Switching to Tirzepatide 5 mg From Glucagon-Like Peptide-1 Receptor Agonists: Clinical Expectations in the First 12 Weeks of Treatment.

OBJECTIVE: This prospective study aimed to describe the clinical course in terms of glycemic outcomes, body weight, and adverse events during the first 12 weeks following a switch from glucagon-like peptide-1 receptor agonists (GLP-1 RAs) directly to tirzepatide 5 mg. METHODS: Participants were ≥18 years with type 2 diabetes (T2D), glycated hemoglobin (HbA1c) ≥6.5% to ≤9.0%, body mass index ≥25 kg/m2 and were on a stable treatment dose of GLP-1 RAs (liraglutide every day [1.2, 1.8 mg], semaglutide once-weekly [0.5, 1.0, 2.0 mg], or dulaglutide once-weekly [0.75, 1.5, 3.0, and 4.5 mg]) for ≥3 months at baseline. The primary end point was HbA1c change from baseline at week 12. Secondary end points included change from baseline in fasting serum glucose, body weight, and glucose assessed by continuous glucose monitoring. Safety was also assessed. RESULTS: Participants were 58.3 years on average, with baseline HbA1c 7.39%, body mass index 35.18 kg/m2, T2D duration around 12.4 years, and included 55% females. Semaglutide (55%) and dulaglutide (42%) were the most commonly used GLP-1 RAs at baseline with semaglutide 1.0 mg and dulaglutide 1.5 mg being the most common treatment doses. At week 12, mean HbA1c changed from baseline by -0.43%, fasting serum glucose by -7.83 mg/dL, and body weight by -2.15 kg (all P < .001). Glycemic outcomes and body weight improved in participants in all baseline GLP-1 RA subgroups. Twenty participants (13.2%) developed gastrointestinal events. Three (2%) participants discontinued tirzepatide due to adverse events. There were no severe hypoglycemic events or deaths. CONCLUSION: In this prospective study, when people with T2D on stable GLP-1 RA treatment were switched directly to tirzepatide 5 mg, they experienced improved glycemic outcomes and additional weight reduction with an acceptable risk of adverse gastrointestinal events over 12 weeks.

Effects of a Long-Acting Diquafosol Ophthalmic Solution on the Ocular Surface, Tolerability, and Usability in Dry Eye Disease.

INTRODUCTION: This study aimed to investigate the tolerability of high-viscosity diquafosol tetrasodium (DQS) ophthalmic solution (DIQUAS LX; DQSLX) and examine its usability and effect on clinical findings in patients with dry eye disease (DED). METHODS: This interventional retrospective study included 66 eyes of 66 patients with DED who switched from conventional DQS to DQSLX ophthalmic solution. Tear function assessments (tear film breakup time [BUT], keratoconjunctival vital staining [VS] score), evaluations of DED symptom relief, and a four-item usability questionnaire ("comfort upon instillation," "irritation upon instillation," "eye mucus discharge," "convenience of instillation frequency") assessed using a visual analog scale from 0 (worst) to 10 (best) were administered 4 weeks after switching to DQSLX. Factors associated with drug tolerability were assessed using multiple regression analysis. RESULTS: The symptoms improved by 64.2% after switching to DQSLX. The BUT value, VS score, and the questionnaire items "comfort upon instillation" and "convenience of instillation frequency" were significantly improved after switching to DQSLX. DQSLX tolerability was reported as acceptable in 56 (84.8%) and unacceptable in 10 (15.2%) patients. Overall, DQSLX tolerability was significantly associated with "comfort upon instillation" and "convenience of instillation frequency" and tended to be associated with a VS score ≥ 1. DQSLX tolerability depended on symptom and VS score improvements and absence of excessive "eye mucus discharge" in patients with a VS score ≥ 1 (39 patients), but on "comfort upon instillation" and absence of excessive "eye mucus discharge" in patients with a VS score = 0 (27 patients). CONCLUSION: The high-viscosity DQSLX ophthalmic solution was generally considered acceptable in the study population. However, drug tolerability seemingly differed between patients with DED with and without epithelial damage. The former were affected by improvements in symptoms and clinical findings, whereas the latter were affected by comfort upon instillation. TRIAL REGISTRATION: University Hospital Medical Information Network identifier, UMIN000051390.

Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide (PTG-300), a hepcidin mimetic, in healthy volunteers: A double-blind first-in-human study.

OBJECTIVES: Rusfertide is a potent peptide mimetic of hepcidin being investigated for the treatment of polycythemia vera. This randomized, placebo-controlled, double-blind study evaluated the safety, pharmacokinetics, and pharmacodynamics of single and repeated subcutaneous doses of an aqueous formulation of rusfertide in healthy adult males. METHODS: Subjects received single doses of 1, 3, 10, 20, 40, or 80 mg rusfertide or placebo. A separate cohort of subjects received two doses of 40 mg rusfertide or placebo 1 week apart. Blood samples for pharmacokinetics and pharmacodynamics were collected, and adverse events, clinical laboratory tests, 12-lead electrocardiograms, and vital signs were monitored. RESULTS: Rusfertide was well tolerated. There were no serious or severe treatment-emergent adverse events, and no patterns of clinically important adverse events, or laboratory, vital sign, or electrocardiogram abnormalities. Mean maximum rusfertide plasma concentration (Cmax) and area under the concentration-time curve increased with dose, but less than dose proportionally. Median time to Cmax was 2-4.5 h for 40 and 80 mg rusfertide and 8-24 h for lower doses. Apparent clearance and half-life increased with dose. Single doses of rusfertide 1-80 mg were associated with dose-dependent decreases in serum iron and transferrin-iron saturation. CONCLUSIONS: Rusfertide was well tolerated and showed dose-dependent pharmacokinetics and pharmacodynamics.

Efficacy and tolerability of oral semaglutide in Japanese patients with type 2 diabetes mellitus: Analysis report from diabetes specialist clinics.

INTRODUCTION: Glucagon-like peptide 1 receptor agonists (GLP1Ras) have emerged as pivotal agents in diabetes management and organ protection. However, their use is limited due to the necessity for injectable administration. The advent of the first oral GLP1Ra (oral semaglutide) in Japan since 2021 is expected to expand its usage. The aim of this study is to survey the efficacy and tolerability of oral semaglutide in clinical practice. MATERIALS AND METHODS: We retrospectively analyzed 120 outpatients diagnosed with type 2 diabetes mellitus who had received oral semaglutide for >6 months. Changes in clinical parameters during oral semaglutide treatment from baseline to 12 months were analyzed. The inverse probability weighting method using the propensity score was used to evaluate the differences in clinical parameters at 6 months after treatment, based on the patients' obesity levels. RESULTS: Body weight (BW), glycated hemoglobin A1c (HbA1c), and alanine aminotransferase (ALT) levels at baseline decreased significantly after treatment compared with those at 12 months (P < 0.001, P < 0.001, and P = 0.03, respectively). The patients were divided into two groups using a cutoff baseline body mass index (BMI) of 30.3 kg/m2. Although no significant difference was observed, changes in body weight and HbA1c indicated a potentially greater decrease in the BMI ≧ 30.3 group than that in the BMI < 30.3 group (P = 0.07 and 0.13, respectively). Among 206 registered patients, 25 (12.1%) discontinued oral-semaglutide treatment owing to adverse effects, including gastrointestinal symptoms. CONCLUSIONS: Oral semaglutide treatment demonstrates efficacy and tolerability for managing type 2 diabetes mellitus in Japan. Significant improvements in metabolic factors induced by oral semaglutide are anticipated, particularly in obese patients.

Comparing the tolerability of preservative-free tafluprost versus preserved latanoprost in the management of glaucoma and ocular hypertension - an observer blinded active-control trial.

