Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

Cai, Yunpeng; Xu, Mingxin; Yuan, Minglu; Liu, Zhenguo; Yuan, Weien

doi:10.2147/ijn.s63507

Cited by 29 publications

(16 citation statements)

References 78 publications

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“…The L-dopa/bensarazide microspheres (LBM) were prepared according to the oil-in-water emulsion solvent evaporation method. The procedure was the same as the method previously reported (Ren et al, 2011b ; Rong et al, 2011 ; Yang et al, 2012 ; Zhao et al, 2013 ; Cai et al, 2014 ; Kang et al, 2014 ). L-dopa methyl ester and benserazide hydrochloride were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease

Wan¹,

Wu²,

Song³

et al. 2017

Front. Aging Neurosci.

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Background: The long-term intermittent Levodopa (L-dopa) stimulation contributes to an aberrant activation of D1 receptor (D1R) mediated extracellular signal-regulated kinases1/2 (ERK1/2) in the striatal medium spiny neurons, resulting in the occurrence of L-dopa induced dyskinesia (LID). Recently, a novel signaling pathway, D1R/Shp-2/ERK1/2, was proposed to be required for the occurrence of LID. Here we designed the study in which two different methods of L-dopa delivery [continuous dopamine stimulation (CDS) vs. intermittent dopamine stimulation] were used to further identify: (1) the role of D1R/Shp-2/ERK1/2 signaling pathway in the occurrence of LID; (2) whether CDS alleviated LID though preventing the over-expression of the D1R/Shp-2/ERK1/2 signaling pathway.Methods: 6-OHDA-lesioned rat models of Parkinson's disease (PD) were randomly divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide standard group, LS group) or CDS (L-dopa/benserazide loaded microspheres, LBM group) for 21 days. Dyskinesia and anti-parkinsonian effect were compared between the two groups through the AIMs assessment and cylinder test. The critical protein changes in the D1R/Shp-2/ERK1/2 signaling pathway were compared between the two groups through Western blotting.Results: Intermittent L-dopa administration induced serious dyskinetic movements in the 6-OHDA-lesioned rats, and the anti-parkinsonian effect of L-dopa was gradually counteracted by the occurrence of dyskinesia. Intermittent L-dopa administration enhanced the expression of membrane D1R, and induced a robust increase of phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. In contrast, CDS played a dose-dependent anti-parkinsonian role, without inducing such apparent dyskinetic movements. Moreover, CDS induced no change of membrane D1R expression or phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum.Conclusion: The aberrant activation of D1R/Shp-2 complex was evidenced to be required for the D1R mediating ERK1/2 phosphorylation and the occurrence of LID. CDS effectively prevented the overexpression of D1R/Shp-2/ERK1/2 signaling pathway, resulting in the reduction of LID in 6-OHDA-lesioned rats model of PD.

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Section: Methodsmentioning

confidence: 99%

Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease

Wan¹,

Wu²,

Song³

et al. 2017

Front. Aging Neurosci.

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“…LB03002 is a sustained release preparation of GH incorporated into sodium hyaluronate microparticles that has demonstrated similar efficacy to daily GH in prepubertal GH naïve children with GHD (Khadilkar et al 2014). There are many other long-acting GH preparations under development utilising hydrogels, implants and modifications of GH by pegylation, conjugation with albumin, conjugation with specific amino acid sequences (XTEN) and fusion to Fc domains of human immunoglobulin (Cai et al 2014). In view of the discussions above regarding the significance of pulsatility of GH secretion associated with both ultradian and infradian rhythms, it will be interesting to understand how the efficacy of these long-acting GH preparations relates to normal physiology.…”

Section: Gh Deficiencymentioning

confidence: 99%

“…Alternative routes of administration that have been studied include intranasal, transdermal and pulmonary routes. Intranasal administration has been limited by poor bioavailability, whereas transdermal administration with microneedle patches and self-dissolving micropiles has demonstrated high bioavailability but at the expense of localised skin irritation (Cai et al 2014). Pulmonary delivery requires the development of uniform low density powders to reach the lower lung; initial reports suggested low bioavailability but addition of dimethyl-b-cyclodextrin substantially increased bioavailability in rats (Jalalipour et al 2008).…”

Section: Gh Deficiencymentioning

confidence: 99%

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Murray¹,

Higham²,

Clayton³

2015

Journal of Endocrinology

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At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.

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“…For example, sustained release of proteins differentially affects stem cell proliferation, migration and differentiation both in vitro and in vivo when compared to bolus administration 10–12 . Additional studies demonstrate that sustained release of proteins may not lead to an improvement in therapeutic efficacy 13,14 . Instead, differing protein release profiles (bolus, sustained, delayed and pulsed) may activate distinct biochemical cascades that determines overall therapeutic outcome 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal presentation of exogenous SDF-1 with PLGA nanoparticles modulates SDF-1/CXCR4 signaling axis in the rodent cortex

et al. 2017

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Stromal cell-derived factor-1 (SDF-1) and its key receptor CXCR4 have been implicated in directing cellular recruitment for several pathological/disease conditions thus also gained considerable attention for regenerative medicine. One regenerative approach includes sustained release of SDF-1 to stimulate prolonged stem cell recruitment. However, the impact of SDF-1 sustained release on the endogenous SDF-1/CXCR4 signaling axis is largely unknown as auto-regulatory mechanisms typically dictate cytokine/receptor signaling. We hypothesize that spatiotemporal presentation of exogenous SDF-1 is a key factor in achieving long-term manipulation of endogenous SDF-1/CXCR4 signaling. Here in the present study, we sought to probe our hypothesis using a transgenic mouse model to contrast the spatial activation of endogenous SDF-1 and CXCR4 in response to exogenous SDF-1 injected in bolus or controlled release (PLGA nanoparticles) form in the adult rodent cortex. Our data suggests that the manner of SDF-1 presentation significantly affected initial CXCR4 cellular activation/recruitment despite having similar protein payloads over the first 24 hrs (∼30ng for both bolus and sustained release groups). Yet, one week post-injection, this response was negligible. Therefore, the transient nature CXCR4 recruitment/activation in response to bolus or controlled release SDF-1 indicated that cytokine/receptor auto-regulatory mechanisms may demand more complex release profiles (i.e. delayed and/or pulsed release) to achieve sustained cellular response.

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Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

Cited by 29 publications

References 78 publications

Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease

Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Spatiotemporal presentation of exogenous SDF-1 with PLGA nanoparticles modulates SDF-1/CXCR4 signaling axis in the rodent cortex

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