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| 2. |
- Ahlstedt, Jonas, et al.
(author)
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Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.
- 2015
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In: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 5:4, s. 333-347
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Journal article (peer-reviewed)abstract
- Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.
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| 3. |
- Ahlstedt, Jonas, et al.
(author)
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Human Anti-Oxidation Protein A1M-A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.
- 2015
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 16:12, s. 30309-30320
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Research review (peer-reviewed)abstract
- Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.
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| 4. |
- Ahlstedt, Jonas, et al.
(author)
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Non-invasive imaging methodologies for assessment of radiation damage to bone marrow and kidneys from peptide receptor radionuclide therapy. : -
- 2019
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In: Neuroendocrinology. - : S. Karger AG. - 1423-0194 .- 0028-3835. ; 110:1-2, s. 130-138
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Journal article (peer-reviewed)abstract
- Background/Aims: Peptide receptor radionuclide therapy (PRRT) is becoming clinical routine for management of neuroendocrine tumours. The number of PRRT cycles is correlated with treatment effect but theoretically limited by off-target radiation damage to kidneys and bone marrow. New imaging biomarkers for assessment of PRRT tissue damage would enable evaluation of novel renal and bone marrow protective agents, as well as personalised PRRT treatment regiments. Methods: Mice treated with [177Lu]Lu-DOTA-TATE PRRT or vehicle were examined at baseline and following treatment with [18F]fluorothymidine (FLT) positron emission tomography (PET) and technetium-99m-mercapto-acetyl-tri-glycine ([99mTc]Tc-Mag3) single-photon emission tomography (SPECT) to assess dynamic changes in bone marrow proliferation and renal function, respectively. Results: Bone marrow proliferation as assessed by [18F]FLT was decreased 2 days after PRRT treatment, but not vehicle, compared to baseline (target-to-background ratio [TBRmax] baseline:1.69 ± 0.29 vs. TBRmax PRRT: 0.91 ± 0.02, p < 0.01). Renal function as assessed by [99mTc]Tc-Mag3 SPECT was similarly decreased 2 days following PRRT compared to vehicle (fractional uptake rate [FUR] vehicle: 0.030 ± 0.014 s–1 vs. FUR PRRT: 0.0051 ± 0.0028 s–1, p < 0.01). Conclusion: [18F]FLT PET and [99mTc]Tc-Mag3 SPECT are promising techniques for assessing bone marrow and renal injury from [177Lu]Lu-DOTA-TATE PRRT and may potentially improve patient management by allowing evaluation of protective interventions as well as enabling personalised PRRT treatments.
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| 5. |
- Alattar, Abdul Ghani, et al.
(author)
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Recombinant alpha(1)-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-177-DOTATATE Mouse Radiation Model
- 2023
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In: Biomolecules. - 2218-273X. ; 13:6
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Journal article (peer-reviewed)abstract
- Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-177-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. alpha (1)-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse Lu-177-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-Lu-177-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with Lu-177-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with Lu-177-DOTATATE.
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| 6. |
- Eriksson, Jonas, 1984, et al.
(author)
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Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden
- 2012
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In: The Clinical Respiratory Journal. - 1752-699X .- 1752-6981. ; 6:3, s. 159-168
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Journal article (peer-reviewed)abstract
- Background: Allergic rhinitis (AR) is the most common immunologic disease, and it renders a considerable burden on both sufferers and society. The prevalence of AR has been increasing worldwide over the past century. The aim of this study was to assess the present prevalence, risk factor patterns and comorbidity of self-reported AR and chronic nasal symptoms in different age groups in Stockholm, Sweden. Methods: A postal questionnaire was sent on two occasions, in 2006 to a population aged 30-80 years, randomly selected 10 years previously, and in 2007 to a randomly selected sample of subjects aged 20-69 years. The response rates were 83% and 68%, respectively, and in total, 9792 subjects participated. The questionnaire included questions on self-reported AR, asthma, respiratory and nasal symptoms and possible determinants. Results: The prevalence of self-reported AR was 28.0% (men 26.6%, women 29.1%, P<0.01) similar to 10 years previously and 33.6% in ages 30-40 years. Allergic heredity [odds ratio (OR) 4.76, confidence interval (CI) 95% 4.25-5.33], physician-diagnosed asthma (OR 5.29, CI 95% 4.49-6.24) and occupational exposure to dust, gases and fumes (OR 1.49, CI 95% 1.30-1.72) were determinants for AR. Prevalence of chronic nasal congestion was 16.1% and of chronic rhinorrhea 14.1%. Conclusions: As a basis for understanding the disease, as well as in planning and prioritising health-care resources, the study provides information about the current prevalence and determinants of self-reported AR and chronic nasal symptoms. Further, comparing with previous studies, the present study suggests that a plateau in the prevalence of AR may have been reached in Sweden. Please cite this paper as: Eriksson J, Ekerljung L, Rönmark E, Dahlén B, Ahlstedt S, Dahlén S-E and Lundbäck B. Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden
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| 7. |
- Kristiansson, Amanda, et al.
