Efficacy Profile Research Articles

An update on the pharmacotherapy of postpartum depression.

Extensive research has been conducted on postpartum depression (PPD) over the past century, and yet no definitive answer regarding its etiopathogenesis, risk factors, genetic predilection, and treatment has been found. The few preclinical and clinical studies propose that maternal brain adaptations to the endocrinological, immunological, and behavioral changes and external sociodemographic risk factors in the perinatal period make women more vulnerable to anxiety and depression. Irrespective of the cause, a dilemma exists regarding the type of help to provide postpartum mothers. With very few treatment options at our disposal, deciding between psychotherapy, pharmacological, and non-pharmacological therapy on a case-by-case basis is unproductive because in developing countries infrastructure is limited and the availability of medications, especially for psychiatric illnesses, is still evolving. Hence, regardless of psychotherapy, antidepressants remain the first line of treatment with selective serotonin reuptake inhibitors (SSRIs); sertraline has the best efficacy and safety profile in breastfeeding women. As endocrine factors play a significant role in etiopathogenesis, hormonal therapy with oxytocin has been shown to be efficacious, and studies investigating the role of testosterone in treating PPD are also under way. In 2019, the US Food and Drug Administration (FDA) approved the first and only drug for the sole purpose of treating PPD, brexanolone. Zuranolone, a drug recently approved by the FDA, has a similar mechanism of action to brexanolone. For breastfeeding mothers reluctant to use pharmacotherapy, somatic therapy has been studied, including bright light therapy, vagal nerve stimulation, and newer noninvasive interventions. This article encompasses a short note on PPD, including its etiopathogenesis and clinical characteristics, and recapitulates the various available and evolving pharmacological and nonpharmacological therapies.

Unveiling the Therapeutic Potentials of Water Hyacinth (Eichhornia crassipes (Mart.) Solms) Flower against Oxidative Stress, Inflammation and Depressive Disorders: GC-MS/MS, In Vitro, In Vivo and In Silico Approaches.

Water hyacinth (Eichhornia crassipes (Mart.) Solms) is a highly invasive aquatic weed native to the Amazonia basin, known for its rapid propagation, adaptability, and utilization in traditional medicine. The study aims to unveil the therapeutic potential of water hyacinth flowers methanolic extract (EC CME) and its four kupchan fractions (EC PESF, EC DCMSF, EC EASF, EC ASF) through diversified chemical-pharmacological approaches. GC-MS/MS of EC-CME uncovered a rich tapestry of 72 phytochemical components. In vitro DPPH scavenging assay and total phenolic content determination assay deciphered promising antioxidant assays with remarkably low IC50 values of 0.353 and 0.485 μg/mL, respectively for EC-ESF and EC-ASF. Besides, different in vivo tests, including tail emersion, acetic acid-induced writhing, and thiopental-induced sleeping test of EC-CME, yielded a remarkable 8.61±0.29 min of tail immersion time compared to the control's 2.05±0.11 min at the highest dose (600 mg/kg). The best % inhibition of writhing was recorded as 47.96 % accrued in 400 mg/kg dose, indicating robust pain-relieving properties. The onset and duration of sleep are significantly ameliorated for EC-CME, unveiling its antidepressant potential. Besides, molecular docking studies along with ADME/T analysis also validated the wet lab findings as well as their safety, efficacy, and drug-likeliness profile. Finally, this work can be an essential hint for utilizing aquatic weeds in drug development research.

[Translated article] Trichotillomania Treatment Update

Trichotillomania (TTM) is an obsessive–compulsive disorder in which affected individuals recurrently pull-out hair from any region of the body, causing hair loss or alopecia. The management of TTM is a therapeutic challenge for dermatologists and consists of a combination of pharmacological and non-pharmacological alternatives. Cognitive-behavioral therapy has successfully been used to treat TTM. However, not all patients are willing to follow this treatment strategy. Unconventional support tools are proposed, such as electronic devices, Internet therapies and microneedling. N-acetylcysteine and memantine are considered suitable first-line therapies thanks to their favorable safety and efficacy profile, low risk of adverse effects, and significant benefits. The use of other drugs, including fluoxetine, clomipramine, olanzapine, and naltrexone has limited evidence of variable efficacy. The present review illustrates the current treatment modalities for the management of TTM.

