Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS: In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285.

Immunogenicity, Safety, and Efficacy of a Standalone Universal Influenza Vaccine, FLU-v, in Healthy Adults: A Randomized Clinical Trial.

Background: FLU-v is a broad-spectrum influenza vaccine that induces antibodies and cell-mediated immunity. Objective: To compare the safety, immunogenicity, and exploratory efficacy of different formulations and dosing regimens of FLU-v versus placebo. Design: Randomized, double-blind, placebo-controlled, single-center phase 2b clinical trial. (ClinicalTrials.gov: NCT02962908; EudraCT: 2015-001932-38). Setting: The Netherlands. Participants: 175 healthy adults aged 18 to 60 years. Intervention: 0.5-mL subcutaneous injection of 500 µg of adjuvanted (1 dose) or nonadjuvanted (2 doses) FLU-v (A-FLU-v or NA-FLU-v) or adjuvanted or nonadjuvanted placebo (A-placebo or NA-placebo) (2:2:1:1 ratio). Measurements: Vaccine-specific cellular responses at days 0, 42, and 180 were assessed via flow cytometry and enzyme-linked immunosorbent assay. Solicited information on adverse events (AEs) was collected for 21 days after vaccination. Unsolicited information on AEs was collected throughout the study. Results: The AEs with the highest incidence were mild to moderate injection site reactions. The difference between A-FLU-v and A-placebo in the median fold increase in secreted interferon-γ (IFN-γ) was 38.2-fold (95% CI, 4.7- to 69.7-fold; P = 0.001) at day 42 and 25.0-fold (CI, 5.7- to 50.9-fold; P < 0.001) at day 180. The differences between A-FLU-v and A-placebo in median fold increase at day 42 were 4.5-fold (CI, 2.3- to 9.8-fold; P < 0.001) for IFN-γ-producing CD4+ T cells, 4.9-fold (CI, 1.3- to 40.0-fold; P < 0.001) for tumor necrosis factor-α (TNF-α), 7.0-fold (CI, 3.5- to 18.0-fold; P < 0.001) for interleukin-2 (IL-2), and 1.7-fold (CI, 0.1- to 4.0-fold; P = 0.004) for CD107a. At day 180, differences were 2.1-fold (CI, 0.0- to 6.0-fold; P = 0.030) for IFN-γ and 5.7-fold (CI, 2.0- to 15.0-fold; P < 0.001) for IL-2, with no difference for TNF-α or CD107a. No differences were seen between NA-FLU-v and NA-placebo. Limitation: The study was not powered to evaluate vaccine efficacy against influenza infection. Conclusion: Adjuvanted FLU-v is immunogenic and merits phase 3 development to explore efficacy. Primary Funding Source: SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project.

Prefilled Cyclic Olefin Sterilized Syringes of Norepinephrine Injection Solution Do Not Need to Be Stabilized by Antioxidants.

Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, prefilled cyclic olefin polymer syringes are not compatible with sodium metabisulfite. The aim of this study was to develop a new formulation of 0.1-mg/mL norepinephrine solution without sodium metabisulfite which is chemically stable and sterile and can be stored in prefilled polymer syringes. Formulation studies were performed with 0.1-mg/mL norepinephrine solution with 0, 0.05, or 0.1% ascorbic acid added as antioxidant. The syringes were filled under nitrogen gassing, stored at 20 ± 5°C, and protected from daylight. Based on the formulation test results, the final formulation was defined and stability testing at 20 ± 5°C was performed measuring norepinephrine concentration, pH, clarity, color of the solution, subvisible particles, and sterility at time intervals up to 12 months. The norepinephrine concentrations at t = 22 weeks were 100.4%, 95.4%, and 92.2% for the formulations with no ascorbic acid and with 0.05% and 0.10% ascorbic acid, respectively. Three batches for the stability study were produced containing norepinephrine, sodium edetate, sodium chloride, and water for injections filled under nitrogen gassing and stored at 20 ± 5°C. Norepinephrine concentrations were respectively 98.8%, 98.6%, and 99.3% for batches 1, 2, and 3 at t = 12 months. It can be concluded that norepinephrine (0.1 mg/mL) solution without metabisulfite is stable for at least 12 months at room temperature when protected from daylight.

