Recommendations for cyclin­dependent kinase 4/6 inhibitor treatments in the context of co­morbidity and drug interactions (Review).

Breast cancer is most frequently diagnosed among women aged 65-74 years and the prevalence of comorbidities in elderly patients with breast cancer is 32.2%. In addition, polypharmacy is quite common in these patients. Understanding the interaction between breast cancer treatment modalities and comorbidities is important, particularly in elderly patients, as comorbidities affect the choice of appropriate treatment and are independent risk factors for survival. A total of three oral cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), palbociclib, ribociclib and abemaciclib, notably prolonged progression-free survival when combined with endocrine therapy (ET), compared with ET alone in patients with advanced breast cancer (ABC). The present review article therefore addressed the safety, tolerability and toxicity of CDK4/6i treatment in ABC management, compiled real-world data on how multiple clinical and pharmacological features may affect the choice of these drugs and provided practical recommendations for clinical approaches. Before starting treatment with CDK4/6i drugs, all ongoing medical conditions should be inventorized and re-graded, and examination should be performed for any additional disease that the patient may not be aware of. It is also important to obtain a detailed history of concomitant drugs, including prescription and over-the-counter drugs, vitamins, supplements and herbal products. In addition, patients should be advised to consult their oncologist before starting any new medication.

Listening to music during intranasal (es)ketamine therapy in patients with treatment-resistant depression correlates with better tolerability and reduced anxiety.

Background: Although the effectiveness of (es)ketamine for therapy-resistant depression (TRD) has been established, potential treatment-limiting factors include side effects like dissociation, anxiety, or elevated blood pressure. Music can reduce stress and negative emotions as anxiety. This study aimed to investigate the impact of listening to music during intranasal (es)ketamine administration on both tolerability and efficacy. Methods: Records of 494 sessions (of 37 patients) with intranasal (es)ketamine administration, each containing data of blood pressure measurements, DSS-IV (dissociation symptoms scale-IV), anxiety and euphoria analogue scale, MADRS (Montgomery-Åsberg Depression Rating Scale) and BDI (Beck's Depression Inventory) were evaluated. Results: The between-group analysis, comparing participants who listened to music with those who did not, revealed significant differences in the administered dose (p-value: 0.003, mean: 131.5 mg with music vs. 116.7 mg without music), scores on the DSS Item 1 (p-value: 0.005, mean: 3 points vs. 2.4 points), levels of anxiety (p-value: <0.001, mean: 0.4 points vs. 1.4 points), and measurements of maximal systolic blood pressure after administration (p-value: 0.017, mean: 137.9 mmHg vs. 140.3 mmHg). Listening to music had no impact on the MARDS-change score between the sessions. Limitations: Key limitations include a non-randomized naturalistic design and the non-standardized selection of music, which was based on individual patient preferences. Conclusion: Listening to music during intranasal (es)ketamine therapy appears to be linked to reduced anxiety and lower blood pressure, stable or increased dissociation levels, and improved tolerance for higher doses. These findings could potentially contribute to the optimization of (es)ketamine therapy, both in terms of treatment efficacy and managing side effects.

