Brasofensine Treatment for Parkinson's Disease in Combination with Levodopa/Carbidopa

Frackiewicz, Edyta J; Jhee, Stanford; Shiovitz, Thomas; Webster, Jonathan; Topham, Christine; Dockens, Randy C.; Whigan, Daisy B.; Salazar, Daniel E.; Cutler, Neal R.

doi:10.1345/aph.1a152

Cited by 25 publications

(23 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the primary role of brasofensine is to conserve the greatly reduced level of endogenous dopamine within the synaptic cleft and also to extend the potency and duration of action of exogenous dopamine from the administration of levodopa. This appears to be true in a marmoset model of Parkinson's disease (Pearce et al, 2002) but has not yet been shown in the clinic (Frackiewicz et al, 2002).…”

mentioning

confidence: 88%

Disposition and Metabolism of [¹⁴C]Brasofensine in Rats, Monkeys, and Humans

Zhu

Whigan²,

Chang³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Brasofensine is an inhibitor of the synaptic dopamine transporter. These studies were conducted to characterize the pharmacokinetics, absolute bioavailability, disposition, and metabolism of brasofensine after i. Some of the desmethyl metabolites were further converted to glucuronides. These primary metabolites and glucuronides of demethyl brasofensine (M1 and M2) were major circulating metabolites in humans and were also observed in rat and monkey plasma.

show abstract

mentioning

confidence: 88%

Disposition and Metabolism of [¹⁴C]Brasofensine in Rats, Monkeys, and Humans

Zhu

Whigan²,

Chang³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…In a small escalating-dose study, brasofensine did not enhance L-DOPA antiparkinsonian action and did not alter L-DOPA-induced dyskinesia severity (Archibald, 2000;Cutler et al, 2000;Frackiewicz et al, 2002). In a phase II trial, the administration of brasofensine as monotherapy to patients with recently diagnosed PD initially improved parkinsonism, but the improvement was not maintained after 2 weeks (Yu, 2000).…”

Section: Dual Dat and Nat Inhibitorsmentioning

confidence: 99%

“…It seems likely that they have potential to supply antiparkinsonian benefits as monotherapy and in some situations, at least, can enhance L-DOPA benefits, although this might be at the expense of exacerbating dyskinesia. Interestingly, methylphenidate improved speed of movement without extending on-time duration, suggesting that dual DAT/NAT inhibitors (Singh, 2000) Undisclosed None Antiparkinsonian action as monotherapy (Pearce et al, 1995) No effect on L-DOPA antiparkinsonian action (Archibald, 2000;Cutler et al, 2000;Frackiewicz et al, 2002) Does not elicit dyskinesia as monotherapy (Pearce et al, 1995) No effect on L-DOPA-induced dyskinesia severity (Archibald, 2000;Cutler et al, 2000;Frackiewicz et al, 2002) Enhances the antiparkinsonian action of low-dose L-DOPA (Moldt et al, 1998;Pearce et al, 2002) Transient antiparkinsonian benefit as monotherapy (Yu, 2000) Not tested in combination with high-dose L-DOPA in primed, dyskinetic parkinsonian monkeys BTS-74,398 DAT = NAT = SERT (Cheetham et al, 1998) Undisclosed None Antiparkinsonian action as monotherapy (Hansard et al, 2002b(Hansard et al, , 2004 n/a …”

Section: Dual Dat and Nat Inhibitorsmentioning

confidence: 99%

Dopamine Reuptake Inhibitors in Parkinsons Disease: A Review of Nonhuman Primate Studies and Clinical Trials

Fox

Brotchie

2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Striatal dopamine deficiency is the core feature of the pathology of Parkinson's disease (PD), and dopamine replacement with L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay of PD treatment. Unfortunately, chronic L-DOPA administration is marred by the emergence of dyskinesia and wearing-off. Alternatives to L-DOPA for alleviation of parkinsonism are of interest, although none can match the efficacy of L-DOPA to date. Catechol-O-methyltransferase and monoamine oxidase inhibitors are currently used to alleviate wearing-off, but they do not increase "on-time" without exacerbating dyskinesia. Alternate approaches to dopamine replacement in parkinsonism generally (and to wearing-off and dyskinesia, specifically) are therefore urgently needed. Inasmuch as they increase synaptic dopamine levels, dopamine transporter (DAT) inhibitors, whether they are selective or have actions on noradrenaline or serotonin transporters, theoretically represent an attractive way to alleviate parkinsonism per se and potentially enhance L-DOPA antiparkinsonian action (provided that sufficient dopamine terminals remain within the striatum). Several nonhuman primate studies and clinical trials have been performed to evaluate the potential of DAT inhibitors for PD. In this article, we review nonhuman primate studies and clinical trials, we summarize the current knowledge of DAT inhibitors in PD, and we propose a hypothesis as to how tailoring the selectivity of DAT inhibitors might maximize the benefits of DAT inhibition in PD.

