Preference for a Novel Oral Alternative to Parenterally Administered Medications.

Background: Rani Therapeutics is developing a robotic pill (RP), an oral drug delivery platform called RaniPill™ that can deliver a number of biotherapeutics with high bioavailability; eliminating the need for injections. While patients in general prefer oral to injectable therapies, preference for a more frequent oral regimen compared to a less frequent injectable regimen is unknown. Two marketing surveys were conducted to gather data on preference for oral versus injectable therapies. A clinical study gathered data on participant preference for oral pills vs injections before and after swallowing a Mock-RP capsule. Methods: A total of 1689 adults taking injections (mean duration 3-7 years) to treat endocrine or inflammatory conditions were anonymously surveyed online for their preference to administer/prescribe medications orally via the RP. In the clinical study, 150 participants currently taking injections for chronic conditions evaluated the swallowability of a Mock-RP and completed a questionnaire regarding their preferences. Results: Majority of respondents surveyed stated they would be willing to convert to an oral alternative over their current parenteral therapy regardless of drug or disease. In the clinical study, all participants were able to swallow the Mock-RP and 91% indicated their preference for the oral route versus their current parenteral route of drug administration. Survey respondents and those in the clinical study using frequent injections were more willing to select a once-daily capsule compared to those injecting infrequently. Even study participants who inject infrequently (≥monthly: 80%) would prefer a once-daily pill over their injection regimen. Conclusion: Patients taking injections and prescribing physicians strongly prefer oral dosing to parenteral administration of biologics even if dosing frequency with the oral option, such as the RP, is increased.

Impact of clozapine once-daily versus multiple-daily dosing regimen on relapse in patients with treatment-resistant schizophrenia: A 1-year retrospective cohort study.

RATIONALE: Clozapine, the standard treatment for treatment-resistant schizophrenia (TRS), is generally recommended in a multiple-daily dosing regimen. However, it is commonly administered once daily in clinical practice. Few studies have compared the longitudinal clinical outcomes of these two dosing regimens. OBJECTIVE: To investigate the effect of once-daily versus multiple-daily dosing regimens of clozapine on relapse in patients with TRS. METHODS: This retrospective cohort study included patients with TRS who commenced treatment with clozapine during hospitalization and were discharged between April 2012 and January 2022 from a tertiary psychiatric hospital in Japan. Relapse, defined as a psychiatric exacerbation requiring re-hospitalization within the first-year post-discharge, was analyzed. Multivariable Cox proportional hazards regression analysis compared the relapse risk between once-daily and multiple-daily dosing regimens. A subgroup analysis was conducted to examine the potential interactions between dosing regimen and dose category (low versus high dose). RESULTS: Among 179 patients, 107 (59.8%) received clozapine once daily. No significant difference in the relapse risk was observed between once-daily and multiple-daily dosing regimens (adjusted hazard ratio [aHR]: 1.16; 95% confidence interval [CI]: 0.68-1.99; p = 0.58). However, in patients receiving high doses of clozapine (> 300 mg/day), multiple-daily dosing increased the relapse risk compared to once-daily dosing (aHR: 2.23; 95% CI: 1.00-4.97; p = 0.049). CONCLUSIONS: Once-daily clozapine dosing may not be associated with an increased relapse risk. The increased relapse risk in high-dose multiple-daily dosing may be confounded by unmeasured non-adherence. Further randomized controlled trials are required to validate these findings.

