Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.

Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice.

BACKGROUND/AIMS: We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice. METHODS: Male mice were fed for 2 h (re-feeding) following a 22-h fast. Indomethacin (IND; 10 mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24 h after IND treatment. In another experiment, mice were fed for 2 h after a 22-h fast, after which the stomachs were removed 1.5 h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination. RESULTS: IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8. CONCLUSIONS: These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

Minimal adverse events occur when inducing emesis with apomorphine in brachycephalic, mesocephalic, and dolichocephalic dogs.

OBJECTIVE: To determine risks of complications with emesis induction and whether facial conformation is associated with the frequency of complications. ANIMALS: 1,788 client-owned dogs that presented immediately or by referral from a primary care veterinarian following ingestion of toxic or foreign materials. METHODS: Patients with emesis induced with apomorphine for removal of toxic or foreign materials were retrospectively identified. Collected data included patient factors, routes of apomorphine administration, other therapies, adverse events, and patient outcomes. RESULTS: 2 types of complications were identified in a very small number of patients (11 [0.6%]), with 3 (0.17%) having regurgitation postemesis and 8 (0.44%) having prolonged vomiting. No significant difference was found in the rates of repeated vomiting or regurgitation between brachycephalic dogs and nonbrachycephalic dogs (P = .375 and P = 1.00, respectively). Brachycephalic dogs had 1.6 times greater odds of having emesis induction due to toxin ingestion compared to foreign material ingestion. The presence of clinical signs of toxicity at the time of emesis induction was associated with regurgitation (P < .001), and the development of regurgitation was associated with admission to hospital (P = .001). CLINICAL RELEVANCE: This study found no increased risk of complications when emesis was induced using apomorphine in brachycephalic breeds compared to nonbrachycephalic breeds, regardless of indication for emesis induction. Facial conformation is not a reason to withhold emesis induction.

D2 dopamine receptor-mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine.

The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene-related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c-Fos levels in the brainstem were determined by enzyme-linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated nociceptive reactions by further enhancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migraine-like conditions.

Safety and tolerability of long-term apomorphine infusion in advanced Parkinson's disease: an Indian multi-center (APO-IND) experience.

Advanced Parkinson's Disease (APD) is complicated by the emergence of motor and non-motor fluctuations, which are initially predictable and eventually become unpredictable, in part due to erratic gastric absorption and short half of oral levodopa. Attempts to manage such fluctuations with oral dopaminergic drugs often lead to disabling dyskinesias. Continuous Subcutaneous Apomorphine Infusion (CSAI), despite being approved for the treatment of APD since 1993, was approved in India only in 2019. We studied the safety, tolerability and efficacy of CSAI in Indian patients with APD in a registry design to raise local awareness of this important treatment. We conducted a prospective registry-based observational audit at 10 centers across different states of India. Patients with APD, not responding to or with significant side effects from oral dopaminergic therapy, were assessed at baseline and at month 6 and 12 following CSAI infusion. Fifty-one patients completed the study, CSAI significantly reduced the functional impact of dyskinesia (p < 0.01 at 6 months and p < 0.001 at 12 months). There was a significant improvement in the OFF-state from baseline (p < 0.01 at 6 months and p < 0.001 at 12 months) No discernible side effects were observed apart from mild site reaction (n = 7), nausea (n = 7) skin nodules (n = 2). CSAI demonstrated safety, efficacy, tolerability and improved quality of life in patients with APD, as shown in previous studies. Our study highlighted current existing inequalities in treatment availability, lack of awareness, knowledge gap, affordability and cost remains a concern regarding apomorphine use in Indian PD population.

Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice.

BACKGROUND/AIMS: We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. METHODS: We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. RESULTS: IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. CONCLUSIONS: These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

Dose Optimization of Apomorphine Sublingual Film for OFF Episodes in Parkinson's Disease: Is the Prophylactic Use of an Antiemetic Necessary?

BACKGROUND: Nausea is common upon initiating dopamine agonists in patients with Parkinson's disease (PD); however, pretreatment with an antiemetic is recommended only when initiating apomorphine formulations. OBJECTIVE: Evaluate the need for prophylactic antiemetic use during dose optimization of apomorphine sublingual film (SL-APO). METHODS: A post hoc analysis of a Phase III study evaluated nausea and vomiting treatment-emergent adverse events in patients with PD who underwent SL-APO dose optimization (10-35 mg; 5-mg increments) to achieve a tolerable FULL ON. Frequencies of nausea and vomiting were described for patients who did versus did not use an antiemetic during dose optimization and by patient subgroups based on extrinsic and intrinsic factors. RESULTS: Overall, 43.7% (196/449) of patients did not use an antiemetic during dose optimization; most of these patients (86.2% [169/196]) achieved an effective and tolerable SL-APO dose. In patients who did not use an antiemetic, nausea (12.2% [24/196]) and vomiting (0.5% [1/196]) were uncommon. An antiemetic was used in 56.3% (253/449) of patients, with 17.0% (43/253) and 2.4% (6/253) experiencing nausea and vomiting, respectively. All events of nausea (14.9% [67/449]) and vomiting (1.6% [7/449]) were of mild-to-moderate severity except for 1 event each. Irrespective of antiemetic use, among patients without baseline dopamine agonist use, nausea and vomiting rates were 25.2% (40/159) and 3.8% (6/159); in those already using dopamine agonists, rates were 9.3% (27/290) and 0.3% (1/290). CONCLUSION: Prophylactic treatment with an antiemetic is not necessary for most patients who initiate SL-APO for the treatment of OFF episodes in PD.

