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Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption, allowing for longer treatment intervals similar to intravenous immunoglobulin (up to once monthly). fSCIG 10% is indicated in the USA for treating adults and children aged ≥ 2 years with primary immunodeficiency diseases (PIDs). This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from November 2015 to October 2021 to assess the long-term safety of fSCIG 10% in routine clinical practice. Patients with PIDs aged ≥ 16 years who were prescribed and/or had started fSCIG 10% treatment were enrolled. In total, 253 patients were enrolled and included (full analysis set). Participants received fSCIG 10% treatment for a median (interquartile range) of 10.0 (3.5-11.8) months, with the majority of infusions administered every 4 weeks (54.4% [1197/2201 infusions]) and at home (62.6% [1395/2230 infusions]). Overall, 98.5% of infusions were administered without rate reduction, interruption, or discontinuation due to adverse events (AEs). Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Development of antibodies against rHuPH20 was uncommon; 14/196 patients (7.1%) tested positive for binding antibodies (titer ≥ 1:160) with no neutralizing antibodies detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated self-administration of fSCIG 10% was well tolerated in US clinical practice by patients with PIDs.

INTRODUCTION: Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag. METHODS: Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures. RESULTS: In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4%; diarrhea, 37.8%; jaw pain, 33.3%). There was a notable decline in AEs after reaching and maintaining a stable dose. At month 24 after entering the OLE, 6MWD significantly increased by a mean of 36.3 m (P = 0.004) from OLE baseline, and most participants remained stable in their functional class (84.8%). Post-baseline PVR in 1 or 2 years decreased by a median of 52.2 dyn.s/cm5 and mean pulmonary arterial pressure decreased by a median of 2.0 mmHg (P = 0.05). CONCLUSION: Ralinepag produced sustained, durable improvements in 6MWD along with durable reductions in PVR and a manageable AE profile. Most participants continuing treatment with ralinepag maintained functional measures throughout the OLE and those switching from placebo to ralinepag often experienced functional improvements.

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single‐center, open‐label, two‐period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8‐day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat‐to‐epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC0‐16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%‐125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0‐τ,ss, the zamicastat plus epoprostenol‐to‐zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0‐τ,ss and the zamicastat plus epoprostenol‐to‐zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0‐τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Difelikefalin is a selective kappa opioid receptor agonist that is approved for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis (HD). In this study, we assessed the pharmacokinetics (PK) of intravenous (IV) difelikefalin in healthy subjects, in non–dialysis-dependent (NDD) subjects with varying stages of kidney disease, and in subjects with end-stage renal disease (ESRD) undergoing HD. Methods: The PK and safety of single IV doses of difelikefalin (3.0 mcg/kg) were initially evaluated in NDD subjects with mild, moderate, or severe renal impairment compared with matched healthy subjects. Based on those data, the PK and safety of 3 dose levels of IV difelikefalin (0.5, 1.0, or 2.5 mcg/kg) were compared with matched placebo in subjects undergoing HD with each dose administered following dialysis, 3 times over a 1-week treatment period). Results: Single IV dosing of difelikefalin in NDD subjects (N = 36) with mild renal impairment demonstrated comparable exposure to healthy subjects with normal renal function, while subjects with moderate or severe renal impairment had higher total exposure. NDD subjects with severe renal impairment had higher total exposure compared with those with moderate renal impairment (i.e., exposure in severe NDD > moderate NDD > mild NDD ≈ healthy subjects). Clearance of difelikefalin correspondingly decreased with increasing renal impairment. In the multiple-dose study in subjects with ESRD undergoing HD (N = 19), IV difelikefalin demonstrated dose proportionality and was shown to be mostly cleared by dialysis; steady state was achieved with the second dose on day 3. Safety findings for all subjects were consistent with the known profile of IV difelikefalin. Conclusions: IV difelikefalin was well tolerated. Similar exposure was observed in NDD subjects with mild renal impairment compared with healthy subjects with normal renal function, with reduced clearance and higher exposure in NDD subjects with moderate or severe renal impairment. Dose proportionality was demonstrated in subjects with ESRD undergoing HD administered IV difelikefalin 3 times per week following dialysis and was shown to be mostly cleared by dialysis. Trial registration: Single-dose study: NA; multiple-dose study: ClinicalTrials.gov registration number NCT02229929, first registration 03/09/2014. [ABSTRACT FROM AUTHOR]

Background: Controversy exists whether prophylactic drugs are necessary in the treatment of medication overuse headache (MOH). Objectives: To determine comparative benefits and safety of available drugs for the treatment of MOH including elimination of medication overuse (MO). Methods: We systematically reviewed randomized controlled trials though an extensive literature search comparing different drug effects on MOH. A random-effect network meta-analysis was conducted to rank comparative effects of interventions. Outcome improvements from baseline include responder rate defined as ≥ 50% reduction of headache frequency, proportion of patients who revert to no acute medication overuse (nMO), and reduction in monthly headache and acute medication intake frequency. Certainty of evidence was classified using the Grading of Recommendations, Assessment, Development & Evaluation (GRADE). Results: Of 8,248 screened publications, 28 were eligible for analysis. Topiramate was found to be beneficial based on its responder rate (odds ratios [OR] 4.93), headache frequency (weighted mean difference [WMD] -5.53) and acute medication intake frequency (WMD − 6.95), with fewer safety issues (i.e., tolerability, or more adverse events) than placebo (OR 0.20). Fremanezumab, galcanezumab and botulinum toxin type A (BTA) were beneficial for increased responder rates (OR 3.46 to 3.07, 2.95, and 2.57, respectively). For reversion to nMO, eptinezumab, fremanezumab and BTA were superior to placebo (OR 2.75 to 2.64, 1.87 to1.57, and 1.55, respectively). Eptinezumab, fremanezumab, erenumab 140 mg, and BTA were more efficacious than erenumab 70 mg (OR 3.84 to 3.70, 2.60 to 2.49, 2.44 and 2.16, respectively) without differences in safety and tolerability. Conclusion: Despite lower safety and greater intolerability issues, topiramate has large beneficial effects probably on increasing responder rates, reducing headache frequency, and might reduce monthly medication intake frequency. Fremanezumab, galcanezumab, and eptinezumab are promising for increasing responder rates. For reversion to nMO, eptinezumab has large beneficial effects, fremanezumab has a smaller effect. BTA might have a moderate effect on responder rates and probably has a small effect on reversion to nMO. Trial registration: PROSPERO, CRD42021193370. [ABSTRACT FROM AUTHOR]