Acquired Human Immunodeficiency Virus Type 1 Drug Resistance in Rhode Island, USA, 2004-2021.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) acquired drug resistance (ADR) compromises antiretroviral therapy (ART). METHODS: We aggregated all HIV-1 protease-reverse transcriptase-integrase sequences over 2004-2021 at the largest HIV center in Rhode Island and evaluated ADR extent, trends, and impact using Stanford Database tools. Trends were measured with Mann-Kendall statistic, and multivariable regressions evaluated resistance predictors. RESULTS: Sequences were available for 914 ART-experienced persons. Overall ADR to any drug decreased from 77% to 49% (-0.66 Mann-Kendall statistic); nucleoside reverse transcriptase inhibitors 65% to 32%, nonnucleoside reverse transcriptase inhibitors 53% to 43%, and protease inhibitors 28% to 7% (2004-2021), and integrase strand transfer inhibitors 16% to 13% (2017-2021). Multiclass resistance decreased from 44% to 12% (2-class) and 12% to 6% (3-class). In 2021, 94% had at least one 3-drug or 2-drug one-pill-once-daily (OPOD) option. Males and those exposed to more ART regimens were more likely to have ≥2-class resistance, and higher regimen exposure was also associated with fewer OPOD options. CONCLUSIONS: Comprehensive analyses within a densely-sampled HIV epidemic over 2004-2021 demonstrated decreasing ADR. Continued ADR monitoring is important to maintain ART success, particularly with rising INSTI use in all lines of therapy and 2-drug and long-acting formulations.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

Once-weekly insulin icodec versus once-daily long-acting insulins for type 2 diabetes mellitus: Systematic review and meta-analysis.

Background: Insulin icodec is a novel, long-acting, once-weekly basal insulin analog. Its comparative efficacy and safety with basal once-daily insulins in type 2 diabetes mellittus is uncertain. Objective: Evaluate potential efficacy, benefits and risks associated with icodec compared to once-daily basal insulin analogs (degludec or glargine). Methods: We systematically searched PubMed, Cochrane, and Embase for randomized controlled trials (RCTs) published until June 2023 comparing icodec versus long-acting insulin analogs (degludec and glargine) in type 2 diabetes mellitus (T2DM) with at least 12 weeks of follow-up. Binary endpoints were assessed with risk ratios (RRs) and continuous endpoints were compared using mean differences (MDs), with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD42023452468). Results: A total of seven RCTs and 3286 patients with T2DM were included, of whom 1509 (60.6%) received icodec treatment. The follow-up period ranged from 16 to 78 weeks. Compared with once-daily basal insulin analogs, icodec led to a greater improvement in HbA1c (MD -0.15%; 95% CI -0.21, -0.10; p < 0.0001; I2 = 0%) and time in range (TIR) (MD 2.83%; 95%CI 0.94; 4.71; p = 0.003; I2 = 22%). Body weight was increased with icodec treatment (MD 0.78 Kg; 95%CI 0.42, 1.15; p < 0.01; I2 = 86%). There was also a higher rate of injection site reactions (RR 1.89; 95%CI 1.12, 3.18; p = 0.016; I2 = 0%) and nasopharyngitis (RR 1.94; 95%CI 1.11, 3.38; p = 0.020; I2 = 0%) in the icodec group, compared with once-daily regimens. There was no significant difference between groups in fasting plasma glucose. Conclusions: In this meta-analysis of RCTs, insulin icodec led to better control of HbA1c and TIR as compared with once-daily insulin regimens, albeit with increased weight gain and a higher rate of injection site reaction in the Icodec group.

Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times.

Purpose: Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Patients and methods: Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Results: Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. Conclusion: While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder.

INTRODUCTION: Amphetamine preparations are one of the two categories of stimulant medications approved for the treatment of attention deficit hyperactivity disorder (ADHD). Optimal treatment of ADHD aims to reduce core symptoms for as much of the waking hours as possible, leading to longer-acting delivery formats. In addition, the pediatric population commonly has difficulty swallowing pills and manufacturers have developed a variety of options to facilitate this concern. These include chewable tablets, capsules that may be sprinkled on soft food, liquids and transdermal patches. AREAS COVERED: This article reviews the once-daily extended-release preparations currently available for amphetamine compounds, their pharmacodynamics, and common adverse effects. EXPERT OPINION: There is an extensive evidence base supporting use of amphetamine preparations in the treatment of ADHD. Rapid onset of action and a favorable side effect profile make these widely used. The availability of once-daily extended-release chewable tablets, capsules that can be opened and sprinkled, and liquid formulations provides clinicians with multiple options to meet the specific needs of patients with difficulty swallowing whole pills.

A Bioequivalence Comparison Between the Once-Daily Extended-Release Tablet and the Twice-Daily Tablet Formulations of Deutetrabenazine at Steady State.

Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once-daily (test) and twice-daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24 mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7 days. Plasma concentrations were collected on Days 4-6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α-dihydrotetrabenazine (α-HTBZ) and ß-dihydrotetrabenazine (ß-HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration-time curve over 24 hours at steady state (AUC0-24 h,ss ) and for maximum plasma concentrations at steady state (Cmax,ss ). The GMRs for AUC0-24 h,ss were 115% for deutetrabenazine and 95% for deuterated total (α+ß)-HTBZ; and the GMR for Cmax,ss for deutetrabenazine was 95%. Relative bioavailability was assessed for Cmax,ss of the active metabolites; the GMR was 78% for total (α+ß)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and Cmax, and the active metabolites were bioequivalent with regard to AUC0-24 h,ss .

Epinastine Cream: A Novel Once-Daily Therapeutic Agent for Allergic Conjunctivitis.

Purpose: To investigate the in vivo efficacy of epinastine cream in type I allergic models. Methods: The dose, timing, and antiallergic effect of epinastine cream on the conjunctiva were evaluated postapplication to the eyelid skin of guinea pigs with histamine- or ovalbumin-induced allergic conjunctivitis. Additionally, we assessed its antiallergic effects on the skin postapplication to the dorsal skin of guinea pigs with ovalbumin-induced passive cutaneous anaphylaxis. Efficacy was estimated by determining the amount of dye that leaked from conjunctival or dorsal skin tissue vessels as a measure of vascular permeability, scoring the severity of allergic symptoms, and observing the scratching behaviors using clinical parameters. Results: In the histamine-induced conjunctivitis model, epinastine cream strongly inhibited conjunctival vascular permeability in a dose-dependent manner. The inhibitory effect of 0.5% epinastine cream 24 h postapplication was significantly higher than that of 0.1% epinastine hydrochloride ophthalmic solution 8 h postadministration. Additionally, the 0.5% epinastine cream inhibited conjunctival vascular permeability 15 min postapplication, and the effect was sustained over 24 h. Furthermore, the 0.5% epinastine cream effectively suppressed clinical symptom scores and exhibited ameliorated scratching bouts in conjunctival allergic reactions in the experimental allergic conjunctivitis model. Additionally, it significantly inhibited vascular permeability in skin allergic reactions in the passive cutaneous anaphylaxis model. Conclusions: The results suggest that epinastine cream is a strong, long-lasting, and skin-penetrating inhibitor of type I allergic reactions. The 0.5% epinastine cream applied once daily could be a promising, potent, and long-acting therapeutic agent for allergic conjunctivitis.

Neonatal Serum Gentamicin Concentrations and Outcomes Following Maternal Once-Daily Gentamicin Dosing.

OBJECTIVE: This study evaluated newborn gentamicin serum concentrations after birth and the effects on the newborn after extended interval gentamicin dosing in peripartum mothers. METHODS: This was a single-center, retrospective chart review of neonates born to mothers that received peripartum once-daily gentamicin dosing of approximately 5 mg/kg within 12 hours of delivery. A gentamicin serum concentration was obtained immediately after birth in the newborn. The primary outcome was initial neonatal gentamicin serum concentration after birth. Several secondary outcomes were evaluated including nephrotoxicity and ototoxicity. A subgroup analysis comparing baseline demographics of mother-newborn dyads with birth neonatal serum concentrations of less than 2 mcg/mL versus 2 mcg/mL or greater was performed. RESULTS: A total of 32 mother-newborn dyads were included. Newborns had a median gestational age of 39.4 weeks and median birth weight of 3.4 kg. The mean initial gentamicin serum concentration was elevated at 3.1 ± 1.9 mcg/mL among all newborns. The median maternal dose based on actual body weight in newborns with gentamicin serum concentrations less than 2 mcg/mL was 3.5 (IQR, 3.3-4.8) mg/kg versus 4.8 (IQR, 4.3-5.2) mg/kg in those that had serum concentrations of 2 mcg/mL or greater (p = 0.025). All newborn gentamicin serum concentrations were less than 2 mcg/mL for maternal doses given less than 1 hour prior to delivery (n = 8). There were no significant differences in nephrotoxicity or ototoxicity. CONCLUSIONS: Peripartum once daily dosing of gentamicin administered between 1 to 12 hours of birth may lead to clinically significant serum concentrations in newborns.