The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects.

INTRODUCTION: Female sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as T+S. AIM: The aim of this study was to compare the effect of a fed and a fasted state on the pharmacokinetics of sildenafil following administration of T+S. METHODS: Eighteen healthy women were administered T+S under fed and fasted conditions during 2 separate overnight visits in this randomized, open-label, balanced, 2-period, 2-treatment, 2-sequence crossover study. MAIN OUTCOME MEASURES: The pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil were determined over a 24-hour period. Total testosterone was assessed only at a limited number of time points for quality purposes, as sublingual uptake is not expected to be affected by food intake. RESULTS: The observed geometric mean ratios (GMRs) and 90% confidence intervals of sildenafil were not all contained within the prespecified bounds (0.80, 1.25). The GMR (90% CI) for plasma AUC0-last was 1.2753 (0.9706-1.6755); for AUC0-14h, it was 1.7521 (1.0819-2.8374); and for Cmax, it was 1.5591 (0.8634-2.8153). Only lower limits of the CIs fell within the bounds. For N-desmethyl sildenafil, the GMR (90% CI) for AUC0-last was 0.8437 (0.6738-1.0564); for AUC0-10h, it was 1.0847 (0.7648-1.5383); and for Cmax, it was 1.0083 (0.6638-1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone Cmax and Tmax under fed and fasted conditions, which is in line with expectations for a sublingual administration. CLINICAL IMPLICATIONS: The T+S combination tablet ruptures too late when taken in a fasted state and should therefore not be taken on an empty stomach. STRENGTHS & LIMITATIONS: This is a well-controlled study that provides important insights into the performance characteristics of the delayed-release coating of the combination tablet. The higher variability of the pharmacokinetic parameters in the fasted state was caused by severely delayed rupture in one-third of the women. A reason for this is proposed but the present data do not explain this phenomenon. CONCLUSION: The pharmacokinetics of sildenafil from this modified-release tablet are more robust under fed conditions as compared to the artificial fasted condition where no food is consumed 10 hours prior to and 4 hours after dosing. The dosing situation under the tested fasting condition does not represent the expected common use of this product. Patients should, however, be instructed not to take the tablet on an empty stomach. Bloemers J, Gerritsen J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Sildenafil After Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects. J Sex Med 2019; 19:1433-1443.

A systematic review and meta-analysis of microbial contamination of parenteral medication prepared in a clinical versus pharmacy environment.

PURPOSE: Preparation of parenteral medication in hospitals is a complex process with a risk of microbial contamination of the product, especially when inappropriately prepared. Contaminated parenteral medications can cause severe complications to patients and increase morbidity in hospitals. The aim of this literature review is to systematically evaluate the contamination rate of parenteral medications in hospitals prepared in a pharmacy environment and a clinical environment. METHODS: A literature search of PubMed and EMBASE from 2000 to 2018 was performed. Two different environments where preparation may be carried out were defined. Point estimates and 95% confidence intervals for contamination rates were calculated for each environment of medication preparation. The meta-analysis was performed using a random effects model. RESULTS: The contamination rates in the clinical environment (n = 13 studies) varied between 1.09 and 20.70%. In the pharmacy environment (n = 5), all contamination rates were 0.00% except for one study (0.66%). The point estimates (random effect model) for the overall contamination rate of doses prepared in the clinical environment was 7.47% (5.16-9.79%), and 0.08% for doses prepared in the pharmacy environment. The point estimates (random effect model) for the overall contamination rate of doses prepared by nursing/ medical staff was 7.85% (5.18-10.53%), and 0.08% for doses prepared by pharmacy staff. CONCLUSIONS: Significantly higher contamination rates were found for the preparation of parenteral medication in the clinical environment compared to pharmacy environment. In accordance with recent guidance, the almost 100-fold higher changes of contamination when reconstitution is performed in the clinical environment should urge hospitals to review their reconstitution process and apply risk-reducing measures to improve patient safety of parenteral therapy.