Pharmacological Treatment of Obesity in Older Adults.

Obesity is a complex health issue with growing prevalence worldwide. It is also becoming more prevalent in the population of older adults (i.e., 65 years of age and older), affecting frequency and severity as well as other comorbidities, quality of life and consequently, life expectancy. In this article we review currently available data on pharmacotherapy of obesity in the population of older adults and its role in obesity management. Even though there is growing evidence, in particular in the general population, of favourable efficacy and safety profiles of glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide and semaglutide, and recently dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide, concise guidelines for older adults are not available to this day. We further discuss specific approaches to frequently represented phenotype of obesity in older adults, in particular sarcopenic obesity and rationale when to treat and how. In older adults with obesity there is a need for more drug trials focusing not only on weight loss, but also on geriatric endpoints including muscle mass preservation, bone quality and favourable fat distribution changes to get enough data for evidence-based recommendation on obesity treatment in this growing sub-population.

Clinical pharmacokinetics and pharmacodynamics of ongericimab: A potential long-acting PCSK9 monoclonal antibody in healthy subjects and patients with hypercholesterolemia: Randomized, double-blind, placebo-controlled phase Ia and Ib/II studies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein-cholesterol (LDL-C) by decreasing the expression of the LDL-receptor on hepatic cells. Ongericimab (JS002) is a novel PCSK9 monoclonal antibody that exhibits a long-acting LDL-C lowering effect by exclusively inhibiting PCSK9 in pre-clinical studies. Two randomized, double-blind, placebo-controlled trials were conducted to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetic, and pharmacodynamic profiles of ongericimab in healthy subjects and patients with hypercholesterolemia. Eighty-four healthy subjects in the phase Ia study received a single dose of placebo or ongericimab (15-450 mg). Ninety patients with hypercholesterolemia in the phase Ib/II study received placebo or ongericimab 150 mg Q2W, 300 mg Q4W, or 450 mg Q4W for 12 weeks. Ongericimab exhibited non-linear kinetics. The apparent clearance decreased as the dosage increased, with terminal elimination half-life (t1/2) values of 4.5-6.5 days. Overall, ongericimab was well tolerated in both studies. A single dose of ongericimab reduced LDL-C levels by 30%-73% in healthy subjects, and repeated doses of ongericimab reduced LDL-C levels by 67%-80% in patients with hypercholesterolemia. At the end of the dosing interval in the phase Ib/II study, over 70% of patients' LDL-C levels decreased by more than 50% from baseline. The results showed that ongericimab had a significant long-acting LDL-C lowering effect with good safety and potential for clinical application.

Efficacy and safety profile of oral creatine monohydrate in add-on to cognitive-behavioural therapy in depression: An 8-week pilot, double-blind, randomised, placebo-controlled feasibility and exploratory trial in an under-resourced area

Pre-clinical and clinical evidence proposes that creatine monohydrate, an affordable nutraceutical, could be a useful adjunct to conventional antidepressant treatments. In this pilot feasibility and exploratory study, we investigate the 8-week effects of creatine in addition to cognitive-behavioural therapy (CBT) versus placebo plus CBT in depression. For the primary efficacy outcome of change in Patient Health Questionnaire-9 depression score at study endpoint, we used mixed-model repeated measures analysis of covariance. Logistic regressions were employed to assess acceptability (any-cause dropouts), tolerability (dropouts for adverse events), and safety (patients experiencing one or more adverse events). We calculated effect sizes adjusted for age, sex, and baseline depression score. One-hundred participants (50 females, mean age= 30.4 ± 7.4 years) with depression (mean PHQ-9 = 17.6 ± 6.3) were randomised to either creatine+CBT (N = 50) or placebo+CBT (N = 50). At 8 weeks, PHQ-9 scores were lower in both study arms, but significantly more so in participants taking creatine (mean difference= -5.12). Treatment discontinuations due to any cause and to adverse events, and proportion of participants with at least one adverse event were comparable between study arms. This hypothesis-generating trial suggests that creatine could be a useful and safe supplement to CBT for depression. Longer and larger clinical trials are warranted.

