Phase II, Double-Blinded, Randomized, Placebo-Controlled Clinical Trial Investigating the Efficacy of Mebendazole in the Management of Symptomatic COVID-19 Patients.

The outbreak of the COVID-19 pandemic has spread throughout the world, affecting almost all nations and territories. The current double-blind, randomized, placebo-controlled, phase II clinical trial sought to evaluate the clinical efficacy and safety of mebendazole as an adjuvant therapy for outpatients with COVID-19. The patients were recruited and divided into two groups: a Mebendazole-treated group and placebo group. The mebendazole and placebo groups were matched for age, sex, and complete blood count (CBC) with differential and liver and kidney function tests at baseline. On the third day, the C-reactive protein (CRP) levels were lower (2.03 ± 1.45 vs. 5.45 ± 3.95, p < 0.001) and the cycle threshold (CT) levels were higher (27.21 ± 3.81 vs. 24.40 ± 3.09, p = 0.046) significantly in the mebendazole group than in the placebo group on the third day. Furthermore, CRP decreased and CT dramatically increased on day three compared to the baseline day in the mebendazole group (p < 0.001 and p = 0.008, respectively). There was a significant inverse correlation between lymphocytes and CT levels in the mebendazole group (r = -0.491, p = 0.039) but not in the placebo group (r = 0.051, p = 0.888). Mebendazole therapy increased innate immunity and returned inflammation to normal levels in COVID-19 outpatients faster than it did in the placebo group in this clinical trial. Our findings add to the growing body of research on the clinical and microbiological benefits of repurposing antiparasitic therapy, specifically mebendazole, for SARS-CoV-2 infection and other viral infections.

Relative Lung and Systemic Bioavailability Along with Oropharyngeal Deposition of Salbutamol Post-Inhalation: A Pharmacokinetic Evaluation of Novel Inhaler Technique Training Gadgets.

Background: Suboptimal use of pressurized metered dose inhaler (pMDI) remains a major barrier to inhaled therapy success. Verbal inhaler technique training (VT) fails to maintain patients' good pMDI use, thus training tools might help. Trainhaler® (THR device) and Flo-Tone® CR (FTCR device), two novel pMDI technique training tools, were evaluated and compared in terms of relative lung and systemic bioavailability and oropharyngeal deposition of salbutamol inhaled from Ventolin® Evohaler® (GlaxoSmithKline) either alone following THR or connected to FTCR. Methods: Sixteen healthy adults inhaled 2 × 100 µg salbutamol puffs (1 minute apart) from Ventolin using the THR device or FTCR device in a two-period, randomized crossover study. A 7-day washout separated THR and FTCR approaches. Immediately after each puff inhalation, each subject gargled with 20 mL water for oropharyngeal deposition determination. Urine samples were collected 0.5 hour (pre-inhalation) and 0.5, 1.0, and 2.0 hours post-inhalation. Urine was then pooled till 24-hour post-inhalation. The relative lung bioavailability (0- to 0.5-hour urinary salbutamol excretion-USAL0.5) and relative systemic bioavailability (0- to 24-hour urinary excretion of salbutamol and its metabolite-USALMET24) were determined. Results: The mean (standard deviation [SD]) USAL0.5 of the THR and FTCR groups was 5.70 (6.43) and 11.39 (9.67) µg, respectively. The mean (SD) oropharyngeal deposition was 11.11 (4.37) and 6.09 (1.89) µg, respectively. The THR and FTCR devices were statistically significantly different in USAL0.5 and oropharyngeal deposition (p < 0.001), whereas there was no statistically significant difference in USALMET24. Conclusion: The THR device and the FTCR device showed positive impact on inhaled pMDI delivery. Indeed, the FTCR device doubled the relative lung bioavailability and minimized the unwanted oropharyngeal deposition of inhaled salbutamol. In practice, these pMDI trainers would complement and maintain VT. Study Registration: The study was registered on the ISRCTN registry (Reference: ISRCTN88332465-06/12/2017 [Prospectively Registered]).

ATTACHED, DETACHED and WITHOUT inhaler technique coaching tools to optimize pMDI use competence, asthma control and quality-of-life in asthmatic adults.

