Modeling the subcutaneous pharmacokinetics of antibodies co-administered with rHuPH20.

Predicting the subcutaneous (SC) pharmacokinetics (PK) of antibodies in humans is challenging, with clinical data currently being the only reliable data source for modeling SC absorption and bioavailability. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that facilitates SC delivery of high-dose, high-volume therapeutics. Numerous monoclonal antibodies have been co-administered SC with rHuPH20 in a clinical setting, establishing an extensive PK database. The goal of this work is to demonstrate how aggregated clinical data can be leveraged in a universal modeling framework for characterizing SC antibody PK, resulting in parameterization that can be used in predictive simulations of new antibodies. Data for 10 individual antibodies co-administered SC with rHuPH20 were obtained from publicly available sources. PK modeling of each antibody was conducted using the same model structure, but uniquely parameterized. The model structure consisted of a two-compartment model to capture linear kinetics, plus a target-binding mechanism to accommodate nonlinear kinetics driven by antibody-target complex formation and elimination. The clinical PK profiles for all antibodies were accurately described using the universal modeling framework. The SC PK parameters of absorption and bioavailability were consistent across the range of antibody and target properties evaluated. SC administration with rHuPH20 yielded a 30% increase in absorption rate on average and similar or better bioavailability. These parameter values can serve as initial conditions for model-based PK predictions for new antibodies co-administered SC with rHuPH20 to enable evaluation of optimal SC dose and schedule regimens prior to and during clinical development.

The effect of hydatid cyst protoscolex somatic antigens on full-thickness skin wound healing in mouse.

BACKGROUND: Wound healing has evolved in recent years, resulting in diverse therapeutic options. OBJECTIVE: This study evaluated the effects of the somatic antigen of the hydatid cyst protoscolex on wound healing in mice with full-thickness skin wounds. METHODS: Fifty-four adult mice, weighing 25 ± 5 g and approximately 60 days old, were divided into three groups (A, B, and C), each further divided into three subgroups. Subgroups A1, A2, and A3 were assigned negative controls. B1, B2, and B3 received hydatid cyst somatic antigen tests at 10 µg/SC, whereas C1, C2, and C3 received somatic antigen tests at 20 µg/SC. Under general anesthesia, a wound biopsy puncture of 9.8 mm in diameter was performed on the mice's back and spine. In the experimental group, antigen and alum adjuvant were administered subcutaneously around the wound, while the control group received Phosphate-Buffered Saline (PBS). Using digital images, a geometric assessment was conducted on days 0, 1, 3, 6, 9, 12, 15, 18, and 21 post-wounding. The obtained images were analyzed by Image J software and after analyzing the data by SPSS software. RESULTS: A significant difference in terms of epithelization was observed in the antigen treatment group with a dose of 20 µg on days 3 and 6 (P < 0.05). Furthermore, the 20 µg antigen group was significantly higher than the 10 µg antigen group in terms of this factor on day 3 (P < 0.05). Skin samples were taken from all wounds on days 3, 10 and 21 for microscopic evaluation. Regarding epithelization, on day 10, a significant difference was observed in the treatment group with a concentration of 10 µg with the control group and the treatment group with a concentration of 20 µg (P < 0.05). CONCLUSION: Based on the results of the present study, it can be concluded that somatic antigens of protoscolex hydatid cyst are dose-dependent and antigens with a dose of 20 µg by subcutaneous injection accelerate wound healing and epithelialization.

Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Clinical Investigation of Large Volume Subcutaneous Delivery up to 25 mL for Lean and Non-Lean Subjects.

PURPOSE: To evaluate the clinical feasibility and tolerability of large volume subcutaneous delivery at different injection depths for lean and non-lean subjects. METHODS: A single-center, randomized, subject-blinded, crossover study in 62 healthy subjects was conducted to evaluate delivery of a 10-cP solution containing hyaluronic acid. Subjects were separated into lean and non-lean cohort by SC thickness. A syringe pump was used to study the effect of different volumes (5, 12, 25 mL) of a viscous placebo solution and needle lengths (6, 9 and 12 mm) delivered at 0.5 mL/min. RESULTS: Across all treatments, injection sites were observed to have negligible leakage, ~34 kPa of back pressure, and VAS of mild pain with higher pain from needle insertion than during injection. While mild to moderate erythema was the most frequently reported ISR and edema was most prominent for 25 mL injections, all ISRs were resolved within 4 hours post injection. Subjects were unbothered by ISRs across all treatments and rated them as low distress scores (average 1.0-1.5 out of 6). CONCLUSION: SC injection of 25 mL is feasible and tolerable using a low-pain formulation for abdomen injection irrespective of subcutaneous thickness and injection depths at a delivery rate of 0.5 mL/min.

