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Pharmacological Insights into the Use of Apomorphine in Parkinson’s Disease: Clinical Relevance
Abstract
The present paper consists of a comprehensive review of the literature on apomorphine pharmacological properties and its usefulness in Parkinson’s disease (PD). The chemistry, structure–activity relationship, pharmacokinetics and pharmacodynamics of apomorphine are described with regard to its effects on PD symptoms, drug interactions, interindividual variability and adverse events. Apomorphine chemical structure accounts for most of its beneficial and deleterious properties, both dopaminergic and non-dopaminergic. Its pharmacokinetics and pharmacodynamics are complex and subject to interindividual variability, particularly for subcutaneous absorption and metabolism. Subcutaneous apomorphine, either as injections or infusion, is particularly useful for the treatment of PD motor symptoms and growing evidence supports its clinical value for nonmotor disorders. Owing to interindividual variability and sensitivity, apomorphine treatment must be tailored to each patient. While the subcutaneous route has been the gold standard for decades, the search for alternative routes is ongoing, with promising results from studies of pulmonary, sublingual and transdermal routes. In addition, the potential of apomorphine as a disease-modifying therapy deserves to be investigated, as well as its ability to induce brain plasticity through chronic infusion. Moreover, the ongoing progress in the development of analytical methods should be accompanied by new pharmacokinetic and pharmacodynamic studies of apomorphine metabolism and sites of action in humans, as its biochemistry has yet to be fully described.
... Benzillizokinolin alkoloid sınıfına ait aporfin alkoloididir. [3] Parkinson hastalığında etkili olduğu ilk kez Schwab ve ark. [4] tarafından bildirilmiştir. ...
... Non-enzimatik yollar ile 37°C, Ph 7.4'deki solüsyonlarda, ışıkta ve O 2 varlığında okside olur. [3] d) eliminasyon: Çoğunlukla karaciğerde metabolize olur ve idrarla atılır, ancak %5 kadarı idrardan değişmeden atılır. Yaş, cinsiyet, ağırlık, tedavi süresi eliminasyonu etkilemez. ...
... Yaş, cinsiyet, ağırlık, tedavi süresi eliminasyonu etkilemez. [3,16] Renal ve hepatik yetmezliği olanlarda dikkatli kullanılması gerekir. etkİlerİ Dopamine çok benzer ve nonselektif olarak tüm D1 benzeri (D1, D5) ve D2 benzeri (D2, D3, D4) reseptörleri uyarır. ...
... Intravenous Administration of APO Mean (±SEM) APO plasma concentration vs. time following intravenous administration is shown in Fig. 2 (a). Pharmacokinetic parameters were calculated from the obtained plot and compared to human as described in literature 27,30,31 (Table 1). Volume of distribution and CL in pigs were found to be approximately threefold higher than in human. ...
... The latter two are products of direct Phase II metabolism. 31 Quantification was not performed for peak areas from the chromatogram due to the lack of standards. Therefore, only a plot of profile trends as a function of time was attained. ...
... Furthermore, this issue does not raise concern in clinical setup when APO is administered subcutaneously, even though its metabolism in humans is almost full with an unchanged urinal excretion of less than 4%. 31 Nevertheless, while Phase II metabolism of APO following subcutaneous administration occurs mainly in the liver, with buccal administration there is a possibility of metabolism in the buccal mucosa before APO reaches the blood circulation. [34][35][36][37][38][39] As will be further discussed, 55e80% of the dose released from the ABPD reached blood circulation. ...
In the current work, prolonged systemic delivery of apomorphine via buccal mucosa was shown to be a promising treatment for Parkinson`s disease as a substitute for clinically utilized subcutaneous infusions. Due to extensive ‘first-pass’ metabolism, apomorphine is administered parenterally to bypass liver metabolism. Drawbacks of parenteral administration cause low patient compliance and adherence to treatment. On the other hand, while also bypassing the liver, delivery through buccal mucosa has a superior safety profile, is less costly, lacks pain and discomfort, and possesses excellent accessibility, overall augmenting patient compliance. Current in vivo study in pigs showed: (1) steady plateau levels of apomorphine in plasma were obtained 30 min following administration and remained constant for eight hours until a delivery device was removed, (2) bioavailability of apomorphine was 55%-80% as opposed to <2% peroral and (3) simulation of the pharmacokinetic profile obtained in pigs predicted therapeutically relevant levels of apomorphine in human. Furthermore, antipyrine was incorporated as a permeation marker to enable mechanistic investigation of apomorphine release from the delivery device and its permeation through the buccal mucosa. In addition, limitations of an Ussing diffusion chamber as an ex vivo research tool were also discussed.
... Since its use in clinical practice 30 years ago, apomorphine has never generated as much interest until the present time with the emergence of new delivery formulations including sublingual, subcutaneous infusion and inhaled presentations [36]. Apomorphine is a potent non-ergoline dopamine receptor agonist with very high D2, D3, and D4 affinity [37]. ...
... It is absorbed entirely from the subcutaneous tissue with a bioavailability of 100% [37]. For many years apomorphine has been used as an intermittent, self-administered subcutaneous injection, as a rescue therapy for the rapid relief of motor fluctuations [36]. Overall, apomorphine has generally been viewed as a drug with a shorter duration of effect compared to LD, but with the same quality of motor response [36]. ...
... For many years apomorphine has been used as an intermittent, self-administered subcutaneous injection, as a rescue therapy for the rapid relief of motor fluctuations [36]. Overall, apomorphine has generally been viewed as a drug with a shorter duration of effect compared to LD, but with the same quality of motor response [36]. ...
Significant advances in the symptomatic treatment of Parkinson disease (PD) have occurred since the discovery of levodopa (LD). Perhaps as a testament to its unparalleled efficacy, novel formulations aiming to optimize LD delivery to obtain better bioavailability, longer duration of effect and less plasma level fluctuations remain a major focus of drug development, nearly 5 decades since it was first commercially used. In addition, alternative apomorphine delivery formulations are also in development to provide rapid-acting, needle-free agents for the management of “off” episodes in patients experiencing motor fluctuations. “Non-dopaminergic” approaches have also emerged as promising treatments targeting different pathways to enhance the modulation of dopaminergic and neuroprotective mechanisms. This paper focuses on reviewing the evidence on the latest advances in non-surgical, symptomatic motor PD treatment.
... The definition of advanced PD is not only an academic exercise but also has various practical implications. There are three device-aided therapies available and generally considered as options for this stage of disease: deep brain stimulation (DBS) [2,3], continuous subcutaneous apomorphine infusion (APO) [4,5], and intrajejunal levodopa infusion [6,7]. Some more are in the experimental phase [8]. ...
... All patients with advanced PD (defined as the first-line therapy insufficient to provide good motor control) attending the Movement Disorder Unit over 12 years, from February 2006 to June 2018, and treated with DBS and APO were included in the analysis. Eligibility criteria for DBS treatment were based on the Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease (CAPSIT-PD) [9] with some modifications: (1) advanced stage PD, (2) disease duration over 5 years, (3) reduction in Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores over 50% after levodopa (LD) trial or apomorphine challenge test, (4) age below 71 years, (5) magnetic resonance imaging with no significant vascular damage or structural abnormalities, (6) absence of significant cognitive decline according to selected neuropsychological scales, (7) lack of serious psychiatric conditions, except drug-induced psychosis, (8) absence of on-time major gait problems, (9) good general health, and (10) realistic expectations. ...
... Besides, dyskinesias did not change in the study after APO but improved after DBS. This observation matches the previous data, which have shown variable effects of APO on dyskinesia [5,11,18], but a quite favourable effect of DBS [18,23]. Therefore, using this regimen (APO before DBS), we can provide patients with better disease control in the months before surgery. ...
Introduction
Deep brain stimulation (DBS) is an effective therapy for patients with advanced Parkinson’s disease (PD). However, sometimes, it is not sufficient to adequately control motor symptoms. We describe our experience with continuous subcutaneous apomorphine infusion (APO) in patients with DBS.
Methods
We undertook a retrospective analysis of all patients treated with DBS and APO at our centre over 12 years. Subjects were allocated to four groups: (1) APO temporarily before DBS, (2) APO after DBS complications before a new DBS, (3) APO after definitive DBS removal, and (4) APO in patients with DBS and declining response. Motor state and other parameters were analysed and compared for the different treatments.
Results
Data for 71 patients were evaluated. Group 1: (n = 18) patients improved their motor function significantly with both APO and DBS (off-hours before APO 5.4 ± 1.4; after APO 1.4 ± 1.2, p > 0.001; after DBS 0.7 ± 0.8, p < 0.001). Group 2: (n = 11) patients were found to have mild but significant worsening of motor state between the first DBS treatment (off-hours 0.7 ± 1.0) and APO (2.2 ± 1.5, p = 0.02), and improvement between APO and the second DBS treatment (off-hours 0.6 ± 0.8, p = 0.03). Group 3: (n = 12) patients had mild but significant worsening of motor function between DBS (off-hours 1.1 ± 1.0) and APO (2.0 ± 0.9, p = 0.03). Group 4: (n = 13) significant improvement in motor function was observed between DBS alone (off-hours 3.9 ± 2.6) and DBS combined with APO (2.2 ± 1.3, p = 0.03).
Conclusion
In advanced PD, DBS may be not sufficient or may fail to control motor symptoms adequately. In these cases, APO, whether alone or in combination with DBS, is a good choice to improve the disease control.
... This target-centered approach of a drug previously known as an emetic can therefore be considered as the first major repositioning of apomorphine. However, the rich empirical history, complex pharmacological profile and pleiotropic biological functions of this 150-year old drug (Ribarič, 2012;Auffret et al., 2018b) suggest further therapeutic and diagnostic applications. To investigate its full potential, we conducted a review of https://doi.org/10.1016/j.ejphar.2018.10.052 ...
... Apomorphine (C 17 H 17 NO 2 ) is an aporphine alkaloid derived from morphine, with a number of pharmacological targets, excluding opioid receptors (Ribarič, 2012;Schulze et al., 2013;Auffret et al., 2018b). The mechanistic underpinning its pleiotropic biological functions is both dopaminergic and non-dopaminergic (Ribarič, 2012;Auffret et al., 2018b). ...
... Apomorphine (C 17 H 17 NO 2 ) is an aporphine alkaloid derived from morphine, with a number of pharmacological targets, excluding opioid receptors (Ribarič, 2012;Schulze et al., 2013;Auffret et al., 2018b). The mechanistic underpinning its pleiotropic biological functions is both dopaminergic and non-dopaminergic (Ribarič, 2012;Auffret et al., 2018b). The semirigid and polycyclic structure ( Fig. 1) accounts for the dopaminergic activity (catechol moiety) and the rapid crossing of the blood-brain-barrier (lipophilicity). ...