BACKGROUND: Poor pressurized metered dose inhaler (pMDI) technique is prevalent, which will diminish treatment gains. In a two-visit study, two novel pMDI training devices with feedback mechanisms; Trainhaler (THR) and Flo-Tone CR (FTCR), were evaluated alongside the traditional verbal inhaler training (VT) in asthma outpatients. METHODS: On visit 1, 18-60 year-old asthmatics with incorrect pMDI use [including peak inhalation flow (PIF) >60 L/min] signed consent and baseline pMDI technique, lung function, asthma control and quality-of-life were measured. Participants were randomized to receive pMDI technique training using VT, THR or FTCR. One hour post-training, the pMDI coordination and PIF were re-assessed. The THR and FTCR patients were given their assigned tools to take home to facilitate regular training. All outcomes were re-evaluated 6-8 weeks later (visit 2). RESULTS: Ninety-two asthmatics completed visit 1 (46 attended visit 2). Pre-training, 61.3% (VT), 61.5% (THR) and 65.0% (FTCR) patients similarly made ≥2 pMDI errors with mean PIFs 175.2, 187.1 and 158.9 L/min, respectively. pMDI use was significantly improved 1 h post-training. The subjects that completed visit 2 had significantly, yet equally, maintained the improved inhaler use; only 28.0% (VT), 26.2% (THR) and 21.7% (FTCR) patients made ≥2 pMDI errors with PIF improvements; 115.3, 94.6 and 96.1 L/min, respectively. Clinical outcomes remained comparable. CONCLUSIONS: VT improves the overall pMDI technique, however patients gradually forget their VT. The THR and FTCR devices are retained by the patients as their self-monitoring, all-time personal trainers that boost and maintain their VT between routine clinic visits.

Comparative pharmacokinetics of salbutamol inhaled from a pressurized metered dose inhaler either alone or connected to a newly enhanced spacer design.

BACKGROUND: Coordination between actuation of a pressurized metered dose inhaler (pMDI) and inhalation is a critical manoeuvre that many patients fail to perform correctly. pMDIs connected to spacers do not require hand-lung coordination. This study evaluated the relative lung and systemic bioavailability and oropharyngeal deposition of salbutamol post-inhalation from Ventolin® Evohaler® (GlaxoSmithKline) either alone following verbal inhaler technique counselling (VC) or connected to a newly improved Able Spacer® (AS). METHODS: In a two-period, randomized crossover study, 16 healthy adults inhaled 2 × 100 µg salbutamol puffs (1 min gap) from Ventolin using VC or AS. Immediately after each puff inhalation, each subject gargled with 20 mL water for oropharyngeal deposition (OD) determination. Urine samples were collected 0.5 h (pre-) and 0.5, 1.0 and 2.0 h post-inhalation. Urine was then pooled 2-24 h post-inhalation. The relative lung bioavailability (0-0.5 h urinary salbutamol excretion - USAL0.5) and systemic bioavailability (0-24 h urinary excretion of salbutamol and its metabolite - USALMET24) were determined. A one week washout separated VC and AS use. RESULTS: The mean (SD) USAL0.5 of VC and AS was 5.36 (4.48) and 12.80 (10.83) µg, respectively. The mean (SD) OD was 11.35 (3.37) and 0.48 (0.30) µg, respectively. VC and AS were significantly different in USAL0.5 and OD (p<0.001). USALMET24 was comparable (p>0.05). CONCLUSIONS: Compared with VC, AS doubled the inhaled salbutamol lung dose and minimised its precipitation in the oral cavity. The results suggest this inhalation aid can add therapeutic and safety benefits particularly in patients with continued pMDI technique issues despite repeated VC.

Evaluation of patients' real-world post-dispensing use and storage environments of tiotropium bromide Respimat® soft mist inhaler on its in vitro dose delivery and lung deposition.