Persistence on subcutaneous tocilizumab as monotherapy or in combination with synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients in Greece (EMBRACE study): a multicenter, post-marketing, non-interventional, observational trial.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic, inflammatory disease affecting multiple organs and causing physical disability over time. OBJECTIVE: The primary objective was to evaluate treatment persistence to subcutaneous tocilizumab (TCZ-SC). Additionally, treatment effects on persistence and their associations with clinical and patient-reported outcomes were assessed. METHOD: We performed a multicenter, non-interventional, 52-week observational study on 222 patients with moderate or severe RA. Clinical outcomes were evaluated by using disease activity score for 28 joints (DAS28) and European League Against Rheumatism (EULAR) response, and patients' perceptions were evaluated by using Health Assessment Questionnaire (HAQ), Visual Analog Scale (VAS) for pain, and patient global assessment (PtGA) of disease activity. Safety was assessed throughout the study. RESULTS: The mean age of the overall cohort was 62.2 ± 12.3 years, and 83.8% were females. Persistence to TCZ-SC was 89.6% at week 24 and 85.1% at week 52 in the overall cohort with slightly increased persistence in the combination group. At week 52, changes from the baseline were - 2.68 in DAS28, - 0.76 in HAQ, - 43.21 in VAS pain, and - 41.66 in PtGA (p < 0.0001 for all). Moderate and good EULAR response was achieved in 83.2% of patients. Non-serious and serious adverse events occurred in 18.5% and 3.2% of the participants, respectively. CONCLUSIONS: The current study confirms the favorable safety and effectiveness of TCZ-SC as well as its acceptability by RA patients in Greece, with sustained high persistence rates up to 52 weeks. TCZ-SC offers a sustainable treatment response in RA. Key Points • Based upon clinical and patient-reported outcomes, TCZ-SC is a highly effective and safe treatment modality in patients with moderate-to-severe RA. • Persistence to TCZ-SC was high throughout the study, both as monotherapy and in combination with csDMARDs. • TCZ-SC is effective both as monotherapy and when used in combination with other csDMARDs regardless of the line of treatment.

Safety, pharmacokinetics, and pharmacodynamics of anti-IL-4Rα antibody SHR-1819 in healthy subjects: A randomized, controlled phase I study.

SHR-1819 is a novel anti-IL-4Rα monoclonal antibody currently under clinical development for use in patients with type 2 inflammatory diseases. In this randomized, double-blind, placebo-controlled, single-dose escalation phase I trial, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR-1819 in healthy subjects. Subjects received a single subcutaneous injection of SHR-1819 or placebo, with dose escalation starting at 60 mg and subsequently increasing to 120, 240, 360, and 720 mg. A total of 42 eligible subjects were randomized, and 33 received SHR-1819 (1 subject in the 60 mg cohort and 8 subjects each in the 120, 240, 360 , and 720 mg cohorts) and 9 received placebo. SHR-1819 was well-tolerated, with the majority of adverse events being mild in severity. The exposure of SHR-1819 increased in a manner greater than proportionally with a dose range of 120 to 720 mg. The median Tmax was within 4-7 days (60-720 mg), and the mean half-life ranged from 2.88 to 5.97 days (120-720 mg). The clearance rate of SHR-1819 exhibited a decrease with increasing dose level. Administration of SHR-1819 resulted in a certain degree of reduction in the percentage change from baseline in concentrations of inflammatory biomarkers TARC/CCL17 and IgE, while the reduction of TARC/CCL17 concentrations showed a dose-dependent trend. More than half of the total subjects treated with SHR-1819 were reported antidrug antibody-negative. The preliminary data from this phase I study support further development of SHR-1819 for the treatment of type 2 inflammatory diseases.

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.

How spray drying processing and solution composition can affect the mAbs stability in reconstituted solutions for subcutaneous injections. Part II: Exploring each protein stabilizer effect.