Apomorphine is a 150-year old nonspecific dopaminergic agonist, currently indicated for treating motor fluctuations in Parkinson's disease. At the era of drug repurposing, its pleiotropic biological functions suggest other possible uses. To further explore new therapeutic and diagnostic applications, the available literature up to July 2018 was reviewed using the PubMed and Google Scholar databases. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn, to give a broad overview of the potential of apomorphine. Apomorphine may play a role in neurological diseases like restless legs syndrome, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease and disorders of consciousness, but also in sexual disorders, neuroleptic malignant(-like) syndrome and cancer. Further work is needed in both basic and clinical research; current developments in novel delivery strategies and apomorphine derivatives are expected to open the way.
... The same ranking, with CSAI as the least used DAT, is found in most countries (Ezat et al. 2017;Richter et al. 2019;Henriksen et al. 2020;Nordin et al. 2021;Thaler et al. 2022). Of note, CSAI remains unavailable in many countries, including the United States of America 1 and Japan (Auffret et al. 2018;Fasano et al. 2022;Fujioka et al. 2023). Although specialised clinical settings (including access to neurosurgery/gastroenterologist) are needed for DBS and LCIG/LECIG implementation (Richter et al. 2019;Henriksen et al. 2020), it is not the case for CSAI, which is considered as the easiest DAT to implement . ...
... Although specialised clinical settings (including access to neurosurgery/gastroenterologist) are needed for DBS and LCIG/LECIG implementation (Richter et al. 2019;Henriksen et al. 2020), it is not the case for CSAI, which is considered as the easiest DAT to implement . This striking lack of access to CSAI is, therefore, concerning, given its ease of initiation (minimally invasive, completely reversible, and no need of any kind of surgery), its strongly established efficacy on PD motor and nonmotor symptoms, and its good safety profile (Auffret et al. 2018;Katzenschlager et al. 2018Katzenschlager et al. , 2021De Cock et al. 2022). LECIG has still limited data regarding its rate of implementation and repartition at the time of our writing, being a very recent addition to DAT therapies (Nyholm and Jost 2022). ...
Device-aided therapies (DAT), which include deep brain stimulation and pump-based continuous dopaminergic stimulation with either levodopa or apomorphine, are among the major advances in the clinical management of Parkinson’s disease (PD). Although DAT are being increasingly offered earlier in the disease course, their classical indication remains advanced PD. Theoretically, every patient should be offered transition to DAT when faced with refractory motor and nonmotor fluctuations and functional decline. Worldwide clinical reality is far from these ideal, and, therefore, question the “real-world” equal opportunity of access to DAT for PD patients with advanced PD—even within a single health care system. Differences in access to care, referral pattern (timing and frequency), as well as physician biases (unconscious/implicit or conscious/explicit bias), and patients’ preferences or health-seeking behaviour are to be considered. Compared to DBS, little information is available concerning infusion therapies, as well as neurologists’ and patients’ attitudes towards them. This viewpoint aims to be thought-provoking and to assist clinicians in moving through the process of DAT selection, by including in their decision algorithm their own biases, patient perspective, ethical concerns as well as the current unknowns surrounding PD prognosis and DAT-related long-term side effects for a given patient.
... Apo acts as a potent D1 and D2 receptor agonist that can enter the brain and accumulates in the striatum, displaying antiparkinsonian properties similar to those of levodopa [16]. Like other catechols, Apo is reported to exhibit cytotoxicity due to the oxidative damage triggered by some degradation products from its spontaneous oxidation, which leads to the production of reactive oxygen species (ROS), quinones, semiquinones, and melanin-like polymers in neutral and alkaline solution [17,18]. ...
... In clinical practice, levodopa therapy remains the first choice of treatment for PD and Apo is utilized as a rescue medication in late stages of the disease, being the only drug with efficacy comparable to that of levodopa [46,47]. However, as reported for levodopa, beneficial response to Apo does not last long [16] and motor impairments become gradually worse in most PD patients, which is thought to be due to a druginduced desensitization of dopaminergic receptors or aggravation of the loss of dopaminergic neurons [48]. Apo is known for its instability in aqueous solution in which it rapidly undergoes spontaneous decomposition to form oxidative quinone derivatives. ...
The misfolding and aggregation of the protein α-synuclein (aSyn) into potentially neurotoxic oligomers is believed to play a pivotal role in the neuropathogenesis of Parkinson's disease (PD). Herein we explore how apomorphine (Apo), a nonselective dopamine D1 and D2 receptor agonist utilized in the therapy for PD, affects the aggregation and toxicity of aSyn in vitro. Our data indicated that Apo inhibits aSyn fibrillation leading to the formation of large oligomeric species (Apo-aSyn-O), which exhibit remarkable toxicity on mesencephalic dopaminergic neurons in primary cultures. Interestingly, purified Apo-aSyn-O, even at very low concentrations, seems to be capable of converting unmodified aSyn monomer into neurotoxic species. Collectively, our findings warn for a possible dangerous effect of Apo on aSyn misfolding/aggregation pathway.
... If conflicting results are found on the neuropsychiatric effect of apomorphine, growing evidence tends to suggest that it is safe, and could even be beneficial for mood and apathy [59,159], as well as induce a decrease in visual hallucinations [182][183][184] caused by visual problems [183,185], possibly through an action on the serotonin 2 A receptor [183]. Further work is needed to better understand this phenomenon. ...
... Apomorphine is a remarkable example of an old drug being rediscovered. Its peculiar pharmacological profile (nonspecific dopaminergic and nondopaminergic agonist [58,59]) has made it one of the most intensively studied drugs, and it can be safely assumed that apomorphine will continue to intrigue scientists and clinicians in years to come. Thanks to technical and galenic development, it is destined to become a key feature of future therapeutic strategies, and rightly so. ...
Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with advanced Parkinson’s disease (PD) with motor fluctuations. However, its history is far from being limited to movement disorders. This paper traces the history of apomorphine, from its earliest empirical use, to its synthesis, pharmacological development, and numerous indications in human and veterinary medicine, in light of its most recent uses and newest challenges. From shamanic rituals in ancient Egypt and Mesoamerica, to the treatment of erectile dysfunction, from being discarded as a pharmacological tool to becoming an essential antiparkinsonian drug, the path of apomorphine in the therapeutic armamentarium has been tortuous and punctuated by setbacks and groundbreaking discoveries. Throughout history, three main clinical indications stood out: emetic (gastric emptying, respiratory disorders, aversive conditioning), sedative (mental disorders, clinical anesthesia, alcoholism), and antiparkinsonian (fluctuations). New indications may arise in the future, both in PD (palliative care, nonmotor symptoms, withdrawal of oral dopaminergic medication), and outside PD, with promising work in neuroprotection or addiction.
... The role of the concomitant domperidone as a pre-treatment to apomorphine is to combat peripheral dopaminergic effects of apomorphine including nausea, hiccups and orthostatic hypotension (Buffery & Strother, 2015;Grandas, 2013;Zwar et al., 2016). Borgemeester et al. (2015) refers to the introduction of domperidone as successfully antagonizing peripheral and cardiovascular effects of apomorphine, this is also supported by Auffret et al. (2018) who describes apomorphine as a valuable drug in the anti-Parkinson's armamentarium, especially when combined with domperidone to treat nausea. ...
Apomorphine is generally a safe and well tolerated therapy used in acute and intermittent treatment of the motor symptoms, the ‘off’ motor state in Parkinson’s disease, and there is growing evidence supporting its clinical value in non-motor symptoms. It has an excellent efficacy profile in clinical practice, though the use of the agent continues to be underutilised. One of the most common reasons of this is most likely the perception of how difficult it is to use the agent, and the management of the adverse events (AE’s). The discontinuation due to AE’s is not as common as it has been believed. Apomorphine is generally well tolerated by most patients and if AE’s do develop, they are manageable in most cases.
The objective of this literature review was to examine the body of literature regarding the risk of Electrocardiogram (ECG) changes, and cardiac arrest in apomorphine challenges; and to look for safety parameters for people commencing and continuing apomorphine therapy. There is evidence that apomorphine can prolong a QTc interval, leading to cardiac arrhythmias. During the apomorphine challenge the drug domperidone is widely used to combat the side effects of nausea and vomiting, and vasodilation side effects of postural hypotension from the apomorphine. Domperidone has also been identified and studied as a medication with risks of QTc prolongation.
... 103 By virtue of the ortho-catechol ring and phenethylamine moiety, apomorphine shares structural similarity to dopamine (a fundamental rationale for its affinity to dopamine receptors). 104,105 Due to almost complete first-pass hepatic metabolism (via catechol-O-methylation, sulfation, and glucuronidation), apomorphine has very limited oral bioavailability (<4%) and has a short duration of action. 106 However, apomorphine has the ability to cross the blood−brain barrier freely due to its lipophilic tetracyclic structure. ...
Due to their evolutionary bias as ligands for biologically relevant drug targets, natural products offer a unique opportunity as lead compounds in drug discovery. Given the involvement of dopamine receptors in various physiological and behavioral functions, they are linked to numerous diseases and disorders such as Parkinson’s disease, schizophrenia, and substance use disorders. Consequently, ligands targeting dopamine receptors hold considerable therapeutic and investigative promise. As this perspective will highlight, dopamine receptor targeting natural products play a pivotal role as scaffolds with unique and beneficial pharmacological properties, allowing for natural product-inspired drug design and lead optimization. As such, dopamine receptor targeting natural products still have untapped potential to aid in the treatment of disorders and diseases related to central nervous system (CNS) and peripheral nervous system (PNS) dysfunction.
... Apomorphine, a potent dopamine agonist, exhibits a nity for all dopamine receptor subtypes [5]. D1 and D2 receptors, in particular, hold primary relevance concerning motor function, while D3 and D4 receptors are more closely associated with affective disorders and impulse control [6]. ...
Objective:This study aims to assess the safety and efficacy of apomorphine in addressing sleep disorders among individuals with Parkinson’s disease (PD).
Methods: A comprehensive search was conducted across multiple databases, including MEDLINE/PubMed, Cochrane Library, Embase, Web of Science, and CBM, to identify relevant studies.
Results: After eliminating duplicate data and applying predefined inclusion and exclusion criteria, a total of 117 patients from four studies (including one randomized controlled trial) were selected for analysis based on the PICOS criteria. The findings indicate that nocturnal apomorphine injections may offer benefits in terms of enhancing sleep quality and duration. Furthermore, apomorphine exhibits favorable tolerability and maintains a high safety profile.
Conclusions: In conclusion, this study provides supporting evidence for the efficacy of apomorphine in improving sleep quality and maintenance in PD patients, while also highlighting its safety. Nonetheless, further large-scale clinical trials are warranted to establish definitive guidelines for apomorphine treatment in PD-related sleep disorders.