Introduction: Surgical interventions in mice require appropriate pain relief to ensure animal welfare and to avoid influence of pain on research findings. Carprofen is a non-steroidal anti-inflammatory drug commonly used as an analgesic for interventions inducingmild tomoderate pain in laboratory rodents. Despite its frequent use, species-specific data on pharmacokinetics (PK), side effects, and potential impact on behavioral pain indicators are limited. Methods: We determined PK and tolerability profiles of carprofen in healthy male and female C57BL/6Jmice (n = 42), administered at highest recommended doses via single subcutaneous (s.c.) injection (20 mg/kg) and oral self-administration (25 mg/kg/24 h) per drinking water (d.w.) for 5 days. Plasma concentrations were measured at various time points after the start of the treatment (n = 6 per time point), and side effects were evaluated using amodified Irwin test battery, hematology, and histopathology. Additionally, potential interference with cage-side behaviors commonly used for pain assessment, such as the mouse grimace scale, wheel running, burrowing, nesting, and grooming activity, was investigated. Results: Maximum plasma concentrations of 133.4 ± 11.3µg/ml were reached 1 h after single s.c. injection with an elimination half-life of 8.52 h. Intake from d.w. resulted in a steady state within 24 h after the start of the treatment with plasma levels of around 60µg/ml over 5 days in both sexes. The medicated water was well-accepted, and increased d.w. intake was observed in the first 24 h after exposure (p < 0.0001). The Irwin test revealed only minor influence on tested behavior and physiological functions. However, during treatment via d.w., an increase in body temperature (p < 0.0001) was observed, as well as a reduction in voluntary wheel running activity by 49-70% inmalemice. Moreover, grooming behavior was slightly affected. Hematology and histopathology were without pathological findings that could be attributed to carprofen treatment. High-dose carprofen can be considered safe and of favorable PK for both administration routes assessed in healthy C57BL/6J mice of both sexes. Further efficacy evaluation of carprofen as monoanalgesic or component of multimodal post-surgical regimens is clearly encouraged; however, the impact on behavioral markers used for pain assessment should be considered in this context. [ABSTRACT FROM AUTHOR]

Antiviral therapy such as oseltamivir has been recommended for hospitalized children with suspected and confirmed influenza for almost 20 years. The therapy is officially authorized for newborns two weeks of age or older, however, questions about its safety and effectiveness still surround it. Our goals were to assess the epidemiological features of two consecutive seasonal influenza cases in children following the COVID-19 pandemic; to observe the clinical effectiveness and tolerability of oseltamivir in hospitalized children who were not vaccinated against influenza and had different influenza subtypes, including A(H1N1), A(H3N2), and B; and to identify specific comorbidities associated with influenza in children. We performed an observational study on 1300 children, enrolled between 1 October 2022 and 30 May 2023 and between 1 October 2023 and 4 May 2024, to the IX Pediatric Infectious Diseases Clinical Section of the National Institute of Infectious Diseases "Prof. Dr. Matei Balș". During the 2022–2023 influenza season, 791 pediatric patients tested positive for influenza and received oseltamivir. Of these, 89% (704/791) had influenza A, with 86.4% having subtype A(H1N1) and 13.6% of cases having A(H3N2), and for influenza B, 11% (87/791) of the pediatric patients. Of the total group, 59% were male, and the median age was 2.4 years (1.02–9.28). For the 2023–2024 influenza season, 509 pediatric patients tested positive for influenza, with 56.9% being of the male gender and who were treated with oseltamivir. Of these patients, 81.6% had influenza A and 18.4% had influenza B. Treatment with neuraminidase inhibitors, specifically oseltamivir, 2 mg/kg/dose administered twice daily for 5 days, was well tolerated by the children, and we recorded no deaths. The duration of hospitalization for patients with a fever after the oseltamivir administration was significantly longer for patients with A(H1N1) infection than A(H3N2), during both seasons. We identified more complications in the 2022–2023 season and a decreasing number of influenza B for the 2023–2024 season. Among children with comorbidities, the most common were asthma, gastrointestinal diseases, and metabolic and endocrine diseases. In terms of effectiveness, oseltamivir significantly reduced the intensity of influenza symptoms, thus reducing the number of days of hospitalization (p = 0.001) as well as post-infection complications (p = 0.005) in both groups. In this study, we evaluated the clinical effectiveness of oseltamivir therapy for all influenza types/subtypes in children, and the length of hospitalization. We identified comorbidities associated with the prolonged duration of hospitalization. Influenza vaccination should be the main tool in the prevention of influenza and its complications in children, especially those with comorbidities. [ABSTRACT FROM AUTHOR]

Purpose: The Functional Assessment of Cancer Therapy item (FACT-GP5) has the potential to provide an understanding of global treatment tolerability from the patient perspective. Longitudinal evaluations of the FACT-GP5 and challenges posed by data missing-not-at-random (MNAR) have not been explored. Robustness of the FACT-GP5 to missing data assumptions and the responsiveness of the FACT-GP5 to key side-effects are evaluated. Methods: In a randomized, double-blind study (NCT00065325), postmenopausal women (n = 618) with hormone receptor-positive (HR+), advanced breast cancer received either fulvestrant or exemestane and completed FACT measures monthly for seven months. Cumulative link mixed models (CLMM) were fit to evaluate: (1) the trajectory of the FACT-GP5 and (2) the responsiveness of the FACT-GP5 to CTCAE grade, Eastern Cooperative Oncology Group (ECOG) Performance Status scale, and key side-effects from the FACT. Sensitivity analyses of the missing-at-random (MAR) assumption were conducted. Results: Odds of reporting worse side-effect bother increased over time. There were positive within-person relationships between level of side-effect bother (FACT-GP5) and severity of other FACT items, as well as ECOG performance status and Common Terminology Criteria for Adverse Events (CTCAE) grade. The number of missing FACT-GP5 assessments impacted the trajectory of the FACT-GP5 but did not impact the relationships between the FACT-GP5 and other items (except for nausea [FACT-GP2]). Conclusions: Results support the responsiveness of the FACT-GP5. Generally speaking, the responsiveness of the FACT-GP5 is robust to missing assessments. Missingness should be considered, however, when evaluating change over time of the FACT-GP5. Trial Registration: NCT00065325. Trial Registration Year: 2003. [ABSTRACT FROM AUTHOR]

Background: Despite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients. Methods: The study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment. Results: One hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction. Conclusions: Irinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration. [ABSTRACT FROM AUTHOR]

This study evaluated the acceptability and tolerability of three alcohol-based hand rubs (ABHRs) at Sarawak General Hospital, Malaysia. Conducted from 12-26 November 2021 using a modified WHO Protocol, it involved a survey among health workers and concessionaires, with a 35% response rate (1,598 of 4,628 participants). The majority were nurses (60.8%), with the medical division most represented (28.4%). Most respondents (93.2%) used ABHRs at least five days a week and found them easily accessible (72.3%). Product B was the preferred ABHR (65%), primarily for its color and fragrance, surpassing WHO's 50% approval rate in these aspects. However, no other product features met WHO criteria. There were no significant differences in self-reported skin tolerability across the products, and none achieved overall WHO approval. These results offer important insights for ABHR selection in developing countries and highlight the value of the WHO Protocol in assessing product acceptability and tolerability. [ABSTRACT FROM AUTHOR]

Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders. We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects. We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms. APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Psychedelic agents have regained the attention of pharmaceutical companies as promising treatments for depressive episodes. 5-Methoxy-N,Ndimethyltryptamine (5-MeO-DMT), an atypical psychedelic, is emerging as a potentially effective, novel rapid-acting antidepressant. In this systematic review, we analyze the safety and tolerability evidence from clinical trials. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, electronic databases (PubMed, SCOPUS, Web of Science, EMBASE, and EBSCO) were searched from inception until 15 May 2024 to identify clinical trials (regardless of phase) reporting on short-term safety and tolerability profile of 5-MeO-DMT using the following keywords in various combinations: 5-methoxy-N, N-dimethyltryptamine, 5-MeO-DMT, safety, adverse, adverse reaction, side effects, tolerability, dropout, healthy volunteer, healthy participant, depression, major depressive disorder. Only studies written in English were considered. Results: Initial search yielded 100 records, out of which 3 met the inclusion criteria. These studies reported on the results from clinical trial phases I and I/II, with a total of 78 participants included; two studies involved healthy volunteers, and one included patients with treatment-resistant depression. Although the data is limited, it confirms a good short-term safety and tolerability profile for 5-MeO-DMT, with no serious adverse events (SAEs) reported. Furthermore, no drop-outs were reported. Conclusion: 5-MeO-DMT administration in human subjects presents favorable short-term safety and tolerability profile. Importantly, no SAEs have been documented, and no adverse events led to participant withdrawal from the studies There is a need for future randomized, double-blind, placebo-controlled trials with larger samples and follow-up to assess potential chronic adverse events. [ABSTRACT FROM AUTHOR]

Background: Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. Methods: This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. Results: By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild. Conclusions: In the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant. Trial registration: Clinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01. [ABSTRACT FROM AUTHOR]

Background: Efficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab's tolerability and safety profile in individuals experiencing episodic and chronic migraines. Methods: The study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption ('drug holiday') of up to 24 weeks. Results: 701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed. Conclusions: APOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment. Trial registration: ClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusions To evaluate, in patients with chronic migraine (CM) in real‐world conditions, the persistence, effectiveness, and tolerability of erenumab, fremanezumab, and galcanezumab anti‐calcitonin gene–related peptide (anti‐CGRP) monoclonal antibodies (mAbs) and the persistence and effects of switching.Anti‐CGRP mAbs represent a novel therapeutic approach to the management of CM; however, real‐world data on persistence, effectiveness, and tolerability, especially after switching, are scarce.This was a retrospective observational cohort study including all patients with CM treated with erenumab, fremanezumab, and/or galcanezumab in a tertiary hospital between January 2019 and December 2022. Treatment persistence was measured as the number of days between treatment start and end dates or the end of follow‐up and also as a percentage of persistent patients at 3, 6, and 12 months; effectiveness as a ≥50% reduction in monthly migraine days (MMD); and tolerability as the number and type of adverse events.Included were 281 patients (383 treatments) with CM (91.5% [257/281] female) receiving anti‐CGRP mAbs. Median (interquartile range [IQR]) treatment persistence was 267 (103–550) days. At 12 months, persistence was greater for the first (66.7%) compared to the second (49.8%) and third (37.2%) anti‐CGRP mAb treatments (hazard ratio [HR] = 1.93, 95% confidence interval [CI]: 1.35–2.74; HR = 2.75, 95% CI: 1.69–4.47, respectively). Persistence minimum observed median (IQR) was also greater for the first (291 [112–594] days) compared to both the second (188 [90–403] days; p < 0.001) and third (167 [89–352] days; p < 0.001) anti‐CGRP mAb treatments. For the first anti‐CGRP mAb treatment, there were no differences in persistence among the different drugs. In terms of effectiveness of the first, second, and third anti‐CGRP mAb treatments, a ≥50% reduction in MMD was achieved by 57.6% (117/203), 25.0% (11/44), and 11.8% (2/17) of patients, respectively, at 3 months, and by 55.8% (87/156), 29.6% (8/27), and 12.5% (1/8) of patients, respectively, at 6 months. At 12 months, no significant effectiveness differences were observed among anti‐CGRP mAb treatments. As for tolerability, 55 adverse events were reported by 43 (15.3%) patients, mostly mild and leading to treatment discontinuation in only 14 (5.0%) patients. The most common adverse events were constipation, injection site reaction, and pruritus. Erenumab patients (3%, 3/99) experienced a higher rate of discontinuation for constipation.Our findings showed a 12‐month higher treatment persistence with the use of a first anti‐CGRP mAb treatment when the switch to a second treatment was due to ineffectiveness or severe side events. This persistence was lower after a second or third anti‐CGRP. Additionally, in terms of effectiveness, the first anti‐CGRP treatment achieved a higher response in terms of ≥50% reduction in MMD; however, some patients may benefit from a switching strategy. Finally, the tolerability profile for anti‐CGRP mAbs was favorable. Further studies are needed to identify predictors of response after switching from the first anti‐CGRP mAb treatment. [ABSTRACT FROM AUTHOR]

Background: Digital phenotyping, the in-situ collection of passive (phone sensor) and active (daily surveys) data using a digital device, may provide new insights into the complex relationship between daily behaviour and mood for people with type 2 diabetes. However, there are critical knowledge gaps regarding its use in people with type 2 diabetes. This study assessed feasibility, tolerability, and user experience of digital phenotyping in people with and without type 2 diabetes after participation in a 2-month digital phenotyping study in Ireland. At study completion, participants rated methodology elements from "not a problem" to a "serious problem" on a 5-point scale and reported their comfort with the potential future use of digital phenotyping in healthcare, with space for qualitative expansion. Results: Eighty-two participants completed baseline. Attrition was 18.8%. Missing data ranged from 9–44% depending on data stream. Sixty-eight participants (82.9%) completed the user experience questionnaire (51.5% with type 2 diabetes; 61.8% female; median age-group 50–59). Tolerability of digital phenotyping was high, with "not a problem" being selected 76.5%—89.7% of the time across questions. People with type 2 diabetes (93.9%) were significantly more likely to be comfortable with their future healthcare provider having access to their digital phenotyping data than those without (53.1%), χ2 (1) = 14.01, p = <.001. Free text responses reflected a range of positive and negative experiences with the study methodology. Conclusions: An uncompensated, 2-month digital phenotyping study was feasible among people with and without diabetes, with low attrition and reasonable missing data rates. Participants found digital phenotyping to be acceptable, and even enjoyable. The potential benefits of digital phenotyping for healthcare may be more apparent to people with type 2 diabetes than the general population. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of psychological interventions is undisputed. But while in other fields of health care the safety of interventions is studied alongside effectiveness, adverse events (AEs) have only recently been assessed in clinical studies of psychological interventions. This critical review summarizes the definition, assessment and current research status of AEs of psychological interventions. Summary: AEs are defined as any untoward event or unfavorable change that occurs in the course of a psychological intervention. AEs that are caused by the intervention can be classified into side effects of correctly applied treatment, malpractice (i.e., incorrectly applied treatment) and unethical conduct (e.g., sexual abuse). Ideally, they are assessed by independent raters or alternatively by self-report questionnaires that should also cover serious adverse events (SAEs, e.g., suicide attempts or self-injurious behaviors). About 1 to 2 in 3 patients report at least 1 AE and results of meta-analyses suggest that treatments might differ in frequency and/or severity of AE and in treatment acceptability (measured as dropout rates). Key Messages: Measures of AEs and SAEs as well as more nuanced descriptions of dropout should be included in all clinical studies of psychological interventions. If this happens, we might learn that psychological interventions differ with respect to AEs, SAEs and acceptability. As many psychological interventions are about equally effective, they might one day be chosen based on differences in their safety profile rather than their differential effectiveness. Ideally, reducing AEs might also lead to more effective interventions. [ABSTRACT FROM AUTHOR]