Despite extensive research in spray drying of biopharmaceuticals, identifying the optimal formulation composition and process conditions to minimize the various stresses a biopharmaceutical undergoes during this drying process. The current study extends previous research on investigating how spray drying processing and solution composition can affect the stability of monoclonal antibodies (mAbs) in reconstituted solutions for subcutaneous injections. The decoupling process stresses on a model mAb (mAb-A) compared to the effect of coupled spray-drying stresses revealed that excipients and protein concentration had a more pronounced effect on stabilizing mAb-A against shear and thermal/dehydration stresses than spray drying operating conditions. These results prompted the continuation of the study, with the aim to investigate in greater depth the effect of mAb-A concentration in the formulation designated to spray-drying and then the effect of type and the concentration of individual excipients (sugars, amino acids and surfactants). The outcomes of this investigation suggest that a general increase in the concentration of excipients, particularly surfactants, correlates with a reduction in aggregation and turbidity observed in the reconstituted spray-dried mAb-A powders. These results, contribute to the identification of a suitable composition for a spray-dried mAb-A powder that ensures robust stability of the protein in reconstituted solutions intended for subcutaneous injection. This valuable insight has important implications for advancing the development of pharmaceutical formulations with enhanced stability and efficacy.

How spray drying processing and solution composition can affect the mAbs stability in reconstituted solutions for subcutaneous injections. Part I: Contribution of processing stresses against composition.

Spray drying is increasingly being applied to process biopharmaceuticals, particularly monoclonal antibodies (mAbs). However, due to their protein nature, mAbs are susceptible to degradation when subjected to various stresses during a drying process. Despite extensive research in this domain, identifying the appropriate formulation composition and spray drying conditions remains a complex challenge, requiring further studies to enhance the understanding on how process and formulation parameters impact mAb stability in reconstituted solutions. This research aims to explore spray drying as technique for producing pharmaceutical mAbs-based powders intended for reconstitution and subcutaneous injection. In the initial phase of this study, using a model mAb (mAb-A), the influence of dissociated and coupled process stresses on protein stability after solution reconstitution was investigated. The findings revealed a detrimental interplay of mechanical, interfacial, and thermal/dehydration stresses on mAb-A stability, notably characterized by an increase in protein aggregation. Subsequently, in a second phase, the study delved into the impact of spray drying processing conditions, the level of excipients, and protein concentration on mAb-A aggregation in reconstituted solutions. The obtained results highlighted the critical role of formulation composition as a parameter deserving further study, specifically concerning the selection of type and concentration of stabilizers to be added in the liquid mAb-A solution to be dried.

Dupilumab in real-life settings: a review of adverse events and their pathogenesis.

INTRODUCTION: Dupilumab is a safe and effective biological drug that revolutionized the treatment of atopic dermatitis (AD). Concerning adverse events (AEs), the most commonly reported included ocular involvement, nasopharyngitis, and injection site reactions in clinical trials. Anyway, its use in daily practice is revealing novel dupilumab-induced manifestations. AREAS COVERED: Relevant English literature (real-life studies, case series, reviews, and meta-analyses) regarding real-life adverse events induced by dupilumab were searched for up to 10 June 2023. EXPERT OPINION: Dupilumab is an effective treatment for AD, showing favorable safety profile since no routine laboratory monitoring is recommended. However, several cutaneous and extracutaneous AEs have been reported in real-life setting expanding the pool emerged from clinical trials. In detail, dupilumab may determine de-novo onset or exacerbation of preexisting conditions, whose pathogenesis is still unclear and seems to involve Th1/Th2 and Th2/Th17 immune-response imbalance. Also, the heterogeneity and the variable onset time of AEs with respect to dupilumab initiation warrant a thorough patients' history collection and strict short- and long-term monitoring. Finally, the most appropriate management of patients with AEs related to dupilumab should take into consideration efficacy for AD as well as severity and nature of the AE, available treatment and patients' preferences.

Inhibition of CD40L with Frexalimab in Multiple Sclerosis.

BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Complications of Injectables.