... In line with a previous report [10] and owing to its pharmacological properties [14,15], apomorphine was indicated for symptoms relief (both during day and night [16]) and administered as a 24-h infusion to optimize patient's comfort while avoiding repeated injections, deemed unsuitable in this context. Less invasive than the intravenous route, the subcutaneous route is widely used in PC, especially in the terminal phase, with good safety [17]. ...
Background
There are currently no recommendations on the therapeutic management of Parkinson’s disease (PD) patients at the end of life.
Objective
To describe a cohort of patients with PD who benefited from continuous subcutaneous apomorphine infusion (CSAI) initiation at the end of their life as comfort care.
Methods
This real-life cohort includes 14 PD patients, who benefited from 24-h, low-dose CSAI (0.5–3 mg/h) in the context of terminal care. Patient’s comfort (pain, rigidity, and/or ability to communicate) and occurrence of CSAI-related side-effects (nausea/vomiting, cutaneous and behavioral manifestations) were evaluated based on medical records.
Results
All patients (age 62–94 years, disease duration 2–32 years) presented with late-stage PD and a compromised oral route. Treatment lasted from a few hours to 39 days. CSAI led to substantial functional improvement, with a good safety profile. Overall clinical comfort was deemed improved by the medical team, the patient, and/or caregivers.
Conclusions
CSAI might be a promising approach in PD terminal care, as it reduces motor symptoms and overall discomfort, with an apparent good safety profile. Use of the apomorphine pen, sublingual film or a classic syringe pump might be considered when apomorphine pumps are not available. Larger observational cohorts and randomized controlled trials are needed to establish the efficacy and tolerability of apomorphine in the context of terminal care and more broadly, in an advance care planning perspective.
... -Advanced therapies are cumbersome, pumps are relatively large, intra-intestinal infusions are relatively dif-ficult to handle and not very practical for the patient, and compliance is generally low (Stocchi and Olanow 2004). Recently, the search for alternative routes is ongoing, with promising results from studies of pulmonary, sublingual, and transdermal routes (Auffret et al. 2018); and the search for new solutions (e.g. highly concentrated infusion solutions) to reduce pump size and weight; smaller pumps are being designed which will represent a significant advance in antiparkinsonian pharmacotherapy. ...
The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current scientific evidence and the level of medical knowledge available in the field. For Parkinson’s disease (PD), the standard care is mostly considered to be oral treatment with dopaminergic drugs, particularly levodopa which remains the ‘gold standard’. However, effective management with levodopa during the later stages of the disease becomes increasingly challenging due to the ongoing neurodegenerative process, the consequences of its pulsatile dopaminergic stimulation, and the gastrointestinal barriers to effective drug absorption. As a result, the concept of applying continuous dopaminergic stimulation has emerged with infusion therapies (continuous subcutaneous apomorphine, levodopa–carbidopa intestinal gel, and levodopa–entacapone–carbidopa intestinal gel infusion). These therapies seek to provide continuous stimulation of striatal dopamine receptors that is efficient not only in alleviating clinical symptoms, but also in delaying, reducing, and possibly preventing the onset of levodopa-related motor (fluctuations, dyskinesia) and non-motor complications; and they are also associated with clinically relevant side effects. Clinical studies and real-life experience support the notion that infusion therapies should be accepted as part of the standard of care for patients with advanced PD who have refractory, severe, and disabling motor complications that affect their quality of life. However, they should be considered based on the needs of individualized patients and the access to these advanced therapies needs to be made more accessible to the general PD population.
... For instance, as a catechol-containing nonnarcotic morphine derivative, Apomorphine is reported and acts as a potent dopaminergic agonist. Its metabolism occurs through several enzymatic pathways, including N-demethylation, sulfation, glucuronidation, and O-methyltransferase as well as by nonenzymatic oxidation (Auffret et al. 2018). From a plasma samples analysis, metabolites including 7-methoxy-8-hydroxyflavone (7M8H-flavone), 7-hydroxy-8-metoxyflavone (7H8M-flavone) were detected, in addition to the parent drug of 7,8-DHF and the glucuronidated product of 7,8-DHF ). ...
... Despite its proven efficacy and safety, apomorphine infusion is still underused and often used too late to be optimally effective (Auffret et al. 2018a(Auffret et al. , 2018bPoewe and Wenning 2000). One explanation may be that it is perceived as complicated to initiate and supervise. ...
Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson’s disease that can be considered when motor fluctuations become persistent and are no longer adequately controlled by oral/transdermal medication. Apomorphine infusion is less invasive than enteral levodopa, deep brain stimulation or focused ultrasound, and is often indicated even when neurosurgical approaches are contraindicated. This article aims to provide practical guidance for doctors and nurses initiating and treating patients with apomorphine infusion, and is based on both trial data and clinical experience from movement disorders specialists. A post hoc analysis of data from the TOLEDO randomized clinical trial of apomorphine infusion was conducted along with an analysis of ‘real world’ experience from 13 movement disorders specialists using a questionnaire that focused on starting patients on apomorphine infusion. Practical guidelines for starting treatment with apomorphine infusion are provided taking into consideration the regional disparities in healthcare. Apomorphine infusion is straightforward to administer but to be successful it requires concordance from the patient and family, and clinical support from an experienced team of doctors and nurses, particularly in the early months of treatment.
... It is commonly referred to as a DA agonist but differs from other oral DA agonists used to treat PD. Apomorphine is a potent non-ergoline DA receptor agonist with a wide range of effects on the D2-and D1-like receptors in the corpus striatum (Lieberman and Goldstein, 1985;Chaudhuri and Schapira, 2009;Wohlfart et al., 2012;Moss and Siccardi, 2014;Auffret et al., 2018;de Souza Xavier and Miranda, 2018;Subramony, 2006;LeWitt et al., 2009). Additionally, apomorphine has antagonistic effects on serotonergic 5HT2C, 5HT2A, and 5HT2B receptors, and agonistic effects on serotonergic 5HT1A receptors, as well as adrenergic 2A, 2B, and 2 C receptors (Tsai et al., 2011). ...
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The degeneration of dopaminergic neurons in the midbrain is primarily responsible for the onset of the disease. The major challenge faced in the treatment of PD is the blood-brain barrier (BBB), which impedes the delivery of therapeutics to targeted locations. To address this issue, lipid nanosystems have been used for the precise delivery of therapeutic compounds in anti-PD therapy. In this review, we will discuss the application and clinical significance of lipid nanosystem in delivering therapeutic compounds for anti-PD treatment. These medicinal compounds include ropinirole, apomorphine, bromocriptine, astaxanthin, resveratrol, dopamine, glyceryl monooleate, levodopa, N-3,4-bis(pivaloyloxy)- dopamine and fibroblast growth factor, which have significant potential to treat PD in the early stage. This review, in a nutshell, will pave the way for researchers to develop diagnostic and potential therapeutic approaches using nanomedicine to overcome the challenges posed by the BBB in delivering therapeutic compounds for PD.
... From a structural perspective, apomorphine is an ergoline that bears a strong resemblance to dopamine, but it is the receptor profile of apomorphine that may provide clues to its greater efficacy when compared to the oral non-ergoline dopamine agonists, ropinirole and pramipexole (Auffret et al. 2018a(Auffret et al. , 2018b(Auffret et al. , 2019Jenner 1995Jenner , 2002Jenner and Katzenschlager 2016;Kvernmo et al. 2006). The actions of the latter drugs are restricted to the D-2-like receptors whilst apomorphine interacts with both D-1-like and D-2like receptor populations (De Keyser et al. 1995;Fici et al. 1997;Jenner 2002;Lam 2000;Lataste 1984). ...
Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson’s disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others—levodopa and apomorphine—but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals ‘unknown’ aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as ‘known unknowns’ or ignored as ‘unknown unknowns’. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.
... Interestingly, a pocket present at the KD-SDD surface is exposed in the B chain while in the A chain it is The apomorphine is a phenylethylamine with an orthocatechol moiety attached to it. The OH group present in this moiety confers the ability to bind to dopamine receptors and also produce neuroprotective actions (Auffret et al. 2018;Csutoras et al. 2004). Surprisingly, the same OH group was involved in the binding to Glu 97 and Cys 99 with IKKB via hydrogen bonding as seen in Fig. 9. Hydrogen bonds primarily facilitate stronger protein and ligand interactions. ...
In Alzheimer's disease (AD), neuroinflammation is detrimental in causing neurodegeneration. In the central nervous system, inhibitor of nuclear factor kappa B kinase subunit beta (IKK2/IKKβ/IKKB/IKBKB) signaling is linked to neuroinflammation-mediated learning and memory deficits through canonical pathway, while dopamine agonists have been known to reverse such effects. Our in silico analysis predicted if dopaminergic agonists could have IKKB inhibitory actions, to ameliorate neuroinflammation-associated learning and memory deficits. Here, the FDA-approved Zinc 15 database was screened with IKKB (PDB ID 4KIK). Potential molecules with IKKB inhibition were identified through docking, which also possessed dopaminergic activity. Molecular mechanics—generalized Born and surface area (MMGBSA), induced fit docking (IFD) and molecular dynamic (MD) studies of 100 ns simulation time were done. Apomorphine and rotigotine showed greater non-bonding and bonding interactions with amino acids of IKKB as compared to Aripiprazole in docking studies. The IFD studies predicted improved interactions with IKKB. MMGBSA scores indicated that the complex binding free energies were favorable, and MD studies showed an acceptable root mean square deviation between protein and ligands. The protein–ligand interactions showed hydrogen bonds, water and salt bridges necessary for IKKB inhibition, as well as solvent system stability. On the protein–ligand contact map, the varying color band intensities represented the ligand’s ability to bind with amino acids. Dopamine agonists apomorphine, rotigotine, and aripiprazole were predicted to bind and inhibit IKKB in in silico system.
Graphical Abstract
... Apomorphine is a dopaminergic agent and FDA-approved to treat off episodes in adults with Parkinson's disease. Kynmobi ® is a brand-name sublingual film, which dissolves in about 3 minutes and releases the medication [28]. ...
The development of new dosage forms with the active pharmaceutical ingredients that are immobilized on polymeric carriers-drug films that are used in various fields of medicine is gaining considerable popularity in the world. Transdermal therapeutic systems are designed to deliver the active pharmaceutical ingredient through the skin to achieve a systemic effect, an example of these transdermal therapeutic systems are buccal, dental, oral drug films. The main advantage of using fast dissolving oral forms is the possibility of their use by patients with dysphagia. The study examines the scientific publications of the last decade and the analysis of the range of drugs available on the US pharmaceutical market. The range of medical films on the US market is formed as follows: 74% transdermal films, 11.1%-transdermal systems, 14% of the range-buccal and sublingual films, 0.9%-oral films. In the US pharmaceutical market, 33.63 % of the range of medical films has been used to relieve the pain of various origins. The share of the transdermal system containing estradiol is 26.55 %, estradiol and its combinations in the form of films are used to treat the manifestations and symptoms of estrogen deficiency in postmenopausal or artificial menopausal women. The share of the transdermal systems for the treatment of neurodegenerative movement disorders is 15.49 %. Transdermal drug delivery systems provide an attractive alternative to the oral route of delivery of biotherapeutic drugs. A focus on the further development of drugs in the transdermal system remains the finding of sufficiently potent drugs that can penetrate the skin or tissue with appropriate technology.