Is it preferable to administer a bronchodilator once- or twice-daily when treating COPD?

Nocturnal and early morning symptoms are common and uncomfortable in many patients with COPD, and are likely to affect their long-term outcomes. However, it is still debated whether it is better to give long-acting bronchodilators once- or twice-daily to symptomatic COPD patients. The functional link between circadian rhythms of autonomic tone and airway calibre explains why the timing of administration of bronchodilators in chronic airway diseases can induce different effects when taken at different biological (circadian) times. However, the timing also depends on the pharmacological characteristics of the bronchodilator to be used. Because the profile of bronchodilation produced by once-daily vs. twice-daily long-acting bronchodilators differs throughout 24 h, selecting long-acting bronchodilators may be customized to specific patient preferences based on the need for further bronchodilation in the evening. This is especially helpful for people who experience respiratory symptoms at night or early morning. Compared to placebo, evening bronchodilator administration is consistently linked with persistent overnight improvements in dynamic respiratory mechanics and inspiratory neural drive. The current evidence indicates that nocturnal and early morning symptoms control is best handled by a LAMA taken in the evening. In contrast, it seems preferable to use a LABA for daytime symptoms. Therefore, it can be speculated that combining a LAMA with a LABA can improve bronchodilation and control symptoms better. Both LAMA and LABA must be rapid in their onset of action. Aclidinium/formoterol, a twice-daily combination, is the most studies of the available LAMA/LABA combinations in terms of impact on daytime and nocturnal symptoms.

Bilastine 0.6% preservative-free eye drops, an effective once-daily treatment to reduce signs and symptoms of allergic conjunctivitis: A pooled analysis of two randomized clinical trials.

BACKGROUND AND OBJECTIVE: Allergic conjunctivitis is the most common type of ocular allergy. The objective of this study was to evaluate the efficacy of a new once-daily, preservative-free, bilastine 0.6% eye drop formulation for the treatment of allergic conjunctivitis. METHODS: Two double-masked, vehicle controlled, clinical studies (a Phase 2 Dose Ranging Study and a Phase 3 Efficacy Study) were conducted to assess the efficacy of bilastine ophthalmic solution for the treatment of signs and symptoms of allergic conjunctivitis. Both studies used the Ora-CAC® Conjunctival Allergen Challenge (CAC) Model to allow observations of allergic responses under controlled conditions. Each study was analyzed separately and then combined to create an integrated dataset. RESULTS: Efficacy was achieved for the primary efficacy endpoint of ocular itching for three bilastine concentrations (0.2%, 0.4%, and 0.6%) at 15 minutes and 8 hours post-instillation and bilastine 0.6% ophthalmic solution was also efficacious at 16 hours post-instillation. Bilastine 0.6% ophthalmic solution demonstrated non-inferiority to ketotifen 0.025% at the onset of action. From the integrated data set, differences between vehicle and bilastine 0.6% were significant at all time points both at onset (15 minutes) and at a prolonged duration (16 hours) after instillation. CONCLUSION: This multi-trial assessment suggests that bilastine 0.6% ophthalmic solution is efficacious for the treatment of the signs and symptoms of allergic conjunctivitis, with a rapid and prolonged duration of action, and has a favorable safety profile. The added convenience of a once-a-day dosing regimen may contribute to patient adherence and improve their quality of life.

Comparison of the Effectiveness and Safety of Clozapine Between Once-Daily and Divided Dosing Regimen in Patients With Treatment-Resistant Schizophrenia.