(author)
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177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging
- 2021
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 11:2
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Journal article (peer-reviewed)abstract
- Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3-4 days and 3-4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.
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| 8. |
- Kristiansson, Amanda, et al.
(author)
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Kidney protection with the radical scavenger α1-microglobulin (A1m) during peptide receptor radionuclide and radioligand therapy
- 2021
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In: Antioxidants. - : MDPI AG. - 2076-3921. ; 10:8, s. 1-18
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Journal article (peer-reviewed)abstract
- α1-microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models. In this review, we focus on A1M as a radioprotector of the kidneys during peptide receptor radionuclide/radioligand therapy (PRRT/RLT). Patients with, e.g., neuroendocrine tumors or castration resistant prostate cancer can be treated by administration of radiolabeled small molecules which target and therefore enable the irradiation and killing of cancer cells through specific receptor interaction. The treatment is not curative, and kidney toxicity has been reported as a side effect since the small, radiolabeled substances are retained and excreted through the kidneys. In recent studies, A1M was shown to have radioprotective effects on cell cultures as well as having a similar biodistribution as the somatostatin analogue peptide177Lu-DOTA-TATE after intravenous infusion in mice. Therefore, several animal studies were conducted to investigate the in vivo radioprotective potential of A1M towards kidneys. The results of these studies demonstrated that A1M co-infusion yielded protection against kidney toxicity and improved overall survival in mouse models. Moreover, two different mouse studies reported that A1M did not interfere with tumor treatment itself. Here, we give an overview of radionuclide therapy, the A1M physiology and the results from the radioprotector studies of the protein.
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| 9. |
- Kristiansson, Amanda, et al.
(author)
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Protection of Kidney Function with Human Antioxidation Protein α 1 -Microglobulin in a Mouse 177 Lu-DOTATATE Radiation Therapy Model
- 2019
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In: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1523-0864 .- 1557-7716. ; 30:14, s. 1746-1759
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Journal article (peer-reviewed)abstract
- Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α 1 -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 ( 177 Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177 Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177 Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment. © Amanda Kristiansson et al. 2018; Published by Mary Ann Liebert, Inc.
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| 10. |
- Åkerström, Bo, et al.
(author)
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rA1M-035, a Physicochemically Improved Human Recombinant α-Microglobulin, Has Therapeutic Effects in Rhabdomyolysis-Induced Acute Kidney Injury
- 2019
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In: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 30:4, s. 489-504
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Journal article (peer-reviewed)abstract
- AIMS: Human α1-microglobulin (A1M) is an endogenous reductase and radical- and heme-binding protein with physiological antioxidant protective functions. Recombinant human A1M (rA1M) has been shown to have therapeutic properties in animal models of preeclampsia, a pregnancy disease associated with oxidative stress. Recombinant A1M, however, lacks glycosylation, and shows lower solubility and stability than A1M purified from human plasma. The aims of this work were to (i) use site-directed mutagenesis to improve the physicochemical properties of rA1M, (ii) demonstrate that the physicochemically improved rA1M displays full in vitro cell protective effects as recombinant wild-type A1M (rA1M-wt), and (iii) show its therapeutic potential in vivo against acute kidney injury (AKI), another disease associated with oxidative stress.RESULTS: A novel recombinant A1M-variant (rA1M-035) with three amino acid substitutions was constructed, successfully expressed, and purified. rA1M-035 had improved solubility and stability compared with rA1M-wt, and showed intact in vitro heme-binding, reductase, antioxidation, and cell protective activities. Both rA1M-035 and rA1M-wt showed, for the first time, potential in vivo protective effects on kidneys using a mouse rhabdomyolysis glycerol injection model of AKI.INNOVATION: A novel recombinant A1M-variant, rA1M-035, was engineered. This protein showed improved solubility and stability compared with rA1M-wt, full in vitro functional activity, and potential protection against AKI in an in vivo rhabdomyolysis mouse model.CONCLUSION: The new rA1M-035 is a better drug candidate than rA1M-wt for treatment of AKI and preeclampsia in human patients. Antioxid. Redox Signal. 00, 000-000.
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