| 1. |
- Al-Mahdi Al-Karagholi, Mohammad, et al.
(author)
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Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers
- 2021
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In: Pharmacology Research & Perspectives. - : John Wiley & Sons. - 2052-1707. ; 9:2
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Journal article (peer-reviewed)abstract
- The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.
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| 3. |
- Amirkhani, Ardeshir, et al.
(author)
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Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients
- 2005
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 12:8, s. 625-631
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Journal article (peer-reviewed)abstract
- Tryptophan and its metabolites are of great interest in understanding the pathogenesis of multiple sclerosis (MS). The total levels of tryptophan and its metabolites, kynurenine and kynurenic acid were determined in plasma by capillary liquid chromatography electrospray ionisation tandem mass spectrometry. This is the first report of the plasma levels of these analytes in healthy controls and relapsing-remitting MS patients receiving long-term and acute interferon-beta (IFN-beta) treatment. Twenty-four hours post-administration increased kynurenine levels (first IFN MS versus healthy, P = 0.042) and kynurenine/tryptophan ratio (K/T; first IFN MS versus healthy, P =0.027; first IFN MS versus long-term IFN MS, P = 0.036) were found. The long-term IFN MS group had higher K/T ratios at 4 and 12 h post-administration (P = 0.015 and 0.009, respectively). The increase of K/T ratio in the first IFN MS group indicate an induction of the enzyme indolamine-2,3-dioxygenase (IDO), as reported earlier in experimental allergic encephalomyelitis. As IDO is participating in both inflammatory and neurodegenerative processes, further knowledge of its involvement in the pathogenesis of MS is of great importance.
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| 4. |
- Dezsi, Livia, et al.
(author)
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Inclusion body myositis - a rarely recognized disorder
- 2013
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In: Ideggyogyaszati Szemle - Clinical Neuroscience. - Budapest, Hungary : Literatura Medica Kiado. - 0019-1442. ; 66:3-4, s. 89-101
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Research review (peer-reviewed)abstract
- Inclusion body myositis is the most common disabling inflammatory myopathy in the elderly. It is more frequent in men and after the age of 50 years. Inflammatory and degenerative features coexist. There is a T-cell mediated autoimmunity driven by in situ clonally expanded cytotoxic CD8-positive T-cells invading non-necrotic muscle fibres expressing MHC-I antigen. The hallmarks of degeneration are the deposition of protein aggregates and the formation of vesicles. The course of the disease is slow and the diagnosis is usually set after several years. The muscle weakness and wasting is assymetric, affecting predominantly distal muscles of the upper extremity and proximal muscles of the legs. The signs and clinical course can be characteristic, but the diagnosis is established by muscle biopsy. less thanbrgreater than less thanbrgreater thanThere is currently no evidence based effective treatment for sIBM. Prednisone, azathioprine, methotrexate, cyclosporine and IFN-beta failed. Oxandrolon did not improve symptoms. Treatment with intravenous immunglobuline (IVIG) induced in some patients a transient improvement of swallowing and of muscle strenght, but the overall study results were negative. less thanbrgreater than less thanbrgreater thanA T-cell depleting monoclonal antibody (alemtuzumab), in a small uncontrolled study slowed down disease progression for a six-month period. Repeated muscle biopsies showed the reduction of T-cells in the muscle and the suppression of some degeneration associated molecules. An effective therapeutic mean should act on both aspects of the pathomechanism, on the inflammatory and the degenerative processes as well.
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| 5. |
- Edvinsson, Lars, et al.
(author)
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PACAP and its role in primary headaches
- 2018
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In: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 19:1
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Research review (peer-reviewed)abstract
- Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC1, VPAC1, and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that PACAP is involved in nociception. In support, abolishment of PACAP synthesis or reception leads to diminished pain responses, whereas systemic PACAP-38 infusion triggers pain behavior in animals and delayed migraine-like attacks in migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute migraine attacks and in cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of PACAP, a change that can be reduced when headache is treated. The data presented in this review indicate that PACAP and its receptors may be promising targets for migraine therapeutics.
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| 6. |
- Karsan, Nazia, et al.