Safety of Supplementation of Omega-3 Polyunsaturated Fatty Acids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is no comprehensive review of the evidence to support omega-3 polyunsaturated fatty acids (PUFAs) as a relatively safe and tolerable intervention. This study aimed to provide a meta-analytic and comprehensive review on the adverse effects of all kinds of ω-3 PUFA supplementation reported in randomized controlled trials (RCTs) in human subjects. A systematic review of RCTs published between 1987 and 2023 was carried out based on searches of 8 electronic databases. All RCTs that compared the adverse effects of ω-3 PUFAs containing eicosapentaenoic acid, docosahexaenoic acid, or both compared with controls (a placebo or a standard treatment) were included. The primary outcome was the adverse effects related to ω-3 PUFA prescription. A total of 90 RCTs showed that the ω-3 PUFA group, when compared with the placebo, had significantly higher odds of occurrence of diarrhea (odds ratio [OR] = 1.257, P = 0.010), dysgeusia (OR = 3.478, P < 0.001), and bleeding tendency (OR = 1.260, P = 0.025) but lower rates of back pain (OR = 0.727, P < 0.001). The subgroup analysis showed that the prescription ω-3 PUFA products (RxOME3FAs) had higher ω-3 PUFA dosages than generic ω-3 PUFAs (OME3FAs) (3056.38 ± 1113.28 mg/d compared with 2315.92 ± 1725.61 mg/d), and studies on RxOME3FAs performed more standard assessments than OME3FAs on adverse effects (63% compared with 36%). There was no report of definite ω-3 PUFA-related serious adverse events. The subjects taking ω-3 PUFAs were at higher odds of experiencing adverse effects; hence, comprehensive assessments of the adverse effects may help to detect minor/subtle adverse effects associated with ω-3 PUFAs. This study was registered at PROSPERO as CRD42023401169.

The current role of cannabis and cannabinoids in health: A comprehensive review of their therapeutic potential.

There has been an increased interest of the scientific community in cannabis and its constituents for therapeutic purposes. Although it is believed that cannabinoids can be effective for a few different conditions and syndromes, there are little objective data that clearly support the use of cannabis, cannabis extracts or even cannabidiol (CBD) oil. This review aims to explore the therapeutic potential of phytocannabinoids and synthetic cannabinoids for the treatment of several diseases. A broad search covering the past five years, was performed in PubMed and ClinicalTrial.gov databases, to identify papers focusing on the use of medical phytocannabinoids in terms of tolerability, efficacy and safety. Accordingly, there are preclinical data supporting the use of phytocannabinoids and synthetic cannabinoids for the management of neurological pathologies, acute and chronical pain, cancer, psychiatric disorders and chemotherapy-induced emetic symptoms. However, regarding the clinical trials, most of the collected data do not fully support the use of cannabinoids in the treatment of such conditions. Consequently, more studies are still needed to clarify ascertain if the use of these compounds is useful in the management of different pathologies.

Geriatric Nutritional Risk Index is a predictor of tolerability of antifibrotic therapy and mortality risk in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung fibrosis of unknown aetiology. Epidemiological studies have suggested that IPF progression may negatively affect nutritional status. Weight loss during antifibrotic therapy is also frequently encountered. The association of nutritional status and outcome has not been fully evaluated in IPF patients. METHODS: This retrospective multicohort study assessed nutritional status of 301 IPF patients receiving antifibrotic therapy (Hamamatsu cohort, n = 151; Seirei cohort, n = 150). Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). The GNRI was calculated based on body mass index and serum albumin. The relationship between nutritional status and tolerability of antifibrotic therapy as well as mortality was explored. RESULTS: Of 301 patients, 113 (37.5%) had malnutrition-related risk (GNRI < 98). Patients with malnutrition-related risk were older, had increased exacerbations and worse pulmonary function than those without a GNRI status <98. Malnutrition-related risk was associated with a higher incidence of discontinuation of antifibrotic therapy, particulary due to gastrointestinal disturbances. IPF patients with malnutrition-related risk (GNRI < 98) had shorter survival than those without such risk (median survival: 25.9 vs. 41.1 months, p < 0.001). In multivariate analysis, malnutrition-related risk was a prognostic indicator of antifibrotic therapy discontinuation and mortality, independent of age, sex, forced vital capacity, or gender-age-physiology index. CONCLUSION: Nutritional status has significant effects on the treatment and outcome in patients with IPF. Assessment of nutritional status may provide important information for managing patients with IPF.

Physicians' Perception of Oral Nutritional Supplement Acceptance and Tolerability in Malnourished Outpatients: PerceptiONS Study.