BACKGROUND: Oral inhalation is the main drug delivery route for treating obstructive lung conditions. Thus, many inhaler devices with various design and pharmaceutical formulation have been introduced. The fine particle dose (FPD) and mass median aerodynamic diameter (MMAD ≤ 5 µm) of the aerosol delivered dose (DD) dictate the therapeutically effective peripheral lung deposition. This study evaluated the in vitro aerosol emission performance of tiotropium bromide emitted from Spiriva® Respimat® soft mist inhalers (R) after living under patients' real-world, post-dispensing handling environments. METHODS: This was a two-stage investigation. In the first clinical stage, research ethical approval was obtained to enrol patients already been using R for at least 3 months. Those who signed consent were given both new R to use and temperature and relative humidity (RH) handheld, portable data loggers to keep in the vicinity of the given R. The participants returned the given R and data loggers after 2 weeks. Patient recruitment took place in Amman, Jordan, during the summer (RS) and winter (RW). Subsequently, in the second laboratory stage, other R were strictly stored at an average of 21.0 °C and 46.9% RH as control (RC). The Next Generation Impactor (NGI) was used to evaluate the RS, RW and RC. The NGI was operated at a flow rate of 30 L/min. RESULTS: The RS were exposed to an average (range) 23.6 °C (18.2-37.5 °C) and 43.8% RH (21.4-60.0% RH) that were statistically comparable (p > 0.05) to that of the RW; 17.3 °C (13.2-26.7 °C) and 52.8% RH (26.3-69.1% RH). The RW and RC retention environments were statistically different (p < 0.05), whilst the RS and RC had comparable (p > 0.05) conditions. No significant differences (p > 0.05) were found in the tiotropium bromide DD (2.39 vs 2.43 µg), FPD (0.88 vs 0.90 µg) and MMAD (5.1 vs 4.98 µm) between the RS and RW, respectively. Compared to the RC inhalers, both the RS and RW devices had significantly higher FPD and relatively smaller tiotropium bromide particles. CONCLUSIONS: Using the R under the fluctuating summer and winter environments of our patients would not affect its overall tiotropium bromide emission performance. The significant increase in the respirable mass of the RS and RW might be offset by the increase in particles <1 µm particularly in patients with poor inhaler technique.

Delivered Lung Dose and Aerodynamic Particle Size Distribution of Salbutamol Pressurized Metered Dose Inhaler After Living Under Patients' Realistic Retention Environments.

Background: The impact of inhalers' postdispensing, real-life temperature and relative humidity (RH) environments on their delivered dose (DD) and aerodynamic particle size distribution (APSD) is usually overlooked. This work evaluated the salbutamol DD and APSD of Ventolin® Evohaler® (V) inhalers already been used and stored by respiratory patients. Methods: Adult patients, prescribed V for ≥3 months before study enrollment, were dispensed both new V to use and portable, handheld electronic temperature and RH data loggers to keep close to the given V before returning them both after 2-3 weeks. Patients' enrollment took place during summer (VS) and winter (VW) seasons. The returned V was then in vitro evaluated using the Next Generation Impactor, and compared with control V (VC) counterparts stored under 21°C and 46% RH. Results: The VS survived in fluctuating habitats of 21.2°C-40.4°C and 16.2%-63.2% RH, which significantly (p < 0.05) decreased the salbutamol DD from 80.4 to 70.5 µg compared with VC. This 12.3% DD reduction was accompanied with a decrease in the fine particle dose from 26.2 to 20.4 µg (p < 0.05), and an increase in the mass median aerodynamic diameter from 2.3 to 2.5 µm (p < 0.05). The VW and VC had equivalent DD and APSD. Conclusion: Patients using V are expected to receive smaller lung doses during the hot summer season compared with intentionally well-kept VC. To have equivalent lung deposition, V users should be advised to retain their inhalers around 20°C with minimal daily environmental fluctuations during summer times.

The impact of patients' real-life environmental temperature and humidity use conditions of tiotropium dry powder inhaler on its aerosol emission characteristics.