... Apomorphine has been described as an agonist of dopamine, but it varies greatly from other oral agonists of dopamine used in Parkinson's disease. Apomorphine functions as a potent agonist dopamine receptor with a wide range on both D1and D2-like receptors, due to its catechol moiety (Auffret and Drapier and Vérin, 2018). In contrast, oral dopamine agonists pramipexole and ropinirole predominantly bind to D1, D2, and D3 receptors. ...
Apomorphine is currently used as a dopamine agonist to treat advanced Parkinson Disease. In the present study, we developed a sensitive, simple, reliable, and robust HPLC method for quality control of apomorphine hydrochloride in bulk drug and pharmaceutical formulations. C18 column was used for separation. Isocratic elution was performed using mobile phase A: 50 mM potassium dihydrogen phosphate solution (pH:3 with ortho-phosphoric acid), B: acetonitrile in the ratio of 85:15 (A: B), and the mobile-phase flow rate was kept at 1 mL min-1. Analyses were carried out at 272 nm using a UV detector. A perfect linear relationship between peak-area versus drug concentration in the range of 10‑100 μg mL-1 was observed (r2, 0.9999). It has been found that the developed method is sensitive (Detection and quantification limits were determined as 1.3 μg mL-1 and 3.8 μg mL-1, respectively), precise (RSD
... Motor fluctuations can be managed with continuous dopaminergic drug delivery using either continuous subcutaneous apomorphine infusion (CSAI) or levodopa-carbidopa intestinal gel (LCIG) 4,5 . Apomorphine is a dopamine agonist with affinity for D1 and D2 receptors 6 . Several uncontrolled studies have highlighted the efficacy of apomorphine in managing motor complications [7][8][9] and nonmotor symptoms [10][11][12][13] in patients with advanced PD. ...
Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson’s disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson’s disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
... Unfortunately, apomorphine presents a short half-life (33 min), which necessitates administration through subcutaneous injections several times a day. The administration of this therapy is usually applied in the advance stage of PD to reduce off-time and dimmish motor fluctuations from levodopa treatment [25][26][27]. ...
Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.
... While the metabolism of eptaloprost is via the process of beta oxidation of carbonic acid into the metabolite cicaprost, 25 the predicted regions matched this area, and these findings were thought to indicate a valid level of contribution. Although the most easily metabolized part of R-apomorphine was the catechol part, 26 the predicted region was the neighboring aromatic ring part with high lipid solubility, and it is thought that this is a valid suggestion as the structure contributing factor inferred to degrade the metabolic stability. The metabolisms that propofol undergoes are known to be O-glucuronic acid conjugation of the phenol and hydroxylation of the para position of its OH group. ...
Research into pharmacokinetics plays an important role in the development process of new drugs. Accurately predicting human pharmacokinetic parameters from preclinical data can increase the success rate of clinical trials. Since clearance (CL) which indicates the capacity of the entire body to process a drug is one of the most important parameters, many methods have been developed. However, there are still rooms to be improved for practical use in drug discovery research; “improving CL prediction accuracy” and “understanding the chemical structure of compounds in terms of pharmacokinetics”. To improve those, this research proposes a multimodal learning method based on deep learning that takes not only the chemical structure of a drug but also rat CL as inputs. Good results were obtained compared with the conventional animal scale-up method; the geometric mean fold error was 2.68 and the proportion of compounds with prediction errors of 2-fold or less was 48.5%. Furthermore, it was found to be possible to infer the partial structure useful for CL prediction by a structure contributing factor inference method. The validity of these results of structural interpretation of metabolic stability was confirmed by chemists.
... The dopamine agonist rotigotine showed an improvement in bladder capacity in urologic assessments of 20 patients three months after the drug initiation [20]. Another study about the D1-D2 agonist apomorphine showed that the acute administration of the drug improved bladder emptying and detrusor hyperactivity [21,22]. A brief study on 20 patients showed an improvement on urodynamic values and urologic questionnaire scores with rasagiline [23]. ...
Background: Urinary symptoms are common, disabling and generally unresponsive to treatment in Parkinson´s disease (PD). Safinamide is approved as an add-on therapy to levodopa to improve fluctuations. Methods: Retrospective analysis of electronic records of nondemented PD patients seen consecutively in a Movement Disorders Unit (November 2018–February 2019). All were assessed with Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms-Urinary subscale (SCOPA-AUT-U) by the attending neurologist, and a month afterwards by an independent researcher blinded to treatment and clinical records in a routine clinical practice setting. Clinical variables were compared among patients who were prescribed safinamide (SA+) for the treatment of motor fluctuations and those with different treatment regimes (SA−). Results: From 169 patients screened initially, 54 were excluded due to severe incontinence, absence of urinary symptoms or previous safinamide treatment. Thirty-five patients were included in SA+ and 79 in SA−. Both groups were comparable in terms of clinical variables, except in basal urinary symptoms, with more severity in the SA+ group. In the follow-up assessment, total SCOPA-AUT-U, as well as urgency, incontinence, frequency and nocturia subscales improved significantly in the SA+ group, while the SA− group remained unchanged. Conclusions: Safinamide could be helpful in the improvement of urinary symptoms in PD.
... [9] Its chemical structure [ Figure 2] accounts for its dopaminergic and non-dopaminergic properties. [10] The ortho-catechol group confers structural similarity to dopamine, [3] whereas the piperidine moiety confers possible antipsychotic action. [9] Apomorphine is lipophilic and moderately soluble in saline and water. ...
... A positive effect of RTG in improving RLS and PLM has also been found [87], as well as in pain, especially nocturnal pain [92]. Additionally, evidence from case-based reports have suggested a beneficial effect of RTG on nocturia, a key NMS of PD [110], as well as RBD Apomorphine is the only DA that has been proven to have the same efficacy of levodopa, because of its potent dopamine receptor agonism towards a broad spectrum of D1 and D2 family receptors [111,112]. ...
Introduction
Dopamine agonists have been widely used to treat patients with Parkinson’s disease, but concerns related to their well-known side effects might prevent their use even when indicated. In this review, the authors describe for the first time the concept of “Dopamine Agonist Phobia”, a pharmacophobia that the authors believe might affect clinicians, and they provide evidence of the benefits of dopamine agonists, focusing on non-motor symptoms.
Areas covered
The authors performed an extensive literature research, including studies exploring the use of dopamine agonists for the treatment of non-motor symptoms. The authors indicate the highest level of evidence in each section.
Expert Opinion
“Dopamine Agonist Phobia” may preclude valid therapeutic options in selected cases, specifically for the treatment of non-motor symptoms. Thus, the authors propose a personalized approach in Parkinson’s disease treatment, and encourage a thoughtful use of dopamine agonists, rather than an overall nihilism.
... Apomorphine has been used in clinical practice for many years around the world and has proved to be effective and well tolerated for the management of motor fluctuations and dyskinesias in a range of open-label studies [39][40][41][42]. Due to its name, a common misperception is that 'apomorphine' has similar effects to 'morphine' but both clinicians and patients alike should be made aware that, unlike morphine, apomorphine has no narcotic properties [43,44]. While there is no formal study documenting this misconception in Thailand, it was raised by Thai Experts Panel members as a common issue in their clinical practice experience. ...
Introduction: The increasing global burden of Parkinson’s disease (PD) poses a particular challenge for developing countries, such as Thailand, when delivering care to a geographically diverse populace with limited resources, often compounded by a lack of expertise in the use of certain PD medications, such as device-aided therapies (DAT).
Areas covered: A panel of local, regional and international PD experts convened to review the unmet needs of PD in Thailand and share insights into effective delivery of DAT, focusing on experience with apomorphine infusion. Despite its proven efficacy and safety, implementation of apomorphine infusion as a new option was not straightforward. This has prompted a range of healthcare professional and patient-focused initiatives, led by the Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders in Bangkok, to help establish a more coordinated approach to PD management throughout the country and ensure patients have access to suitable treatments.
Expert opinion: Overcoming the challenges of education, proficiency, resource capacity and standard of care for PD patients in developing countries requires a coordinated effort both nationally and beyond. The best practices identified in Thailand following the introduction of apomorphine infusion might be helpful for other countries when implementing similar programs.
... Apomorphine, an aporphine alkaloid derived from acidification of morphine, is a potent DA with a broad spectrum of effects on both D1-and D2-like receptors [156]. This is in contrast to the oral DAs that mainly bind to D2 and D3 receptors. ...
Parkinson’s disease is a chronic, neurodegenerative disease, which manifests with a mixture of motor, cognitive and behavioural symptoms. Levodopa is the most effective antiparkinsonian treatment to date, although chronic use engenders a mixture of complications in a substantial proportion of patients. Amongst these is the occurrence of episodes of worsening symptoms—‘off’ phenomena. These episodes can manifest with either motor or non-motor symptoms or a combination of these features and have been found to have profound impacts on patients’ quality of life. Although preventative measures are poorly evidenced, avoiding excessive total daily levodopa intake in selected populations that are deemed to be of a higher risk for developing these episodes warrants further exploration. Methods to improve levodopa bioavailability and delivery to the brain are currently available and are of value in addressing these episodes once they have become established. These include modifications to levodopa formulations as well as the use of complimentary agents that improve levodopa bioavailability. The deployment of device-assisted approaches is a further dimension that can be considered in addressing these debilitating episodes. This review summarises the clinical manifestations of ‘off’ phenomena and the current approaches to treat them. Although we briefly discuss clinical advances on the horizon, the predominant focus is on existing, established treatments.
... Apomorphine is often described as a dopamine agonist, but it has some differences from other oral dopamine agonists used in PD. Thanks to its catechol moiety, apomorphine acts as a potent dopamine receptor agonist with a broad spectrum on all D 1 -and D 2 -like receptors (D 1 , D 2S , D 2L , D 3 , D 4 , D 5 ) [30]. In comparison, the oral dopamine agonists ropinirole and pramipexole mainly bind to D 2 and D 3 receptors without significant affinity to D 1 receptors [31]. ...