Associations of AMP and adenosine induced dyspnea sensation to large and small airways dysfunction in asthma.

BACKGROUND: Bronchial provocation is often used to confirm asthma. Dyspnea sensation, however, associates poorly with the evoked drop in FEV1. Provocation tests only use the large airways parameter FEV1, although dyspnea is associated with both large- and small airways dysfunction. Aim of this study was to explore if adenosine 5'-monophosphate (AMP) and adenosine evoke an equal dyspnea sensation and if dyspnea associates better with large or small airways dysfunction. METHODS: We targeted large airways with AMP and small airways with dry powder adenosine in 59 asthmatic (ex)-smokers with ≥5 packyears, 14 ± 7 days apart. All subjects performed spirometry, impulse oscillometry (IOS), and Borg dyspnea score. In 36 subjects multiple breath nitrogen washout (MBNW) was additionally performed. We analyzed the association of the change (Δ) in Borg score with the change in large and small airways parameters, using univariate and multivariate linear regression analyses. MBNW was analyzed separately. RESULTS: Provocation with AMP and adenosine evoked similar levels of dyspnea. ΔFEV1 was not significantly associated with ΔBorg after either AMP or adenosine provocation, in both univariate and multivariate analyses. In multivariate linear regression, a decrease in FEF25-75 during adenosine provocation was independently associated with an increase in Borg. In the multivariate analyses for AMP provocation, no significant associations were found between ΔBorg and any large or small airways parameters. CONCLUSION: AMP and adenosine induce equally severe dyspnea sensations. Our results suggest that dyspnea induced with dry powder adenosine is related to small airways involvement, while neither large nor small airways dysfunction was associated with AMP-induced dyspnea. TRAIL REGISTRATION: NCT01741285 at www.clinicaltrials.gov , first registered Dec 4th, 2012.

Predictors of clinical response to extrafine and non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma.

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD. STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201-216.

Realising the potential of various inhaled airway challenge agents through improved delivery to the lungs.

Inhaled airway challenges provoke bronchoconstriction in susceptible subjects and are a pivotal tool in the diagnosis and monitoring of obstructive lung diseases, both in the clinic and in the development of new respiratory medicines. This article reviews the main challenge agents that are in use today (methacholine, mannitol, adenosine, allergens, endotoxin) and emphasises the importance of controlling how these agents are administered. There is a danger that the optimal value of these challenge agents may not be realised due to suboptimal inhaled delivery; thus considerations for effective and reproducible challenge delivery are provided. This article seeks to increase awareness of the importance of precise delivery of inhaled agents used to challenge the airways for diagnosis and research, and is intended as a stepping stone towards much-needed standardisation and harmonisation in the administration of inhaled airway challenge agents.

Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial.

BACKGROUND: Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses. METHODS: In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18-60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 µg FLU-v in saline (arm 1), one dose of emulsified 500 µg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity. DISCUSSION: Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated. TRIAL REGISTRATION: EudraCT number 2015-001932-38 ; retrospectively registered clinicaltrials.gov NCT02962908 (November 7th 2016).

Personalized Medicine in Pediatrics: The Clinical Potential of Orodispersible Films.