BACKGROUND: Clozapine is the most effective antipsychotic with respect to the incidence of discontinuation and is indicated for treatment-resistant schizophrenia. Although the recommendation for clozapine administration is divided dosing, once-daily dosing of clozapine is commonly prescribed in many countries. However, there is currently no clinical data comparing all-cause discontinuation between the 2 methods of administration of clozapine. OBJECTIVES: To compare the all-cause discontinuation and safety of clozapine administration between once-daily and divided dosing regimens. METHODS: This was a retrospective cohort study. Participants were patients with treatment-resistant schizophrenia who had received 300 to 600 mg/day of clozapine for at least 3 months. Data were collected from outpatient medical records at Somdet Chaopraya Institute of Psychiatry. Eligible patients were classified into 2 groups: once-daily dosing and divided dosing. The primary outcome was the all-cause discontinuation rate between groups. The duration of the study was 2 years. RESULTS: One hundred eighteen patients were included and analyzed in this study (once-daily dosing group: n = 58; divided dosing group: n = 60). There was no significant difference in all-cause discontinuation between the 2 groups (odds ratio 1.03; 95% confidence interval: [0.28, 3.79]: P = 1.00), or adverse events between groups. CONCLUSION AND RELEVANCE: In patients with treatment-resistant schizophrenia, there were no significant differences in effectiveness or safety between once-daily and divided dosing of clozapine. Further prospective studies with larger sample sizes are required to confirm these findings.

Tapinarof Cream 1% Once Daily for the Treatment of Plaque Psoriasis: Case Photography of Clinical Outcomes from Three Phase 3 Trials.

Tapinarof cream 1% (VTAMA®; Dermavant Sciences, Inc.) is a non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis in adults and under investigation for the treatment of psoriasis in children down to 2 years of age, and for atopic dermatitis in adults and children down to 2 years of age. The PSOARING phase 3 clinical trial program evaluated tapinarof cream 1% once daily (QD) in adults with mild to severe plaque psoriasis for up to 52 weeks (NCT03956355, NCT03983980, NCT04053387). Here we present case photography documenting outcomes in the PSOARING trials. Cases illustrate various outcomes across different body areas, including responses meeting the formal FDA-mandated regulatory endpoint of a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points from baseline at week 12, meaningful clinical improvement not meeting this formal endpoint, patient-reported outcomes, and pre-specified adverse events of special interest (AESIs). Tapinarof cream 1% QD demonstrated rapid and highly statistically significant efficacy, with improvements in disease activity and quality of life. In addition, a high rate (40.9%; n = 312/763) of complete disease clearance (PGA = 0) was achieved, and improvements exceeding National Psoriasis Foundation treatment goals were demonstrated. After first achieving complete disease clearance (PGA = 0), patients treated with tapinarof experienced an approximately 4-month remittive effect off therapy. Incidence and severity of folliculitis and contact dermatitis AESIs were generally mild or moderate, localized to the site of application, and associated with low discontinuation rates. Medical images are of importance in trials of dermatologic therapies to inform clinical decision-making and enhance patient assessment. Tapinarof cream 1% QD is efficacious and well tolerated in patients with mild to severe plaque psoriasis, with clinically relevant improvements seen early in the course of treatment.Clinicaltrials.gov numbers: NCT03956355, NCT03983980, NCT04053387.

Chronic Urticaria Biomarkers IL-6, ESR and CRP in Correlation with Disease Severity and Patient Quality of Life-A Pilot Study.

(1) Background: To assess the relationship between serum interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values and disease severity in patients with chronic spontaneous urticaria (CSU) and to examine which of these serum biomarkers better indicates disease severity. (2) Methods: Our pilot study included 20 patients with CSU who filled out questionnaires concerning disease severity and quality of life (the Urticaria Activity Score summed over 7 days [UAS7], the once-daily Urticaria Activity Score [UAS], the Urticaria Control Test [UCT], and the Dermatology Life Quality Index [DLQI]). Blood samples were taken to measure IL-6, ESR and CRP. (3) Results: ESR significantly correlated with the UAS7 (linear and moderate correlation; r = 0.496; p = 0.026), while CRP did not correlate with disease severity. IL-6 correlated with the once-daily UAS (r = 0.472; p = 0.036) and DLQI (r = 0.504; p = 0.023) (linear and moderate correlation) but not the UAS7 or UCT. (4) Conclusions: IL-6 was a better indicator of the once-daily UAS and DLQI, while ESR was a better indicator of the UAS7 (there was no correlation between IL-6, CRP and ESR parameters). Although our results are promising, this study should be conducted with a larger number of CSU patients.

