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J M Rowe - One of the best experts on this subject based on the ideXlab platform.
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dermatologic changes associated with Roquinimex immunotherapy after autologous bone marrow transplant
Journal of The American Academy of Dermatology, 2000Co-Authors: Yasuko Ohsuga, J M Rowe, Jane L Liesveld, Robert P Burns, A A GaspariAbstract:Abstract Background: Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects. Objective: We documented the incidence of acute cutaneous GVHR associated with Roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent Roquinimex immunotherapy in the period after the transplant. Methods: Fifteen patients undergoing bone marrow transplantation and Roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed. Results: Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with Roquinimex. Ten of 11 evaluable patients receiving Roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different. Conclusion: Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by Roquinimex did not correlate with a GVL effect in our study of 15 patients with CML. (J Am Acad Dermatol 2000;43:437–41.)
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use of Roquinimex in the myeloid leukemias
1996Co-Authors: J M Rowe, Bi Nilsson, Bengt SimonssonAbstract:The increasing use of allogeneic bone marrow transplantation has led to unequivocal evidence for the efficacy of immunotherapy in the treatment of acute leukemia. It is now known that syngeneic transplantation, T lymphocyte depletion and the absence of graft-versus-host disease all increase the risk of relapse following allogeneic transplantation for the myeloid leukemias, both acute and chronic. Leukemia-specific immune responses appear to play a major role in the therapy of the myeloid leukemias. In recent years attempts have been made to better characterize and effectively utilize these antileukemic immune responses. A beneficial effect is more likely to be seen when the tumor burden is low and such efforts have therefore concentrated on clinical states of minimal residual disease. This review will discuss the role of the novel immunomodulator Roquinimex following autologous bone marrow transplantation for myeloid leukemias, and will focus on recent experience and ongoing clinical trials in acute myelogenous leukemia and chronic myelogenous leukemia.
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Roquinimex induced graft versus host reaction after autologous bone marrow transplantation
Journal of The American Academy of Dermatology, 1995Co-Authors: A A Gaspari, S F Cheng, J F Dipersio, J M RoweAbstract:Abstract Background: Roquinimex is being used for posttransplantation immunotherapy of autologous bone marrow transplantation for acute and chronic myelogenous leukemia. This immunotherapeutic agent is a cytokine inducer and may induce an autologous graft-versus-host (GVH) and graft-versus-tumor reaction. Objective: Our purpose was to examine patients undergoing this immunotherapy for clinical signs and symptoms of acute GVH reactions and to correlate these symptoms with their clinical outcome. Methods: We studied eight patients receiving Roquinimex therapy. Results: We found autologous GVH reactions in three of eight patients (38%) treated with this immunotherapy. Their disease was manifested by localized or widespread violaceous papules that on histologic evaluation were compatible with a grade II GVH reaction. The acute cutaneous GVH reaction was associated with eccrine sweat gland necrosis, a dermatologic toxicity usually associated with chemotherapy. Conclusion: Long-term studies of larger numbers of patients treated with this immunotherapy will determine whether these GVH reactions confer significant, sustained, antitumor effects.
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Roquinimex-induced graft-versus-host reaction after autologous bone marrow transplantation.
Journal of the American Academy of Dermatology, 1995Co-Authors: A A Gaspari, S F Cheng, J F Dipersio, J M RoweAbstract:Roquinimex is being used for posttransplantation immunotherapy of autologous bone marrow transplantation for acute and chronic myelogenous leukemia. This immunotherapeutic agent is a cytokine inducer and may induce an autologous graft-versus-host (GVH) and graft-versus-tumor reactions. Our purpose was to examine patients undergoing this immunotherapy for clinical signs and symptoms of acute GVH reactions and to correlate these symptoms with their clinical outcome. We studied eight patients receiving requinimex therapy. We found autologous GVH reactions in three of eight patients (38%) treated with this immunotherapy. Their disease was manifested by localized or widespread violaceous papules that on histologic evaluation were compatible with a grade II GVH reaction. The acute cutaneous GVH reaction was associated with eccrine sweat gland necrosis, a dermatologic toxicity usually associated with chemotherapy. Long-term studies of larger numbers of patients treated with this immunotherapy will determine whether these GVH reactions confer significant, sustained, antitumor effects.