Intranasal insulin for the treatment of olfactory dysfunction: a protocol for a systematic review and meta-analysis

IntroductionOlfactory dysfunction (OD) is a prevalent nasal affliction that has detrimental effects on the patients’ quality of life and safety. Conventional therapeutic strategies have various limitations such as high costs,...

Safety and Efficacy Profile of Bimekizumab in Patients With Psoriasis and Psoriatic Arthritis: An 18-Patient Case Series

Safety and Efficacy Profile of Bimekizumab in Patients With Psoriasis and Psoriatic Arthritis: An 18-Patient Case Series

Long-term safety and efficacy of the fully human CAR-T therapy CT103A in relapsed/refractory multiple myeloma

CT103A is a fully human chimeric antigen receptor T-cell (CAR-T) product for targeting B-cell maturation antigen (BCMA). This study presents the updated safety and efficacy profiles of CT103A in patients with relapsed/refractory multiple myeloma (RRMM) after long-term follow-up. As of July 31, 2023, the median follow-up time after CAR-T-cell infusion was 45.0 months (range, 0.7-58.3 months). During long-term follow-up, the incidence of adverse events gradually decreased over time. One patient had a maximum duration of response of nearly five years. All 18 patients (100%) achieved partial remission or better; 77.8% (14 of 18) of patients eventually exhibited complete response (CR) or stringent complete response (sCR), with response increasing over time. At the time of data cut-off, nine patients were still alive, and seven patients had an sCR status with negative minimal residual disease (MRD). The median progression-free survival (PFS) was 22.6 months, and the median overall survival (OS) was 50.2 months for all 18 patients. The median CAR transgene persistence was 14.0 months (range, 0.7-57.3 months). Long-term follow-up demonstrated that CT103A confers durable clinical benefit for RRMM patients based on the sustained presence of fully human CAR-T cells.

Bispecific antibodies in follicular lymphoma.

Bispecific antibodies, specifically anti-CD20 T-cell engaging constructs, are poised to alter the treatment paradigm of multiple B-cell malignancies, including follicular lymphoma. Two CD20xCD3 bispecific antibodies, mosunetuzumab and epcoritamab, are now approved in the United States for third-line or later treatment of follicular lymphoma. A third agent, odronextamab, remains under review by regulatory agencies. In pivotal phase II trials, these bispecific antibodies demonstrated overall response rates of approximately 80%, with complete response rates of 60-70%, the majority of which have been durable at two years. Important safety signals included risk of infections, neutropenia, and cytokine release syndrome, which occurred in approximately half of patients, but was rarely high grade. Despite similar efficacy and toxicity profiles, key differences exist among agents, primarily relating to treatment duration, route of administration, and prophylactic corticosteroid use. Several ongoing studies are exploring bispecific antibodies in earlier lines of treatment, either as single agents or in combination with other active therapies. This novel class of agents is likely to play a pivotal role in improving outcomes for patients with follicular lymphoma.

Pharmacological profiles of neglected tropical disease drugs

According to the World health Organization there are a group of 20 diverse infectious Neglected Tropical Disease (NTD) conditions that primarily affect populations in low-income and developing regions. Despite the limited attention and funding compared to other health concerns, significant efforts to develop drugs for treating and controlling NTDs have been made. However, there is room for developing NTD drugs with improved safety, efficacy and ecotoxicological profiles. In order to facilitate this, we have adapted our existing validated data-driven workflows for understanding disease comorbidity to systematically evaluate the approved drugs that target the major World Health Organization defined NTDs. The foundation for this work comprised assembling the physicochemical, biological and clinical properties of each NTD drug and identifying patterns that reveal the underlying cause of their efficacy and side-effect profiles. Subsequently, computational methods were employed to identify analogs with potentially improved profiles and validated in a case study focusing on the teratogenic antileishmanial drug miltefosine. The wider impact of NTD drugs with regards to a One Health cross-disciplinary perspective at the human-animal-environment interface are also discussed.

