related manganese-containing compounds are unsuited for co-treatment with platinum-containing compounds. For use as a therapeutic adjunct in rescue treatment, like in ischemia-reperfusion of the heart or other organs, or in acetaminophen (paracetamol)-associated liver failure, there is little or nothing speaking against the use of PledOx or other PLED compounds. However, this must be thoroughly documented in more carefully designed clinical trials.
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| 11. |
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| 12. |
- Karlsson, Jan Olof G., et al.
(författare)
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Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca4Mn(DPDP)5, MnDPDP and DPDP
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:8
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Forskningsöversikt (refereegranskat)abstract
- Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)(5); PledOx (R)], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)(5) in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)(5), a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)(5). The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)(5) may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)(5) as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO-) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O-2(center dot-)) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)(5) mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.
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| 13. |
- Karlsson, Jan Olof G., et al.
(författare)
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The Damaging Outcome of the POLAR Phase III Trials Was Due to Avoidable Time-Dependent Redox Interaction between Oxaliplatin and PledOx
- 2021
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Ingår i: Antioxidants. - : MDPI AG. - 2076-3921. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- On 2 July 2021, highly negative results were reported from the POLAR A and M phase III trials in patients with colorectal cancer, treated with an oxaliplatin-based regimen and co-treated with calmangafodipir (CaM; PledOx®; PledPharma AB/Egetis Therapeutics AB) or placebo. The results revealed persistent chemotherapy-induced peripheral neuropathy (CIPN) in 54.8% of the patients treated with PledOx, compared with 40.0% of the patients treated with the placebo (p < 0.05), i.e., a 37% increase in incidence of the side effect that the trial was aimed to prevent. The damaging outcome of the trials differed diametrically from an in-parallel conducted mice study and from a clinical trial with mangafodipir, the active ingredient of CaM. According to the authors of the POLAR report, the etiology of the profound increase in CIPN in the PledOx arm is unclear. However, these devastating effects are presumably explained by intravenous administrations of PledOx and oxaliplatin being too close in time and, thereby, causing unfavorable redox interactions between Mn2+ and Pt2-. In the mice study as well as in the preceding phase II clinical trial (PLIANT), PledOx was administered 10 min before the start of the oxaliplatin infusion; this was clearly an administration procedure, where the devastating interactions between PledOx and oxaliplatin could be avoided. However, when it comes to the POLAR trials, PledOx was administered, for incomprehensible reasons, "on Top of Modified FOLFOX6" at day one, i.e., after the two-hour oxaliplatin infusion instead of before oxaliplatin. This is a time point when the plasma concentration of oxaliplatin and Pt2+-metabolites is at its highest, and where the risk of devastating redox interactions between PledOx and oxaliplatin, in turn, is at its highest.
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| 14. |
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| 15. |
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| 16. |
- Karlsson, Jan Olof, et al.
(författare)
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Mangafodipir a Selective Cytoprotectant - with Special Reference to Oxaliplatin and Its Association to Chemotherapy-Induced Peripheral Neuropathy (CIPN)
- 2017
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Ingår i: Translational Oncology. - : ELSEVIER SCIENCE INC. - 1944-7124 .- 1936-5233. ; 10:4, s. 641-649
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Forskningsöversikt (refereegranskat)abstract
- Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has increased survival substantially in stage III colorectal cancer and prolonged life in stage IV patients, but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral neuropathy (CIPN) is the most problematic dose-limiting toxicity of oxaliplatin. Oncologists included for years calciumand magnesium infusion as part of clinical practice for preventing CIPN. Results from a phase III prospective study published in 2014, however, overturned this practice. No other treatments have been clinically proven to prevent this toxicity. There is a body of evidence that CIPN is caused by cellular oxidative stress. Clinical and preclinical data suggest that the manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) is an efficacious inhibitor of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy. MnPLED, the metabolite of MnDPDP, attacks cellular oxidative stress at several critical levels. Firstly, MnPLED catalyzes dismutation of superoxide (O-2(center dot-) ), and secondly, having a tremendous high affinity for iron (and copper), PLED binds and disarms redox active iron/copper, which is involved in several detrimental oxidative steps. A case report from 2009 and a recent feasibility study suggest that MnDPDP may prevent or even cure oxaliplatin-induced CIPN. Preliminary results from a phase II study (PLIANT) suggest efficacy also of calmangafodipir, but these results are according to available data obscured by a surprisingly low number of adverse events and a seemingly lower than expected efficacy of FOLFOX.