Malnutrition is a common condition associated with various pathologies such as infections, neoplasms and digestive system disorders. Patients can be managed using different strategies, which include dietary modifications or oral nutritional supplements (ONS). It is important to promote good ONS adherence in order to attain clinical efficacy and cost-effectiveness. Several factors (amount, type, duration and tolerability) may have an impact on ONS adherence. PerceptiONS is a descriptive, cross-sectional observational study based on an ad hoc electronic survey designed to explore physicians' perception of malnourished outpatients prescribed ONS. The survey considered adherence, acceptance/satisfaction, tolerability and benefits within the context of Spain's healthcare system. The perceptions of 548 physicians regarding the experience of 2516 patients were analyzed. From the physicians' perspective, 57.11% of patients adhered to over 75% of the prescribed ONS. The organoleptic properties of ONS represented the aspect with the most positive impact on adherence, with smell (43.72%) ranking as the top characteristic. In general, patients were satisfied (90.10%) with the ONS, with their related benefits (88.51%) and their organoleptic properties (90.42%), and accepted ONS in their daily diet (88.63%). ONS improved patients' general condition (87.04%), quality of life (QoL) (81.96%) and vitality/energy (81.28%). Physicians would prescribe the same ONS again in 96.4% of the cases.

Efficacy of Silexan in patients with anxiety disorders: a meta-analysis of randomized, placebo-controlled trials.

INTRODUCTION: We report on a meta-analysis of Silexan, a proprietary active substance produced from Lavandula angustifolia, in subthreshold anxiety, mixed anxiety and depressive disorder (MADD), and generalized anxiety disorder (GAD). METHODS: The present analyses are based on all currently completed 5 double-blind, randomized, placebo-controlled trials investigating Silexan in adult out-patients who received Silexan 1 × 80 mg/day or placebo for ten weeks according to random assignment (n = 1213). Efficacy was assessed based on the Hamilton Anxiety Rating Scale (HAMA), several anxiety self-rating scales, the Clinical Global Impression (CGI) scale, and the Short Form-36 (SF-36) health status questionnaire. RESULTS: After ten weeks' treatment, Silexan was significantly superior to placebo in reducing the HAMA total score (including the psychic and somatic anxiety sub-scores) and self-rated anxiety. Based on a ≥ 50% HAMA total score reduction, the responder rate ratio was 1.34 favoring Silexan, and the rate ratio of subjects much or very much improved according to the CGI was 1.51. Silexan was also significantly superior in improving the physical and mental health summary scores of the SF-36. There were no significant between-group differences concerning the occurrence of adverse events (AEs), serious AEs, and premature withdrawal due to AEs. CONCLUSIONS: This meta-analysis demonstrates that Silexan exerts significant anxiolytic effects in subthreshold anxiety, GAD and MADD that were consistently reflected in investigator ratings and patient-reported outcomes, including improvement of health-related life-quality, while showing favorable tolerability and safety.

A systematic review on the outcomes of local anaesthetic transperineal prostate biopsy.

OBJECTIVE: To conduct a systematic review of the literature to assess the diagnostic ability, complication rate, patient tolerability, and cost of local anaesthetic (LA) transperineal prostate biopsy. METHODS: Two reviewers searched Medline, the Cochrane Library, and Embase for publications on LA transperineal prostate biopsy up to March 2021. Outcomes of interest included cancer detection rates, complication rates, pain assessments and cost. RESULTS: A total of 35 publications with 113 944 men were included in this review. The cancer detection rate for LA transperineal prostate biopsy in patients undergoing primary biopsy was 52% (95% confidence interval [CI] 0.45-0.60; I2 = 97) and the clinically significant cancer detection rate (Gleason≥3 + 4) was 37% (95% CI 0.24-0.52; I2 = 99%). The rate of infection-related complications in the included studies was 0.15% (95% CI 0.0000-0.0043; I2 = 86). The LA transperineal procedures had a low rate of procedural abandonment (26/6954, 0.37%), with the greatest pain scores measured during LA administration. No formal cost analyses on LA transperineal prostate biopsies were identified in the literature. The overall risk of bias in the included studies was high, with considerable study heterogeneity and publication bias. CONCLUSION: Transperineal prostate biopsy performed under LA is a viable option for centres interested in avoiding the risk of infection associated with transrectal biopsy, and the logistical burden of general anaesthesia. Further investigation into LA transperineal prostate biopsy with comparative studies is warranted for its consideration as the standard in prostate biopsy technique.