Oral Janus kinase inhibitors (JAKi), a class of advanced targeted systemic therapy, have demonstrated efficacy and safety in the treatment of moderate-to-severe atopic dermatitis (AD). Like other small molecules, oral JAKi have the potential for off-target effects including laboratory-related adverse events (AEs). Product labels for oral JAKi recommend an initial laboratory assessment and follow-up 4–12 weeks later to monitor for potential changes, based on evidence from clinical trials across therapeutic indications for oral JAKi, which may not reflect a population of moderate-to-severe AD patients typically seen in routine clinical practice. To address this gap, a panel of eight dermatologists with clinical and research experience with oral JAKi for the management of AD conducted a targeted review of the literature focused on key laboratory-related AEs associated with oral JAKi in the moderate-to-severe AD population. Based on the synthesis of evidence and informed opinion, a set of best practice statements related to fundamental standards of care and consensus recommendations on laboratory monitoring were suggested, and level of agreement was ascertained using a Likert scale from 0 to 100. There was a high level of agreement on three of the four suggested recommendations related to assessment and monitoring of key laboratory parameters and to dose reduction or switching in response to laboratory changes; there was a lower level of agreement related to the frequency of ongoing laboratory monitoring. Appropriate patient selection and laboratory assessment is an important strategy to mitigate the potential risks associated with oral JAKi when treating AD. [ABSTRACT FROM AUTHOR]

This study aimed to examine blood pressure changes during ketamine infusion for depression and exploring the factors associated with these changes. This study is a retrospective chart-review of patients with depression undergoing ketamine infusion at Yale Psychiatry Hospital during a 7-year period. Blood pressure (BP) was recorded every 10 min during the infusion. Surges in systolic and diastolic blood pressure (SBP, DBP), along with severe hypertension events, were analyzed in relation to patient demographics. A total of 138 patients received a total of 2342 infusions. SBP and DBP peaked at 40 min after the start of the infusion with a mean change of 16.0 (SD: 11.2) and 11.0 mmHg (SD: 8.45) respectively. Severe hypertension was observed in 17 patients (12.5%) and 23 infusion sessions (0.98%), occuring more frequently during the first three infusions (43.4%). Age (OR = 1.04 [1.02,1.05], p -value <0.001) was significantly associated with a surge in SBP and all patients with a past medical history of hypertension experienced a BP surge during their infusions. Ketamine infusions can cause significant blood pressure increases, particularly in older and hypertensive patients, highlighting the need for careful cardiovascular monitoring to mitigate risks during treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aim of this pre-registered (NCT05051462), randomized controlled trial was to investigate the efficacy and safety of a pandemic-adjusted version of family/systemic constellation therapy in the general population. Altogether, 80 individuals were randomized (85% retained; 67.6% women, M age = 41.9 ± 9.2 years) and followed up 1- and 6 months after participation in the single-day intervention. Numerous indicators of psychopathology and addiction as well as wellbeing were assessed. Members of the intervention group improved significantly in terms of the a priori primary outcome (overall psychopathology: d 1-month = 0.41, p 1-month = 0.003; d 6-month = 0.31, p 6-month = 0.028) as well as numerous secondary outcomes (obsession-compulsion, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and paranoid ideation). However, the magnitude of improvements was small and mostly disappeared by 6-months. Further, no significant treatment benefit emerged considering time x group interactions regarding any of the outcomes (although statistical power was low). Due to the significant, pandemic-related deviations from the protocol of the intervention, these results may not be generalizable to systemic constellation interventions in general; instead – considering the previous, more favorable data regarding efficacy/effectiveness and tolerability – they rather call attention to the importance of process-related factors regarding this intervention specifically as well as the potential disadvantages of pandemic-related treatment modifications of in-person (non-virtual) group interventions in general. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Introduction: Urinary incontinence (UI), especially stress UI, is common after prostatectomy. Penile compression devices (PCDs) may be a safe, tolerable option for conservative management in men who are not candidates for or not interested in surgical intervention for their UI. Areas covered: This article examines the epidemiology of post-prostatectomy urinary incontinence (PPI), and options for management. All available studies on PCDs are explored, including those on biomechanics, safety, tolerability, and user experience. History, availability of PCDs, and areas for future development are discussed. Expert opinion: PCDs are an option for conservative management of PPI. They are recommended for those men without impairment in cognition, dexterity, or sensation. They should be worn for short periods of time and are best used during situations when incontinence might be precipitated. Overall, data suggest they are well tolerated and effective when tested, but large randomized comparative trials and studies of long-term use with relevant patient reported outcome measures are lacking. More studies are needed on commercially available PCDs. Biomechanical studies suggest that there are superior designs and materials both for efficacy and tolerability. With an aging population, and more older men going for prostate surgery, a larger market for these devices is likely. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and tolerability of pooled human immune globulins, Flebogamma® 5% DIF and Flebogamma® 10% DIF, administered by topical ophthalmic instillation to New Zealand White (NZW) rabbits. Methods: Male NZW rabbits were used in this study. In the acute single dose tolerability study, rabbits (n = 12) received a single topical dose of Flebogamma® 5% DIF. In the two-week repeated-dose tolerability study, rabbits (n = 5 for each group) were administered either Flebogamma® 5% DIF or Flebogamma® 10% DIF by topical bilateral administration four times daily (q.i.d.) between 8 am and 6 pm for a period of two weeks. Full ophthalmic examinations were conducted to evaluate ocular tolerability at baseline, Day 7, and Day 14. Results: In the acute single dose study, mild hyperaemia was observed in 1 out of 4 eyes at each 4 h and 24 h post-instillation of Flebogamma® 5% DIF. In the repeated dose study, no ocular signs were detected after q.i.d. topical instillation of Flebogamma® 5% DIF, while Flebogamma® 10% DIF resulted in mild hyperaemia in 8 out of 10 eyes on Day 7, and 5 out of 10 eyes on Day 14. No positive corneal fluorescein staining was detected. Schirmer tear test results were unremarkable. No other ocular signs were observed. Administration of immune globulins had no effect on intraocular pressure. Conclusions: Flebogamma® 5% DIF and Flebogamma® 10% DIF were well-tolerated by NZW rabbits following single and repeat dose topical ophthalmic administration, supporting the future development of topical pooled human immune globulins for the treatment of ocular surface disease. [ABSTRACT FROM AUTHOR]