Satisfactory management of Parkinson’s disease is a challenge that requires a tailored approach for each individual. In the advanced phase of the disease, patients may experience motor complications despite optimized pharmacological therapy. Apomorphine, a short-acting D1- and D2-like receptor agonist, is the only drug proven to have an efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. Clinical trials have shown that intermittent apomorphine injections provide rapid and effective relief from unpredictable “off” periods. Continuous apomorphine infusion reduced around 50% of the daily “off” time in several studies. Dopaminergic side effects such as nausea, somnolence and hypotonia, as well as administration site reactions, are often mild or treatable, but somnolence and skin reactions in particular can sometimes be reasons for premature discontinuation. We provide an overview of the pharmacological mechanism of action of the drug in light of its effects on Parkinson’s disease symptoms. We then summarize the evidence regarding the efficacy and tolerability of apomorphine, both in its established formulations (subcutaneous intermittent injection and continuous infusion) and in the new preparations currently under investigation.
... PD occurs mainly in old people with a slightly higher incidence and prevalence in males compared to females (reviewed in Georgiev et al. (2017)). It is well known that PD is due to a reduction of dopaminergic transmission to the basal ganglia, especially to the caudate-putamen nucleus (reviewed in Jenner and Katzenschlager (2016), and Auffret et al. (2018b)) and consequently, apomorphine, as a non-specific dopamine receptor agonist, is a dopaminergic stimulant that, activating DA receptors, reduces the symptoms of PD (tremors, hypokinemia o akinesia and muscular rigidity) and is useful in the early stages of the disease to reduce resulting motor deficits. ...
Apomorphine is a non-specific dopamine receptor agonist that has been used in the treatment of some diseases and mental disorders. Its use has particularly well documented in Parkinson's disease (PD). The dopaminergic agonists like apomorphine are related to oxidative processes that could induce cell damage and the functional impairment of some structures in the brain. However, most information about apomorphine in literature is focused on the improvement of the motor problems characteristic of PD, but little is known about the effects on cognitive behaviors and brain structures indirectly related to motor function. The presence of dopaminergic receptors in the hippocampus has recently been discovered, in connection with cognitive behaviors like learning and memory, these receptors are needed in neuronal plasticity. There has been a growing interest to know if this structure could be compromised by the effect of apomorphine and elucidate if part of the cognitive impairment present in the PD is due to the effect of apomorphine. In this mini-review, we summarized how apomorphine has been used since its creation, we discuss the latest information about its effect on the hippocampus and also the future perspectives to fully understand the effects of this compound.
This concise, yet authoritative, clinical reference guide fulfils the needs of diverse clinicians, pharmacists and allied health professionals prescribing for Parkinson's disease and movement disorders in contemporary clinical practice. With chapters on newly approved drugs and their effects on motor and non-motor symptoms, information is also given on their use in particular populations including the elderly and patients with cognitive impairment. Each chapter includes pharmacological/biochemical rationale for drug use, a general guide to therapeutic use, pharmacokinetics, interaction profile, adverse effects, dosing and use, special population considerations, costs and value for money considerations, clinical vignette, a summary overview, and suggested reading. Ordered alphabetically and perfect for quick reference use, the guide is practical and essential for all prescribers with responsibility for patients with Parkinson's disease, including neurologists, geriatricians, internists, neurosurgeons, psychiatrists, family physicians, pharmacists as well as allied health professionals and resident, fellow, and student trainees in all related medical fields.
This concise, yet authoritative, clinical reference guide fulfils the needs of diverse clinicians, pharmacists and allied health professionals prescribing for Parkinson's disease and movement disorders in contemporary clinical practice. With chapters on newly approved drugs and their effects on motor and non-motor symptoms, information is also given on their use in particular populations including the elderly and patients with cognitive impairment. Each chapter includes pharmacological/biochemical rationale for drug use, a general guide to therapeutic use, pharmacokinetics, interaction profile, adverse effects, dosing and use, special population considerations, costs and value for money considerations, clinical vignette, a summary overview, and suggested reading. Ordered alphabetically and perfect for quick reference use, the guide is practical and essential for all prescribers with responsibility for patients with Parkinson's disease, including neurologists, geriatricians, internists, neurosurgeons, psychiatrists, family physicians, pharmacists as well as allied health professionals and resident, fellow, and student trainees in all related medical fields.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) resulting in dopamine (DA) deficiency, which manifests itself in motor symptoms including tremors, rigidity and bradykinesia. Current PD treatments aim at symptom reduction through oral delivery of levodopa (L-DOPA), a precursor of DA. However, L-DOPA delivery to the brain is inefficient and increased dosages are required as the disease progresses, resulting in serious side effects like dyskinesias. To improve PD treatment efficacy and to reduce side effects, recent research focuses on the encapsulation of L-DOPA into polymeric- and lipid-based nanoparticles (NPs). These formulations can protect L-DOPA from systemic decarboxylation into DA and improve L-DOPA delivery to the central nervous system. Additionally, NPs can be modified with proteins, peptides and antibodies specifically targeting the blood-brain barrier (BBB), thereby reducing required dosages and free systemic DA. Alternative delivery approaches for NP-encapsulated L-DOPA include intravenous (IV) administration, transdermal delivery using adhesive patches and direct intranasal administration, facilitating increased therapeutic DA concentrations in the brain. This review provides an overview of the recent advances for NP-mediated L-DOPA delivery to the brain, and debates challenges and future perspectives on the field.
Background
We recently demonstrated in a randomized controlled trial (APOMORPHEE, NCT02940912) that night‐time only subcutaneous apomorphine infusion improves sleep disturbances and insomnia in patients with advanced Parkinson's disease and moderate to severe insomnia.
Objectives
To identify the best candidates for receiving night‐time only subcutaneous apomorphine infusion in routine care.
Methods
In this post‐hoc analysis of APOMORPHEE, we compared the characteristics of patients according to whether they chose to continue night‐time only subcutaneous apomorphine infusion at the end of the study period or not.
Results
Half of the patients (22/42) chose to continue the treatment. Off duration (day or night), painful Off dystonia, and insomnia severity at baseline were associated with night‐time only apomorphine continuation. Multivariate analysis retained only Off duration as an independent predictor of continuation.
Conclusions
The best candidates for night‐time only apomorphine are patients with severe and prolonged Off periods (day or night) and severe insomnia.
Parkinson’s disease (PD) psychosis affects up to 60% of PD patients and is recognized as one of the most debilitating non-motor symptoms in PD due to increased caregiver burden, nursing home placement, and mortality risk. The phenomenology of PD psychosis is diverse and includes hallucinations, delusions, illusions, and false sense of presence. Neuroimaging studies have reported structural and functional brain changes in PD patients with visual hallucinations, which align with reports of an association between higher densities of Lewy bodies in temporal areas and visual hallucinations. The pathophysiology underlying PD psychosis is complex and not well understood, but there is evidence to support the role of dopaminergic, serotonergic, cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic systems. Of the therapeutic agents tested in clinical trials, only clozapine and pimavanserin, both of which inhibit serotonin 2A receptor activity, are designated clinically useful with acceptable risk in PD psychosis. Several atypical anti-psychotics have demonstrated questionable efficacy in double-blind placebo-controlled clinical trials and/or deteriorated motor function. Among acetyl-cholinesterase inhibitors, rivastigmine showed promise in a single double-blind placebo-controlled trial, and further studies are required to confirm its anti-psychotic potential in PD. Anti-depressants have shown positive results in case reports and open-label trials, but their effectiveness has not been demonstrated in randomized controlled trials. Emerging therapies in clinical trials include new targets such as modulation of the glycinergic, serotonergic, and endocannabinoid systems, as well as kinase inhibition.
Background
Insomnia is a frequent complaint of patients with Parkinson's disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson's disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson's disease and insomnia.
Methods
We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson's disease and sleep centres in France. Participants aged 35–90 years with fluctuating Parkinson's disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson's disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912.
Findings
Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88–19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041).
Interpretation
Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson's disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson's disease and moderate to severe insomnia.
Funding
Orkyn and Aguettant Pharma.
Translation
For the French translation of the abstract see Supplementary Materials section.
Parkinson’s disease (PD) is the second commonest neurodegenerative disorder in the older adult and is characterized by progressive disabling motor symptoms of bradykinesia, tremor, rigidity, postural instability and also non motor symptoms that affect quality of life. The pharmacotherapy of PD consists of oral, transdermal, and subcutaneous medications, as well as invasive advanced therapies at later stages of the disease. PD medications are often started as monotherapy but with the progression of the illness often there is a need to add more medications and frequently comprises of a challenging polypharmacotherapy. Adverse effects of pharmacotherapy often add to the problems of adequate treatment. Patients and physicians have to prioritize treatment goals on the most disabling symptoms and the safest and most effective treatments. Almost every year newer medications and modes of delivery continue to be researched and added to the therapeutic armamentarium. This review article outlines existing and emerging pharmacotherapies for motor symptoms in PD.
Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic “first pass” metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol : propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease.
The apomorphine challenge test can be a distressing experience for some patients and, if they are not experienced, a discouraging option for some healthcare professionals (HCPs). The test is repeated exposure to bolus-dose injection of the medication to assess response and patient-specific dose before embarking on apomorphine therapy. Recent changes in prescribing of the anti-emetic domperidone (limited use because of QT prolongation), a drug which is a prerequisite for most patients embarking on therapy, has also added a possible complication. While recognising the value of the apomorphine challenge test, the author suggests an alternative approach of establishing apomorphine by subcutaneous infusion pump (SCAI) without the challenge test. This approach makes it more ‘user friendly’ for people with complex Parkinson's disease (PwPd) and their HCPs, and can eliminate the need for preloading with domperidone or other anti-emetic (if one is available in the country of practice). It is a viable option in acute situations, such as nil by mouth, surgery and oral dopamine agonist withdrawal, because of the associated harmful impulsive behaviour. Starting immediately with SCAI without the challenge test has proven both helpful and beneficial in clinical practice, especially in PwPd who have potential to abuse the intermittent injection, have complicated regimens and are vulnerable to drug-induced adverse effects. Some patients only need nocturnal infusions; injections during the night are difficult to administer and miss the objective of better sleep. Facilitating the process of initiation with the SCAI could improve uptake of this underused treatment through easier use and positive experience, and overcome the need for short- and longer-term domperidone use.
A systematic rational search for newly designed melatonin derivatives, was performed using a computer-assisted protocol. A total of 116 derivatives were generated by adding functional groups (i.e., -OH, -NH2, -SH and -COOH) to the melatonin structure. A selection score (SS) was built to sample the search space, simultaneously considering ADME (absorption, distribution, metabolism, excretion) properties, toxicity and manufacturability (i.e., synthetic accessibility). The search characterized the whole set of designed melatonin derivatives and allowed the selection of a reduced subset of 20 melatonin derivatives that are expected to be the most promising, regarding drug-like behavior. For this subset, several reactivity indices were estimated, as well as their pKa values. According to the gathered data, 5 melatonin derivatives have been identified as the most likely candidates to act as chemical antioxidant (directly scavenging free radicals, by electron transfer and/or H transfer). All of them are predicted to be better for that purpose than melatonin itself or trolox (water soluble vitamin E analog). The findings from this work are expected to motivate further investigations on these molecules, using both theoretical and experimental approaches.