The field of non-surgical esthetic procedures has witnessed a significant surge in demand in recent years, with neuromodulators, skin treatments, and dermal fillers contributing significantly to the industry's growth. These procedures have become increasingly popular, reflecting the broader acceptance of esthetic enhancements in society. Neuromodulators play a pivotal role in facial rejuvenation, but they require precise knowledge of facial anatomy to optimize results and prevent complications. They include rare hypersensitivity reactions, local injection reactions, and brow and eyelid ptosis. Dermal fillers, both non-permanent and permanent, are widely used to restore volume and improve facial contours. However, they also carry risks, including bruising, temporary edema, and lumps. Permanent fillers present higher complication rates, and their use should be approached with caution. Vascular occlusion is a rare but severe complication associated with dermal fillers. To mitigate these risks, practitioners must have a comprehensive understanding of their compositions and potential complications. Overall, while non-surgical esthetic procedures offer remarkable results with minimal downtime, the importance of training, anatomic knowledge, and effective complication management cannot be overstated in ensuring patient safety and satisfaction in this evolving field of medicine.

An Open-Label Study to Assess Monthly Risperidone Injections (180 mg) Following Switch from Daily Oral Risperidone (6 mg) in Stable Schizophrenic Patients.

BACKGROUND AND OBJECTIVE: Long-acting injectable antipsychotics have shown benefits over oral medications with reduced hospitalization rates and improved health-related quality of life. RBP-7000 (PERSERIS®) is a monthly risperidone formulation (90 or 120 mg) for the treatment of schizophrenia administered by subcutaneous abdominal injection. The objective of this study was to assess a higher dose of 180 mg RBP-7000 and an alternate injection site. METHODS: Following stabilization on 6 mg/day (3 mg twice daily) oral risperidone, clinically stable schizophrenic participants received 3 monthly doses of 180 mg RBP-7000 in the abdomen followed by a fourth monthly dose of 180 mg RBP-7000 in the upper arm (each dose administered as two 90-mg injections). The primary endpoint was the steady-state average plasma concentration (Cavg(ss)) of risperidone and total active moiety after oral and RBP-7000 administration. Secondary endpoints included measures of clinical efficacy (Positive and Negative Syndrome Scale, Clinical Global Impression Scale for Severity of Illness), safety, and local injection-site tolerability to assess the switch from oral risperidone and compare injection sites. RESULTS: In all, 23 participants received at least one dose of RBP-7000, 16 received all four doses, and 15 completed the study. Monthly doses of 180 mg RBP-7000 provided similar Cavg(ss) of total active moiety compared with 6 mg/day oral risperidone. The pharmacokinetics of RBP-7000 were similar after injection in the abdomen versus upper arm. Clinical efficacy measures remained stable throughout the study. All RBP-7000 injections were well tolerated with no unexpected safety findings. CONCLUSIONS: The results support the use of 180 mg RBP-7000 in schizophrenic patients stable on 6 mg/day oral risperidone and a second injection site in the upper arm. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03978832.

Perioperative Insulin Pump Therapy Decreases Readmission Risk and Improves Outcomes in Patients with Diabetes.

OBJECTIVE: To evaluate the impact of temporary insulin pump use during hospitalization on glycemia, postoperative complications, and cost/utilization in perioperative patients with diabetes. METHODS: Patients (n=159) with type 2 diabetes and hospitalized for elective surgery were recruited from three hospitals. Subjects were categorized into the insulin pump group and the multiple daily subcutaneous insulin injection group according to their treatment therapy. Data were collected at admission, discharge, and 3 months post-discharge. RESULTS: Subjects in the CSII group who were still on insulin therapy transitioned from CSII to MDII; however, their daily insulin dosages were lower than those in the MDII group (15.31±10.98 U/d vs. 23.48±17.02 U/d, P=0.015) after discharge. In terms of medical costs, the CSII group had significantly higher hospitalization costs than the MDII group (112.36±103.43 thousand RMB vs. 82.65±77.98 thousand RMB, P=0.043). After 3 months, the CSII group had significantly lower outpatient costs than the MDII group (3.17±0.94 thousand RMB vs. 3.98±1.76 thousand RMB, P ˂ 0.001). In the MDII group, 10 patients reported severe postoperative complications requiring re-hospitalization; there were no similar reports in the CSII group. CONCLUSION: Temporary use of insulin pump therapy for perioperative patients with diabetes results in a reduction in blood glucose and blood glucose fluctuation during hospitalization, HbA1c, and the risk of postoperative complication and readmission, thus significantly decreasing costs in this complex patient cohort. Further work is needed to better understand indications for utilizing pump therapy based on diabetes phenotype and the complexity of planned surgical intervention.