Comparative efficacy and safety profile of once-weekly Semaglutide versus once-daily Sitagliptin as an add-on to metformin in patients with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: The emergence of genetically-modified human proteins and glucagon-like peptide-1 (GLP-1) receptor agonists have presented a promising strategy for effectively managing diabetes. Due to the scarcity of clinical trials focusing on the safety and efficacy of semaglutide as an adjunctive treatment for patients with type 2 diabetes who had inadequate glycemic control with metformin, we conducted a systematic review and meta-analysis. This was necessary to fill the gap and provide a comprehensive assessment of semaglutide compared to sitagliptin, a commonly prescribed DPP-4 inhibitor, in this patient population. METHODS: A comprehensive and systematic search was carried out on reputable databases including PubMed, the Cochrane Library, and Elsevier's ScienceDirect to identify relevant studies that compared the efficacy of once-weekly Semaglutide with once-daily Sitagliptin in individuals diagnosed with type 2 diabetes mellitus. The analysis of the gathered data was performed utilizing the random-effects model, which considers both within-study and between-study variations. RESULTS: The meta-analysis incorporated three randomized controlled trials (RCTs), encompassing 2401 participants, with a balanced distribution across the treatment groups. The primary focus of the study revolved around evaluating changes in HbA1C, blood pressure, pulse rate, body weight, waist circumference, and BMI. The findings revealed that once-weekly Semaglutide showed substantially improved HbA1C (WMD: -0.98; 95% CI: -1.28, -0.69, p-value: < 0.0001; I2: 100%), systolic (WMD: -3.73; 95% CI: -5.42, -2.04, p-value: <0.0001; I2: 100%) and diastolic blood pressures (WMD: -0.66; 95% CI: -1.02, -0.29, p-value: 0.0005; I2: 100%), and body weight (WMD: -3.17; 95% CI: -3.84, -2.49, p-value: <0.00001; I2: 100%) compared to once-daily Sitagliptin. However, there was an observed increase in pulse rate (WMD: 3.33; 95% CI: 1.61, 5.06, p-value: <0.00001; I2: 100%) associated with Semaglutide treatment. Regarding secondary outcomes, there was an elevated risk of total adverse events and premature treatment discontinuation with Semaglutide. The risk of serious, severe, moderate, and mild adverse events did not significantly differ between the two treatments. CONCLUSIONS: In conclusion, the administration of once-weekly Semaglutide exhibited a substantial reduction in HbA1c, average systolic blood pressure (SBP), mean diastolic blood pressure (DBP), body weight, waist circumference, body mass index (BMI), and a rise in pulse rate, as opposed to the once-daily administration of Sitagliptin.

Safety and Efficacy of Conversion to Once-Daily Tacrolimus from Twice-Daily Tacrolimus in Pediatric Liver Transplant Recipients.

BACKGROUND: Nonadherence to immunosuppression is the most common cause of late acute rejection in pediatric liver transplant (LT) recipients. A prolonged-release once-daily tacrolimus formulation was developed to improve adherence and long-term allograft survival. METHODS: We screened 179 pediatric LT recipients who converted from twice-daily tacrolimus (TD-TAC) to once-daily tacrolimus (OD-TAC) between February 2011 and September 2019. RESULTS: One hundred seventy-nine recipients converted to OD-TAC and were followed for 18 months. 152 OD-TAC-converted recipients (84.9%) experienced uneventful follow-up, while 21 recipients showed LFT elevation. Four recipients had biopsy-proven acute rejection within six months of conversion, all of which were successfully treated with steroid pulse. 166 recipients (92.7%) remain on OD-TAC and 13 (7.3%) were switched back to TD-TAC. The mean tacrolimus trough level significantly decreased three months following conversion (3.14 ± 1.9 ng/mL) compared with pre-conversion levels (3.69 ± 1.98 ng/mL). Mean tacrolimus trough levels remained unchanged from 3 months to 12 months following conversion. Percent coefficient of variation of tacrolimus trough levels decreased significantly from 32.5 ± 16.4 ng/mL to 27.5 ± 15.6 ng/mL after conversion to OD-TAC, reflecting a decrease in variation of tacrolimus trough levels following conversion. CONCLUSIONS: Conversion to OD-TAC in pediatric LT recipients with stable graft function is safe and effective. LEVEL OF EVIDENCE: Level IV.