PURPOSE: Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 20% will allow reduced infusion volumes and frequency versus existing subcutaneous therapies such as fSCIG 10% and conventional subcutaneous immunoglobulin 20%, respectively. We assessed the tolerability, safety, and immunogenicity of warmed and unwarmed fSCIG 20%. METHODS: This phase 1, single-dose, open-label, three-arm study enrolled healthy adults aged 19-50 years (inclusive) at a single US center (NCT05059977). Post-screening, participants received a single fSCIG 20% dose comprising recombinant human hyaluronidase and varying doses of in-line warmed or unwarmed immunoglobulin G (IgG) during a 4-day treatment period in a sentinel and sequential dosing design (treatment arm 1, warmed IgG 20% 0.4 g/kg; treatment arm 2, warmed IgG 20% 1.0 g/kg; treatment arm 3, unwarmed IgG 20% 1.0 g/kg). Participants were followed for 12 (± 1) weeks post-infusion. The primary endpoint was tolerability (tolerable infusions were not interrupted, stopped, or reduced in rate owing to fSCIG 20%-related treatment-emergent adverse events (TEAEs)). Secondary endpoints included occurrence of TEAEs. RESULTS: Overall, 24 participants were included, 8 per treatment arm (mean age 39.0 years, 54.2% men). All participants tolerated the infusions. All TEAEs were mild (107 events, in all participants), and all participants experienced fSCIG 20%-related (105 events) and local (102 events) TEAEs. Infusion site erythema and infusion site swelling were most frequently reported. No serious TEAEs occurred, and no participants discontinued the study owing to TEAEs. CONCLUSION: fSCIG 20% was well-tolerated with a favorable safety profile in healthy adults. Future studies will evaluate fSCIG 20% in primary immunodeficiency diseases. Trial registration number (ClinicalTrials.gov): NCT05059977 (registered 28 September 2021).

Abstract Background Difelikefalin is a selective kappa opioid receptor agonist that is approved for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis (HD). In this study, we assessed the pharmacokinetics (PK) of intravenous (IV) difelikefalin in healthy subjects, in non–dialysis-dependent (NDD) subjects with varying stages of kidney disease, and in subjects with end-stage renal disease (ESRD) undergoing HD. Methods The PK and safety of single IV doses of difelikefalin (3.0 mcg/kg) were initially evaluated in NDD subjects with mild, moderate, or severe renal impairment compared with matched healthy subjects. Based on those data, the PK and safety of 3 dose levels of IV difelikefalin (0.5, 1.0, or 2.5 mcg/kg) were compared with matched placebo in subjects undergoing HD with each dose administered following dialysis, 3 times over a 1-week treatment period). Results Single IV dosing of difelikefalin in NDD subjects (N = 36) with mild renal impairment demonstrated comparable exposure to healthy subjects with normal renal function, while subjects with moderate or severe renal impairment had higher total exposure. NDD subjects with severe renal impairment had higher total exposure compared with those with moderate renal impairment (i.e., exposure in severe NDD > moderate NDD > mild NDD ≈ healthy subjects). Clearance of difelikefalin correspondingly decreased with increasing renal impairment. In the multiple-dose study in subjects with ESRD undergoing HD (N = 19), IV difelikefalin demonstrated dose proportionality and was shown to be mostly cleared by dialysis; steady state was achieved with the second dose on day 3. Safety findings for all subjects were consistent with the known profile of IV difelikefalin. Conclusions IV difelikefalin was well tolerated. Similar exposure was observed in NDD subjects with mild renal impairment compared with healthy subjects with normal renal function, with reduced clearance and higher exposure in NDD subjects with moderate or severe renal impairment. Dose proportionality was demonstrated in subjects with ESRD undergoing HD administered IV difelikefalin 3 times per week following dialysis and was shown to be mostly cleared by dialysis. Trial registration Single-dose study: NA; multiple-dose study: ClinicalTrials.gov registration number NCT02229929, first registration 03/09/2014.

Abstract Background Controversy exists whether prophylactic drugs are necessary in the treatment of medication overuse headache (MOH). Objectives To determine comparative benefits and safety of available drugs for the treatment of MOH including elimination of medication overuse (MO). Methods We systematically reviewed randomized controlled trials though an extensive literature search comparing different drug effects on MOH. A random-effect network meta-analysis was conducted to rank comparative effects of interventions. Outcome improvements from baseline include responder rate defined as ≥ 50% reduction of headache frequency, proportion of patients who revert to no acute medication overuse (nMO), and reduction in monthly headache and acute medication intake frequency. Certainty of evidence was classified using the Grading of Recommendations, Assessment, Development & Evaluation (GRADE). Results Of 8,248 screened publications, 28 were eligible for analysis. Topiramate was found to be beneficial based on its responder rate (odds ratios [OR] 4.93), headache frequency (weighted mean difference [WMD] -5.53) and acute medication intake frequency (WMD − 6.95), with fewer safety issues (i.e., tolerability, or more adverse events) than placebo (OR 0.20). Fremanezumab, galcanezumab and botulinum toxin type A (BTA) were beneficial for increased responder rates (OR 3.46 to 3.07, 2.95, and 2.57, respectively). For reversion to nMO, eptinezumab, fremanezumab and BTA were superior to placebo (OR 2.75 to 2.64, 1.87 to1.57, and 1.55, respectively). Eptinezumab, fremanezumab, erenumab 140 mg, and BTA were more efficacious than erenumab 70 mg (OR 3.84 to 3.70, 2.60 to 2.49, 2.44 and 2.16, respectively) without differences in safety and tolerability. Conclusion Despite lower safety and greater intolerability issues, topiramate has large beneficial effects probably on increasing responder rates, reducing headache frequency, and might reduce monthly medication intake frequency. Fremanezumab, galcanezumab, and eptinezumab are promising for increasing responder rates. For reversion to nMO, eptinezumab has large beneficial effects, fremanezumab has a smaller effect. BTA might have a moderate effect on responder rates and probably has a small effect on reversion to nMO. Trial registration PROSPERO, CRD42021193370.

Abstract Background Despite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients. Methods The study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment. Results One hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction. Conclusions Irinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

Abstract Background Efficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab’s tolerability and safety profile in individuals experiencing episodic and chronic migraines. Methods The study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption (‘drug holiday’) of up to 24 weeks. Results 701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed. Conclusions APOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment. Trial registration ClinicalTrials.gov ID: NCT04084314 ( https://clinicaltrials.gov/study/NCT04084314 ), First submitted: 2019-09-06.