Parkinson's disease (PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients, apomorphine is normally administered subcutaneously with frequent injections because of the compound's extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance. The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD, such as sublingual delivery and transdermal delivery.
Background: Subcutaneous infusion of apomorphine is being increasingly used in Parkinson’s disease (PD) patients, notably in those with contraindications for subthalamic deep brain stimulation. Though very few studies have investigated the effect of continuous subcutaneous apomorphine infusion on cognitive functions, this treatment is considered to be safe regarding cognition. However, the effect of apomorphine infusion on cognitive action control, and more specifically on the activation and suppression of impulsive responses, has not been studied. Methods: We investigated cognitive action control using an oculomotor version of the Simon task in a group of 20 PD patients at baseline (M0) and 6 months (M6) after instauration of continuous subcutaneous apomorphine infusion. We used the activation-suppression model to determine whether this treatment had an effect on impulsive error rate in conflict situation or the suppression of such impulsive responses. This experimental paradigm has proved to be efficient in detecting change in cognitive action control in PD. Results: We found no effect of treatment on the classic congruence effect on both reaction time and accuracy. This showed that the overall conflict resolution was not influenced by continuous subcutaneous apomorphine infusion. Furthermore, the amount of fast errors in the incongruent situation and the last slope of the delta plots (reflecting suppression of impulsive responses) were unaffected by the treatment. Confidence intervals obtained for the treatment effect on these two measures fell below the range of usual meaningful effects. Conclusions: Our results revealed no difference between M0 and M6 and strongly suggest that continuous subcutaneous apormorphine infusion does not alter cognitive action control. Both the selection and suppression mechanisms of impulsive responses were unaffected. This is in line with previous studies reporting that apomorphine is safe regarding cognitive functions.
Continuous apomorphine infusion (APO) is one of the treatments available for advanced Parkinson disease (PD). Over 10?years, we have treated 230 patients with APO. Mean age was 66.8 and average evolution time at APO onset was 13.0?years. Mean duration of the treatment was 26.3?months. As of June 2016, 93 remained on the medication (active group), while 137 had stopped. This active group had mean age 67.3 at recruitment and mean evolution 14.2?years. The main indication for APO was lack of deep brain stimulation criteria (DBS). Twelve patients were on waiting list for DBS. Average time since APO onset was 40.0?months. In the active group, APO decreased off-state in 4?h and allowed reducing levodopa and dopamine agonists. Dyskinesia and balance did not worsen. Cognitive decline did not change within the first 15?months. Hallucinations were the same within the first 39?months. The presence of subcutaneous nodules was the most frequent adverse event in this group. The main reason for discontinuation was side effects, being psychosis the most common. Within the first year, 82 patients stopped APO. Eighteen of these patients eventually got DBS. APO is a good option for advanced PD, since it permits a significant reduction in off-time and other antiparkinsonian drugs. This effect is sustained over time. We have treated 132 patients for over a year. Dyskinesia seems not to worsen. Combining APO with DBS simultaneously or alternatively provides good results.
Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson’s disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson’s to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson’s is a multi-organ disorder. The Parkinson’s phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease.
Background: There are not many data about the beneficial effect of nocturnal continuous subcutaneous apomorphine infusion (NCSAI) over sleep disturbances in advanced Parkinson’s disease (PD).
Objective: Evaluate the effect of the NCSAI in sleeping problems and insomnia due to nocturnal hypokinesia inadvanced PD.
Methods: We assessed 17 advanced PD patients with several sleep disturbances measured by SCOPA-SLEEP and PDSS scales. All the patients were on apomorphine infusion during daytime. This therapy was extended to nighttime. We evaluated the patients before the onset and after six weeks with NCSAI.
Results: NCSAI allowed highly significant improvements in SCOPA-SLEEP and PDSS scales (p<0.0001), and daytime somnolence. NCSAI was well tolerated with no major adverse effects were noticed.
Conclusion: This study shows and confirms the efficacy of NCSAI on the sleep disturbances related to advanced PD. We provide an easy protocol to start this therapy.
Background
In patients with motor fluctuations complicating Parkinson's disease (PD), delays in time‐to‐ON with levodopa are common. This open‐label study aimed to assess the effect of apomorphine on time‐to‐ON in PD patients with morning akinesia.
Methods
The safety population included 127 enrolled patients, and the full analysis set (FAS) included 88 patients. Patients completed a 7‐day levodopa baseline period recording their time‐to‐ON following each morning dose of levodopa. Patients were titrated to an optimal dose of apomorphine (2–6 mg) while taking trimethobenzamide antiemetic therapy. Apomorphine was injected each morning for a 7‐day treatment period and time‐to‐ON was self‐recorded in 5‐minute blocks. The primary efficacy variable was time‐to‐ON in the apomorphine treatment period versus the baseline levodopa period. Secondary assessments included and global impression scales. Safety and tolerability were assessed through adverse events (AEs).
Results
Patients receiving apomorphine achieved mean ± standard deviation (SD) time‐to‐ON 23.72 ± 14.55 minutes, reduced from 60.86 ± 18.11 minutes with levodopa (P < 0.0001). Dose failures (defined as time‐to‐ON >60 minutes) were more commonly reported with levodopa versus apomorphine (46% vs. 7% of diary entries, respectively).
Secondary endpoints supported the primary efficacy findings, with significant improvements from levodopa baseline to apomorphine treatment period (all P < 0.0001). The most common AEs were nausea and dizziness. Most patients who discontinued because of AEs did so in the titration phase.
Conclusions
Apomorphine injections significantly reduced time‐to‐ON in PD patients experiencing delayed onset of their morning levodopa dose, and was well tolerated in most patients. After apomorphine treatment, fluctuating patients with morning akinesia experienced rapid and reliable improvement of time‐to‐ON.
To report on OPTIPUMP, a cohort study, investigating the impact in real-life clinical settings of continuous subcutaneous apomorphine infusion (CSAI) on the quality of life (HRQoL) of patients with Parkinson's disease. OPTIPUMP was a prospective, open-label, observational cohort study involving 30 investigational sites in France. CSAI was proposed as part of routine clinical care to patients aged ≥18 years, in absence of dementia, with a PD diagnosis and based on the presence of motor fluctuations not controlled by oral treatments. The impact of APO-pump on quality of life was evaluated as the difference in PDQ-39 scores between the initiation treatment and the follow-up visit after 6 months' treatment. All adverse events were recorded. Hyper- and hypodopaminergic behavioral tolerance was assessed on the Ardouin Scale of Behavior in Parkinson's Disease. Between September 2011 and January 2013, we enrolled 142 patients: 42 patients were withdrawn due to pump removal (33), death (4), lost of follow-up (4), no available data (1). 100 completed the study. At 6 months, their HRQoL had significantly improved (p = 0.011), as had their total UPDRS score (p < 0.001). Regarding the safety profile, Ardouin scale scores indicated that their hyperdopaminergic behaviors had not increased. CSAI had a favorable impact on HRQoL, with benefits outweighing risks. The analysis of the withdrawn patients highlights the heterogeneity of the use of the pump having an impact on its efficacy and tolerability.
Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as 'critically important;' these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome 'off' periods (>1-2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS.
Copyright © 2015. Published by Elsevier Ltd.
Apomorphine (APO) is an aporphine derivative used in human and veterinary medicine. APO activates D₁, D(2S), D(2L), D₃, D₄, and D₅ receptors (and is thus classified as a non-selective dopamine agonist), serotonin receptors (5HT(1A), 5HT(2A), 5HT(2B), and 5HT(2C)), and α-adrenergic receptors (α(1B), α(1D), α(2A), α(2B), and α(2C)). In veterinary medicine, APO is used to induce vomiting in dogs, an important early treatment for some common orally ingested poisons (e.g., anti-freeze or insecticides). In human medicine, it has been used in a variety of treatments ranging from the treatment of addiction (i.e., to heroin, alcohol or cigarettes), for treatment of erectile dysfunction in males and hypoactive sexual desire disorder in females to the treatment of patients with Parkinson's disease (PD). Currently, APO is used in patients with advanced PD, for the treatment of persistent and disabling motor fluctuations which do not respond to levodopa or other dopamine agonists, either on its own or in combination with deep brain stimulation. Recently, a new and potentially important therapeutic role for APO in the treatment of Alzheimer's disease has been suggested; APO seems to stimulate Aβ catabolism in an animal model and cell culture, thus reducing the rate of Aβ oligomerisation and consequent neural cell death.
Camptocormia is defined as a marked dystonic flexion of the trunk in the sagittal plane. Camptocormia responds poorly to botulinum toxin injections, manipulation with dopaminergic treatment, and deep brain stimulation. We designed a prospective pilot study to assess the effect of apomorphine infusions on camptocormia. Five patients were enrolled. All five patients responded well to this treatment. The fact that camptocormia responds so well to apomorphine may be explained by the sustained stimulation of the ventrolateral striatal D1 receptors, alleviating this type of dystonia.
Continuous subcutaneous apomorphine infusion therapy (CSAI) has proved to be effective in advanced Parkinson's Disease patients with motor fluctuations not controlled by oral or transdermal medication. In this clinical setting it competes directly with intrajejunal levodopa and deep brain stimulation (DBS), however randomised controlled comparative studies are lacking. The advantages of CSAI is that it is the least invasive of these three therapeutic options, is reversible, practical to use and has shown significant efficacy for the management of both peak-effect dyskinesias and off-period nonmotor-symptoms. Contraindications to the use of CSAI are severe dementia or neuropsychiatric symptoms and severe biphasic dyskinesias, however unlike DBS, advanced age is not a contraindication. This review summarises the evidence regarding efficacy, safety and tolerability of CSAI, provides guidance on the selection of suitable patients and gives practical instructions on how to initiate CSAI and manage possible adverse events.
Continuous infusion of levodopa or apomorphine provide constant dopaminergic stimulations are good alternatives to deep brain stimulation to control motor fluctuations in patients with advanced Parkinson's disease (PD). Apomorphine provides motor benefit similar to dopamine, but its long-term use is limited by compliance, mostly injection site skin reactions. Administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement of a satisfactory therapeutic response paralleled by a reduction in motor complication severity. However, this procedure is more invasive than apomorphine as it requires a percutaneous endoscopic gastrostomy Clinical experience with infusions shows that continuous dopaminergic stimulation of dopaminergic medications reduces dyskinesia and widens the therapeutic window in advanced PD.
Apomorphine is a well established treatment for the management of sudden, unexpected and refractory levodopa-induced "off" states in fluctuating Parkinson's disease either as bolus injections or as continuous infusions. Incidents of atrial fibrillation associated with the administration of the drug have been reported in the past but no incidents of ventricular arrhythmias. We report a case of ventricular bigeminy recorded in a female patient after the administration of apomorphine.