show abstract

“…For example, a new class of drugs (monoamine uptake inhibitors) that had produced promising results in MPTP-treated nonhuman primate models resulted in only a very limited level of functional improvement and a high incidence of side effects when tested in humans for the first time. 39 In this way, inconsistencies between animal models of Parkinson's disease and the human condition make it particularly difficult to accurately predict both the potential risks and the potential efficacy during first-in-human trials.…”

Section: The Translational Gap: Moving From Bench and Beast To Bedsidementioning

confidence: 99%

Uncertain Translation, Uncertain Benefit and Uncertain Risk: Ethical Challenges Facing First‐in‐human Trials of Induced Pluripotent Stem (Ips) Cells

Fung

Kerridge

2011

Bioethics

View full text Add to dashboard Cite

The discovery of induced pluripotent stem (iPS) cells in 2006 was heralded as a major breakthrough in stem cell research. Since then, progress in iPS cell technology has paved the way towards clinical application, particularly cell replacement therapy, which has refueled debate on the ethics of stem cell research. However, much of the discourse has focused on questions of moral status and potentiality, overlooking the ethical issues which are introduced by the clinical testing of iPS cell replacement therapy. First-in-human trials, in particular, raise a number of ethical concerns including informed consent, subject recruitment and harm minimisation as well as the inherent uncertainty and risks which are involved in testing medical procedures on humans for the first time. These issues, while a feature of any human research, become more complex in the case of iPS cell therapy, given the seriousness of the potential risks, the unreliability of available animal models, the vulnerability of the target patient group, and the high stakes of such an intensely public area of science. Our paper will present a detailed case study of iPS cell replacement therapy for Parkinson's disease to highlight these broader ethical and epistemological concerns. If we accept that iPS cell technology is fraught with challenges which go far beyond merely refuting the potentiality of the stem cell line, we conclude that iPS cell research should not replace, but proceed alongside embryonic and adult somatic stem cell research to promote cross-fertilisation of knowledge and better clinical outcomes.

show abstract

Brasofensine Treatment for Parkinson's Disease in Combination with Levodopa/Carbidopa

Abstract: Brasofensine was safe and well tolerated in the patient cohort studied at daily doses of up to 4 mg. Adverse events were generally mild in intensity, and included headache, insomnia, phlebitis, dizziness, ecchymosis, and vomiting.

Cited by 25 publications

References 17 publications

Disposition and Metabolism of [¹⁴C]Brasofensine in Rats, Monkeys, and Humans

Disposition and Metabolism of [¹⁴C]Brasofensine in Rats, Monkeys, and Humans

Dopamine Reuptake Inhibitors in Parkinsons Disease: A Review of Nonhuman Primate Studies and Clinical Trials

Uncertain Translation, Uncertain Benefit and Uncertain Risk: Ethical Challenges Facing First‐in‐human Trials of Induced Pluripotent Stem (Ips) Cells

Contact Info

Product

Resources

About

Brasofensine Treatment for Parkinson's Disease in Combination with Levodopa/Carbidopa

Abstract: Brasofensine was safe and well tolerated in the patient cohort studied at daily doses of up to 4 mg. Adverse events were generally mild in intensity, and included headache, insomnia, phlebitis, dizziness, ecchymosis, and vomiting.

Cited by 25 publications

References 17 publications

Disposition and Metabolism of [14C]Brasofensine in Rats, Monkeys, and Humans

Disposition and Metabolism of [14C]Brasofensine in Rats, Monkeys, and Humans

Dopamine Reuptake Inhibitors in Parkinsons Disease: A Review of Nonhuman Primate Studies and Clinical Trials

Uncertain Translation, Uncertain Benefit and Uncertain Risk: Ethical Challenges Facing First‐in‐human Trials of Induced Pluripotent Stem (Ips) Cells

Contact Info

Product

Resources

About

Disposition and Metabolism of [¹⁴C]Brasofensine in Rats, Monkeys, and Humans

Disposition and Metabolism of [¹⁴C]Brasofensine in Rats, Monkeys, and Humans