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Allografting in chronic myelogenous leukemia followed by immunotherapy
Stem Cells, 1993Co-Authors: J M Rowe, A A Gaspari, J F Dipersio, Jane L Liesveld, Bo Nilsson, Daniel H. Ryan, P. Kouides, L. Larsson, Bengt SimonssonAbstract:: Patients with chronic myelogenous leukemia (CML) can be cured with allogeneic bone marrow transplantation. Over the past decade, it has become clear that immunological mechanisms, in the form of graft-versus-leukemia, constitute an integral part of this therapy. Because of limitations imposed by a lack of suitable donors, age, and toxicity, only a minority of patients can be offered allogeneic bone marrow transplantation (BMT). Recently, attempts have been made to employ autologous bone marrow transplantation (ABMT) for the therapy of CML using a variety of pre- and post-transplantation manipulations. This report describes the rationale for an ongoing clinical trial using the immunomodulator Roquinimex (Linomide), following autologous bone marrow transplantation, in an attempt to stimulate the immunological responses thought to be critical for successful therapy in CML.
A A Gaspari - One of the best experts on this subject based on the ideXlab platform.
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dermatologic changes associated with Roquinimex immunotherapy after autologous bone marrow transplant
Journal of The American Academy of Dermatology, 2000Co-Authors: Yasuko Ohsuga, J M Rowe, Jane L Liesveld, Robert P Burns, A A GaspariAbstract:Abstract Background: Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects. Objective: We documented the incidence of acute cutaneous GVHR associated with Roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent Roquinimex immunotherapy in the period after the transplant. Methods: Fifteen patients undergoing bone marrow transplantation and Roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed. Results: Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with Roquinimex. Ten of 11 evaluable patients receiving Roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different. Conclusion: Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by Roquinimex did not correlate with a GVL effect in our study of 15 patients with CML. (J Am Acad Dermatol 2000;43:437–41.)
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Roquinimex induced graft versus host reaction after autologous bone marrow transplantation
Journal of The American Academy of Dermatology, 1995Co-Authors: A A Gaspari, S F Cheng, J F Dipersio, J M RoweAbstract:Abstract Background: Roquinimex is being used for posttransplantation immunotherapy of autologous bone marrow transplantation for acute and chronic myelogenous leukemia. This immunotherapeutic agent is a cytokine inducer and may induce an autologous graft-versus-host (GVH) and graft-versus-tumor reaction. Objective: Our purpose was to examine patients undergoing this immunotherapy for clinical signs and symptoms of acute GVH reactions and to correlate these symptoms with their clinical outcome. Methods: We studied eight patients receiving Roquinimex therapy. Results: We found autologous GVH reactions in three of eight patients (38%) treated with this immunotherapy. Their disease was manifested by localized or widespread violaceous papules that on histologic evaluation were compatible with a grade II GVH reaction. The acute cutaneous GVH reaction was associated with eccrine sweat gland necrosis, a dermatologic toxicity usually associated with chemotherapy. Conclusion: Long-term studies of larger numbers of patients treated with this immunotherapy will determine whether these GVH reactions confer significant, sustained, antitumor effects.
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Roquinimex-induced graft-versus-host reaction after autologous bone marrow transplantation.
Journal of the American Academy of Dermatology, 1995Co-Authors: A A Gaspari, S F Cheng, J F Dipersio, J M RoweAbstract:Roquinimex is being used for posttransplantation immunotherapy of autologous bone marrow transplantation for acute and chronic myelogenous leukemia. This immunotherapeutic agent is a cytokine inducer and may induce an autologous graft-versus-host (GVH) and graft-versus-tumor reactions. Our purpose was to examine patients undergoing this immunotherapy for clinical signs and symptoms of acute GVH reactions and to correlate these symptoms with their clinical outcome. We studied eight patients receiving requinimex therapy. We found autologous GVH reactions in three of eight patients (38%) treated with this immunotherapy. Their disease was manifested by localized or widespread violaceous papules that on histologic evaluation were compatible with a grade II GVH reaction. The acute cutaneous GVH reaction was associated with eccrine sweat gland necrosis, a dermatologic toxicity usually associated with chemotherapy. Long-term studies of larger numbers of patients treated with this immunotherapy will determine whether these GVH reactions confer significant, sustained, antitumor effects.