Tapinarof cream 1% once daily for the treatment of plaque psoriasis: Patient-reported outcomes from the PSOARING 3 trial.

BACKGROUND: Tapinarof cream 1% once daily demonstrated significant efficacy versus vehicle and was well tolerated in two 12-week, phase 3 pivotal trials in adults with mild-to-severe plaque psoriasis. OBJECTIVE: To assess long-term, health-related quality of life and patient satisfaction with tapinarof. METHODS: Patients completing the 12-week trials were eligible for 40 weeks of open-label tapinarof based on Physician Global Assessment score in PSOARING 3, with a 4-week follow-up. Dermatology Life Quality Index was assessed at every visit; Patient Satisfaction Questionnaire responses were assessed at week 40 or early termination. RESULTS: Seven hundred sixty-three (91.6%) eligible patients enrolled; 78.5% completed the Patient Satisfaction Questionnaire. DLQI scores improved and were maintained. By week 40, 68.0% of patients had a DLQI of 0 or 1, indicating no impact of psoriasis on health-related quality of life. Most patients strongly agreed or agreed with all Patient Satisfaction Questionnaire questions assessing confidence in tapinarof and satisfaction with efficacy (62.9%-85.8%), application ease and cosmetic elegance (79.9%-96.3%), and preference for tapinarof versus prior psoriasis therapies (55.3%-81.7%). LIMITATIONS: Open-label; no control; may not be generalizable to all forms of psoriasis. CONCLUSIONS: Continued and durable improvements in health-related quality of life, high rates of patient satisfaction, and positive perceptions of tapinarof cream were demonstrated.

Bilastine 0.6% preservative-free eye drops, a once-daily treatment for allergic conjunctivitis.

BACKGROUND: Bilastine is a second-generation antihistamine approved for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. This trial evaluated the efficacy and safety of a new bilastine 0.6% preservative-free eye-drops formulation for the symptomatic treatment of allergic conjunctivitis. METHODS: This phase 3, multicenter, double-masked, randomized study evaluated the efficacy, safety and tolerability of bilastine 0.6% ophthalmic solution compared to ketotifen 0.025% and vehicle. The primary efficacy endpoint was ocular itching reduction. The Ora-CAC® Allergen Challenge Model was used to assess ocular and nasal symptoms at 15 minutes (onset of action) and 16 hours post-treatment. RESULTS: Subjects (N=228) were 59.6% male, and the mean (SD) age was 44.1 (13.4) years. Bilastine demonstrated efficacy in reducing ocular itching compared to vehicle at both onset of action and 16 hours post-treatment (P <0.001). Ketotifen showed improvement compared to vehicle 15 minutes post-treatment (P <0.001). Bilastine demonstrated statistical non-inferiority to ketotifen for all 3 post-CAC timepoints at 15 minutes post-instillation, based on an inferiority margin of 0.4. Bilastine demonstrated improvement over vehicle (P <0.05) for conjunctival redness, ciliary redness, episcleral redness, chemosis, eyelid swelling, tearing, rhinorrhea, ear and palate pruritus and nasal congestion at 15 minutes post-treatment. Ophthalmic bilastine was safe and well tolerated. Mean drop comfort scores were significantly better (P <0.05) for bilastine compared with ketotifen immediately upon instillation, and similar compared with vehicle. CONCLUSIONS: Ophthalmic bilastine effectively reduced ocular itching for 16 hours post-treatment, suggesting that it could be used as a once-daily treatment for the signs and symptoms of allergic conjunctivitis. ClinicalTrials.gov identifier: NCT03479307.