Abstract Background Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. Methods This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. Results By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p

Abstract Background Digital phenotyping, the in-situ collection of passive (phone sensor) and active (daily surveys) data using a digital device, may provide new insights into the complex relationship between daily behaviour and mood for people with type 2 diabetes. However, there are critical knowledge gaps regarding its use in people with type 2 diabetes. This study assessed feasibility, tolerability, and user experience of digital phenotyping in people with and without type 2 diabetes after participation in a 2-month digital phenotyping study in Ireland. At study completion, participants rated methodology elements from “not a problem” to a “serious problem” on a 5-point scale and reported their comfort with the potential future use of digital phenotyping in healthcare, with space for qualitative expansion. Results Eighty-two participants completed baseline. Attrition was 18.8%. Missing data ranged from 9–44% depending on data stream. Sixty-eight participants (82.9%) completed the user experience questionnaire (51.5% with type 2 diabetes; 61.8% female; median age-group 50–59). Tolerability of digital phenotyping was high, with “not a problem” being selected 76.5%—89.7% of the time across questions. People with type 2 diabetes (93.9%) were significantly more likely to be comfortable with their future healthcare provider having access to their digital phenotyping data than those without (53.1%), χ2 (1) = 14.01, p =

ABSTRACT 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

This review presents the latest data on the long-term use of the selective Janus kinase inhibitor (JAKi) baricitinib (BARI) in patients with rheumatoid arthritis (RA) in real-world clinical practice. The results of long-term use (up to 9.5 years) of BARI in RA suggest that its efficacy is comparable or even superior to that of biologic disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib, while the drug is more effective in patients who have not previously received bDMARDs or JAKi. It has been shown that the BARI dose can be reduced to 2 mg/day once the treatment goal has been reached in most patients without a decrease in efficacy, and that exacerbations that have occurred after reduction of the dosage (or treatment interruption) are relieved when returning to the full dose of the drug. According to data from registries from many countries and open observational studies, BARI is well tolerated during long-term use, even in elderly patients with ≥1 risk factor for cardiovascular disease. A high survival rate with BARI therapy has also been observed, which according to some registries exceeds that of tumor necrosis factor α inhibitors. Against the background of BARI therapy, a rapid (within 1 to 3 months) statistically significant reduction in pain has been demonstrated, regardless of the degree of suppression of disease activity, which correlates with an improvement in the functional status and general condition of patients. The possibility of suppressing the progression of structural damage in patients with RA was also demonstrated, allowing the choice of individualized tactics for the management of such patients.

Abstract Oral Janus kinase inhibitors (JAKi), a class of advanced targeted systemic therapy, have demonstrated efficacy and safety in the treatment of moderate-to-severe atopic dermatitis (AD). Like other small molecules, oral JAKi have the potential for off-target effects including laboratory-related adverse events (AEs). Product labels for oral JAKi recommend an initial laboratory assessment and follow-up 4–12 weeks later to monitor for potential changes, based on evidence from clinical trials across therapeutic indications for oral JAKi, which may not reflect a population of moderate-to-severe AD patients typically seen in routine clinical practice. To address this gap, a panel of eight dermatologists with clinical and research experience with oral JAKi for the management of AD conducted a targeted review of the literature focused on key laboratory-related AEs associated with oral JAKi in the moderate-to-severe AD population. Based on the synthesis of evidence and informed opinion, a set of best practice statements related to fundamental standards of care and consensus recommendations on laboratory monitoring were suggested, and level of agreement was ascertained using a Likert scale from 0 to 100. There was a high level of agreement on three of the four suggested recommendations related to assessment and monitoring of key laboratory parameters and to dose reduction or switching in response to laboratory changes; there was a lower level of agreement related to the frequency of ongoing laboratory monitoring. Appropriate patient selection and laboratory assessment is an important strategy to mitigate the potential risks associated with oral JAKi when treating AD.

Preeya K Gupta,1,2 Rolando Toyos,3 John D Sheppard,4 Melissa Toyos,3 Francis S Mah,5 Brian Bird,6 Pamela E Theriot,7 Don Higgins8 1Triangle Eye Consultants, Raleigh, NC, USA; 2Department of Ophthalmology, Tulane University, New Orleans, LA, USA; 3Toyos Clinic, Nashville, TN, USA; 4Virginia Eye Consultants, Norfolk, VA, USA; 5Scripps Clinic, La Jolla, CA, USA; 6Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, VA, USA; 7Lusk Eye Specialists, Shreveport, LA, USA; 8Dry Eye Treatment Center of Connecticut, Plainville, CT, USACorrespondence: John D Sheppard, Virginia Eye Consultants, 241 Corporate Blvd, Norfolk, VA, USA, Tel +1 757 622-2200, Fax +1 757 622-4866, Email jsheppard@cvphealth.comAbstract: Dry eye disease (DED) is a common, multifactorial ocular disease impacting 5% to 20% of people in Western countries and 45% to 70% in Asian countries. Despite the prevalence of DED and the number of treatment approaches available, signs and symptoms of the disease continue to limit the quality of life for many patients. Standard over-the-counter treatment approaches and behavior/environmental modifications may help some cases but more persistent forms often require pharmacological interventions. Approved and investigational pharmaceutical approaches attempt to treat the signs and symptoms of DED in different ways and tend to have varying tolerability among patients. While several pharmacological approaches are the standard for persistent and severe disease, mechanical options provide alternate treatment modalities that attempt to balance efficacy and comfort. Newer approaches target the causes of DED, utilizing novel delivery methods to minimize irritation and adverse events. Here, we review approved and investigational approaches to treating DED and compare patient tolerability.Keywords: dry eye disease, tolerability, safety, pharmaceutical interventions, mechanical interventions

Abstract Background Alcohol-based handrub (ABHR) is the gold standard for hand hygiene (HH) and is a cornerstone of infection prevention and control (IPC) strategies. However, several factors influence the efficient use of ABHR by health workers. This study evaluated the tolerability and acceptability of a locally produced ABHR product and HH behaviour among health workers. Methods A longitudinal hospital-based intervention study was conducted in accordance with the WHO’s standardized protocol for evaluating ABHR tolerability and acceptability (Method 1). Sixty health workers across 4 hospitals in Sierra Leone were observed over a 30-day period at three separate visits (days 1, 3–5, and 30) by trained observers. The outcomes of interest included skin tolerability and product acceptabilityevaluated using subjective and objective measures. Results Objective and subjective evaluations demonstrated strong skin tolerability and high acceptability with the product. At all three visits, the skin tolerability score assessed by trained observers was 4 (BMS = > 4 in ≥ 75%). The primary acceptability criteria increased up to 95% (colour) and 88% (smell) at visit 3 (BMS = > 4 in ≥ 50%). Despite high acceptability, the product’s drying effect remained low at 52% and 58% during visits 2 and 3, respectively (BMS = > 4 in ≥ 75%). There were positive HH behaviours (n = 53, 88%), with more than half (n = 38, 63%) of them exhibiting HH at almost every HH moment. The mean ABHR was notably high (76.1 ml, SD ± 35), especially among nurses (mean = 80.1 ml) and doctors (mean = 74.0 ml). Conclusion The WHO-formulated, locally produced ABHR was well tolerated and accepted by health workers. These findings support the continuous utilization of evidence-based, cost-effective hand hygiene interventions in resource-limited settings. High handrub consumption and frequent HH practices were noticeable HH behaviours. Further research is recommended to optimize product formulations for skin dryness and investigate the association between ABHR consumption and hand hygiene compliance.