Safety and Tolerability of an Antimalarial Herbal Remedy in Healthy Volunteers: An Open-Label, Single-Arm, Dose-Escalation Study on Maytenus senegalensis in Tanzania.

BACKGROUND: Though Maytenus senegalensis is one of the medicinal plants widely used in traditional medicine to treat infectious and inflammatory diseases in Africa, there is a lack of safety data regarding its use. Therefore, the study aimed to asselss the safety and tolerability of the antimalarial herbal remedy M. senegalensis. MATERIAL AND METHODS: The study design was an open-label, single-arm, dose-escalation. Twelve eligible male healthy Tanzanians aged 18 to 45 years were enrolled in four study dose groups. Volunteers' safety and tolerability post-investigational-product administration were monitored on days 0 to 7,14, and 56. RESULTS: There were no deaths or serious adverse events in any of the study groups, nor any adverse events that resulted in premature discontinuation. The significant mean changes observed in WBC (p = 0.003), Neutrophils (p = 0.02), Lymphocytes (p = 0.001), Eosinophils (p = 0.009), Alanine aminotransferase (p = 0.002), Creatinine (p = 0.03) and Total bilirubin (p = 0.004) laboratory parameters were not associated with any signs of toxicity or clinical symptoms. CONCLUSIONS: M. senegalensis was demonstrated to be safe and tolerable when administered at a dose of 800 mg every eight hours a day for four days. This study design may be adapted to evaluate other herbal remedies.

Effect of Aging on Deferasirox Therapy in Transfusion-dependent Patients. A prospective-retrospective, cohort-study.

BACKGROUND: Iron-chelation therapy is life-saving in patients on a chronic transfusion regimen as it reduces organ damage related to iron deposition in the tissues. Deferasirox, an iron-chelator, is characterized by pharmacokinetics variability, and some patients may discontinue the treatment due to toxicities. OBJECTIVE: Understanding whether deferasirox plasma levels are related to patients' specific characteristics could help optimize DFX dosage. METHODS: We analyzed deferasirox plasma concentration in 57 transfusion-dependent anemic patients using the HPLC method in this prospective-retrospective cohort study. All outpatients (3 to 98 years) were treated with deferasirox (film-coated tablet) for at least one year (median dose, 16.5 mg/Kg once a day). Deferasirox plasma concentration was normalized for dose/Kg (C/dose) and corrected with a linear regression model that relates C/dose and the time of blood sampling (Cref/dose). RESULTS: No significant differences in Cref/dose were found between males and females, either between different types of hemoglobinopathies or depending on the presence of the UGT1A1*28 polymorphism. Cref/dose has a positive and significant correlation with age, creatinine, and direct bilirubin. Cref/dose, instead, has a negative and significant correlation with Liver Iron Concentration (LIC), ferritin, and eGFR. Cref/dose was significantly different between three age categories <18yrs, 18-50yrs, and >50yrs, with Cref/dose median values of 1.0, 1.2, and 1.5, respectively. CONCLUSION: The study evidenced that to ensure the efficacy of deferasirox in terms of control over LIC and, at the same time, a lesser influence on renal function, the dose of the drug to be administered to an elderly patient could be reduced.

Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis.

BACKGROUND: This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. METHODS: Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months' bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. RESULTS: Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. CONCLUSION: Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk-benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.

