Ninety-day Local Tolerability and Toxicity Study of ND0612, a Novel Formulation of Levodopa/Carbidopa, Administered by Subcutaneous Continuous Infusion in Minipigs

Ramot, Yuval; Nyska, Abraham; Maronpot, Robert R.; Shaltiel-Karyo, Ronit; Tsarfati, Yonit; Manno, Rosa Anna; Sacco, Giuseppe; Yacoby-Zeevi, Oron

doi:10.1177/0192623317729891

Cited by 27 publications

(11 citation statements)

References 18 publications

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“…with the future available subcutaneous L-dopa infusion with a pump device. 18 This approach or other currently applied dopamine substitution concepts allow a dosing adaptation to the ongoing neurodegenerative process. This is in contrast to transplantation.…”

Section: Cure or Disease Modification By Dopamine Generating Cell Transplants?mentioning

confidence: 99%

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View Point: Disease Modification and Cell Secretome Based Approaches in Parkinson’s Disease: Are We on the Right Track?

Müller¹

2021

BTT

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The term idiopathic Parkinson’s disease describes an entity of various not well-characterized disorders resembling each other. They are characterized by chronic neuronal dying originating from various disease mechanisms. They result in the onset of motor and related non-motor features, both of which respond to administration of personalized drug combinations and surgical therapies. The unmet need is beneficial disease course modification with repair and neurogenesis. Objectives are to discuss the value of cell secretome based treatments including neuronal graft transplantation and to suggest as an alternative the stimulation of an endogenous available approach for neuronal repair. Chronic neurodegenerative processes result from different heterogeneous, but complementing metabolic, pathological cascade sequences. Accumulated evidence from experimental research suggested neuron transplantation, stem cell application and cell secretome-based therapies as a promising future treatment with cure as an ultimate goal. To date, clinical testing of disease-modifying treatments has focused on substitution or repair of the remaining dopamine synthesizing neurons following diagnosis. At diagnosis, many of the still surviving and functioning, but already affected neurons have lost most of their axons and are primed for cell death. A more promising therapeutic concept may be the stimulation of an existing, endogenous repair system in the peripheral and central nervous systems. The abundant protein repulsive guidance molecule A blocks restoration and neurogenesis, both of which are mediated via the neogenin receptor. Inhibition of the physiological effects of repulsive guidance molecule A is an endogenous available repair pathway in chronic neurodegeneration. Antagonism of this protein with antibodies or stimulation of the neogenin receptor should be considered as an initial repair step. It is an alternative to cell replacement, stem cell or associated cell secretome concepts.

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Section: Cure or Disease Modification By Dopamine Generating Cell Transplants?mentioning

confidence: 99%

“…Future continuous, subcutaneous L-dopa delivery to the brain by pump devices will improve this still popular issue of motor fluctuations considerably. 18 …”

Section: Introduction To Parkinson’s Diseasementioning

confidence: 99%

View Point: Disease Modification and Cell Secretome Based Approaches in Parkinson’s Disease: Are We on the Right Track?

Müller¹

2021

BTT

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“…New formulations in clinical trials currently include inhaled (CVT‐301) (Lipp, Batycky, Moore, Leinonen, & Freed, ) for management of “OFF‐phase” and liquid for subcutaneous administration (ND0612) as a patch‐pump. ND0612 is being developed for moderate and severe disease and could produce much improved control of plasma L‐DOPA levels and therefore dyskinesia (Freitas, Ruiz‐Lopez, & Fox, ; Ramot et al., ).…”

Section: The Future Of L‐dopamentioning

confidence: 99%

L‐DOPA for Parkinson's disease—a bittersweet pill

Lane

2018

Eur J of Neuroscience

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3,4-dihydroxy-L-phenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long-term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L-DOPA-induced dyskinesia. Being unsurpassed as a therapy means that understanding the mechanisms of dyskinesia priming and induction is vital to the search for therapies to treat these side effects and allow optimal use of L-DOPA. However, L-DOPA use may also have consequences (positive or negative) for the development of other interventions, such as cell transplantation, which are designed to treat or repair the ailing brain. This review looks at the issues around the use of L-DOPA with a focus on its potential impact on advanced reparative interventions.

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“…15,16 The future availability of subcutaneous l-dopa/DDC-I pump systems will noticeably reduce the issue of l-dopa associated fluctuations with related disturbances of motor-and nonmotor behavior in PD. 9,17 However, chronic L-dopa therapy has further still under recognized metabolic drawbacks. Only DDC constraint decreases the physiologic methylation potential, since L-dopa is consequently metabolized via COMT mainly.…”

Section: Introductionmentioning

confidence: 99%

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

Müller¹

2021

JEP

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Parkinson's disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa-and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.

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Ninety-day Local Tolerability and Toxicity Study of ND0612, a Novel Formulation of Levodopa/Carbidopa, Administered by Subcutaneous Continuous Infusion in Minipigs

Cited by 27 publications

References 18 publications

View Point: Disease Modification and Cell Secretome Based Approaches in Parkinson’s Disease: Are We on the Right Track?

View Point: Disease Modification and Cell Secretome Based Approaches in Parkinson’s Disease: Are We on the Right Track?

L‐DOPA for Parkinson's disease—a bittersweet pill

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

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