Medicinal Plants Approach for Diabetes Mellitus-A Computational Model

The multidimensional metabolic syndrome that includes diabetes mellitus poses a serious threat to world health. There is an increasing interest in researching herbal remedies for their possible therapeutic advantages, even as traditional allopathic treatments continue to be widely used. This work throws light on the multiple ways of metabolism and biochemical interactions of medicinal plants in the control of glucose level, highlighting their crucial role in the process. The work clarifies several herbal extracts' efficacy and safety profiles, such as Aloe vera, Garlic, Gurmar, Bitter Melon, Neem, Tulsi, and through a thorough literature review and empirical evidence. These plants, which are abundant in bioactive substances like tannins, flavonoids, and alkaloids, show promise in treating insulin resistance, improving pancreatic function, and controlling blood sugar level. A further assessment of the rising risk associated with diabetes mellitus is discussed, and a differential equation model for diabetes mellitus is developed to minimize the complications. When using medicinal plants to treat diabetes, several factors are considered, including blood sugar level, sugar intake activity, and plasma insulin concentrations. The stability criterion for the mathematical model is examined through the system of differential equations. A representation highlighting the medicinal plants that can aid individuals with diabetes mellitus is provided. The blood sugar level, insulin generalization variable and plasma insulin concentration have all been measured at different points in time. Aloe vera, Gurmar, Garlic, Tulsi, Bitter Melon and Neem are among the medicinal plants selected for their demonstrated anti-hyperglycemic properties due to their easy availability in India. Mathematical solutions were calculated for every plant and proved to be steady.

Real-world assessment of the efficacy and tolerability profile of JAK inhibitors in difficult-to-treat rheumatoid arthritis

ObjectiveTo evaluate the effectiveness and tolerability of JAK inhibitors (JAKi) in patients with difficult-to-treat rheumatoid arthritis (D2TRA) in clinical practice. MethodsWe included RA patients initiating a JAKi between 2018 and 2022. Patients meeting EULAR criteria for D2TRA were compared to active non-D2TRA patients. Efficacy was evaluated at the first visit (FV) (6 months following JAKi initiation) and the last available visit (LV) up to December 2022. Results45 patients with D2TRA, all presenting signs of disease activity (imaging, CRP levels), were compared to 29 active non-D2TRA. DAS28 and DAS28-CRP reduction from baseline to FV was significant and similar between both groups, before and after adjusting for several factors including the number and exposure duration to previous targeted therapies. DAS28 and DAS28-CRP remained stable in both groups between FV and LV. The proportion of responders and patients achieving remission or low disease activity at FV and LV was similar in both groups. Thirty-five patients (42 %) discontinued JAKi over a mean observation period of 20±10 months, with no significant difference in discontinuation rates between groups (p = 0.36). Discontinuations due to inefficacy and side effects were evenly distributed. Frequency of infections, herpes zoster, myocardial infarctions, and venous thromboembolism was similar between groups, with a higher likelihood in patients aged ≥65 years and/or with at least one cardiovascular risk factor (30/39, 77 %). ConclusionJAKi effectively reduced disease activity in D2TRA patients with the same extent as active non-D2TRA patients. Tolerability profiles were comparable, with outcomes largely dependent on the presence of age and/or cardiovascular risk factors. Haut du formulaire.

Effect of Atomoxetine on Mouse Isolated Vas Deferens Contractility

Objective: Atomoxetine (ATX), a selective noradrenaline re-uptake inhibitor, is a preferred drug with sufficient efficacy and favorable safety profile for the treatment of attention-deficit hyperactivity disorder. Ejaculatory dysfunctions have been reported in the patients receiving ATX as sexual side effect, of which underlying mechanisms are largely unknown. The present study aimed to investigate the effect of ATX on mouse isolated vas deferens (VD) contractility as a potential mechanism of ATX-induced ejaculatory dysfunction. Material and Methods: Isolated organ bath studies were performed on prostatic parts of VD obtained from adult male Balb/c mice. The effect of ATX (10-6, 10-5, 3x10-5 and 10-4 M) on KCl (80 mM), phenylephrine (PhE, 3x10-4 M), adenosine 5’-triphosphate (ATP, 10-2 M) and electrical field stimulation (EFS; 100 V, 64 Hz)-induced contractions of VD strips were evaluated in concentration dependent manner. Results: ATX at 10-6 and 10-5 did not alter the contractile responses (p>0.05), however, higher concentrations of ATX (3x10-5 or 10-4 M) significantly inhibited the KCl, PhE, ATP and EFS-induced contractions of VD strips (p<0.05). Conclusion: The present study demonstrated for the first time that ATX decreased the contractile responses of mouse isolated VD concentration-dependently. Our results suggest that ejaculatory dysfunction might be related to the inhibitory effect on ATX on VD.