INTRODUCTION: Many factors can affect dry powder inhalers' (DPIs) aerosol emission and lung deposition. The fluctuation of environmental temperature and relative humidity (RH) that inhalers experience in realistic daily use has not been extensively evaluated. This work aimed to evaluate the delivered dose (DD) and aerodynamic particle size distribution (APSD) of tiotropium Handihaler DPI (H) after exposure to patients' real-life use environments. METHODS: Ethical approval was obtained to enrol adult patients already using H. Patients who gave written consent were given new H to use and HygroLog temperature and RH data loggers to keep in the vicinity of the given inhaler. The H and HygroLog were returned after 2 weeks. Patient recruitment was done during the summer (HS) and winter (HW). As control, other HC were stored as per the leaflet storage instructions. The Next Generation Impactor was used to evaluate the inhalers. RESULTS: The HC were stored under an average of 21.0 °C and 46.9% RH. The patients' HS and HW lived in an average (range) temperature (°C) 23.2 (18.3-38.2) and 17.8 (13.5-24.6), respectively, and RH 50.8% (24.3-65.3%) and 50.4% (30.6-72.4%), respectively. All H groups had comparable environments (p > 0.05). The HC, HS and HW gave similar tiotropium DD (µg) 7.60, 8.01 and 7.61, respectively (p > 0.05). Moreover, the fine particle dose µg (median diameter (µm)) were HC 2.41 (3.84), HS 2.55 (3.81) and HW 2.37 (3.83) (p > 0.05). CONCLUSIONS: The aerosol emission behaviour of tiotropium Handihaler was tolerant to real-life retention environments of patients in Amman, Jordan.

Mastery of pMDI technique, asthma control and quality-of-life of children with asthma: A randomized controlled study comparing two inhaler technique training approaches.

OBJECTIVE: Verbal counselling (VC) is the clinical standard for training patients on correct inhaler use. Patients fail to recall their VC with time. Ethical approval was obtained to compare the pressurized metered dose inhaler (pMDI) VC with Trainhaler (TH), a novel pMDI inhalation flow and technique training device, in children with asthma. METHODS: At visit 1, 7-17 year-old children with a pMDI hand-lung coordination problem including a fast peak inhalation flow (PIF) through pMDI >60 L/min were randomized into either VC group that received verbal pMDI training; or into TH group that were trained on- and given TH to practice at home. Whereas, children with correct pMDI use formed the control group (CT). Overall pMDI technique, PIF through inhaler, asthma control (AC) and quality of life (QoL) were evaluated. Participants were re-evaluated 6-8 weeks later (visit 2). RESULTS: Of 105 enrolled children; 76 completed the study (VC = 21, TH = 25 and CT = 30). VC decreased non-significantly (p > 0.05) the mean PIF from 104.0 L/min at visit 1 to 84.8 at visit 2. Whilst, the TH did significantly (p < 0.05) reduce the PIF from 113.5 to 71.4 L/min. The two approaches similarly and significantly (p < 0.05) improved the inhaler technique, AC and QoL scores. CONCLUSIONS: The TH improved the inhalation flow through the pMDI close to the ideal needed for adequate lung deposition. Both methods equally enhanced the children's mastery of pMDI use. This was reflected on better AC and QoL. Accessibility to TH might help maintaining the good inhaler use and decreasing regular VC.

Evaluation of asthma control, parents' quality of life and preference between AeroChamber Plus and AeroChamber Plus Flow-Vu spacers in young children with asthma.

OBJECTIVE: The AeroChamber Plus (AC) valved holding chamber has been enhanced to include the Flow-Vu (FV) inspiratory flow indicator that provides visual inhalation feedback during use. We have investigated if FV alters asthma control and whether parents accept it. METHODS: At visit 1, children with asthma, age 1-5 years, used an AC with their pressurised metered dose inhaler and 2 weeks later (visit 2) they were randomised to use either AC or FV. Subjects returned 6 (visit 3) and 12 (visit 4) weeks later. The Asthma Control (ACQ) and Paediatric Asthma Caregiver's Quality of Life (PACQLQ) questionnaires were scored at each visit, and their peak inhalation flow (PIF) when they used their spacer was measured. RESULTS: Forty participants in each group completed the study. There was no difference in the ACQ scores from visits 2 to 4 between the two groups. The improvements in the PACQLQ scores were greater in the FV group (p = 0.029). The mean difference (95% confidence interval) for the change from visits 2 to 4 between FV and AC groups was 0.05 (-0.33, 0.43) and 0.39 (0.035, 0.737) for the ACQ and PACQLQ, respectively. Most parents preferred the FV (p < 0.001). There was no difference in the PIF rates at each visit and between the two spacers. CONCLUSIONS: There was no change in asthma control of the young children but that of their parents improved. Parents preferred the FV and this could be related to their improved perception of their children's asthma control by better PACQLQ scores.