Apomorphine, therapeutically used for Parkinson disease, is a dopamine D1/D2 receptor agonist that has been determined to be a potent antioxidant and to prevent the reaction of free radicals in the brain. Alcohol is a neurotoxic agent that induces neurodegeneration possibly through the generation of free radicals. In this study, we investigated the antioxidant potential of apomorphine upon ethanol-induced neurodegeneration in the cortex of adult rats. Ethanol-induced apoptotic neurodegeneration was measured via the suppression of Bcl-2, the induction of Bax, the release of cytochrome C and the activation of caspase-9 and caspase-3. Moreover, ethanol-induced elevated levels of cleaved PARP-1 indicated exaggerated neuronal DNA damage. Our results demonstrated the neuroprotective effect of apomorphine by reversing the ethanol-induced apoptotic trend as observed by the increased expression of Bcl-2, down regulation of Bax, inhibition of mitochondrial cytochrome C release and inhibition of activated caspase-9 and caspase-3. Moreover, apomorphine treatment further decreased the expression of cleaved PARP-1 to reveal a reduction in ethanol-induced neuronal damage. Immunohistochemical analysis and Nissl staining also revealed neuroprotective effect of apomorphine after ethanol-induced neuronal cell death. In this study, our results indicated that apomorphine at doses of 1 and 5 mg/kg has neuroprotective effects for ethanol-induced neuronal damage. Finally, we can conclude that apomorphine has effective therapeutic potential to protect the brain against ethanol-induced neurotoxicity.
Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.
The aims of this study were to assess the effects of the dopamine agonist apomorphine on experimental pain models in healthy subjects and to explore the possible association between these effects and a common polymorphism within the dopamine transporter gene. Healthy volunteers (n = 105) participated in this randomized double-blind, placebo-controlled, cross-over trial. Heat pain threshold and intensity, cold pain threshold, and the response to tonic cold pain (latency, intensity, and tolerance) were evaluated before and for up to 120 min after the administration of 1.5 mg apomorphine/placebo. A polymorphism (3'-UTR 40-bp VNTR) within the dopamine transporter gene (SLC6A3) was investigated. Apomorphine had an effect only on tolerance to cold pain, which consisted of an initial decrease and a subsequent increase in tolerance. An association was found between the enhancing effect of apomorphine on pain tolerance (120 min after its administration) and the DAT-1 polymorphism. Subjects with two copies of the 10-allele demonstrated significantly greater tolerance prolongation than the 9-allele homozygote carriers and the heterozygote carriers (p = 0.007 and p = 0.003 in comparison to the placebo, respectively). In conclusion, apomorphine administration produced a decrease followed by a genetically associated increase in cold pain tolerance.
Introduction:
Continuous apomorphine infusion (CAI) is an advanced therapy in fluctuating Parkinson's disease (PD). The use of CAI is controversial in PD patients with cognitive dysfunction including visual hallucinations (VHs), and orthostatic hypotension (OH). This study was set-up to analyze the effectiveness and safety of CAI in elderly PD patients with cognitive dysfunction.
Methods:
This new-user cohort study identified fluctuating PD patients who started CAI treatment at the rehabilitation unit of Parkinson Expertise Center (RU-PEC) Groningen, from November 2004 until 2016. Efficacy and safety data included motor function, cognitive status, OH and VHs, and was analyzed retrospectively. Pre-existent non-motor symptoms were treated optimally before starting CAI.
Results:
Forty-five fluctuating PD patients (age: 70.9 ± 8.1 yrs, disease duration: 10.8 ± 4.8 yrs) were identified, with pre-existing cognitive dysfunction, VHs (71%), and OH (26%). During the stay at RU-PEC (median 52 days) apomorphine was successfully titrated without worsening of pre-existing VHs and OH. The mean daily apomorphine dose was 66 ± 28 mg, accompanied by a reduction of levodopa-equivalent daily dose (LEDD) with 17%. The duration of ON-time and OFF-time significantly improved with +2.36 h (25%) and -1.66 h (-45%), respectively, while dyskinesia duration did not change. During long-term follow-up (median of 26 months) VHs and OH worsened in 9 and 4 patients, which necessitated discontinuation in 4 cases.
Conclusion:
This study demonstrates that CAI is also an effective treatment in advanced PD patients with concomitant cognitive dysfunction including VHs and OH, provided that these comorbidities are treated adequately as well.
Recent studies have shown that dopamine plays an important role in several types of cancer by inhibiting cell growth and invasion via dopamine receptors (DRs), such as dopamine receptor D2. However, the roles of DR agonists in cancer cell growth and invasion remain unclear. In our study, we found that apomorphine (APO), one of the most commonly prescribed DR agonists, inhibited TNF-α-induced matrix metalloprotease-9 (MMP-9) expression and cell invasion in MCF-7 human breast carcinoma cells through DR-independent pathways. Further mechanistic studies demonstrated that APO suppresses TNF-α-induced transcription of MMP-9 by inhibiting activator protein-1 (AP-1), a well-described transcription factor. This is achieved via extracellular signal-regulated kinases 1 and 2 (ERK1/2). Our study has demonstrated that APO targets human MMP-9 in a DR-independent fashion in MCF-7 cells, suggesting that APO is a potential anticancer agent that can suppress the metastatic progression of cancer cells.
Background:
Patients with Parkinson disease (PD) commonly experience motor fluctuations and dyskinesias in response to oral dopaminergic medications. Affected patients may benefit from device-assisted therapy, such as medication infusion or deep brain stimulation surgery. This is the first Australian study of the long-term adherence to apomorphine infusion (AI) in patients with PD.
Aims:
To assess the adherence to AI in patients with PD in a single centre over a 10-year period and to find the reasons for discontinuation in patients who discontinued AI.
Methods:
This is an observational study of patients with PD treated with AI between 2004 and 2014. Outcome measures included changes in motor function and quality of life following AI, change in dose of other dopaminergic medications following AI, duration of infusion, adverse effects, reasons for cessation of AI and subsequent treatment after cessation.
Results:
Mean duration of AI was 21.65 months. No patient achieved apomorphine monotherapy, and the mean reduction in the levodopa-equivalent dose of other dopaminergic medications after AI was 22.7%. The benefit of AI on motor function and quality of life was rated as 'much improved' or 'better' in 83% of patients. The most common reasons for discontinuation of AI were adverse effects and inadequate motor benefit. Most patients who discontinued AI were subsequently treated with another device-assisted therapy.
Conclusion:
AI is an effective therapy for severe motor response complications in PD, especially in the short and medium term. However, many patients cannot be maintained on AI in the longer term.
Apomorphine is often considered an archetypal dopamine agonist used in the treatment of Parkinson's disease (PD). However, it can be clearly differentiated from most other commonly used dopamine agonists on the basis of its pharmacology and on its unique clinical profile. Like levodopa and dopamine, apomorphine acts as a potent, direct and broad spectrum dopamine agonist activating all dopamine receptor subtypes. It also has affinity for serotonin receptors, and α-adrenergic receptors. Apomorphine is usually titrated to a dose that provides an equivalent antiparkinsonian response to that provided by levodopa, and its subcutaneous delivery allows a rapid onset of action, usually within 7–10 min. The mode of apomorphine delivery impacts on its clinical profile so as to provide two very different approaches to therapy in PD. When administered as an acute subcutaneous injection, it induces reliable and rapid relief from OFF periods underscoring its utility as a rescue medication. When given as a subcutaneous infusion, it significantly improves overall daily OFF time and there is also evidence to suggest that, in those patients who replace most or all of their oral drugs with apomorphine infusion, dyskinesia may also improve. In this paper, we review the rich pharmacology of apomorphine and review its efficacy in PD based on data from clinical trials.
Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment.
Non-motor features have a great impact on progression and quality of life in individuals with Parkinson's disease. Current treatments for PD are limited and apomorphine is one of the advanced therapies available with advantageous effects on motor complications. Several studies have suggested that apomorphine has potential benefits in PD patients beyond its established role in the treatment of motor fluctuations and levodopa-induced dyskinesia. This review examines the efficacy of apomorphine in the treatment of non-motor symptoms (NMS), describing recent studies that highlight its possible effect on cognition. Despite a limited number of studies, the available evidence shows that apomorphine has an overall beneficial effect on NMS of PD patients, including neuropsychiatric symptoms, sleep disturbances, pain, urinary dysfunction, and impulse control disorders. If the effects of apomorphine on amyloid deposition are confirmed in the future, its place in the armamentarium of PD treatment could see a shift towards younger and non-demented PD patients.
Apomorphine infusion or injection is an important dopamine agonist non-oral therapy usually used in advanced Parkinson's disease (PD) with refractory motor fluctuations. The drug also has appreciable efficacy for nonmotor fluctuations and is the quickest to reverse predictable “off” periods. Current subcutaneous administration, however, is complicated by problems associated with needle-based therapies, such as skin nodule formation, skin irritation, and avoidance of this treatment option by needle-phobic subjects.
Cinq genes codant pour les recepteurs de la dopamine sont aujourd'hui connus, correspondant a une diversite supplementaire de transcrits et de proteines du fait de phenomenes surajoutes d'epissages alternatifs. Les recepteurs peuvent etre classes en deux groupes, de type D 1 (recepteurs D 1 et D 5 ), couples a l'activation de l'adenylate cyclase par une proteine G s , et du type D 2 (D 2 , D 3 et D 4 ), couples a l'inhibition de l'adenylate cyclase par des proteines G i ou G o . De plus, ces recepteurs peuvent egalement etre couples a l'activation des phospholipases C et A, ou au controle de canaux ioniques
IntroductionEvidence from clinical and pathological studies suggests a role for both alpha-synuclein and amyloid-beta in the pathophysiology of dementia associated with PD. Recent work demonstrated improvement in memory and reduced amyloid-beta burden in transgenic murine Alzheimer's models given subcutaneous apomorphine. The aim of this work was to determine whether antemortem exposure to apomorphine was associated with lower levels of amyloid-beta in brain tissue in a clinicopathological study of PD.Methods
The case notes of donors with pathologically proven PD who had (n = 36) and had not received apomorphine (n = 35) during life for motor complications were reviewed to determine presence or absence of cognitive impairment. The four groups were well matched for disease duration, age at death, sex, and apolipoprotein E4 genotype. The severity of amyloid-beta mature/diffuse plaque load, tau pathology, and alpha-synuclein pathology were all established. Cerebral amyloid angiopathy was determined based on a four-tier grading system.ResultsWithin the cognitively normal cases, significantly reduced amyloid-beta deposition was present in those with antemortem apomorphine exposure; this finding was not replicated in those with cognitive impairment plus previous apomorphine use. In the apomorphine cognitively normal group only, a significant negative association was observed between maximum apomorphine dose received and amyloid-beta burden. Early and maximum doses of apomorphine plus apolipoprotein genotype and sex were significant predictors of total plaque load in an explanatory model.Conclusion
This exploratory study suggests that apomorphine may have a modifying effect on amyloid deposition in nondemented PD cases and thus may represent a potential therapy to reduce cognitive impairment in PD. © 2015 Movement Disorder Society
Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off' periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion(1) is suited for patients whose 'off' periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4-6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with 'off' periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Introduction. In New Zealand domperidone is approved for gastrointestinal motility and nausea and vomiting. The European Medicines Agency (EMA) recently concluded that domperidone poses a significant risk of sudden cardiac death (SCD) and has restricted use in Europe.