Efficacy and safety of nanoparticle albumin-bound paclitaxel plus carboplatin as neoadjuvant chemotherapy for stages III–IV, unresectable ovarian cancer: a single-arm, open-label, phase Ib/II study

BackgroundNeoadjuvant chemotherapy may be considered for patients with ovarian cancer (OC) whose tumors are deemed unlikely to be completely cytoreduced to no gross residual disease (R0) or who are poor surgical candidates. This Ib/II study was designed to assess the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin as neoadjuvant chemotherapy for stages III–IV, unresectable OC.MethodsEligible patients with stage III–IV, unresectable OC were enrolled in this phase Ib/II study. All patients received neoadjuvant nab-paclitaxel (260 mg/m2, day 1, every 3 weeks) plus carboplatin (AUC 5, day 1, every 3 weeks) for 3 cycles before surgery, followed by 3–6 cycles of adjuvant chemotherapy. The phase Ib primary endpoint was safety; the phase II primary endpoint was the R0 resection rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety (for all populations).ResultsSixty-two patients were enrolled and were given neoadjuvant therapy treated between October 2019 and December 2020, of whom 9 were in the phase Ib portion and 53 in the phase II portion. A total of 53 patients underwent surgery with an R0 resection rate of 73.6% (95% CI, 59.7–84.7%). With a median follow-up of 17.5 (range 0.7–36.7) months, for all patients, the best ORR was 83.9% (95% CI, 71.7–92.4%) with 47 partial responses, the median PFS was 18.6 (95% CI, 13.8–23.3%) months, and median OS was not reached. During the neoadjuvant chemotherapy, treatment-related adverse events (TRAEs) of any grade occurred in 91.9% (57/62) of all patients. The most common hematologic TRAEs were neutropenia (55/62, 88.7%), and non-hematologic toxicity was alopecia (36/62, 58.1%). Forty-nine patients (79.0%) experienced at least one grade 3–4 TRAEs, with the most common was neutropenia (44/62, 71.0%). Besides, delays in neoadjuvant chemotherapy and surgery due to AEs were observed in 9 (1 in phase Ib; 8 in phase II) and 7 (phase II) patients, respectively.ConclusionsThe study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant chemotherapy nab-paclitaxel plus carboplatin in stage III-IV, unresectable OC. In addition, AEs resulting in chemotherapy and surgery delays should be cautiously considered in this clinical setting.Trial registrationClinicalTrials.gov, ChiCTR1900026893. Registered at 25 October 2019.

Uncovering the Impact of COVID-19 Mediated Bidirectional Dysregulation of CYP3A4 on Systemic and Pulmonary Drug Concentrations Using Physiologically Based Pharmacokinetic Modeling.

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized COVID-19 patients. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary CYP3A4 impacts drug concentrations, especially in the lung tissue which is most affected by the disease. Herein, PBPK modeling was used to demonstrate the differences in systemic and pulmonary concentrations of four respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19 - CYP3A4 interactions at varying severity levels including outpatients, non-ICU, and ICU patients. The study showed that hepatic metabolism is the primary determinant of both systemic and pulmonary drug concentrations despite the concurrent bidirectional dysregulation of liver and lung CYP3A4. ICU patients had the most systemic and pulmonary drug exposure with a percentage increase in AUCplasma of approximately 44%, 56%, 114%, and 196% for clarithromycin, nirmatrelvir, dexamethasone, and itraconazole, respectively, relative to the healthy group. Within the ICU cohort, clarithromycin exhibited its highest exposure in lung tissue mass with a fold change of 1189, while nirmatrelvir and dexamethasone showed their highest exposure in the plasma compartment, with fold changes of about 126 and 5, respectively, compared to the maximum therapeutic concentrations for their target pathogens. Itraconazole was significantly under-exposed in the lung fluid compartment potentially explaining its limited efficacy for the treatment of COVID-19. These findings underscore the importance of optimizing dosing regimens in at risk ICU patients to enhance both efficacy and safety profiles. Significance Statement This study investigated whether COVID-19-mediated concurrent hepatic downregulation and pulmonary upregulation of CYP3A4 leads to differences in the systemic and pulmonary concentrations of four respiratory medicines. The study demonstrated that intercompartmental differences in drug concentrations were driven by only hepatic CYP3A4 expression. This work suggests that ICU patients with significant COVID-19 - CYP3A4 interactions may be at risk of clinically relevant COVID-19-drug interactions, highlighting the need for optimizing dosing regimens in this patient group to improve safety and efficacy.