Tolerability of Oral Supplementation with Microencapsulated Ferric Saccharate Compared to Ferrous Sulphate in Healthy Premenopausal Woman: A Crossover, Randomized, Double-Blind Clinical Trial.

A single-center, crossover, randomized, double-blind, and controlled clinical study was conducted to assess the tolerability profile, especially with regard to gastrointestinal complaints, of oral supplementation with AB-Fortis®, a microencapsulated ferric saccharate (MFS), as compared with conventional ferrous sulphate (FS) in healthy premenopausal women. A dose of 60 mg/day of elemental iron was used. The test products were administered for 14 consecutive days with a washout period of two menstrual episodes and a minimum of one month between the two intervention periods. The subjects completed simple-to-answer questionnaires daily for 14 days during both the intervention and the washout periods, capturing the symptoms associated with oral iron supplementation and overall health aspects. Following product consumption, the incidences of symptoms, numbers of complaints/symptoms, overall intensity, and total days with symptoms were found to be significantly higher for FS consumption as compared to MFS. The better tolerability profile of MFS over FS was further substantiated when both products were compared to a real-life setting (i.e., the washout period). Overall, the administration of both study products was safe with no serious or significant adverse events reported. In summary, the current study shows the better tolerability of the MFS preparation when compared to that of the FS, presenting MFS as a well-tolerated and safe option for improving iron nutrition.

Tolerability of graded levels of tall oil fatty acids as a nutritional additive for broiler chickens: a 45-day target animal safety study.

1. The following study was conducted to evaluate the tolerability of tall oil fatty acid (TOFA) to broiler chickens, at three graded levels as a nutritional additive in complete feed.2. 256 one-day-old female and male Cobb 500 broiler chickens were assigned to four dietary treatment groups with TOFA at 0 (control), 1.0, 3.0, or 5.0 g/kg within a complete feed for 45 d.3. Birds were weighed individually on days 0, 16, 31 and 45, and the feed intake, bird weight gain, and feed conversion ratio were calculated for the respective starter, grower and finisher phases and over the whole study. On day 45, blood samples were drawn from each bird for haematology and blood chemistry measurements. Two birds per pen were subjected to gross pathological examination and sampling of several tissues for histopathology, including weighing the liver.4. The dietary treatments did not affect zootechnical performance variables or mortality over the whole study period. Bird performance was typical for the breed.5. Haematology, clinical chemistry and histopathology did not reveal any changes associated with dietary TOFA dosing. However, the 5.0 g/kg dose level increased the relative weight of the liver, as a percentage of final body weight, compared to the control group, but there was lack of corresponding histopathology findings.6. In conclusion, the study indicated that oral administration of TOFA for 45 d in feed was well tolerated by the birds at dietary levels of up to 5.0 g/kg.

Tolerability and SCFA production after resistant starch supplementation in humans: a systematic review of randomized controlled studies.

BACKGROUND: Resistant starches (RSs) have been advocated as a dietary supplement to address microbiota dysbiosis. They are postulated to act through the production of SCFAs. Their clinical tolerability and effect on SCFA production has not been systematically evaluated. OBJECTIVES: We conducted a systematic review of RS supplementation as an intervention in adults (healthy individuals and persons with medical conditions) participating in randomized controlled trials. The primary outcome was tolerability of RS supplementation, the secondary outcome was SCFA production. METHODS: MEDLINE, Embase, and the Cochrane Central Register were searched. Articles were screened, and data extracted, independently and in duplicate. RESULTS: A total of 39 trials met eligibility criteria, including a total of 2263 patients. Twenty-seven (69%) studies evaluated the impact of RS supplementation in healthy subjects whereas 12 (31%) studies included individuals with an underlying medical condition (e.g., obesity, prediabetes). Type 2 RS was most frequently investigated (29 studies). Of 12 studies performed in subjects with health conditions, 11 reported on tolerability. All studies showed that RS supplementation was tolerated; 9 of these studies used type 2 RS with doses of 20-40 g/d for >4 wk. Of 27 studies performed in healthy subjects, 20 reported on tolerability. In 14 studies, RS supplementation was tolerated, and the majority used type 2 RS with a dose between 20 and 40 g/d. Twenty-one (78%) studies reporting SCFAs used type 2 RS with a dose of 20-40 g/d for 1-4 wk. In 16 of 23 studies (70%), SCFA production was increased, in 7 studies there was no change in SCFA concentration before and after RS supplementation, and in 1 study SCFA concentration decreased. CONCLUSIONS: Available evidence suggests that RS supplementation is tolerated in both healthy subjects and in those with an underlying medical condition. In addition, SCFA production was increased in most of the studies.