A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease.

A randomized thorough QT study was conducted to assess the effects of apomorphine sublingual film (SL-APO) on corrected QT interval (QTc) and other cardiac conduction parameters in patients with Parkinson's disease (PD) and "OFF" episodes. Patients were titrated to an SL-APO dose that resulted in FULL "ON," followed by up to two additional doses (maximum 60 mg), then randomized at the highest tolerated dose to a treatment sequence of SL-APO, placebo, and moxifloxacin (400 mg, positive control) in a three-way crossover design. Changes from baseline in time-matched, placebo-adjusted Fridericia-corrected QTc interval (ΔΔQTcF) and Bazett-corrected QTc interval (ΔΔQTcB) were analyzed from postdose electrocardiograms. Forty patients were randomized and received single doses of study treatments. Upper limits of 90% confidence intervals (CIs) for ΔΔQTcF of SL-APO were below the 10-millisecond regulatory threshold at all prespecified timepoints, demonstrating no clinically significant effect on QTcF. Lower limits of 90% CIs for ΔΔQTcF of moxifloxacin exceeded the 5-millisecond regulatory threshold at all timepoints up to 3 hours, confirming assay sensitivity. SL-APO had no clinically meaningful effects on QTcB, PR/QRS intervals, heart rate, or electrocardiogram-derived morphology (EudraCT identifier: 2016-001762-29; ClinicalTrials.gov identifier: NCT03187301).

Sublingual apomorphine therapy as an alternative to complex continuous infusion pumps in advanced Parkinson's disease treatment: a district nurse-led intervention.

In the UK, Parkinson's disease (PD) is estimated to affect an annual incidence of 15-20 per 100 000 of the population over the age of 60. Service users living with advanced-stage PD require the use of apomorphine, which is generally used to control symptoms. The district nursing service plays a key role in monitoring and in the administration of apomorphine therapy. Although apomorphine is effective, skin problems such as nodules are commonly reported adverse events that can complicate efficiency of treatment. A sublingual delivery route to apomorphine has been known for years as a feasible alternative to subcutaneous route. Collaboration between the multidisciplinary team is essential to meet the complex needs of service users with advanced PD. However, due to the increase in demands of the district nurse service, this time crucial intervention can be unpredictable to meet. An alternative route can enable district nurses to become less task-orientated. However, an increased risk of oral cavity related adverse events should be taken into consideration with the sublingual administration of apomorphine.

Safety and efficacy of subcutaneous night-time only apomorphine infusion to treat insomnia in patients with Parkinson's disease (APOMORPHEE): a multicentre, randomised, controlled, double-blind crossover study.

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.

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

INTRODUCTION: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath. METHODS: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009. PD patients (n = 24) received placebo or 2, 3 or 4 mg AZ-009 once daily for 5 days, followed by three times daily for 2 days with 2 h between doses. Part B was a double-blind crossover study in 8 PD patients who experience OFF periods. During an OFF state, patients received 4 mg AZ-009 and placebo on two consecutive days in a randomized order. MDS-UPDRS III and ON/OFF state were assessed pre- and post-dose. RESULTS: Three times daily dosing with 2, 3 and 4 mg AZ-009 was relatively well tolerated with no apparent accumulation or changes in safety profile. Mild and transient throat irritation and cough were reported most often. AZ-009 was rapidly absorbed with median Tmax between 1 and 2 min. When corrected for placebo response, the maximum effect of 4 mg AZ-009 based on MDS-UPDRS III scores was observed at 10 and 30 min post-dose with mean (SD) reductions of 6.8 (9.4) and 6.1 (9.1) points respectively. Whereas 0% of patients turned ON after placebo, 50% turned ON 10 min after 4 mg AZ-009 treatment. CONCLUSION: AZ-009 is rapidly systemically absorbed and safe to dose three times daily. AZ-009 could provide a faster-acting and easier to use formulation than currently available therapies.

Antiparkinsonian activity of Tabebuia impetiginosa bark and biochemical analysis of dopamine in rat brain homogenates.