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Allografting in chronic myelogenous leukemia followed by immunotherapy
Stem Cells, 1993Co-Authors: J M Rowe, A A Gaspari, J F Dipersio, Jane L Liesveld, Bo Nilsson, Daniel H. Ryan, P. Kouides, L. Larsson, Bengt SimonssonAbstract:: Patients with chronic myelogenous leukemia (CML) can be cured with allogeneic bone marrow transplantation. Over the past decade, it has become clear that immunological mechanisms, in the form of graft-versus-leukemia, constitute an integral part of this therapy. Because of limitations imposed by a lack of suitable donors, age, and toxicity, only a minority of patients can be offered allogeneic bone marrow transplantation (BMT). Recently, attempts have been made to employ autologous bone marrow transplantation (ABMT) for the therapy of CML using a variety of pre- and post-transplantation manipulations. This report describes the rationale for an ongoing clinical trial using the immunomodulator Roquinimex (Linomide), following autologous bone marrow transplantation, in an attempt to stimulate the immunological responses thought to be critical for successful therapy in CML.
Hans Link - One of the best experts on this subject based on the ideXlab platform.
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Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats.
Journal of neuroimmunology, 2020Co-Authors: Jian-she Yang, Gunnar Hedlund, Ling-yun Xu, Bao-guo Xiao, Hans LinkAbstract:The new orally active drug laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to Roquinimex (Linomide). Furthermore, laquinimod inhibited the inflammation of both CD4+ T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of TH2/TH3 cytokines IL-4, IL-10 and TGF-beta. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.
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linomide Roquinimex affects the balance between pro and anti inflammatory cytokines in vitro in multiple sclerosis
Acta Neurologica Scandinavica, 2009Co-Authors: W Z Tian, Gunnar Hedlund, V Navikas, D Matusevicius, M Soderstrom, S Fredrikson, Hans LinkAbstract:OBJECTIVES: Multiple sclerosis (MS) is characterized by high levels of circulating mononuclear cells (MNC) that respond to myelin proteins like myelin basic protein (MBP) in vitro by expressing mRNA of both pro-inflammatory cytokines, e.g. interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT) that may make MS worse, and anti-inflammatory cytokines like IL-4, IL-10 and transforming growth factor-beta (TGF-beta) that may act beneficially. Substances that down-regulate cytokines such as TNF-alpha or promote IL-10 or TGF-beta can be anticipated to affect MS beneficially. MATERIAL AND METHODS: In situ hybridization to detect and enumerate IFN-gamma, TNF-alpha, LT, IL-4, IL-10 and TGF-beta mRNA expressing blood MNC after stimulation with myelin basic protein (MBP), control antigens and without antigen in presence and absence of Linomide (Roquinimex, LS-2616) was employed. In parallel, ELISPOT assay to detect MBP- and PHA-reactive IFN-gamma secreting blood MNC+/-Linomide was used. RESULTS: Here we report that Linomide, a synthetic immunomodulator, at concentrations effective in vivo reduces the number of MBP-reactive TNF-alpha and increases MBP-reactive IL-10 and TGF-beta mRNA expressing MNC from MS patients' blood when analysed in vitro. Compared to dexamethasone, Linomide up-regulated levels of blood MNC expressing mRNA of TGF-beta after culture in presence of MBP. CONCLUSIONS: Changes of cytokine balance towards a production of anti-inflammatory cytokines could be a desirable effect to be evaluated in future drug studies of Linomide-like substances. At present, Linomide is not evaluable in MS clinical trials due to side-effects.
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Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats
Journal of Neuroimmunology, 2004Co-Authors: Jian-she Yang, Gunnar Hedlund, Ling-yun Xu, Bao-guo Xiao, Hans LinkAbstract:Abstract The new orally active drug laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to Roquinimex (Linomide). Furthermore, laquinimod inhibited the inflammation of both CD4 + T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of T H 2/T H 3 cytokines IL-4, IL-10 and TGF-β. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.
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Effects of Linomide on immune cells and cytokines inhibit autoimmune pathologies of the central and peripheral nervous system.