BACKGROUND: Dry eye is a condition related to long-term topical eye therapy. We wish to evaluate the effectiveness and tolerability of preservative free prostaglandin drops versus benzalkonium chloride containing prostaglandin drops in the treatment of glaucoma. METHODS: Patients undergoing prostaglandin monotherapy underwent a washout period of at least 1 month after which baseline measurements of dry eye severity were taken. Patients were randomised to receive either 0.0015% tafluprost drops or 0.005% latanoprost preserved with 0.02% benzalkonium chloride. Repeat measurements were taken after a 2-month interval. RESULTS: Thirty-five patients completed randomised treatment. No significant difference between groups was found in objective and subjective measurements of dry eye severity. No significant difference was found in measurement of treatment effectiveness. CONCLUSION: Preservative-free and benzalkonium chloride-containing drops were found to be equally effective in lowering IOP with no significant difference in either subjective or objective measurements of dry eye severity.

Off-label higher doses of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: Safety and tolerability.

OBJECTIVE: To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD). METHODS: A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring. RESULTS: SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups. CONCLUSION: OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Background: Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Methods: Eligible participants aged ≥ 12 to < 18 years took 25 mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). Results: At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Conclusions: Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. Trial registration ClinicalTrialsgov ID: NCT05101148.

Towards more tolerable subcutaneous administration: Review of contributing factors for improving combination product design.

Subcutaneous (SC) injections can be associated with local pain and discomfort that is subjective and may affect treatment adherence and overall patient experience. With innovations increasingly focused on finding ways to deliver higher doses and volumes (≥2 mL), there is a need to better understand the multiple intertwined factors that influence pain upon SC injection. As a priority for the SC Drug Development & Delivery Consortium, this manuscript provides a comprehensive review of known attributes from published literature that contribute to pain/discomfort upon SC injection from three perspectives: (1) device and delivery factors that cause physical pain, (2) formulation factors that trigger pain responses, and (3) human factors impacting pain perception. Leveraging the Consortium's collective expertise, we provide an assessment of the comparative and interdependent factors likely to impact SC injection pain. In addition, we offer expert insights and future perspectives to fill identified gaps in knowledge to help advance the development of patient-centric and well tolerated high-dose/high-volume SC drug delivery solutions.

Safety and tolerability of ß-blockers: importance of cardioselectivity.

Cardioselective ß-blockade is generally well tolerated in practice and contraindications to this therapy are uncommon. ß-blockers are a diverse therapeutic class, and their individual tolerability profiles are influenced strongly by their pharmacodynamic effects across different adrenergic receptors. Bisoprolol, probably the ß-blocker with the highest selectivity for blockade of ß1- vs. ß2-adrenoceptors, does not block ß2-adrenoceptors to an appreciable extent at doses in therapeutic use. Side-effects often attributed to ß-blockers, such as erectile dysfunction and adverse metabolic effects are uncommon with bisoprolol and other ß-blockers used at doses which only block ß1-adrenoceptors. Cautious use of a cardioselective ß-blocker is not contraindicated in people with chronic obstructive pulmonary disease or asthma and the outcomes benefits of ß-blockers in patients with coronary heart disease or heart failure are also apparent in patients with concurrent COPD. Starting with a low dose and titrating upwards carefully is important for optimising the tolerability of a ß-blocker. Most people with hypertension will receive combination antihypertensive therapy in practice, and the low-dose combination therapy approach provides a useful strategy for optimising the efficacy and tolerability of a regimen that includes a ß-blocker, compared with up-titrating an existing monotherapy.

Pharmacokinetics and safety of a new generic lurasidone: a phase I bioequivalence study in healthy Chinese subjects.