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| 17. |
- Karlsson, Jan Olof, et al.
(författare)
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May Mangafodipir or Other SOD Mimetics Contribute to Better Care in COVID-19 Patients?
- 2020
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Ingår i: Antioxidants. - : MDPI. - 2076-3921. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by massive inflammation of the arterial endothelium accompanied by vasoconstriction and widespread pulmonary micro thrombi. As a result, due to the destruction of nitric oxide ((NO)-N-center dot) by inflammatory superoxide (O-2(center dot-)), pulmonary (NO)-N-center dot concentration ceases, resulting in uncontrolled platelet aggregation and massive thrombosis, which kills the patients. Introducing (NO)-N-center dot by inhalation (INO) may replace the loss of endothelium-derived (NO)-N-center dot. The first results from clinical trials with INO in SARS-CoV-2 patients show a rapid and sustained improvement in cardiopulmonary function and decreased inflammation. An ongoing phase III study is expected to confirm the methods efficacy. INO may hence become a first line treatment in SARS-CoV-2 patients. However, due to the rapid inactivation of (NO)-N-center dot by deoxyhemoglobin to nitrate, pulmonary administration of (NO)-N-center dot will not protect remote organs. Another INO-related pharmacological approach to protect SARS-CoV-2 patients from developing life-threatening disease is to inhibit the O-2(center dot-)-driven destruction of (NO)-N-center dot by neutralizing inflammatory O-2(center dot-). By making use of low molecular weight compounds that mimic the action of the enzyme manganese superoxide dismutase (MnSOD). The MnSOD mimetics of the so-called porphyrin type (e.g., AEOL 10150), salen type (e.g., EUK-8) and cyclic polyamine type (e.g., M40419, today known as GC4419 and avasopasem manganese) have all been shown to positively affect the inflammatory response in lung epithelial cells in preclinical models of chronic obstructive pulmonary disease. The Manganese diPyridoxyL EthylDiamine (MnPLED)-type mangafodipir (manganese dipyridoxyl diphosphate-MnDPDP), a magnetic resonance imaging (MRI) contrast agent that possesses MnSOD mimetic activity, has shown promising results in various forms of inflammation, in preclinical as well as clinical settings. Intravenously administration of mangafodipir will, in contrast to INO, reach remote organs and may hence become an important supplement to INO. From the authors viewpoint, it appears logical to test mangafodipr in COVID-19 patients at risk of developing life-threatening SARS-CoV-2. Five days after submission of the current manuscript, Galera Pharmaceuticals Inc. announced the dosing of the first patient in a randomized, double-blind pilot phase II clinical trial with GC4419 for COVID-19. The study was first posted on ClinicalTrials.gov (Identifier: NCT04555096) 18 September 2020.
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| 18. |
- Sigurd, Gunnes, et al.
(författare)
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Fundamentals of the Past : Cardioplegia: The First Period Revisited
- 2011
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Ingår i: New Solutions for the Heart. - Wien : Springer. - 9783211855478 ; , s. 15-40
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Bokkapitel (refereegranskat)abstract
- Although cardiac surgery has made an enormous progress during the last decades, the discipline has to cope with essential changes: Patients are increasingly cared for by cardiologists and therefore referred to the surgeon in a later stage of disease. Consequently, they are more often in an increasingly serious state or in advanced age with significant comorbidities. In order to meet the requirements of these different patient groups, cardiosurgical treatments require special protectional strategies for the heart in order to perform the planned operations safely. This book presents the latest knowledge of modern techniques of myocardial protection taking into consideration the different patient groups and current scientific strategies. Furthermore, it discusses present and future scientific approaches in myocardial protection and preservation.
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