OBJECTIVES: Improving economy and well-being in developing nations like India has expanded life expectancy and changed the attention from transmittable to non transmittable diseases such as Parkinson's disease. Tabebuia impetiginosa has been utilized by cultivators as a general tonic, immunostimulant, adaptogen and also in motor disorders. The present investigation was to explore the antiparkinsonian activity of Tabebuia impetiginosa bark by experimental methods. MATERIALS AND METHODS: Control group-I was served with distilled water. Group-II was considered as pathological control [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2mg/nostrils i.n, Reserpine 40mg/kg s.c, Haloperidol 0.5mg/kg, i.p]. Group-III served with standard drug (Apomorphine 40mg/kg, s.c). Group IV and V received aqueous extract of Tabebuia impetiginosa bark in doses of 300 and 500mg/kg/day respectively. Tremor, hypokinesia, muscular rigidity, catatonia, postural immobility, postural instability and catalepsy were assessed for antiparkinsonian activity. RESULTS: The bark extract served group exhibited the increased levels of dopamine (5700±1.84ng/g) when compared to control groups (4300±3.17ng/g). The extract at both the doses displayed a significant reduction in postural flexion, moderate decrease in tremor, muscular rigidity and postural immobility scores but do not exhibit significant lowering of hypokinesia score in reserpine induced Parkinsonian model. The reduction in catatonia and catalepsy scores is more remarkable in case of high dose of extract (500mg/kg) compared to standard drug in Neuroleptic induced Parkinsonism. CONCLUSION: The findings demonstrate that Tabebuia impetiginosa bark extract has significant anti-cataleptic potentials and the antioxidant effect of the bark may also be a significant contributor to its antiparkinsonian activity.

Evaluation of subcutaneous versus intravenous administration of apomorphine for induction of emesis in dogs.

OBJECTIVE: To prospectively compare the effectiveness and any adverse effects of apomorphine administered SC or IV for induction of emesis in dogs. ANIMALS: 42 client-owned dogs. PROCEDURES: Dogs for which emesis induction was deemed appropriate by the attending clinician were prospectively randomized to receive apomorphine (0.03 mg/kg [0.01 mg/lb]) either SC (n = 20) or IV (22). Data collected included whether emesis was successfully induced, time from drug administration to emesis, number of emetic events, and adverse events (eg, sedation, protracted vomiting, or other). RESULTS: Of the 20 dogs given apomorphine SC, 16 (80%) vomited. Of the 22 dogs given apomorphine IV, 18 (82%) vomited. With regard to route of administration, the number of dogs in which emesis was induced did not differ significantly. Median time to the first emetic event was 13.5 minutes (range, 3 to 32 minutes) in the SC treatment group and 2 minutes (range, 1 to 5 minutes) in the IV treatment group; the difference was significant. There was no significant difference in the number of emetic events or frequency of adverse events between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: Apomorphine administered SC or IV reliably induced emesis in dogs. Compared with SC administration of apomorphine, the time from drug administration to emesis associated with IV administration was significantly shorter, a finding that has clinical importance.

Treatment of subcutaneous nodules after infusion of apomorphine; a biopsy-controlled study comparing 4 frequently used therapies.

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology.

Apomorphine hydrochloride: a sublingual tablet for the OFF episodes in Parkinson's disease.

Parkinson's disease is one of the commonest neurodegenerative disorders, particularly in those over 60 years of age. Although the introduction of levodopa was a tremendous advance in its treatment, the condition is a progressive one. It has been found that the longer patients have the condition and are treated with levodopa, the more likely they are to develop OFF episodes in which their ability to do things becomes increasingly limited. The development of a sublingual apomorphine hydrochloride film (APL-130277, Kynmobi) was designed to alleviate this OFF condition by allowing the patients to experience rapid relief of their OFF episodes up to 5 times a day.

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study.

INTRODUCTION: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP). METHODS: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO. RESULTS: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515). CONCLUSIONS: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.

Necrotic Ulcers Secondary to Apomorphine Infusion.

Background: Apomorphine is a potent dopamine agonist used in the treatment of advanced and fluctuating Parkinson's Disease. However the need for its subcutaneous infusion can lead to skin reactions. Phenomenology Shown: We illustrate necrotic ulcers at infusion sites as a rare event during continuous subcutaneous apomorphine infusion. Educational value: This case demonstrates the rare adverse event of necrotic ulcers in a patient with long term apomorphine infusion.

Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and "OFF" episodes.

INTRODUCTION: The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of "OFF" episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. METHODS: Adult patients with levodopa-responsive PD and "OFF" episodes were enrolled. In practically defined "OFF," patients were observed for a FULL "ON" after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10-35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. RESULTS: Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL "ON" (66.1% at 10-20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). CONCLUSION: Among eligible patients with PD and "OFF" episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of "OFF" episodes.