Multiple exposures to high concentrations of selenate significantly improve selenate tolerability, red elemental selenium (Se0) and selenoprotein biosynthesis in Herbaspirillum camelliae WT00C.

Herbaspirillum camelliae WT00C is a gram-negative endophyte isolated from the tea plant. It has an intact selenate metabolism pathway but poor selenate tolerability. In this study, microbiological properties of the strain WT00C were examined and compared with other three strains CT00C, NCT00C and NT00C, which were obtained respectively from four, six and eight rounds of 24-h exposures to 200 mM selenate. The selenate tolerability and the ability to generate red elemental selenium (Se0) and selenoproteins in H. camelliae WT00C has significantly improved by the forced evolution via 4-6 rounds of multiple exposures a high concentration of selenate. The original strain WT00C grew in 200 mM selenate with the lag phase of 12 h and 400 mM selenate with the lag phase of 60 h, whereas the strains CT00C and NCT00C grew in 800 mM selenate and showed a relatively short lag phase when they grew in 50-400 mM selenate. Besides selenate tolerance, the strains CT00C and NCT00C significantly improved the biosynthesis of red elemental selenium (Se0) and selenoproteins. Two strains exhibited more than 30% selenium conversion efficiency and 40% selenoprotein biosynthesis, compared to the original strain WT00C. These characteristics of the strains CT00C and NCT00C make them applicable in pharmaceuticals and feed industries. The strain NT00C obtained from eight rounds of 24-h exposures to 200 mM selenate was unable to grow in ≥ 400 mM selenate. Its selenium conversion efficiency and selenoprotein biosynthesis were similar to the strain WT00C, indicating that too many exposures may cause gene inactivation of some critical enzymes involving selenate metabolism and antioxidative stress. In addition, bacterial cells underwent obviously physiological and morphological changes, including gene activity, cell enlargement and surface-roughness alterations during the process of multiple exposures to high concentrations of selenate.

Real-world experience on the tolerability and safety of emicizumab prophylaxis in paediatric patients with severe haemophilia A with and without FVIII inhibitors.

BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor (F) IX and FX, and maintains haemostasis in patients with haemophilia A (PwHA). As a novel agent, many questions remain unanswered about the loss of emicizumab efficacy due to anti-drug antibody (ADA) development, the incidence of inhibitor recurrence in previously tolerized patients, and the risk of de novo inhibitor development. AIM: To present real-world experience regarding tolerability, side effects, and outcomes of adverse events of emicizumab prophylaxis in paediatric PwHA. METHODS: Data on tolerability, compliance, adverse events, and laboratory results of paediatric patients receiving emicizumab prophylaxis, treated at the Haemophilia Comprehensive Care Centre, at Birmingham Children's Hospital between March 2018 and June 2021, were collected. RESULTS: Our results showed that out of 52 patients, four experienced minor adverse events, two developed headaches, one developed abdominal pain and nausea, and one developed injection site reactions. Moreover, four patients experienced major adverse events, including severe headaches, major bleeding events, development of ADAs, and recurrence of inhibitors. Emicizumab prophylaxis was discontinued in three patients (5.7% of the cohort) due to adverse events. In addition, emicizumab was discontinued in one patient because of poor compliance. No adverse events were reported in previously untreated/minimally treated patients, represented by four patients in our cohort. CONCLUSIONS: The real-world experience of emicizumab prophylaxis in our cohort showed that emicizumab was safe and well tolerated in paediatric PwHA with and without inhibitors. Long-term assessment is crucial to monitor major adverse events, recurrence of inhibitors, and development of ADAs.