International Immunopharmacology, 2001Co-Authors: Gunnar Hedlund, Hans Link, Bao-guo XiaoAbstract:Linomide (Roquinimex, LS 2616) is a quinoline-3-carboxamide with pleiotropic immune modulating capacity and it has therapeutic effects in several experimental animal models of autoimmune diseases. Linomide has been evaluated in clinical trials for multiple sclerosis, and was indeed shown to have disease inhibitory effects. However, due to unexpected side effects recorded in patients treated with Linomide, premature termination of clinical trials was required. The basic mechanism(s) of action of Linomide in inducing beneficial effects in autoimmune diseases is still elusive. Some experimental evidence indicates that Linomide influences the regulation of the cytokine profile, resulting in the inhibition of autoimmune and inflammation pathologies. This review focuses on Linomide applied in models for autoimmune and inflammation pathologies of the central and the peripheral nervous system, and summarises its very encouraging disease inhibitory effects and their potential pharmacological basis. The beneficial effects recorded with Linomide in both experimental and clinical trials emphasise the possible value of substances with Linomide-like activity for clinical use in autoimmune and inflammation pathologies in the near future.
Kerstin Strandgarden - One of the best experts on this subject based on the ideXlab platform.
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Metabolism of Roquinimex in mouse and rat: an in vitro/in vivo comparison
Xenobiotica, 2020Co-Authors: Helen Tuvesson, Kerstin Strandgarden, Per Olov Gunnarsson, Orjan Nordle, Janeric Seidegard, R PerssonAbstract:1.1. In vitro studies with Roquinimex, animmuno-modulator, in liver microsomes from mouse and rat were conducted to evaluate the primary metabolism and compare the metabolite pattern as well as the rate of metabolismwith the in vivo pharmacokinetics of the compound in these two species. 2. In the presence ofNADPH, Roquinimex wasmetabolized to six primary metabolites (R1-6) by liver microsomes from mouse and rat. The formation of these metabolites was qualitatively similar in both species, and was greatly enhanced by pretreatment with PCN, an inducer of cytochrome P4503A. 3. The identification of the R1-6 demonstratedthat Roquinimex had been hydroxylated and demethylated. Hydroxylation at different sites of the quinoline moiety was the dominating reaction in both species. 4. Comparison of the resulting microsomal intrinsic clearance of 0.3 μmol mg−1 protein min−1 in mouse liver microsomes, versus 0.03 μmol mg−1 protein min−1 in rat liver microsomes demonstrated that the mouse possesses about a 10-fold grea...
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absorption and disposition including enterohepatic circulation of 14c Roquinimex after oral administration to healthy volunteers
Biopharmaceutics & Drug Disposition, 2000Co-Authors: Kerstin Strandgarden, Peter Hoglund, Lena Gronquist, Leif Svensson, Per Olov GunnarssonAbstract:The absorption and disposition of Roquinimex (Linomide®) were studied in four male and two female healthy volunteers. The subjects received a single oral aqueous solution of 14C-labelled Roquinimex, about 0.1 mg/kg, after an overnight fast. Blood samples were taken and urine and faeces were collected for 10 days after dosing. The plasma, urine and faeces concentrations of Roquinimex and metabolites were determined by high-performance liquid chromatography (HPLC) with radiochemical detection. The metabolites were identified by HPLC–mass spectroscopy (MS). The plasma concentration–time profiles of Roquinimex exhibited a rapid absorption followed by a bi-exponential disposition. A secondary peak was observed between 6 and 8 h, indicating enterohepatic circulation (EHC) of Roquinimex. The terminal disposition half-life was estimated as 27 h. The primary metabolic pathways of Roquinimex were hydroxylation, demethylation and conjugation. The major compound in plasma was Roquinimex; metabolites were only occasionally detected. In urine and faeces, Roquinimex accounted for 2% of the dose and conjugated and hydroxylated metabolites each accounted for about 30% of the dose. A model was derived for the plasma concentrations of Roquinimex and the amount of urinary excreted Roquinimex to take into account EHC. This model improved the goodness-of-fit according to common goodness-of-fit criteria. The values of the pharmacokinetic parameters were similar using compartmental and non-compartmental methods, indicating that the contribution of EHC of Roquinimex is of minor importance in the evaluation of the pharmacokinetics of Roquinimex. Copyright © 2000 John Wiley & Sons, Ltd.
