Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial.

Importance: Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases ß-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD. Objective: To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations. Interventions: An escalating dose of oral ambroxol to 1.26 g per day. Design, Setting, and Participants: This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018. Main Outcomes and Measures: Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity. Results: Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations. Conclusions and Relevance: The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD. Trial Registration: ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24.

Safety Profile of the Newest Antiepileptic Drugs: A Curated Literature Review.

BACKGROUND: Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. METHODS: In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). RESULTS: The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. CONCLUSION: Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting.

Acid-responsive polymeric nanocarriers for topical adapalene delivery.

PURPOSE: The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery. METHODS: The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit® EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation. RESULTS: Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5 ± 0.6 µg.cm(-2).h(-1)) in comparison to that (3.9 ± 0.4 µg.cm(-2).h(-1)) in the control vehicle (Transcutol®). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did. CONCLUSIONS: The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy.

Topical corticosteroid delivery into human skin using hydrofluoroalkane metered dose aerosol sprays.

Drug loaded hydrofluoroalkane (HFA) sprays can generate effective pharmaceutical formulations, but a deeper understanding of the manner in which these dynamic systems drive the process of in situ semi-solid dosage form assembly is required. The aim of this study was to investigate the effect of the matrix assembly and composition on drug localisation in human skin. Comparing the characteristics of sprays constituting HFA 134a, ethanol (EtOH), poly(vinyl pyrrolidone) K90, isopropyl myristate (IPM), and poly(ethylene glycol) (PEG) demonstrated that the addition of non-volatile solvents acted to delay EtOH evaporation, control the degree of drug saturation (DS) and enhance the corticosteroid delivery from HFA spray formulations. In a dose matched skin penetration study the HFA sprays containing only EtOH as a co-solvent delivered 2.1 µg BMV (DS 13.5) into the tissue, adding IPM to the EtOH HFA delivered 4.03 µg BMV (DS 11.2), whist adding PEG to the EtOH HFA delivered 6.1 µg BMV (DS 0.3). Compared to commercial cream (delivering 0.91 µg BMV) the EtOH/PEG HFA spray deposited over 6 times (p<0.05) more drug into the skin. Post spray deposition characterisation of the semi-solid suggested that the superior performance of the EtOH/PEG HFA spray was a consequence of retarding EtOH evaporation and presenting the drug in an EtOH rich PEG residual phase, which promoted BMV passage through the SC and into epidermis.

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

Pharmacokinetic evaluation of intranasally administered vinyl polymer-coated lorazepam microparticles in rabbits.

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 µm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 µm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 µm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9 min; MP2, T (max) 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.

Free radical facilitated damage of ungual keratin.

Thioglycolic acid (TA) and urea hydrogen peroxide (urea H(2)O(2)) are thought to disrupt alpha-keratin disulfide links in the nail. However, optimal clinical use of these agents to improve the treatment of nail disorders is currently hindered by a lack of fundamental data to support their mechanism of action. The aim of this study was to investigate how the redox environment of ungual keratin, when manipulated by TA and urea H(2)O(2), influenced the properties of the nail barrier. Potentiometric and voltammetric measurements demonstrated that urea H(2)O(2) obeyed the Nernst equation for a proton coupled one-electron transfer redox process while TA underwent a series of redox reactions that was complicated by electrode adsorption and dimer formation. The functional studies demonstrated that nail permeability, measured through TBF penetration (38.51+/-10.94 microg/cm(2)/h) and nail swelling (244.10+/-14.99% weight increase), was greatest when relatively low concentrations of the thiolate ion were present in the applied solution. Limiting the thiolate ion to low levels in the solution retards thiolate dimerisation and generates thiyl free radicals. It appeared that this free radical generation was fundamental in facilitating the redox-mediated keratin disruption of the ungual membrane.