Emerging therapies for Parkinson's disease: From bench to bedside

Tarazi, Frank I.; Sahli, Zeyad T.; Wolny, Martin; Mousa, Shaker A.

doi:10.1016/j.pharmthera.2014.05.010

Cited by 89 publications

(83 citation statements)

References 194 publications

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“…Deep brain stimulation is one of the surgical approaches that involve implantation of CT/MRI guided electrodes in the subthalamic nucleus or in the globus pallidus. The impulse generator creates electrical stimulation affecting the firing pattern of neurons in the implanted area along with the release of neurotransmitters glutamate and adenosine and improves the motor symptoms in PD with neurogenesis in addition to causing an increased blood circulation in the stimulated regions [51]. Several studies have reported that deep brain stimulation as an adjuvant with pharmacotherapy showed significant improvements in patient daily activities and quality of life by reducing motor disability, levodopa induced motor fluctuations [52].…”

Section: Neurostimulation By Surgical Approachesmentioning

confidence: 99%

Nanotechnology platforms in Parkinson’s Disease

2015

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Parkinson's disease (PD) remains a serious concern due to its effects on the quality of life of patients and its socioeconomic burden to society. Present day management of PD has limitations in both diagnosis and treatment. Nanotechnology may provide smart solutions to this problem. The present review highlights the recent advancements in the development of nanotechnology platforms for PD. The review focuses on the use of such platforms in diagnostics, treatments, deep brain stimulation, neurosurgery and other

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Section: Neurostimulation By Surgical Approachesmentioning

confidence: 99%

Nanotechnology platforms in Parkinson’s Disease

2015

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“…Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on their medical history and an extensive neurological and physical examination. The diagnosis is likely when two out of the four cardinal symptoms of PD (tremor, rigidity, akinesia and postural inestability) are present [146], implying that the diagnosis is made only many years after the real onset of the neurodegenerative process [224]. As it was already discussed in the previous section (3.6 Progression) could be up to 10 years after the onset of the disease.…”

Section: Diagnosis Clinical Examination and Managementmentioning

confidence: 92%

“…The genetic approach has been largely explored, Alpha-Nuclein or PARK1, Parkin or PARK2, ubiquitin carboxy terminal hydrolase-L1 or UCHL1, DJ-1 or PARK7 and NR4A2 are some of the known genes involved in PD [142]. For example, autosomal recessive inheritance linked to the PARKIN gene has been reported in a large number of early-onset [146]. Nevertheless, hereditary factors play a minimal role because only 10% of all PD cases are found to have genetic links involved, and these are most closely associated with early-onset PD [146].…”

Section: Causesmentioning

confidence: 99%

“…For example, autosomal recessive inheritance linked to the PARKIN gene has been reported in a large number of early-onset [146]. Nevertheless, hereditary factors play a minimal role because only 10% of all PD cases are found to have genetic links involved, and these are most closely associated with early-onset PD [146]. Other suspected causes include environmental toxins (such as pesticides), medications, and viruses that all result in an increase in oxidative stress (which leads to generation of free radicals, which induces apoptotic cell death in dopamine neurons) [146].…”

Section: Causesmentioning

confidence: 99%

“…Equally, there are many causes for having a tremor apart from Parkinson's disease. PD is typically presented in a sporadic idiopathic fashion [146] and its cardinal signs are resting tremor, muscle rigidity, loss of spontaneous movements (i.e. bradykinesia and akinesia) and impaired posture, balance and gait disturbances [147].…”

Section: Introductionmentioning

confidence: 99%

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A holistic approach to assess the feasability of telehealth for Parkinson's disease management

González¹

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Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease

Jankovic

Goodman

Safirstein³

et al. 2018

JAMA Neurol

233

189

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IMPORTANCE Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression. OBJECTIVE To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). INTERVENTIONS Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. MAIN OUTCOMES AND MEASURES Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. RESULTS Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose-and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F 78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. CONCLUSIONS AND RELEVANCE Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149).

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Emerging therapies for Parkinson's disease: From bench to bedside

Cited by 89 publications

References 194 publications

Nanotechnology platforms in Parkinson’s Disease

Nanotechnology platforms in Parkinson’s Disease

A holistic approach to assess the feasability of telehealth for Parkinson's disease management

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease

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