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metabolism of Roquinimex in mouse and rat an in vitro in vivo comparison
Xenobiotica, 2000Co-Authors: Helen Tuvesson, Kerstin Strandgarden, Per Olov Gunnarsson, Orjan Nordle, Janeric Seidegard, R PerssonAbstract:1.1. In vitro studies with Roquinimex, animmuno-modulator, in liver microsomes from mouse and rat were conducted to evaluate the primary metabolism and compare the metabolite pattern as well as the rate of metabolismwith the in vivo pharmacokinetics of the compound in these two species. 2. In the presence ofNADPH, Roquinimex wasmetabolized to six primary metabolites (R1-6) by liver microsomes from mouse and rat. The formation of these metabolites was qualitatively similar in both species, and was greatly enhanced by pretreatment with PCN, an inducer of cytochrome P4503A. 3. The identification of the R1-6 demonstratedthat Roquinimex had been hydroxylated and demethylated. Hydroxylation at different sites of the quinoline moiety was the dominating reaction in both species. 4. Comparison of the resulting microsomal intrinsic clearance of 0.3 μmol mg−1 protein min−1 in mouse liver microsomes, versus 0.03 μmol mg−1 protein min−1 in rat liver microsomes demonstrated that the mouse possesses about a 10-fold grea...
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dissolution rate limited absorption and complete bioavailability of Roquinimex in man
Biopharmaceutics & Drug Disposition, 1999Co-Authors: Kerstin Strandgarden, Peter Hoglund, Orjan Nordle, Jiri Polacek, Hans Wannman, Per Olov GunnarssonAbstract:In order to investigate the bioavailability and the rate-limiting step of the absorption of Roquinimex, an oral solution and a tablet formulation (Linomide®) were given to healthy volunteers. The study was conducted as a randomized three-period crossover study in seven male and seven female healthy volunteers. The subjects received an intravenous infusion, an oral solution and an oral tablet formulation, each of 5 mg (about 0.07 mg kg−1), as single doses after an overnight fast on three occasions, with a wash-out period of 3 weeks in between. Venous blood samples were taken over 7 days and the plasma concentrations of Roquinimex were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV)-detection. The pharmacokinetics of Roquinimex was characterized by a low plasma clearance, 4.9 mL h−1 kg−1 and a small volume of distribution, 0.22 L kg−1. The oral bioavailability of the drug was complete for both the solution and the tablet formulation. The absorption rate was faster for the solution than for the tablet. The disposition of Roquinimex was biphasic, with a terminal disposition half-life of 32 h. Between 4 and 8 hours after dosing, a secondary plasma peak was observed, indicating enterohepatic circulation of the drug. No major sex differences were shown in the pharmacokinetics of Roquinimex. In conclusion, dissolution rate-limited absorption of Roquinimex was shown, which demonstrates that disintegration and dissolution of the tablet play a major role in the absorption process of Roquinimex. Despite the delayed absorption after administration of the tablet, the extent of absorption was complete. Copyright © 1999 John Wiley & Sons, Ltd.
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Anti-angiogenic treatment with linomide as adjuvant to surgical castration in experimental prostate cancer
The Journal of Urology, 1997Co-Authors: Beryl Hartley-asap, Kerstin Strandgarden, Jiri Polacek, Jasminka Vukanovic, Ingrid B. J. K. Joseph, John T. IsaacsAbstract:AbstractPurpose: Escape from “castration inhibition,” be it surgical or chemically induced, is still the major problem in prostate cancer treatment. New agents that can be given as adjuvant therapy are needed. Linomide has demonstrated both anti-tumor and anti-angiogenic activity with little toxicity in the Dunning R-3327 rat prostate tumor system. Therefore it was deemed essential to study the efficacy of this drug in the adjuvant situation.Materials and Methods: Linomide, Roquinimex, was administered 3 times a week i.p. alone or in conjunction with castration to rats bearing the Dunning R-3327 PAP rat prostate tumor and its effect on tumor growth analyzed. Similar experiments, in which Linomide 25 mg.kg./day was given in the drinking water were carried out in rats with the Dunning R-3327 G tumor. The effect of treatment on blood vessel density and blood flow in the tumor was also assessed using an image analysis system.Results: Linomide, 2.5 & 40 mg./kg., administered from the day after castration inhib...
R Persson - One of the best experts on this subject based on the ideXlab platform.
