| 1. |
- Bengtsson, Anders A, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD). METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks. RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported. CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.
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| 2. |
- Bengtsson, Anders, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose. Methods The efficacy of paquinimod was studied in lupus-prone MRL-lpr/lpr mice and compared with that of established SLE treatments. Dose-response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double-blind, placebo controlled, dose-ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks. Results Paquinimod treatment resulted in disease inhibition in MRL-lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid-sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once-daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported. Conclusion Paquinimod effectively inhibited disease and had a steroid-sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.
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| 3. |
- Hesselstrand, Roger, et al.
(författare)
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An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod
- 2021
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc). Methods: In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study. Results: Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase. Conclusions: Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs. Trial registration: ClinicalTrials.gov, NCT01487551. Registered on 7 September 2011.
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| 4. |
- Sjödin, Torgny, et al.
(författare)
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A clinical and microbiological study on the enantiomers of delmopinol
- 2016
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Ingår i: Acta Odontologica Scandinavica. - : Informa Healthcare. - 0001-6357 .- 1502-3850. ; 74:5, s. 355-361
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Tidskriftsartikel (refereegranskat)abstract
- Objective The clinical part of this study aimed to investigate whether the racemate of delmopinol [(+/-)-delmopinol] is equivalent to its two enantiomers [(+)-delmopinol and (-)-delmopinol] with respect to efficiency and to determine and compare their pharmacokinetic properties. The purpose of the pre-clinical part was to elucidate possible differences in antimicrobial efficiency. Materials and methods The compounds were tested clinically in a double-blind, randomized, cross-over study comprising three treatment periods of 4 days each. The antimicrobial efficacy of the enantiomers was compared in vitro with respect to planktonic and biofilm bacteria of different species. Results No statistically significant differences in prevention of plaque formation were observed. Except for a somewhat higher systemic exposure in terms of AUC and C-max indicated for (-)-delmopinol compared to (+)-delmopinol, the pharmacokinetic properties were similar. The most common adverse event was a transient anaesthetic feeling in the mouth. This event was reported with the same frequency for all three test solutions. The enantiomers showed similar antimicrobial effects on planktonic bacteria and their biofilms. Conclusions The enantiomers were found to be equally effective with respect to inhibition of plaque development and only minor differences were observed with respect to their pharmacokinetic properties. No differences could be observed in the adverse events reports. There is, therefore, no reason to use one of the enantiomers of delmopinol instead of the racemate. This was further supported by the antimicrobial tests. It is suggested that the combined action of cationic and neutral delmopinol is important for its effect on biofilms.
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| 5. |
- Sjödin, Torgny, et al.
(författare)
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Pharmacokinetics and clinical efficacy of delmopinol in an open rinse time study in healthy volunteers
- 2011
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Ingår i: American Journal of Dentistry. - 0894-8275. ; 24:6, s. 383-388
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare three different rinse times with delmopinol (15, 30 and 60 seconds) with respect to inhibition of plaque growth and to determine the pharmacokinetic parameters of delmopinol for these rinse times. Methods: This open and randomized study with a cross-over design was performed in healthy male volunteers and consisted of four treatment periods of 1 week separated by washout periods of at least 6 days. The first test period started with staining of the teeth followed by planimetric recordings before and after professional cleaning. Adverse records were also obtained. The volunteers, randomly assigned to a rinsing time sequence, were instructed to cease all oral hygiene measures except for the mouthrinse with placebo or delmopinol solutions. The rinses were performed without supervision twice daily for 7 days for each rinsing time. On Day 7, plaque % index and planimetric registrations were obtained, adverse effects recorded and the teeth were cleaned professionally. Plasma samples for the pharmacokinetic evaluation were also taken. The remaining test periods were performed in the same way, except that no baseline planimetric recordings were made. During the washout periods the volunteers returned to their normal oral hygiene behavior. Venous blood samples were drawn from all volunteers into sodium heparin-containing tubes. Results: A significant time-response was obtained with respect to the planimetric results. The mean areas of the teeth covered with plaque after the test periods (placebo, 15, 30 and 60 seconds) were 41%, 29%, 23% and 18%, respectively. Statistical analysis showed that rinsing with delmopinol for 30 or 60 seconds differed significantly (P< 0.05) from placebo. There was also a significant difference between rinsing for 15 and 60 seconds. From the plaque % index data it was found that all three rinsing times differed significantly from placebo. However, between the three rinse times with active solution, no significant difference in plaque % index occurred. Statistical analysis of the systemic exposure, in terms of the pharmacokinetic parameters AUC(12h) and C(max) showed a significant treatment effect. The exposure increased with increasing rinse time, although the increase (AUC(12h) and C(max)) was less than proportional to the rinse time.