Latuda® is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40 mg of generic lurasidone or Latuda®. After a 7-day washout period, subjects entered the second period with a crossover administration of 40 mg of generic lurasidone or Latuda®. The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda® were as follows: the Cmax was 28.84 ± 19.34 ng/ml and 28.22 ± 21.19 ng/ml, respectively; the AUC0-t was 121.39 ± 58.47 h*ng/ml and 118.35 ± 52.24 h*ng/ml, respectively; and the AUC0-∞ was 129.63 ± 63.26 h*ng/ml and 126.59 ± 57.99 h*ng/ml, respectively. The primary pharmacokinetic parameter, Cmax, was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC0-t, AUC0-∞) were evaluated using average bioequivalence (ABE). The results indicate that both Cmax and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda® were as follows: the Cmax was 74.89 ± 32.06 ng/ml and 83.51 ± 33.52 ng/ml, respectively; the AUC0-t was 274.77 ± 103.05 h*ng/ml and 289.26 ± 95.25 h*ng/ml, respectively; and the AUC0-∞ was 302.44 ± 121.60 h*ng/ml and 316.32 ± 109.04 h*ng/ml, respectively. The primary pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29).

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial.

BACKGROUND: The PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. OBJECTIVE: We report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. DESIGN, SETTING, AND PARTICIPANTS: A randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018-January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. INTERVENTION: Olaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. RESULTS AND LIMITATIONS: The most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). CONCLUSIONS: Olaparib plus abiraterone has a manageable and predictable safety profile. PATIENT SUMMARY: The PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

Long-term treatment for endometriosis with dienogest: efficacy, side effects and tolerability.

BACKGROUND: Dienogest (DNG) improves endometriosis-associated pain (EAP) and patients' quality of life; however, the modern cornerstone of the management of endometriosis is the long-term adherence of the patient to medical treatment. OBJECTIVE: To evaluate DNG as a long-term treatment of endometriosis, focusing on patients' compliance and side effects, also correlating with different phenotypes of endometriosis. METHODS: This was a cohort study on a group of patients with endometriosis (n = 114) undergoing long-term treatment with DNG. During the follow up visits (12, 24, and 36 months) patients were interviewed: an assessment of EAP was performed by using a visual analogue scale (VAS) and side effects were evaluated by using a specific questionnaire of 15 items. RESULTS: At 12 months, 81% were continuing the DNG treatment, with a significant reduction of dysmenorrhea, dyspareunia, dyschezia, dysuria and chronic pelvic pain. Of the 19% that discontinued the treatment: 62% was due to spotting, reduced sexual drive, vaginal dryness, and mood disorders. The improvement of EAP was significant for all endometriosis phenotypes, especially in patients with the deep infiltrating type. At 36 months, 73% of patients were continuing the treatment, showing a significant reduction of EAP through the follow up, along with an increase of amenorrhea (from 77% at 12 months to 93% at 36 months). In a subgroup of 18 patients with gastrointestinal disorders, DNG was administered vaginally at the same dosage, showing similar results in terms of efficacy and tolerability. CONCLUSIONS: DNG was an effective long-term treatment for all endometriosis phenotypes, with few side effects that caused the discontinuation of the treatment mainly during the first year. Thus, the course of 1-year treatment is a predictive indicator for long-term treatment adherence.

Efficacy and tolerability of tirbanibulin 1% ointment in the treatment of cancerization field: a real-life Italian multicenter observational study of 250 patients.

BACKGROUND: Tirbanibulin 1% ointment is approved for the field treatment of Olsen grade I actinic keratoses (AKs) of the face and scalp. METHODS: We performed a multicenter retrospective study involving 15 dermatologic units in Italy to investigate the efficacy and tolerability of tirbanibulin in a real-life setting. 250 patients were enrolled. Tirbanibulin, 1% ointment, was applied daily for five consecutive days. The efficacy of treatment was measured with modifications of the Actinic Keratosis Area and Severity Index (AKASI). A satisfactory response was defined by complete (100% reduction in the number of lesions) or partial clearance (75-99%) of treated AKs. RESULTS: Overall, the AKASI score was significantly reduced in the studied population (mean, from 4.1 ± 2.7 to 1.4 ± 1.5; P < 0.001). A satisfactory response was observed in 222 (88.8%) cases. The proportion of satisfactory responses was higher when follow-up was performed after 8 weeks (34/35, 97.1%). The reduction in AKASI was significant in patients with Olsen grade II or III lesions (from 5.3 ± 2.8 to 1.6 ± 1.6; P < 0.001). A satisfactory response was observed in 91/104 (87.5%) cases. AKASI reduction was also significant in patients with trunk or limb AKs (from 7.0 ± 1.3 to 2.0 ± 1.6; P = 0.018) since a satisfactory response was observed in 7/8 (87.5%) cases. Tirbanibulin was well tolerated; all adverse events (AEs) included transient local reactions at the site of treatment. Overall, 231 patients had at least one AE. Only 7 (2.8%) grade 4 AEs were recorded. CONCLUSION: Our retrospective study confirmed that tirbanibulin 1% ointment is effective and well tolerated in a real-life setting and is also promising for Olsen grade II and grade III AKs and AKs localized on difficult-to-treat areas.