Aims. To review the risk of QT prolongation and cardiac adverse effects with domperidone and provide information to allow prescribers to make informed decisions on usage.
Methods. A search of two bibliographic databases, the EMA website, Micromedex, Lexicomp and reference texts was undertaken for domperidone related reports of QT prolongation, cardiac arrhythmias and/or SCD. The New Zealand Centre for Adverse Drugs Reaction Monitoring was also contacted for cardiac adverse event reports with domperidone.
Results. Over 30 published papers, EMA documents and other information sources were collated including two studies that met thorough QT study (TQT) criteria (ICH-E14). The first TQT1 was negative while the second was marginally positive. Reports of QT prolongation, ventricular arrhythmias and SCD were located (predominantly high/very high-dose IV domperidone). With oral domperidone, a Dutch case controlled study reported an adjusted odds ratio of SCD of 11.4 (95% CI 1.99-65.2), based on only three patients out of 1366 cases of SCD. A second nested case-controlled study calculated an odds ratio of ventricular arrhythmia or SCD of 1.59 (1.28-1.98) vs. placebo.
Discussion. Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk.
Current research shows that apomorphine is an effective treatment for symptoms of Parkinson's Disease (PD). The highly lipophilic structure allows apomorphine to cross cell membranes rapidly, leading to the rapid onset of action for on/off symptoms of PD. The use of apomorphine was limited in the past due to peripheral side effects, but with the advent of better delivery systems and medications to control side effects, apomorphine is better tolerated and more widely in use. The major delivery systems are continuous subcutaneous infusions and intermittent subcutaneous injections, but other delivery routes are under investigation. The purpose of this article is to discuss the current use of apomorphine, the current delivery systems and to discuss future research.
Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required. © 2014 International Parkinson and Movement Disorder Society.
Background:
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting ∼ 5.2 million people worldwide. Continuous subcutaneous apomorphine (CSAI) represents an alternative treatment option for advanced PD with motor fluctuation. The purpose of this analysis was to estimate the cost-effectiveness of CSAI compared with Levodopa/carbidopa intestinal gel (LCIG), Deep-Brain-Stimulation (DBS) and Standard-of-care (SOC).
Methods:
A multi-country Markov-Model to simulate the long-term consequences, disease progression (Hoehn & Yahr stages 3-5, percentage of waking-time in the OFF-state), complications, and adverse events was developed. Monte-Carlo simulation accounted for uncertainty. Probabilities were derived from RCT and open-label studies. Costs were estimated from the UK and German healthcare provider's perspective. QALYs, life-years (LYs), and costs were projected over a life-time horizon.
Results:
UK lifetime costs associated with CSAI amounts to £78,251.49 and generates 2.85 QALYs and 6.28 LYs (€104,500.08, 2.92 QALYs and 6.49 LYs for Germany). Costs associated with LCIG are £130,011.34, achieves 3.06 QALYs and 6.93 LYs (€175,004.43, 3.18 QALYs and 7.18 LYs for Germany). The incremental-cost per QALY gained (ICER) was £244,684.69 (€272,914.58). Costs for DBS are £87,730.22, associated with 2.75 QALYs and 6.38 LYs (€105,737.08, 2.85 QALYs and 6.61 LYs for Germany). CSAI dominates DBS. SOC associated UK costs are £76,793.49; 2.62 QALYs and 5.76 LYs were reached (€90,011.91, 2.73 QALYs and 6 LYs for Germany).
Conclusions:
From a health economic perspective, CSAI is a cost-effective therapy and could be seen as an alternative treatment to LCIG or DBS for patients with advanced PD.
SUMMARY Apomorphine was introduced before the era of levodopa as a treatment for idiopathic Parkinson's disease (iPD). A number of practical obstacles were to be solved before a wider use of the drug was possible. Today, however, the drug is probably still underutilized. Apomorphine is a strong nonergoline D1 and D2 receptor agonist with a dopaminergic effect comparable with levodopa. In this review motor and non-motor indications for intermittent injections and subcutaneous apomorphine infusions are listed. The reduction of 'off' periods is more than 50% on infusion therapy and if monotherapy is achieved a significant reduction of pre-existing levodopainduced dyskinesias is seen. The aim of this review is to give practical insight into apomorphine treatment, highlighting side effects, and complications and device-related problems are discussed with advice on how to prevent or handle these, should they occur. A number of practical points including the apomorphine test, requirements of the clinical setting, how to increase adherence and troubleshooting are added.
The ability of dopamine (DA) neurons to release other transmitters in addition to DA itself has been increasingly recognized, hence the concept of their multilingual nature. A subset of DA neurons, mainly found in the ventral tegmental area, express VGLUT2, allowing them to package and release glutamate onto striatal spiny projection neurons and cholinergic interneurons. Some dopaminergic axon terminals release GABA. Glutamate release by DA neurons has a developmental role, facilitating axonal growth and survival, and may determine in part the critical contribution of the ventral striatum to psychostimulant-induced behavior. Vesicular glutamate coentry may have synergistic effects on vesicular DA filling. The multilingual transmission of DA neurons across multiple striatal domains and the increasing insight into the role of glutamate cotransmission in the ventral striatum highlight the importance of analyzing DA neuron transmission at the synaptic level.
Background
Continuous subcutaneous infusion of apomorphine (CAI) has shown efficacy in the treatment of motor fluctuations but its place in the therapeutic arsenal remains poorly defined in terms of indication, acceptability and long-term tolerance. Indeed, few studies have been carried out with a follow-up greater than 12 months. The main objective was to assess the quality of life of Parkinson's disease (PD) patients treated with CAI. We also evaluate the effectiveness on the motor fluctuations, the long-term tolerance of this treatment with its causes of discontinuation and the treatment regimens used.
Methods
We conducted a retrospective study of 81 PD patients treated with CAI between April 2003 and June 2012. Data were collected from medical records. A repeated measures analysis of variance by the linear mixed model was used (significance level: 5%).
Results
In August 2012, 27/81 patients were still treated with CAI with a mean duration of 28 months, 46/81 discontinued CAI (9 precociously), and 8 were lost to view. We didn’t show improvement in the quality of life nor efficacy of CAI on the UPDRS IV score (P = 0.54) and dyskinesia score (P = 0.95). The CGI score patient also reflects this result with a majority response suggesting no significant change with CAI. We observed relative good cognitive and psychiatric tolerance. Adverse events were frequent but often benign. The average (± SD) rate of apomorphine was 3.15 ± 1.71 mg/h and the oral dopaminergic treatment was decreased by 37.8%.
Discussion
The results are consistent with the literature except for the lack of efficiency on motor fluctuations which may be due to the use of too small doses of apomorphine. This seems to be a leading cause of discontinuation of CAI, especially when it is associated with side effects or important constraints. For better efficiency on motor fluctuations, we recommend the use of apomorphine at higher doses to obtain an optimal continuous dopaminergic stimulation.
Subcutaneous infusion of apomorphine is a useful treatment for motor and nonmotor complications in Parkinson's disease patients and improves the patient's quality of life. An adequate selection of suitable candidates is crucial for obtaining the best results with this therapy. Parkinsonian patients with severe biphasic dyskinesias, demented or having experienced serious neuropsychiatric side effects with other dopamine agonists should not be offered this treatment. The therapeutic effect of continuous apomorphine infusion is reviewed and practical recommendations on its use are provided.
The population pharmacokinetic parameters of apomorphine, a potent dopamine agonist used in the treatment of on-off fluctuations in 8 Parkinsonian patients, were calculated after subcutaneous and intranasal administration. Compared with the ‘traditional’ standard 2-stage method or naïve pooling, the nonparametric expectation maximization method (NPEM2) program from the USC*PACK collection provides similar results, but more information about the population under investigation. Two available software packages for therapeutic drug monitoring were used: USC*PACK and MW/PHARM. We compared the calculated parameters: elimination constant (kel), distribution volume (Vslope), absorption constant (ka) and bioavailability. Small differences were observed in the following population pharmacokinetic data: Subcutaneous administration (n=8): Vslope=1.89 ±0.97 L/kg, kel=1.46 ±0.63 hour−1, ka=10.5 ±7.6 hour−1. Intranasal administration (n=6): Vslope=1.68 ±0.71 L/kg, kel=1.41 ±0.58 hour−1, ka=9.45 ±4.97 hour−1, bioavailability 1.32 ±0.81.
It was concluded that the nasal route is a good alternative to the subcutaneous route of administration.
In Parkinson's patients, swallowing difficulties may result in inhalation pneumonia, with a potentially serious prognosis. They may be revealed by withdrawal of L-dopa, especially after deep brain stimulation surgery. The following two cases illustrate the usefulness of apomorphine.
The emergency treatment of most ingestion problems involves gastric lavage or induction of emesis. Forceful emesis, superior to lavage, is usually induced by syrup of ipecac. A more rapid, efficient and controlled method utilizing apomorphine hydrochloride and a narcotic antagonist has not been popular because of difficulties in determining dosage in addition to the problems raised by the depressant properties of both the apomorphine and its antagonists. The absence of depressant effects with the newer antagonist, naloxone hydrochloride, renders it safer for use in terminating emesis induced by apomorphine. A dose calculated schedule, based on a level of 0.066 mg/kg for apomorphine and 0.01 mg/kg naloxone is provided along with a simple protocol for the mixing and administration of the drugs in emergencies.
It has been shown that when narcotine is heated with an excess of concentrated hydrochloric or hydriodic acid, one, two, or three molecules of methyl are successively eliminated, and a series of new bases homologous with narcotine obtained. It appeared interesting to see if any similar reactions took place with morphia; and for this purpose a quantity of that base, in a perfectly pure state, kindly furnished by Messrs. M‘Farlane, of Edinburgh, was submitted to experiment. The purity of the substance was shown by the following analysis. It was found that although crystallized morphia does not lose its water of crystallization in an ordinary steam drying-closet ( i. e . slightly below 100°), yet it readily loses the whole when placed in a Liebig’s drying-tube immersed in boiling water, dry air being aspirated over it.
