Safety and pharmacokinetics of multiple dosing with inhalable apomorphine (AZ-009), and its efficacy in a randomized crossover study in Parkinson's disease patients

Thijssen, Eva; Heijer, Jonas M. den; Puibert, David; Brummelen, Emilie M.J. van; Naranda, Tatjana; Groeneveld, Geert Jan

doi:10.1016/j.parkreldis.2022.02.014

Cited by 7 publications

(11 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). Apomorphine administration was: subcutaneous in 29 (50.0%), 5, sublingual in 14 (24.1%), [43][44][45][46][47][48][49][50][51][52][53][54][55][56] intranasal in 6 (10.3%), [57][58][59][60][61][62] inhaled in 5 (8.6%), [63][64][65][66][67] rectal in 3 (5.2%), [68][69][70] and transdermal in 1 (1.7%). 71 54 studies were interventional, most non-randomized open label (33,61.1%), and without control group (25, 46.3%).…”

Section: Resultsmentioning

confidence: 99%

“…Five randomized controlled trials [63][64][65][66][67] demonstrated good motor improvement 63,[65][66][67] and off period reversal 63,64 when compared to placebo. Doses ranged between 1.5 to 4.0 mg, with a mean effective dose to achieve the On state of 2.6 mg. [63][64][65][66][67] Latency of effect ranged between 10 and 13 minutes, and duration between 10 and 77 minutes. [63][64][65] Four studies used domperidone (20 mg t.i.d.)…”

Section: Inhaled Apomorphinementioning

confidence: 99%

“…48 to 72 hours prior to apomorphine administration. [64][65][66][67] Aside from yawning (3.1%-28.6%) and hypotension (3%-5%) no other consistent side effects were observed. [59][60][61] However, in the most recent trials, nearly all patients receiving inhaled apomorphine developed local side effects, namely coughing and throat irritation.…”

Section: Inhaled Apomorphinementioning

confidence: 99%

“…[59][60][61] However, in the most recent trials, nearly all patients receiving inhaled apomorphine developed local side effects, namely coughing and throat irritation. 66,67 Rectal Apomorphine Rectal administration of apomorphine was explored in the 1990s in three studies, two from the Netherlands 69,70 and one from the UK. 68 One used an apomorphine 200 mg suppository, 68 another used a 10 mg/mL solution, 69 and the third one compared apomorphine 10 mg/mL solution, two gelatin-based (25 and 50 mg) and two lipid-based (50 and 100 mg) suppositories.…”

Section: Inhaled Apomorphinementioning

confidence: 99%

See 3 more Smart Citations

Intermittent Apomorphine Use for off Period Rescue in Parkinson's Disease: A Pragmatic Review of over Three Decades of Clinical Experience

Castillo‐Torres¹,

Lees

Merello

2022

Movement Disord Clin Pract

View full text Add to dashboard Cite

Background Although proven very efficacious as treatment for Parkinson's disease by Schwab as far back as the 1950s, and later confirmed by Cotzias and colleagues in the early 1970s, use of intermittent subcutaneous injections of the dopamine agonist apomorphine remains limited worldwide. Objectives To review evidence regarding use of intermittent, on‐demand apomorphine as a treatment for off‐period disability in Parkinson's disease. Methods A PRISMA‐compliant structured literature search was carried out with a focus on clinical effect (motor improvement, daily off time decrease; latency, duration), antiemetic prophylaxis, and adverse events. Results Fifty‐eight studies were evaluated. Apomorphine administration route was subcutaneous in 29 (50%), sublingual in 14 (24.1%), intranasal in 6 (10.3%), inhaled in 5 (8.6%), rectal in 3 (5.2%) and transdermal in 1 (1.7%). Irrespective of the route, motor disability improved 19% to 74% and daily off time decreased 3% to 68%, with subcutaneous having the fastest onset of action ranging from 6 to 24 minutes and lasting 28 to 96 minutes. Antiemetic prophylaxis was used in almost all studies. Systemic side effects like nausea and yawning were mild and well tolerated, but sedation led to discontinuation of subcutaneous apomorphine in 5.5%. Local side effects to subcutaneous administration did not result in discontinuation. Stomatitis with the early sublingual formulations led to discontinuation in nearly half of patients and was reduced to 16.7% with novel film strips. Conclusions Intermittent subcutaneous injections remain the most reliable and safest route of apomorphine administration, with an efficacy for off period treatment supported by nearly four decades of clinical experience.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Inhaled Apomorphinementioning

confidence: 99%

Section: Inhaled Apomorphinementioning

confidence: 99%

Section: Inhaled Apomorphinementioning

confidence: 99%

See 2 more Smart Citations

Intermittent Apomorphine Use for off Period Rescue in Parkinson's Disease: A Pragmatic Review of over Three Decades of Clinical Experience

Castillo‐Torres¹,

Lees

Merello

2022

Movement Disord Clin Pract

View full text Add to dashboard Cite

show abstract

“…However, attempts to further improve the latency to ON with apomorphine have led to the development of AZ-009, an inhaled formulation that is rapidly systemically absorbed with a median Tmax of 1–2 minutes, and with early evidence for clinical efficacy in successfully treating morning OFF amongst PD patients. 95 , 96…”

Section: Rescue Therapiesmentioning

confidence: 99%

Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

Masood

Jimenez-Shahed

2023

NDT

View full text Add to dashboard Cite

Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.

show abstract

Research progress on intranasal treatment for Parkinson's disease

Wen,

Ren

2024

Neuroprotection

View full text Add to dashboard Cite

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally, significantly affecting the quality of life of affected individuals. Systemic drug delivery to the brain is inefficient because of first‐pass metabolism, the blood‐brain barrier (BBB), and the blood‐cerebrospinal fluid barrier. This inefficiency necessitates increased dosage as the disease progresses, leading to severe side effects that compromise the efficacy of the medication. Nose‐to‐brain (N2B) administration bypasses the BBB, allowing delivery of both small molecules and large protein substances to the central nervous system. Compared with systemic administration, this method enhances brain bioavailability, reduces enzymatic degradation, and minimizes systemic adverse reactions. However, the N2B delivery system is associated with several critical challenges, including mucociliary clearance, enzymatic degradation, and drug translocation via efflux mechanisms. This paper provides a comprehensive overview of the current research progress in intranasal treatment of PD, considering both preclinical and clinical studies, and discusses the physiological aspects and limitations of its delivery system.

show abstract

Safety and pharmacokinetics of multiple dosing with inhalable apomorphine (AZ-009), and its efficacy in a randomized crossover study in Parkinson's disease patients

Cited by 7 publications

References 36 publications

Intermittent Apomorphine Use for off Period Rescue in Parkinson's Disease: A Pragmatic Review of over Three Decades of Clinical Experience

Intermittent Apomorphine Use for off Period Rescue in Parkinson's Disease: A Pragmatic Review of over Three Decades of Clinical Experience

Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

Research progress on intranasal treatment for Parkinson's disease

Contact Info

Product

Resources

About