Indacaterol determination in human urine: validation of a liquid-liquid extraction and liquid chromatography-tandem mass spectrometry analytical method.

BACKGROUND: Indacaterol is a novel once-a-day inhaled ultra-long-acting ß2-agonist. Quantitative bioanalysis supports pharmacokinetic and clinical research. The aim of the current work was to validate an in-house developed high performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) analytical method for indacaterol determination in human urine samples. METHODS: A liquid-liquid extraction method has been developed to extract indacaterol from human urine samples using ethyl acetate. Indacaterol dry extract was reconstituted with 200 µL of the mobile phase (acidified water:methanol (30:70, v/v)) of which 5 µL was needed for the HPLC-MS/MS analysis. Indacaterol was eluted on a reversed C18 stationary phase with an isocratic mobile phase at a flow of 1 mL/min. Formoterol was the internal standard (IS). The MS/MS detection was employed with a turbo-ion spray ionization in the positive ion mode. A consensus of the international Guidelines for Bioanalytical Method Validation was followed. RESULTS: Indacaterol was detected at a mass to charge ratio (m/z) of 393.3 and its MS/MS daughter at 173.2. The retention times of indacaterol and IS were 1.60 and 1.20 min, respectively. Validated calibration curves were linear over a range of 0.075-100 ng/mL with correlation coefficients (r)≥0.990. The curves' regression weighting factor was 1/x. Method specificity was established in six different human urine batches. No matrix interference was observed. The intra- and inter-batch precision and accuracy within±20% (at lower limit) and±15% (other quality control (QC) levels) were confirmed. The indacaterol mean recovery (precision) percentages at Low, Mid, and High QC levels were 93.5 (3.84), 89.8 (2.15), and 92.2 (2.17), respectively. Short-term, long-term, freeze-thaw, and auto-sampler stability results were accepted. CONCLUSIONS: A specific, accurate and precise HPLC-MS/MS method has been validated for indacaterol quantification in human urine. This simple method is reproducible and robust to support future, indacaterol-related pharmacokinetic, bioequivalence and clinical studies.

Optimizing the inhalation flow and technique through metered dose inhalers of asthmatic adults and children attending a community pharmacy.

OBJECTIVE: Despite training, many patients continue to misuse their metered dose inhaler (MDI). Research Ethics Committee approval was obtained to evaluate two different methods to help patients use a slow inhalation flow when they use their MDI. METHODS: Asthmatic children (n = 17) and adults (n = 39) prescribed an MDI had their inhaler technique assessed. Those who achieved the recommended inhalation flow rate (IFR) of <90 l/min through their MDI formed the reference group (named (control--CT)). Others that had a poor inhaler technique with an IFR ≥ 90 l/min were randomized into either the verbal counseling (VC) group, who received verbal training on the correct MDI use with emphasis on using a slow IFR or into the 2ToneTrainer (2TT) group, who received the VC and a 2Tone Trainer to take home and use. 2TT is a training aid with audible feedback when the required slow inhalation flow is used. The participants were assessed on two occasions, 0 (baseline) and 6 weeks later. RESULTS: For the asthmatic adults, the median IFR at visit 1 was 68, 200, and 240 l/min for the CT, VC, and 2TT groups, respectively. Whereas on visit 2, the median IFR was 88, 48.5 (p < .001), and 65 (p < .001) l/min for the CT, VC, and 2TT groups, respectively. Improvements in asthma quality of life were achieved in VC and 2TT groups. The asthmatic children showed a similar trend. CONCLUSIONS: Training by VC and a training aid helps patients use a slow IFR with an MDI and improves asthma-related quality of life.