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Metabolism of Roquinimex in mouse and rat: an in vitro/in vivo comparison
Xenobiotica, 2020Co-Authors: Helen Tuvesson, Kerstin Strandgarden, Per Olov Gunnarsson, Orjan Nordle, Janeric Seidegard, R PerssonAbstract:1.1. In vitro studies with Roquinimex, animmuno-modulator, in liver microsomes from mouse and rat were conducted to evaluate the primary metabolism and compare the metabolite pattern as well as the rate of metabolismwith the in vivo pharmacokinetics of the compound in these two species. 2. In the presence ofNADPH, Roquinimex wasmetabolized to six primary metabolites (R1-6) by liver microsomes from mouse and rat. The formation of these metabolites was qualitatively similar in both species, and was greatly enhanced by pretreatment with PCN, an inducer of cytochrome P4503A. 3. The identification of the R1-6 demonstratedthat Roquinimex had been hydroxylated and demethylated. Hydroxylation at different sites of the quinoline moiety was the dominating reaction in both species. 4. Comparison of the resulting microsomal intrinsic clearance of 0.3 μmol mg−1 protein min−1 in mouse liver microsomes, versus 0.03 μmol mg−1 protein min−1 in rat liver microsomes demonstrated that the mouse possesses about a 10-fold grea...
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Identification of cytochrome P4503A as the major subfamily responsible for the metabolism of Roquinimex in man.
Xenobiotica, 2020Co-Authors: Helen Tuvesson, Per Olov Gunnarsson, L C Wienkers, Janeric Seidegard, R PerssonAbstract:1. Roquinimex, a novel immunomodulator, is metabolized in liver microsomes from mouse and rat via cytochrome P450s to four hydroxylated and two demethylated metabolites (R1−6). The study investigated which cytochrome P450 enzyme(s) is responsible for the metabolism of Roquinimex in man. 2. Enzyme kinetic analysis demonstrated an apparent Km = 1.28-7.00 mm and Vmax = 50-159 pmol·mg−1 microsomal protein·min−1 for the primary metabolites in human liver microsomes. The sum of Clint for the primary pathways was 0.167 μl·mg−1 microsomal protein·min−1. 3. A correlation between the formation rate of R1-6 and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 11 individuals (r2 = 0.72-0.97). Furthermore, significant inhibition (
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identification of cytochrome p4503a as the major subfamily responsible for the metabolism of Roquinimex in man
Xenobiotica, 2000Co-Authors: Helen Tuvesson, Per Olov Gunnarsson, L C Wienkers, Janeric Seidegard, R PerssonAbstract:1. Roquinimex, a novel immunomodulator, is metabolized in liver microsomes from mouse and rat via cytochrome P450s to four hydroxylated and two demethylated metabolites (R1−6). The study investigated which cytochrome P450 enzyme(s) is responsible for the metabolism of Roquinimex in man. 2. Enzyme kinetic analysis demonstrated an apparent Km = 1.28-7.00 mm and Vmax = 50-159 pmol·mg−1 microsomal protein·min−1 for the primary metabolites in human liver microsomes. The sum of Clint for the primary pathways was 0.167 μl·mg−1 microsomal protein·min−1. 3. A correlation between the formation rate of R1-6 and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 11 individuals (r2 = 0.72-0.97). Furthermore, significant inhibition (<90%) of Roquinimex primary metabolism was demonstrated by ketoconazole and troleandomycin, specific inhibitors of CYP3A4 as well as with anti-CYP3A4 antibodies. Moreover, a similar metabolite pattern was produced from Roquinimex by incubation with cDNA-ex...
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metabolism of Roquinimex in mouse and rat an in vitro in vivo comparison
Xenobiotica, 2000Co-Authors: Helen Tuvesson, Kerstin Strandgarden, Per Olov Gunnarsson, Orjan Nordle, Janeric Seidegard, R PerssonAbstract:1.1. In vitro studies with Roquinimex, animmuno-modulator, in liver microsomes from mouse and rat were conducted to evaluate the primary metabolism and compare the metabolite pattern as well as the rate of metabolismwith the in vivo pharmacokinetics of the compound in these two species. 2. In the presence ofNADPH, Roquinimex wasmetabolized to six primary metabolites (R1-6) by liver microsomes from mouse and rat. The formation of these metabolites was qualitatively similar in both species, and was greatly enhanced by pretreatment with PCN, an inducer of cytochrome P4503A. 3. The identification of the R1-6 demonstratedthat Roquinimex had been hydroxylated and demethylated. Hydroxylation at different sites of the quinoline moiety was the dominating reaction in both species. 4. Comparison of the resulting microsomal intrinsic clearance of 0.3 μmol mg−1 protein min−1 in mouse liver microsomes, versus 0.03 μmol mg−1 protein min−1 in rat liver microsomes demonstrated that the mouse possesses about a 10-fold grea...