Skin Tolerability of Oleic Acid Based Nanovesicles Designed for the Improvement of Icariin and Naproxen Percutaneous Permeation.

Deformable nanovesicles have a crucial role in topical drug delivery through the skin, due to their capability to pass intact the stratum corneum and epidermis (SCE) and significantly increase the efficacy and accumulation of payloads in the deeper layers of the skin. Namely, lipid-based ultradeformable nanovesicles are versatile and load bioactive molecules with different physicochemical properties. For this reason, this study aims to make oleic acid based nanovesicles (oleosomes) for the codelivery of icariin and sodium naproxen and increase their permeation through the skin. Oleosomes have suitable physicochemical properties and long-term stability for a potential dermal or transdermal application. The inclusion of oleic acid in the lipid bilayer increases 3-fold the deformable properties of oleosomes compared to conventional liposomes and significantly improves the percutaneous permeation of icariin and sodium naproxen through the human SCE membranes compared to hydroalcoholic solutions of both drugs. The tolerability studies on human volunteers demonstrate that oleosomes are safer and speed up the recovery of transepidermal water loss (TEWL) baselines compared to saline solution. These results highlight promising properties of icariin/sodium naproxen coloaded oleosomes for the treatment of skin disorders and suggest the potential future applications of these nanovesicles for further in vivo experiments.

Gastrointestinal tolerability of organic infant formula compared to traditional infant formula: A systematic review.

BACKGROUND: Infants' nutrition significantly influences their growth, development, and overall well-being. With the increasing demand for organic infant formula driven by the perception of health benefits and growing awareness of natural feeding options, it is crucial to conduct a comparative analysis of the gastrointestinal tolerability between organic and traditional infant formulas. AIM: To provide a concise and precise analysis of the gastrointestinal tolerability of organic infant formula compared to traditional infant formula. Due to limited direct comparisons, the review synthesizes available literature on each formula type, presenting insights into their potential effects on infants' digestive health. METHODS: An extensive literature search was conducted, compiling studies on organic and traditional infant formulas, their compositions, and reported effects on gastrointestinal tolerability. We searched academic databases such as PubMed and Google Scholar and specialized nutrition, paediatrics, and infant health journals using relevant keywords till October 1, 2023. . RESULTS: Although specific comparative studies are scarce and formula heterogeneity is a significant limitation, this systematic review provides an in-depth understanding of organic infant formulas' composition and potential benefits. While scientific evidence directly comparing gastrointestinal tolerability is limited, organic formulas strive to use carefully selected organic ingredients to imitate breast milk composition. Potential benefits include improved lipid profiles, higher methionine content, and decreased antibiotic-resistant bacteria levels. Understanding the gastrointestinal tolerability of organic and traditional infant formulas is crucial for parents and healthcare providers to make informed decisions. CONCLUSION: Despite limitations in direct comparisons, this systematic review provides insights into the composition and potential benefits of organic infant formulas. It emphasizes the need for further research to elucidate their gastrointestinal effects comprehensively.

Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

INTRODUCTION: Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. METHODS: For TD, safety data were integrated from two 12-week pivotal studies (ARM-TD and AIM-TD) and through week 15 of the open-label extension (OLE) study (RIM-TD). Data were analyzed by deutetrabenazine treatment group and placebo. For HD, safety data were integrated from the 12-week pivotal study (First-HD) and through week 15 of the OLE study (ARC-HD) for patients previously receiving placebo. Integrated deutetrabenazine data were compared with placebo from the pivotal study. RESULTS: For TD, deutetrabenazine (n = 384) was generally well tolerated compared with placebo (n = 130). Adverse event (AE) incidence was numerically higher in the response-driven deutetrabenazine vs the fixed-dose deutetrabenazine and placebo groups, respectively (any AE, 59.5% vs 44.4-50.0% and 53.8%; treatment-related AE, 38.1% vs 18.1-25.0% and 30.8%). Serious AEs were reported for 2.8-8.3% of patients in the deutetrabenazine groups and 6.9% in the placebo group. Common AEs (≥ 4%) included headache, somnolence, nausea, anxiety, fatigue, dry mouth, and diarrhea. AE incidence was higher during the titration vs maintenance periods. For HD, AE incidence was numerically higher with deutetrabenazine (n = 84) vs placebo (n = 45; any AE, 64.3% vs 60.0%; treatment-related AE, 38.1% vs 26.7%); serious AEs were reported for similar proportions for the deutetrabenazine and placebo groups, 2.4% and 2.2%, respectively. Common AEs (≥ 4%) included irritability, fall, depression, dry mouth, and fatigue. CONCLUSIONS: Data from an integrated analysis of studies in TD and an integrated analysis of studies of chorea in HD showed that deutetrabenazine has a favorable safety profile and is well tolerated across indications. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02291861, NCT02195700, NCT01795859, NCT02198794, NCT01897896.

Unintended movements are often the first sign of Huntington disease. This type of unintended movement is called chorea in Huntington disease. Tardive dyskinesia causes unintended body movements. Deutetrabenazine is a medicine used to treat both types of movements. This report summarizes deutetrabenazine safety across five clinical studies. Safety was assessed via adverse events (side effects). Adverse events were compared between deutetrabenazine and inactive treatment (placebo). Serious adverse events were also compared. Serious adverse events cause substantial impairment or disruption. In tardive dyskinesia and chorea in Huntington disease studies, most patients kept taking deutetrabenazine. Adverse events were not a common reason to stop treatment. For tardive dyskinesia, adverse event rates were similar between deutetrabenazine (≤ 60%) and placebo (54%). Serious adverse event rates were also similar for deutetrabenazine (≤ 8%) and placebo (7%). Adverse events tended to be reported earlier in treatment. Common adverse events were headache, sleepiness, nausea, anxiety, fatigue, dry mouth, and diarrhea. For chorea in Huntington disease, adverse event rates were similar for deutetrabenazine (64%) and placebo (60%). Serious adverse event rates were also similar for deutetrabenazine (2%) and placebo (2%). Irritability, fall, depression, dry mouth, and fatigue were common adverse events. Adverse events were similar between deutetrabenazine and placebo in both conditions. Deutetrabenazine was well tolerated for patients with either tardive dyskinesia or chorea in Huntington disease.

Tolerability and effectiveness of palbociclib in older women with metastatic breast cancer.

PURPOSE: Palbociclib has become the standard of care for estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer, but real-world evidence in older women remains scarce. Therefore, we investigated tolerability of palbociclib in older women with metastatic breast cancer. METHODS: Consecutive women aged ≥ 70 with ER+/HER2- metastatic breast cancer, treated with palbociclib in any treatment line in six hospitals, were included. Primary endpoint was grade ≥ 3 palbociclib-related toxicity. Predictors of toxicity were identified using logistic regression models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier. RESULTS: We included 144 women with a median age of 74 years. Grade 3-4 toxicity occurred in 54% of patients, of which neutropenia (37%) was most common. No neutropenic fever or grade 5 toxicity occurred. Dose reduction during treatment occurred in 50% of patients, 8% discontinued treatment due to toxicity and 3% were hospitalized due to toxicity. Polypharmacy (odds ratio (OR) 2.50; 95% confidence interval (CI) 1.12-5.58) and pretreatment low leukocytes (OR 4.81; 95% CI 1.27-18.21) were associated with grade 3-4 toxicity, while comorbidities were not. In first-line systemic therapy, median PFS was 12 months and median OS 32 months. In second-line, median PFS was 12 months and median OS 31 months. CONCLUSION: Although grade 3-4 toxicity and dose reductions occurred frequently, most were expected and managed by dose reductions, showing that palbociclib is generally well tolerated and thus represents a valuable treatment option in the older population.