Children frequently receive medicines that are designed for adults. The dose of commercially available products is adapted, mostly based on the child's bodyweight, thereby neglecting differences in pharmacokinetic and pharmacodynamics parameters. If commercial products are unsuitable for administration to children or are unavailable, extemporaneous pharmacy preparations are a good alternative. For this particular population, orodispersible films (ODFs) can be a highly attractive dosage form for the oral administration of drugs. ODFs are relatively easy to prepare in a hospital setting, create dose flexibility, and may suit an individual approach, especially for patients having difficulties in swallowing tablets or being fluid restricted. In this article, various aspects related to pharmacy preparations, clinical application, and preparation of ODFs for pediatric patients are highlighted and discussed.

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison.

AIM: The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non-adherence through circumventing the relatively complex temporal dosing scheme. METHODS: Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil. RESULTS: Formulation 2 had a higher maximum concentration (Cmax ) for testosterone, 8.06 ng ml(-1) (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng ml(-1)  h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml(-1) (95% CI 4.63, 6.69) and 5.12 ng ml(-1)  h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng ml(-1) (95% CI 126, 220) and a lower AUC, 476 ng ml(-1)  h (95% CI 401, 551) than formulation 1, 268 ng ml(-1) (95% CI 188, 348) and 577 ng ml(-1)  h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10). CONCLUSIONS: The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking. The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD. In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues. WHAT THIS STUDY ADDS: A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart. This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies.

Combinations of arginine and pullulan reveal the selective effect of stabilization mechanisms on different lyophilized proteins.

The stability of lactate dehydrogenase (LDH) and ß-galactosidase (ß-gal), incorporated in arginine/pullulan (A/P) mixtures at various weight ratios by lyophilization, was determined. The physicochemical characteristics of various A/P mixtures were assessed. With decreasing A/P ratios, the glass transition temperature of the formulations increased. Furthermore, arginine crystallization due to high relative humidity (RH) exposure was prevented at an A/P weight ratio of 4/6 or less. When stored at 0 % RH / 60 °C for 4 weeks, arginine was superior to pullulan as stabilizer. During storage at 43 % RH / 30 ℃ for 4 weeks, the enzymatic activity of LDH was best retained at an A/P weight ratio of 2/8, while ß-gal activity was relatively well-retained at A/P weight ratios of both 8/2 and 2/8. LDH seemed to be more prone to degradation in the rubbery state. In the glassy state, ß-gal degraded faster than LDH. Solid-state nuclear magnetic resonance spectroscopy showed that (labeled) arginine experienced a different interaction in the two protein samples, reflecting a modulation of long-range correlations of the arginine side chain nitrogen atoms (Nε, Nη). In summary, LDH stabilization in the A/P matrix requires vitrification. Further stabilization difference between LDH and ß-gal may be dependent on the interaction with arginine.

Clinical Validation of a Capillary Blood Home-Based Self-Sampling Technique for Monitoring of Infliximab, Vedolizumab, and C-Reactive Protein Concentrations in Patients With Inflammatory Bowel Disease.

BACKGROUND: Therapeutic drug monitoring provides important guidance for treatment of patients with inflammatory bowel disease (IBD) and could help to early identify treatment failure. This study aimed to validate a finger prick-based capillary blood sampling technique to measure biological trough levels and C-reactive protein (CRP) and evaluate patient performance and -support. METHODS: In this prospective cohort study, patients with IBD receiving infliximab (IFX) or vedolizumab (VEDO) therapy performed finger prick-based capillary blood sampling at home. Additionally, blood was collected through routinely performed in-hospital venepuncture prior to biological infusion. IFX, VEDO, and CRP concentrations were measured by enzyme-linked immunosorbent assay. The concordance between methods was statistically evaluated and a survey was conducted to assess practicality and patient support. RESULTS: In total, 81 patients (46 IFX, 35 VEDO) were enrolled. Mean differences between both methods were 0.42 (95% confidence interval, -1.74 to 2.58) µg/mL for IFX and 0.72 (95% confidence interval, -5.50 to 6.94) µg/mL for VEDO. Passing-Bablok regressions demonstrated no evidence for systematic or proportional biases. Venous and capillary IFX (ρ = 0.96, P < .001) and VEDO (ρ = 0.97, P < .001) levels strongly correlated and showed high intermethod agreement (Cohen's kappa: IFX = 0.82; VEDO = 0.94). Similarly, venous and capillary CRP levels were strongly correlated (ρ = 0.99, P < .001). Most patients (>95%) were able to successfully perform the self-sampling at home without prior instructions. CONCLUSIONS: This study clinically validated a finger prick-based capillary blood self-sampling technique allowing concomitant home monitoring of biological levels and CRP for patients with IBD, who reported substantial support, tolerability, and practicality.

