Design and development of a novel supportive care product for the treatment of sialorrhea in Parkinson's disease.

Sialorrhea or excessive drooling is a significant medical issue in Parkinson's disease (PD) and neurodegenerative disorders, although it is often underreported by patients. Sialorrhea affects a large proportion of PD patients, ranging up to 78% in advanced stages, with many PD patients considering drooling as their worst non-motor symptom. Sialorrhea affects up to a million patients with diverse neurological impairments, including cerebral palsy, amyotrophic lateral sclerosis (ALS), Huntington's, survivors of stroke and severe traumatic brain injury. Numerous approaches have been attempted to treat sialorrhea in PD patients, including surgical procedures, prosthetic devices, botulinum injections, systemic anticholinergic drugs, and speech and behavioral therapy. A novel drug treatment (NH004) to control the symptoms of sialorrhea is under development. The active ingredient is the anticholinergic drug tropicamide. Anticholinergic drugs work by blocking acetylcholine muscarinic receptors and ultimately decreasing saliva secretion via the reduction of parasympathetic autonomic nervous system activity. The tropicamide is delivered in a thin film designed to adhere to the buccal mucosa and to slowly dissolve within the oral cavity, allowing the drug to reach the underlying salivary gland. A pilot study testing NH004 in PD patients has suggested a potentially useful sialorrhea-reducing effect with NH004 compared to placebo. The advantages of NH004 include local bioavailability with low systemic exposure, rapid onset of action and, importantly, convenience of use for patients. This review summarizes the current knowledge and impact of sialorrhea as a common non-motor symptom in PD, treatment options, the anticholinergic drug tropicamide, the design and development of the thin film drug delivery system, and NH004 for the treatment of sialorrhea.

A double-blind, placebo-controlled, randomized, crossover pilot study of the safety and efficacy of multiple doses of intra-oral tropicamide films for the short-term relief of sialorrhea symptoms in Parkinson's disease patients.

OBJECTIVE: This proof-of-concept, pilot study aimed to explore the safety and anti-sialorrhea efficacy of single doses of intra-oral slow dissolving thin films containing tropicamide (NH004) or placebo. METHODS: Nineteen non-demented, idiopathic stable or fluctuating PD patients who complained of sialorrhea received 3 doses (0.3, 1, 3mg) of tropicamide and placebo in random order, separated by 7 days. A 10-cm visual analog scale (VAS) was used to measure the patient's subjective feelings of saliva levels at baseline and at 15, 30, 45, 90 and 120 min after treatment administration. For the last 7 patients, saliva volume was measured at baseline and 75 min after treatment. Fluctuating patients were evaluated in the ON-condition. RESULTS: The mean age of included patients was 67±12 years, 78% were male. Median disease duration was 8 years. The mean decrease in VAS score from baseline to 120 min were -0.55±0.54, -1.08±0.54, -1.53±0.52 and -0.81±0.51 for placebo and 0.3, 1 and 3mg tropicamide, respectively (F=0.6 p=0.6, ANOVA). Tropicamide 1mg resulted in a significant VAS score decrease (95%CI: -2.57 to -0.48). Saliva volume was reduced by 27%, 33% or 20% after tropicamide 0.3, 1 or 3mg vs 5% with placebo (p=0.5, Friedman). No adverse events were detected in any of the treatment sequences. DISCUSSION: Results of this pilot, proof-of-concept study show that NH004 was safe and exerted antisialorrhea effects worthy of further exploration.

Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury.

BACKGROUND: The prognosis of long-term severe disorders of consciousness due to traumatic brain injury is discouraging. There is little definitive evidence of the underlying mechanisms, but a deficiency of the dopaminergic system may be involved. METHODS: In a prospective open-labelled clinical study, the feasibility, relative efficacy and safety of continuous subcutaneous (s.c.) administration of apomorphine in Vegetative State (VS) or Minimally Conscious State (MCS) patients due to severe traumatic brain injury (TBI) was tested. Apomorphine was administered to eight patients. Outcome measures were the Coma Near-Coma Scale (CNCS) and Disability Rating Scale (DRS). RESULTS: Drug management was implemented without any problems. There was improvement in the primary outcomes for all patients. Awakening was seen as rapidly as within the first 24 hours of drug administration and as late as 4 weeks. Seven of the patients had completely recovered consciousness. All improvements were sustained for at least 1 year, even after apomorphine was discontinued. Drug-related adverse events were all anticipated and resolved after the dose was reduced. CONCLUSION: Based on this open-label pilot study, continuous s.c. apomorphine infusion appears to be feasible, safe and potentially effective in improving consciousness in patients in VS and MCS due to severe TBI.

Fast awakening from minimally conscious state with apomorphine.

BACKGROUND: Traumatic brain injury (TBI) can induce long-term severe disorders of consciousness. Evidence suggests an underlying dopaminergic deficit. Dopamine agonists may therefore play an important role in recovery of consciousness. OBJECTIVE: To explore the response to continuous subcutaneous administration of apomorphine in a patient who had remained in minimally conscious state for 104 days and to evaluate the anatomical substrate of the effect. DESIGN: A prospective, open-label, daily treatment, dose-escalation single case clinical study, with retrospective diffusion tensor image (DTI) evaluation. RESULTS: On the fist day of treatment, the patient was able to move his limbs on command and answer yes/no questions which had not been the case prior to apomorphine administration. Subsequently there was a full recovery of consciousness and substantial functional recovery that was sustained even after apomorphine discontinuation. At the highest dose, mild dyskinesias were observed. These resolved with a lowering of the dose. DTI demonstrated a decrease of thalamocortical and corticothalamic projections in this MCS patient compared to normal volunteers. CONCLUSION: Although this is an open-label single-patient case report, the data are consistent with the theory that a dopaminergic deficit underlies MCS and that it may be overcome with apomorphine administration.