Safety, tolerability of ES16001, a novel varicella zoster virus reactivation inhibitor, in healthy adults.

PURPOSE: Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults. METHOD: Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants' treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests. RESULTS: In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration. CONCLUSION: ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ. TRIAL REGISTRATION: CRIS, KCT0006066. Registered 7 April 2021-Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071 ).

Safety and tolerability of a natural supplement containing glucosinolates, phytosterols and citrus flavonoids in adult women: a randomized phase I, placebo-controlled, multi-arm, double-blinded clinical trial.

OBJECTIVE: To evaluate the safety and tolerability of an oral herbal supplement containing glucosinolates, phytosterols, and citrus flavonoids (Warmi®, Lima Perú;) in otherwise healthy adult women. METHODS: This was a phase-I, randomized parallel three arms, double-blinded, and a placebo-controlled clinical trial. A total of 55 participants aged 18-40 were randomly assigned to one of three groups to receive for three months: (1) an oral herbal supplement of 1650 mg/day; (2) an oral herbal supplement of 3300 mg/day; or (3) an oral placebo 3300 mg/day. The primary endpoints were oral safety and tolerability of the supplement. The secondary endpoint was its effect on vital functions, anthropometrics, and laboratory tests. We used an exploratory approach by covariance analysis (ANCOVA) adjusted for the variables' baseline value for the secondary outcomes. RESULTS: All women completed three months of follow-up, reporting no side effects. Our exploratory analysis revealed that treatment with the herbal supplement of 1650 mg/day was associated with increased glucose and uric acid levels. In comparison, the herbal supplement 3300 mg/day was associated with reduced breathing rate, increased basal temperature, and systolic blood pressure, both compared to the placebo group. However, despite significant differences, none of these was clinically significant. CONCLUSION: The oral herbal supplement had a favorable safety and tolerability profile in studied women. There is a need to study its potential as an option to treat menopausal symptoms.

Capsaicin 179-mg cutaneous patch in the treatment of post-surgical neuropathic pain: a scoping review of current evidence and place in therapy.

INTRODUCTION: The use of topical agents has been suggested for post-surgical neuropathic pain. A high-concentration capsaicin 179-mg cutaneous patch (Qutenza™) is licensed in adults for chronic neuropathic pain in the EU, and neuropathic pain with post-herpetic neuralgia and neuropathic pain with diabetic peripheral neuropathy in the USA. This article aims to describe the use of a topical capsaicin 179-mg cutaneous patch in the treatment of PSNP. AREA COVERED: This narrative review presents the relevant clinical aspects of the use of a topical capsaicin 179-mg cutaneous patch for the treatment of post-surgical neuropathic pain (PSNP). Randomized control trials, observational studies, case series, and reports investigating the clinical use of the capsaicin patch were searched through MEDLINE, EMBASE, AMED, Cochrane Library, CINAHL, Web of Science, and ROAD databases. Trials from citation lists of reviewed articles and hand-searching were added. The search concluded in September 2020. 10/20 articles were considered. EXPERT OPINION: Some clinical studies demonstrated the efficacy of the capsaicin 179-mg patch in PSNP as monotherapy and concomitant treatment with oral treatments. This topical treatment of PSNP is better tolerated and accepted compared with systemic treatments. To maximize the effectiveness of the treatment, correct administration recommendations should be followed.

Early-Pregnancy Dydrogesterone Supplementation Mimicking Luteal-Phase Support in ART Patients Did Not Provoke Major Reproductive Disorders in Pregnant Mice and Their Progeny.

Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.