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| 6. |
- Stenström, Martin, et al.
(författare)
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Paquinimod reduces skin fibrosis in tight skin 1 mice, an experimental model of systemic sclerosis
- 2016
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Ingår i: Journal of Dermatological Science. - : Elsevier BV. - 0923-1811. ; 83:1, s. 52-59
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic Sclerosis (SSc) is an autoimmune disease characterized by vascular and immune dysfunction. A hallmark of SSc is the excessive accumulation of extracellular matrix in the skin and in internal organs. There is a high and unmet medical need for novel therapies in this disease. The pathogenesis of SSc is complex and still poorly understood, but the innate immune system has emerged as an important factor in the disease. SSc patients show increased numbers of macrophages/monocytes in the blood and in the skin compared to healthy individuals and these cells are important sources of profibrotic cytokines and chemokines. Paquinimod belongs to a class of orally active quinoline-3-carboxamide (quinoline) derivatives with immunomodulatory properties and has shown effects in several models of autoimmune/inflammatory disorders. Paquinimod is currently in clinical development for treatment of SSc. The immunomodulatory effects of paquinimod is by targeting the myeloid cell compartment via the S100A9 protein. Objective: In this study we investigate whether targeting of myeloid cells by paquinimod can effect disease development in an experimental model of SSc, the tight skin 1 (Tsk-1) mouse model. Methods: Seven weeks old female B6.Cg-Fbn1Tsk/J (Tsk-1) mice were treated with vehicle or paquinimod at the dose of 5 or 25 mg/kg/day in the drinking water for 8 weeks. The effect of paquinimod on the level of skin fibrosis and on different subpopulations within the myeloid cell compartment in skin biopsies were evaluated by using histology, immunohistochemisty, a hydroxyproline assay and real-time PCR. Furthermore, the level of IgG in serum from treated animals was also analysed. The statistical analyses were performed using Mann-Whitney nonparametric two tailed rank test. Results: The results show that treatment with paquinimod reduces skin fibrosis measured as reduction of skin thickness and decreased number of myofibroblasts and total hydroxyproline content. The effect on fibrosis was associated with a polarization of macrophages in the skin from a pro-fibrotic M2 to a M1 phenotype. Paquinimod treatment also resulted in a reduced TGFβ-response in the skin and an abrogation of the increased auto-antibody production in this SSc model. Conclusions: Paquinimod reduces skin fibrosis in an experimental model of SSc, and this effect correlates with local and systemic effects on the immune system.
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| 7. |
- Wikner, Birgitta Norstedt, et al.
(författare)
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Maternal use of thyroid hormones in pregnancy and neonatal outcome
- 2008
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 87:6, s. 617-627
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To describe neonatal outcome including the presence of congenital malformations in infants born to women substituted with thyroid hormones, and the maternal characteristics of these women. Design. Register study based on prospectively collected data in relation to delivery. Setting. Swedish Health Registers. Population. All pregnant women (n = 848,468) and all infants born (n = 861,989) in Sweden from 1 July 1995 to 31 December 2004. Methods. Women who reported the use of thyroid hormones in early pregnancy or obtained a prescription for thyroid hormones later in pregnancy (n = 9,866), as well as their infants (n = 10,055) were identified from the Swedish Medical Birth Register. The reference population consisted of all women giving birth and their offspring during the same time interval. Main outcome measures. Neonatal outcome, malformations and maternal characteristics. Data were analyzed with adjustments for identified confounders. Results. Women using thyroxine had an increased rate of pre-eclampsia, diabetes (pre-existing or gestational), cesarean sections and inductions of labour compared to women in the reference population. The risk for preterm birth was marginally increased (OR 1.13, 95% CI 1.03-1.25). Neonatal thyroid disease was found in eight infants (seven with thyreotoxicosis and one unspecified), the expected number was 0.2. No further anomalies in neonatal diagnoses were found. A small but statistically significant risk for congenital malformations (OR = 1.14, 95% CI 1.05-1.26) was found. Conclusion. Women on thyroid substitution during pregnancy had an increased risk for some pregnancy complications, but their infants were only slightly affected.
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