Abstract Background Studies have confirmed the rapid antidepressant action of ketamine in depressive episodes. Nevertheless, a standardized procedure for the delivery of ketamine infusion in individuals suffering from treatment-resistant depression, particularly in terms of infusion frequency and total dosage, remains undetermined. In addition, an efficacious ketamine regimen for persistent pain management involved a continuous 10-day infusion period with no notable adverse effects. Consequently, the primary objective of this study was to evaluate the antidepressant capacity of consecutive ketamine infusions spanning over three successive days, the duration of therapeutic response, and the overall safety profile of the treatment. Methods In this randomized controlled trial, participants aged 18–64 with treatment-resistant depression were randomized to receive either intravenous ketamine or midazolam (used as an active placebo) for 40 min daily over three consecutive days. Statistical analysis using repeated measures ANOVA was employed to assess the changes in the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS) and the clinical global impression-Severity from the initial assessment to 10 and 31 days post-infusion. Additionally, the duration of response and remission was evaluated using Kaplan–Meier survival analysis. Results Out of 33 randomized participants, 20 underwent the treatment as planned. By day 10th, the ketamine group had a mean reduction in MADRS score of 12.55 (95% CI = 6.70–18.09), whereas the midazolam group had a decrease of 17.22 (95% CI = 11.09–23.36). This pattern continued to day 31, with ketamine showing a mean score decrease of 13.73 (95% CI = 7.54–19.91) and midazolam a fall of 12.44 (95% CI = 5.61–19.28). Both treatments were well tolerated, with dissociative symptoms in the ketamine group being temporary and ceasing by the end of each infusion. Conclusion Intravenous ketamine given for three consecutive days did not show a notable antidepressant advantage when compared to the active placebo midazolam, highlighting the need for further research into effective treatments schedules for treatment-resistant depression. Trial registration NCT05026203, ClinicalTrials.gov, registered on 24/08/2021.

Jin Wang, Chaoying Hu, Lan Zhang Department of Pharmacy, Phase I Clinical Trial Center, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Chaoying Hu; Lan Zhang, Email hucarol@126.com; xwzhanglan@126.comPurpose: SHR6390 is an oral, potent and selective small-molecule CDK4/6 inhibitor for the treatment of human breast, ovarian and colon cancer. Previous studies have shown that SHR6390 in combination with rifampicin, a potent inducer of CYP3A4, significantly reduces exposure levels. Therefore, we further investigated the effect of efavirenz, a moderate CYP3A4 inducer, on a single oral dose of SHR6390 in healthy volunteers.Patients and Methods: Twenty healthy subjects were enrolled in this single-center, open, single-dose, self-controlled DDI study. On Day 1, subjects received a single oral dose of 150mg SHR6390; on Day 8-26, subjects received 600 mg efavirenz orally at night, with a single dose of 150 mg SHR6390 on Day 22. Blood samples for pharmacokinetic analyses were collected.Results: The geometric mean ratios of the maximum concentration(Cmax) and the area under the concentration curve from zero to infinity (AUC0-inf) between combination therapy and SHR6390 monotherapy (combination therapy/SHR6390 monotherapy) and their 90% confidence intervals were 0.562 (0.482, 0.654) and 0.328 (0.278, 0.386), respectively. This indicates that the Cmax and AUC0 inf of SHR6390 decreased by approximately 43.8% and 67.2%, respectively. Oral administration of 150 mg SHR6390 alone or together with efavirenz was safe and tolerable in healthy subjects.Conclusion: It is suggested that under the action of the moderate CPY3A4 inducer efavirenz, the exposure AUC of SHR6390 exhibits a moderate level of induction. It is recommended to avoid concomitant administration of moderate inducers of CYP3A4 during treatment with SHR6390.Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20211571/ https://classic.clinicaltrials.gov, NCT04973020.Keywords: SHR6390, efavirenz, drug-drug interaction, pharmacokinetics, tolerability

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide, being the fourth most prevalent cancer and the third most common in terms of mortality. A decrease in the incidence and mortality of CRC has been observed among adults over 50 years of age, screening colonoscopy being a contributory factor for this improvement. Adequate preparation of the colon is essential for obtaining accurate results and minimizing the risks associated with the colonoscopy procedure. Both ESGE (European Society of Gastrointestinal Endoscopy) and UEG (United European Gastroenterology) recommend adequate preparation in at least 90% of cases, calculated both at the endoscopy center level and for each individual endoscopist. The purpose of our article is to review the literature on different bowel preparation products for colonoscopy and demonstrate the non inferiority of low-volume preparations over the standard PEG 4L. Preparations containing PEG are the most common in preparation for colonoscopy. A recent meta-analysis suggests that high-volume, mutiple-dose regimens are superior in terms of efficacy to low-volume, multiple- dose regimens, including low-volume PEG with various adjuvants and sodium phosphate, although with lower tolerability. Due to low levels of compliance, tolerability and acceptability, standard 4L single-dose regimens of PEG have been gradually and successfully replaced by newer regimens that include low-volume solutions. An example of low-volume split-dose preparation is the solution of low-volume PEG4000, sodium sulphate, citric acid, sodium citrate, sodium chloride, potassium chloride and simethicone. In several studies this 2 L low volume preparations exhibit similar effectiveness with safety profiles that are comparable to classic 4 L PEG, with lower incidence of adverse effects and good tolerability. In conclusion, adequate preparation increases the quality of colonoscopy procedures as proper patient preparation is essential to obtain an optimal visualization of the intestinal mucosa. Low-volume bowel preparation is effective, safe and well tolerated by the patients, with higher acceptability compared to the standard volume PEG.

Background: Alcohol-based handrub (ABHR) is the gold standard for hand hygiene (HH) and is a cornerstone of infection prevention and control (IPC) strategies. However, several factors influence the efficient use of ABHR by health workers. This study evaluated the tolerability and acceptability of a locally produced ABHR product and HH behaviour among health workers. Methods: A longitudinal hospital-based intervention study was conducted in accordance with the WHO's standardized protocol for evaluating ABHR tolerability and acceptability (Method 1). Sixty health workers across 4 hospitals in Sierra Leone were observed over a 30-day period at three separate visits (days 1, 3–5, and 30) by trained observers. The outcomes of interest included skin tolerability and product acceptabilityevaluated using subjective and objective measures. Results: Objective and subjective evaluations demonstrated strong skin tolerability and high acceptability with the product. At all three visits, the skin tolerability score assessed by trained observers was < 2 in ≥ 97% of participants, exceeding the WHO benchmark score (BMS = < 2 in ≥ 75%). Participants' self-evaluations of overall skin integrity were 97% (visit 2) and 98% (visit 3) for scores > 4 (BMS = > 4 in ≥ 75%). The primary acceptability criteria increased up to 95% (colour) and 88% (smell) at visit 3 (BMS = > 4 in ≥ 50%). Despite high acceptability, the product's drying effect remained low at 52% and 58% during visits 2 and 3, respectively (BMS = > 4 in ≥ 75%). There were positive HH behaviours (n = 53, 88%), with more than half (n = 38, 63%) of them exhibiting HH at almost every HH moment. The mean ABHR was notably high (76.1 ml, SD ± 35), especially among nurses (mean = 80.1 ml) and doctors (mean = 74.0 ml). Conclusion: The WHO-formulated, locally produced ABHR was well tolerated and accepted by health workers. These findings support the continuous utilization of evidence-based, cost-effective hand hygiene interventions in resource-limited settings. High handrub consumption and frequent HH practices were noticeable HH behaviours. Further research is recommended to optimize product formulations for skin dryness and investigate the association between ABHR consumption and hand hygiene compliance. [ABSTRACT FROM AUTHOR]