Post-marketing surveillance of 10,392 herpes zoster vaccines doses in Australia.

BACKGROUND: Immunisation against herpes zoster is recommended for adults aged ≥ 50 years. Two vaccines, a live attenuated (ZVL, Zostavax®) and an adjuvant recombinant subunit (HZ/su, Shingrix®), are available in Australia. Immunisation guidelines are shifting their recommendations towards HZ/su because of higher efficacy in preventing herpes zoster and associated complications. However, there are limited post-marketing data comparing the safety profiles of these vaccines. METHODS: Data from SmartVax, an active surveillance system for monitoring adverse events following immunisation (AEFIs) utilised by > 450 clinics throughout Australia, were analysed. Data from patients aged ≥ 50 years, who received ZVL or HZ/su, from 1 June 2021 to 31 May 2022, at clinics that utilised SmartVax were included. The proportion of records where patients who reported any, local, and systemic AEFIs after receiving ZVL or HZ/su were compared using multivariable logistic regression models. RESULTS: Data from 10,392 immunisation records (n = 8341 ZVL; n = 2051 HZ/su) were included. The proportion of AEFIs reported was higher with HZ/su (41.9 % [any], 33.8 % [local], 25.2 % [systemic]) than with ZVL (8.7 % [any], 6.2 % [local], 3.5 % [systemic]). After controlling for demographic variables, HZ/su presented a 6-fold increase in the odds (OR 6.44; 95 %CI: 5.57-7.46) of a reported AEFI compared to ZVL. Only 59 (0.6 %) of vaccinations lead to medical attention being sought due to an AEFI. CONCLUSIONS: While rates of AEFIs was higher with HZ/su than ZVL, most AEFIs were mild and did not require medical attention. Our findings support the change in vaccine recommendations and the use of HZ/su in immunisation programs.

Safety of an Intracameral Fixed Combination for Mydriasis and Intraocular Anaesthesia During Cataract Surgery.

Purpose: To compare the safety of a standardized, commercially available intracameral combination of mydriatics and anesthetic (ICMA) with a reference topical mydriatic regimen for cataract surgery. Patients and Methods: The safety results from two international, randomized, controlled clinical studies were combined to compare ICMA at the beginning of cataract surgery (ICMA group) to the reference topical mydriatic regimen (reference group). Data were collected on ocular and systemic adverse events, corneal and anterior chamber examination, endothelial cell density, retinal thickness and visual acuity. Analysis was performed on a pooled safety set from both studies, preoperatively and up to 1 month postoperatively. Results: 342 patients received ICMA and 318 the reference topical regimen. Ocular adverse events were reported in 17.0% of patients in the ICMA group and 18.6% in the reference group. No difference was shown between groups in endothelial cell density (2208 ± 498 cells/mm2 for ICMA group versus 2241 ± 513 cells/mm2 for the reference group; p=0.547) and retinal thickness (change from baseline less than 50 µm in 94.7% versus 95.0% of patients, respectively) at 1 month postoperatively. At 1-day post-surgery, less patients in the ICMA group had moderate or severe (Grades 2 and 3) superficial punctate corneal staining (3.9% versus 7.0% for the reference group; p=0.064). Postoperatively, some ocular symptoms were also less frequently reported in the ICMA group. Best-corrected visual acuity increased in 96.0% of patients in the ICMA group and 95.8% in the reference group at 1 month. Conclusion: ICMA injection at the beginning of cataract surgery was demonstrated to be safe and may also provide perioperative and postoperative advantages over the standard topical mydriatic regimen.