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

Comparative pharmacokinetic and intracerebral distribution of MDMB-4F-BICA in mice following inhalation ('vapor') and subcutaneous injection.

MDMB-4F-BICA, also known as 4F-MDMB-BICA, is a new psychoactive substance that emerged in 2020. It is often illegally added to electronic cigarette oil for inhalation abuse, leading to serious adverse symptoms and even death. There are significant differences in pharmacokinetics between inhalation administration and conventional drug delivery methods. Inhalation administration can pass through the blood-brain barrier to enter the brain directly. However, the specific distribution of the drug in the brain following inhalation has not been well investigated. In order to scientifically compare the absorption and distribution of MDMB-4F-BICA after two administration methods (inhalation and subcutaneous injection), this study analyzed the drug concentration in mice blood and brain by LC-MS/MS after systemic exposure inhalation in the form of electronic cigarettes. The aim was to conduct the pharmacokinetics study of MDMB-4F-BICA after inhalation('vapor') administration. Pharmacokinetics and distribution of the compound revealed that the maximum concentrations in blood of this compound were reached at 0.5 min and 15 min, respectively, and the concentration in the brain reached the maximum at the same time after two modes of administration. The drug concentration in the brain was higher than that of subcutaneous injection, and the drug remained at a low concentration in the brain for a long period (20 ng/g brain tissue) with a significant distribution in several olfactory primary cortex brain regions. Taken together, the pharmacokinetics of the synthetic cannabinoid MDMB-4F-BICA after single systemic exposure inhalation were investigated for the first time in this study. A basis for subsequent evaluation research of inhalation-related harmfulness is provided by comparing the distribution of drugs in the brain after the two administration modes.

Clinically Meaningful Responses to Dupilumab Among Children Aged 6 Months to 5 Years with Moderate-to-severe Atopic Dermatitis who did Not Achieve Clear or Almost Clear Skin According to the Investigator's Global Assessment: A Post Hoc Analysis of a Phase 3 Trial.

In young children, atopic dermatitis (AD) imposes a multidimensional burden on many aspects of their quality of life (QoL) and that of their families. LIBERTY AD PRESCHOOL part B was a randomized, double- blinded, placebo-controlled phase 3 trial in 162 children (aged 6 months to 5 years) with moderate-to- severe AD receiving dupilumab or placebo, plus low-potency topical corticosteroids. Post hoc analyses were performed on the full analysis set (FAS) and a subset of patients with Investigator's Global Assessment score > 1 at week 16. The primary outcome was the proportion of patients at week 16 achieving a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms and QoL: ≥ 50% improvement in Eczema Area and Severity Index; and/or ≥ 4-point reduction in worst scratch/itch numerical rating scale; and/or ≥ 6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients receiving dupilumab vs placebo achieved the composite endpoint in both the FAS (77.7% vs 24.6%, p < 0.0001) and subgroup (68.9% vs 21.5%, p < 0.0001). Dupilumab provided rapid and significant, clinically meaningful improvements in AD signs, symptoms, and QoL in the overall group and subgroup of patients who did not achieve clear or almost clear skin at week 16.

Lipolytic agents for submental fat reduction: Review.

RESULT: The review delves into the realm of reducing submental fat, presenting a comprehensive analysis of various lipolytic agents used in plastic surgery and dermatology. The introduction establishes the context by defining the key indicators of a youthful neck and emphasizing the significant influence of fat in the aging process, particularly in the submental area. The usage of aminophylline involves subcutaneous injections, facilitating fat breakdown by increasing cyclic adenosine monophosphate and inhibiting adenosine receptors. Hypotonic pharmacologic lipo-dissolution induces fat dissolution via injected compounds under pressure, while lipolytic lymphatic drainage employs hyaluronidase to reduce tissue viscosity, aiding fat circulation. Glycerophosphorylcholine containing choline alfoscerate claims to activate fat metabolism, whereas the utilization of phosphatidylcholine combined with deoxycholate lacks cosmetic approval due to safety concerns. Deoxycholic acid has FDA approval for submental fat reduction, yet its mechanisms remain incompletely understood. Understanding the complex anatomy and mechanisms of lipolytic agents is essential for safe and effective submental fat reduction, despite evolving practices and off-label utilization. Clinical guidelines and references support this discussion, offering insights for safer applications.