| 1. |
- Caronna, Edoardo, et al.
(författare)
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Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world
- 2024
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Ingår i: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY. - 0022-3050 .- 1468-330X.
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Tidskriftsartikel (refereegranskat)abstract
- Background Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. Methods European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as >= 50% and >= 75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. Results Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. Conclusions This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.
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| 2. |
- Hernández-Alvarez, María Isabel, et al.
(författare)
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Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
- 2019
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Ingår i: Cell. - : Cell Press. - 0092-8674 .- 1097-4172. ; 177:4, s. 881-895.e17
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
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| 3. |
- Inoue, Juliana, et al.
(författare)
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Plasmodium falciparum Plasmepsin 2 Duplications, West Africa
- 2018
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention. - 1080-6040 .- 1080-6059. ; 24:8, s. 1591-1593
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Tidskriftsartikel (refereegranskat)abstract
- Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.
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| 4. |
- Mendes Veiga, Maria Isabel
(författare)
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Plasmodium falciparum drug transporter genes in emerging malaria multidrug resistance
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malaria is caused by an intracellular protozoan parasite of the genus Plasmodium. The use of chemotherapy, the foremost tool available for the control of the disease, has been challenged in the last decades by the development and spread of drug resistance among malaria parasites. A clear understanding behind the mechanisms of parasite resistance is required for the improvement of treatment efficacy, policy assessment and in the development of new drugs. A common strategy used by parasites in achieving resistance involves decreasing drug accumulation inside the cell. This is typically accomplished by increasing the availability of transporter proteins that mediate the efflux of the active compound. The goal of this thesis was to better understand the involvement of drug transporter genes in the molecular mechanisms underlying drug susceptibility in Plasmodium falciparum malaria. The approaches involved clinical drug trials, clinical isolates and extensive studies of laboratory P. falciparum parasites. The contribution of pfmrp1 polymorphisms in in vivo parasite drug response was studied in P. falciparum infected patients from drug efficacy clinical trials. After Sulphadoxine-Pyrimethamine treatment, recrudescent infections selected for parasites that had a lysine at amino acid position 1466 in pfmrp1, thus providing the first indication that this transporter gene may have a role in P. falciparum antifolate drug responses in vivo. We examined the effect of the ACT partner drug, mefloquine, on the intra-erythrocytic cell cycle of P. falciparum laboratory parasites having different in vitro drug susceptibilities, while in parallel investigating the expression of four pivotal drug transporter genes: pfcrt, pfmdr1, pfmrp1 and pfmrp2. This study revealed a delay in the cell cycle of the parasite after drug pressure, accompanied by gene induction of the transporter genes studied. The genetic background of the drug transporter genes pfcrt, pfmdr1, pfmrp1 and pfmrp2 were further studied at length in field isolates collected at the Thai-Myanmar border, a historically known epicenter of resistance. The isolates were characterized in vitro for their sensitivity against a broad range of ACT relevant antimalarials. Correlation analyses revealed novel candidate markers for multidrug resistance against structurally unrelated antimalarial drugs used extensively in ACT regimens worldwide. In conclusion, these studies reinforce the concept of malaria drug resistance as a multi-factorial and complex phenomenon that may involve not only the parasite’s handling of the incoming drug, but also concomitant responses of its basic physiology.
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| 5. |
- Ursing, Johan, et al.
(författare)
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Chloroquine-susceptible and -resistant Plasmodium falciparum strains survive high chloroquine concentrations by becoming dormant but are eliminated by prolonged exposure
- 2022
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 77:4, s. 1005-1011
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Tidskriftsartikel (refereegranskat)abstract
- Background: Plasmodium falciparum strains that are resistant to standard-dose chloroquine can be treated by higher chloroquine concentrations maintained for a longer time in vivo.Objectives: To determine the relative importance of chloroquine concentrations versus exposure time for elimination of chloroquine-susceptible and -resistant P. falciparum in vitro.Methods: Chloroquine-susceptible (3D7) and -resistant (FCR3) strains were exposed in vitro to 1, 2, 4, 8, 16 or 32 times their respective 90% inhibitory chloroquine concentrations for 3, 5, 7 or 14 days and then followed until recrudescence, or not, by 42 days after the end of exposure.Results: Exposure to chloroquine appeared to eliminate susceptible and resistant parasites, leaving small pyknotic apparently dead parasites. Chloroquine-susceptible and -resistant parasites recrudesced after 3 and 5 days of chloroquine exposure. Recrudescence occurred in one out of four 7 day exposure series but not after 14 days exposure. The median time to recrudescence was 13 to 28 days with a range of 8 to 41 days after the end of exposure. Time to recrudescence after the end of exposure increased with duration of exposure for susceptible and resistant strains (P < 0.001). Time to recrudescence did not correlate with concentrations greater than 1x IC90.Conclusions: Chloroquine-susceptible and -resistant P. falciparum probably become dormant. Elimination of dormant parasites is primarily dependent upon the duration of chloroquine exposure. Exposure to effective drug concentrations for 7 days eliminates most parasites in vitro. The results support in vivo data indicating that elimination of chloroquine-resistant P. falciparum correlates with Day 7 chloroquine concentrations.
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