Nanoparticle formulation of a poorly soluble cannabinoid receptor 1 antagonist improves absorption by rat and human intestine.

The inclusion of nanoparticles dispersed in a hydrophilic matrix is one of the formulation strategies to improve the bioavailability of orally administered Biopharmaceutics Classification System (BCS) class II and IV drugs by increasing their dissolution rate in the intestine. To confirm that the increased dissolution rate results in increased bioavailability, in vitro and in vivo animal experiments are performed, however, translation to the human situation is hazardous. In this study, we used a range of in vitro and ex vivo methods, including methods applying human tissue, to predict the in vivo oral bioavailability of a model BCS class II CB-1 antagonist, formulated as a nanoparticle solid dispersion. The enhanced dissolution rate from the nanoparticle formulation resulted in an increased metabolite formation in both rat and human precision-cut intestinal slices, suggesting increased uptake and intracellular drug concentration in the enterocytes. In Ussing chamber experiments with human tissue, both the metabolite formation and apical efflux of the metabolite were increased for the nanoparticulate solid dispersion compared with a physical mixture, in line with the results in intestinal slices. The pharmacokinetics of the different formulations was studied in rats in vivo. The nanoparticle formulation indeed improved the absorption of the cannabinoid receptor 1 (CB-1) antagonist and the delivery into the brain compared with the physical mixture. In conclusion, the combined approach provides a valuable set of tools to investigate the effects of formulation on the absorption of poorly soluble compounds in human intestine and may provide relevant information on the oral bioavailability in humans early in the development process.

Quantitative characterization of agglomerate abrasion in a tumbling blender by using the Stokes number approach.

Removal of microcrystalline cellulose agglomerates in a dry-mixing system (lactose, 100 M) predominantly occurs via abrasion. The agglomerate abrasion rate potential is estimated by the Stokes abrasion (StAbr) number of the system. The StAbr number equals the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. Basically, the StAbr number concept describes the blending condition of the dry-mixing system. The concept has been applied to investigate the relevance of process parameters on agglomerate abrasion in tumbling blenders. Here, process parameters such as blender rotational speed and relative fill volumes were investigated. In this study, the StAbr approach revealed a transition point between abrasion rate behaviors. Below this transition point, a blending condition exists where agglomerate abrasion is dominated by the kinetic energy density of the powder blend. Above this transition point, a blending condition exists where agglomerates show (undesirable) slow abrasion rates. In this situation, the blending condition is mainly determined by the high fill volume of the filler.

Inhalation of vaccines and antiviral drugs to fight respiratory virus infections: reasons to prioritize the pulmonary route of administration.

Many of the current pandemic threats are caused by viruses that infect the respiratory tract. Remarkably though, the majority of vaccines and antiviral drugs are administered via alternative routes. In this perspective, we argue that the pulmonary route of administration deserves more attention in the search for novel therapeutic strategies against respiratory virus infections. Firstly, vaccines administered at the viral portal of entry can induce a broader immune response, employing the mucosal arm of the immune system; secondly, direct administration of antiviral drugs at the target site leads to superior bioavailability, enabling lower dosing and reducing the chance of side effects. We further elaborate on why the pulmonary route may induce a superior effect compared to the intranasal route of administration and provide reasons why dry powder formulations for inhalation have significant advantages over standard liquid formulations.