Objectives: Saccharin test (ST) is a convenient method to assess the efficiency of mucociliary clearance, the primary defense mechanism of the upper airways' tract. The study objectives are to: (1) substantiate its short- (3 days) and long-term (30 days) repeatability; (2) assess its tolerability; (3) conduct a systematic literature review and to compare our results with the existing evidence. Methods: Twenty-nine healthy subjects were enrolled in an observational prospective study to perform an ST on three separate visits (at baseline; at follow-up visits at day 3 and at day 30). Transit times were recorded and self-reported nasal and general symptoms noted. A systematic review of the literature was conducted to compare our results with the existing literature. Results: The mean values (±SD) of ST transit time (STTT) were 7.085 (±2.19), 7.788 (±2.11), and 7.790 (±2.06) minutes at baseline, day 3, and day 30, respectively. Significant linear regression analysis was observed between day 3 and baseline (r =.193; P =.019) and day 30 and baseline (r =.182 P =.024). Significant agreement for the intrasession repeatability was observed with an ICC =.354 (P =.001). Outcomes' comparisons between baseline vs day 3 (P =.197) and baseline vs day 30 (P =.173) were not statistically significant. ST was well tolerated. Concordance with existing literature's data and high level of STTT repeatability were confirmed by the qualitative analysis. Conclusion: STTT reproducibility was good both in the short- and long-term. ST tolerability was very good. Our study data are consistent with the existing literature, indicating ST as a sound methodology for detection of early respiratory health changes and for specific regulatory application in respiratory research. [ABSTRACT FROM AUTHOR]

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 the European First Episode Schizophrenia Trial, 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 were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 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 sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health. [ABSTRACT FROM AUTHOR]

Around 91% of migraine patients use over-the-counter medicines to treat attacks, often without further treatment or medical consultation. This therapeutic principle is established in most countries, regardless of how the healthcare system is otherwise structured or financed. Using Germany as an example, the basis for an expansion of attack therapy with rizatriptan as an over-the-counter triptan is described. To achieve the best possible tolerability and safety in the context of self-medication, the lowest possible dose should be selected to provide the most favourable tolerability and safety profile in the context of self-medication through low dosages. The lowest approved dose of rizatriptan is 5 mg. This was investigated in three randomized controlled trials with 752 patients. The results show that rizatriptan at a dose of 5 mg is more effective than the triptans naratriptan 2.5 mg, almotriptan 12.5 mg and sumatriptan 50 mg, which were previously available for self-medication in Germany. There was no significant difference in the frequency of adverse events with rizatriptan 5 mg compared to placebo. Rizatriptan 5 mg does not have a higher side effect potential than sumatriptan 50 mg, which is already exempt from the prescription requirement. The reasons given show that rizatriptan in a dose of 5 mg for the treatment of acute migraine attacks fulfils the requirements for a transfer from prescription to pharmacy-only status at least as well as sumatriptan 50 mg, naratriptan 2.5 mg and almotriptan 12.5 mg. From a clinical care perspective, it is desirable for affected patients to have other options available for self-medication. Non-responders to other substances also have a further treatment option with rizatriptan 5 mg, with the same or even better risk–benefit profile, to treat migraine attacks safely, effectively and in a tolerable manner as part of self-medication. [ABSTRACT FROM AUTHOR]

Introduction: Shankhaprakshalana (SP) is a yogic method aiming to cleanse the bowel. It involves the use of warm saline water and a combination of five asanas. This study was designed to assess the effectiveness and safety of bowel preparation by SP. Methods: This is a retrospective observational study of prospectively collected data. Patients planned for colonoscopy were screened and enrolled to undergo bowel preparation by SP on the day of the colonoscopy. Patients having comorbid conditions, poor performance status, suspected or previously diagnosed intestinal stricture and past history of major abdominal surgery and those unable to perform asanas of SP were excluded. A low-fiber diet was advised for one day before the colonoscopy. Patients were advised to drink 400 mL of lukewarm saline water followed by five asanas (exercises) of SP, each done eight times dynamically and sequentially. After completing six such cycles, patients underwent colonoscopy. Boston Bowel Preparation Scale (BBPS) score was used to assess the quality of bowel preparation. Results: Total 238 patients were included. The major indications for colonoscopy were abdominal pain (35.3%), hematochezia (23.9%), diarrhea (20.2%), constipation (10.9%) and anemia (9.7%). The mean age was 37.7 (± 12) years. The mean BBPS was 8 (± 1.2). Bowel preparation was inadequate (BBPS < 6) in only two patients. Mean segmental BBPS for the three segments of the colon (right, transverse and left) was 2.6 (± 0.5), 2.7 (± 0.4) and 2.6 (± 0.7), respectively. Minor adverse events (nausea, abdominal pain, vomiting, giddiness and bloating) were noted in 10 participants (4.2%), which did not require hospitalization. Bowel preparation was completed in 133 (± 35) minutes. Conclusion: Shankhaprakshalana is an effective and safe method to achieve adequate bowel preparation before colonoscopy. Since this is a single-center and retrospective study, future multi-centric, prospective studies comparing it with the standard bowel preparation regimens are warranted. [ABSTRACT FROM AUTHOR]

Featured Application: The use of a cymenol-based mouth rinse is safe and well-tolerated by patients, with no reports of side effects or adverse events. The aim of this study was to evaluate a newly formulated mouth rinse containing cymenol in patients undergoing supportive periodontal care in terms of safety (primary outcome) and the impact on dental biofilm and gingival inflammation (secondary outcomes). This research was designed as a pilot, controlled, randomized, parallel, triple-blinded, single-center, clinical trial of a 12-week duration. Adverse events and product perception were assessed by a questionnaire. Clinical, patient-reported outcomes (PROs), compliance, tooth staining, dentin hypersensitivity and microbiological variables were also evaluated. Student T, Mann–Whitney-U and Chi-square tests were applied. Thirty participants (15 per group) were included, randomized and followed for 12 weeks. No adverse events were reported. The questionnaire showed an overall rating of 7.2 (out of 10) in the experimental group and of 8.2 in the control group (p = 0.165) at 12 weeks. No statistically significant differences were observed in terms of gingival health, tooth staining, dentin hypersensitivity or microbiological outcomes between groups at baseline, 6- and 12-week visits. The adjuvant use of the new mouth rinse formulation proved to be as safe as the control product and no significant differences were observed in terms of clinical efficacy. [ABSTRACT FROM AUTHOR]