Glutathione‐PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first‐in‐human study

2区 · 医学

Article

作者: Zuiker, R. G. J. A. ; Klaassen, E. S. ; Stavrakaki, I. ; Groeneveld, G. J. ; Gladdines, W. ; Kanhai, K. M. S. ; Gaillard, P. J.

AimsIntravenous high‐dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing–remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione‐PEGylated liposomes, creating a slow‐release formulation with reduced toxicity and prolonged peripheral efficacy. This first‐in‐human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione‐PEGylated liposomes containing MP (2B3–201).MethodsThe first part was a double‐blind, three‐way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3–201, active comparator (free MP) or placebo. Part 2 of the study was an open‐label infusion of 2B3–201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross‐over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests.ResultsThe most frequent recorded AE related to 2B3–201 was an infusion related reaction (89%). 2B3–201 was shown to have a plasma half‐life between 24 and 37 h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose.Conclusion2B3–201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3–201 shows a long plasma half‐life and prolonged immunosuppressive effects.

2014-12-01·Acta Neuropathologica Communications2区 · 医学

CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis

2区 · 医学

ArticleOA

作者: Daniel C Anthony ; Rick Dorland ; Pieter J Gaillard ; Nicola R Sibson ; Helen B Stolp ; Marco de Boer ; Matthew C Evans ; Chantal Appeldoorn ; Martin R Turner

BACKGROUNDHallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis.RESULTSAll SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100 days. SOD1G93A animals showed a significant increase in signal intensity on T2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss.CONCLUSIONSIn contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.

2014-09-01·Journal of Neuroimmunology3区 · 医学

Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis

3区 · 医学

Article

作者: Rötger, Caroline ; Gladdines, Werner ; Linker, Ralf A ; Lee, De-Hyung ; Gaillard, Pieter J ; Appeldoorn, Chantal C M ; Reijerkerk, Arie

Methylprednisolone (MP) pulses are the mainstay for relapse therapy in multiple sclerosis (MS). To improve the efficacy of treatment and reduce the side effects of MP, a long circulating brain-targeted formulation was developed; glutathione polyethylene glycol (PEG)ylated liposomal MP (2B3-201). Here we investigate the efficacy of 2B3-201 in murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of MS. After disease onset, mice were randomized to receive either saline, three injections of free MP (high dose MP, 100mg/kg i.v.), two injections of free MP (low dose MP, 10mg/kg; i.v.), or two injections of 2B3-201 (10mg/kg i.v.). Treatment with a low dose of 2B3-201 significantly reduced the severity of EAE as compared to saline control, similar to treatment with high dose free MP, while a low dose of free MP was not effective. In a histological analysis of the spinal cord, treatment with 2B3-201 significantly decreased T cell as well as macrophage/microglia infiltration in the CNS by about 50%. Moreover, application of a low dose of 2B3-201 or a high dose of free MP reduced the amount of astrocyte activation as well as the extent of axonal loss and also demyelination in spinal cord lesions as compared to low dose MP or sham treatment. In summary, in the murine MOG-EAE model of MS, a glutathione PEGylated liposomal formulation of MP (2B3-201) is clinically and histologically as effective as free MP at one tenth of the dosage as well as at a lower application frequency and clearly more effective than the same dosage of free MP. These positive proof-of-concept efficacy studies warrant further development of 2B3-201 for the treatment of neuroinflammatory conditions such as MS.

100 项与 2B3-201 相关的药物交易

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