(author)
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Pituitary cyclase-activating polypeptide targeted treatments for the treatment of primary headache disorders
- 2024
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In: Annals of Clinical and Translational Neurology. - 2328-9503. ; 11:7, s. 1654-1668
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Research review (peer-reviewed)abstract
- Objective: Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years. Methods: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope. Results: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results. Interpretation: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.
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| 7. |
- Korponay-Szabó, Ilma R., et al.
(author)
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Deamidated gliadin peptides form epitopes that transglutaminase antibodies recognize
- 2008
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In: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - 0277-2116 .- 1536-4801. ; 46:3, s. 253-261
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Deamidated gliadin peptides are efficient antigens in diagnostic tests for celiac disease, and results correlate better with transglutaminase 2-based assays than those with native gliadin. We investigated whether deamidated gliadin antigens are structurally similar to transglutaminase 2 or could mimic transglutaminase epitopes. PATIENTS AND METHODS: Serum samples from 74 celiac and 65 control patients, and 13 different transglutaminase 2-specific monoclonal mouse antibodies were investigated for their binding to commercially available deamidated gliadin peptides using enzyme-linked immunosorbent assay, competition studies, and molecular modelling. RESULTS: The enzyme-linked immunosorbent assay with deamidated gliadin peptides had 100% sensitivity and 98.5% specificity in patients. Deamidated gliadin epitopes also were recognized by 3 transglutaminase-specific monoclonal antibodies, and antibodies affinity-purified with deamidated gliadin peptides from celiac patient sera reacted with transglutaminase but did not show endomysial binding. The binding of the monoclonal antibodies to deamidated gliadin was inhibited dose dependently by full-length recombinant human transglutaminase, its fragments containing the binding sites of these monoclonal antibodies, or by celiac patient antibodies. Deamidated gliadin peptides decreased the binding of transglutaminase-specific monoclonal antibodies to transglutaminase. Three different cross-reacting transglutaminase epitopes were found, of which 2 are located in the C-terminal domain and 1 is conformational. The binding of celiac serum samples to deamidated gliadin peptides could not be abolished by transglutaminase or by any of the transglutaminase-specific monoclonals, indicating that celiac sera also contain additional antibodies to gliadin epitopes different from transglutaminase. CONCLUSIONS: Certain deamidated gliadin-derived peptides and transglutaminase 2 epitopes have similar 3-dimensional appearance. This homology may contribute to the induction of transglutaminase autoantibodies by molecular mimicry.
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| 8. |
- Mattsson, Niklas, 1979, et al.
(author)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
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Journal article (peer-reviewed)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 9. |
- Petzold, Axel, et al.
(author)
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Neurofilament ELISA validation
- 2010
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In: JOURNAL OF IMMUNOLOGICAL METHODS. - 0022-1759. ; 352:1-2, s. 23-31
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Journal article (peer-reviewed)
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| 10. |
- Petzold, Axel, et al.
(author)
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Neurofilament ELISA validation
- 2010
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In: JIM - Journal of Immunological Methods. - : Elsevier BV. - 0022-1759 .- 1872-7905. ; 352:1-2, s. 23-31
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Journal article (peer-reviewed)abstract
- BACKGROUND: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance. METHODS: The UmanDiagnostics NF-light (R)enzyme-linked immunoabsorbent assays (ELISA) for the neurofilament light chain (NfL, 68kDa) was used to test the intra-assay and inter-laboratory coefficient of variation (CV) between 35 laboratories worldwide on 15 cerebrospinal fluid (CSF) samples. Critical factors, such as sample transport and storage, analytical delays, reaction temperature and time, the laboratories' accuracy and preparation of standards were documented and used for the statistical analyses. RESULTS: The intra-laboratory CV averaged 3.3% and the inter-laboratory CV 59%. The results from the test laboratories correlated with those from the reference laboratory (R=0.60, p<0.0001). Correcting for critical factors improved the strength of the correlation. Differences in the accuracy of standard preparation were identified as the most critical factor. Correcting for the error introduced by variation in the protein standards improved the correlation to R=0.98, p<0.0001 with an averaged inter-laboratory CV of 14%. The corrected overall inter-rater agreement was subtantial (0.6) according to Fleiss' multi-rater kappa and Gwet's AC1 statistics. CONCLUSION: This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online.
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