JAK inhibitors: an evidence-based choice of the most appropriate molecule.

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis.

Direct Oral Anticoagulants versus Vitamin K Antagonists for the management of left ventricular thrombus after myocardial infarction: A meta-analysis

Abstract Background/Introduction Left ventricular (LV) thrombus formation is not an uncommon complication after acute myocardial infarction (AMI) in the modern era of early reperfusion. The optimal anticoagulation regimen in this clinical scenario remains poorly-defined. Purpose The present meta-analysis sought to investigate the efficacy and safety profile of direct oral anticoagulants (DOACs) compared with Vitamin K antagonists (VKAs) for the management of LV thrombus following AMI. Methods A systematic literature review was conducted in electronic databases to identify studies reporting efficacy and safety outcome data regarding the use of DOACs versus VKAs for patients with LV thrombus after MI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and random-effects meta-analyses were conducted to synthesize pooled ORs. Results Eight studies comprising a total of 605 patients were included (Table). DOACs were associated with an almost 2-fold higher likelihood for achieving thrombus resolution compared to VKAs (pooled OR 1.95 [1.25-3.04]; p =0.003, I2 =0 %), while they achieved a 70% lower risk for systemic embolism (pooled OR 0.30 [0.12-0.75]; p =0.01, I2 =0%). The use of DOACs was associated with a 54% lower risk for bleeding compared to VKAs (pooled OR 0.46 [0.26-0.84]; p =0.01, I2 =0 %). Overall, patients receiving DOACs had a 63% lower risk to reach the composite outcome of any bleeding, systemic embolism, cardiovascular hospitalization, or all-cause death, compared with patients using VKAs (pooled OR 0.37 [0.23-0.60]; p <0.0001, I2 =0%) (Figure). Conclusion DOACs appear to have a more favorable efficacy and safety profile compared to VKAs for the management of LV thrombus following AMI.Graphical abstractTable

Lipid-lowering therapy with Inclisiran in the real-world setting: initial data from a national health care service

Abstract Introduction Inclisiran, a first-in-class siRNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in randomized clinical trials. Challenges for real-life use of inclisiran include limited access to therapy, injections by medical staff, lack of cardiovascular outcome data, and concern from adverse effects considering the novel mechanism and long-term activity. Real-life data on the potential to attain lipid-goals and reduce treatment gaps is lacking. We investigated the implementation of inclisiran in real-world clinical setting in Israel. Methods Data from a nationwide healthcare organization on patients initiating inclisiran therapy during the period of 3/2022-11/2023. Patients’ characteristics, efficacy, use of combination lipid-lowering therapies, and attainment of low-density lipoprotein cholesterol (LDL-C) goals, were evaluated. Results Inclisiran was initiated by 503 patients (57% women; mean age 66±11 years). Atherosclerotic cardiovascular disease was present in 54%, and peak historical LDL-C levels >190 mg/dL documented in 64%. Prior exposure to PCSK9 monoclonal antibodies was evident in 28%. Follow-up lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n=254), median LDL-C reduction from peak historical levels was 57% (IQR, 48%-67%), and from pre-injection levels 40% (19%-54%). In those with concomitant oral lipid-lowering therapies (n=143), median LDL-C reduction from peak levels was 66% (IQR, 55%-73%), and from pre-injection levels 46% (23%-59%) (Figure). LDL-C <70 mg/dL was attained by 39% and LDL-C <55 mg/dL by 21.9%. Of those treated with concomitant statin therapy, 38% attained LDL-C <55 mg/dL. Overall, 6.5% did not persist with inclisiran therapy after initial injection. Conclusions In real-life practice, inclisiran showed good efficacy with positive short-term adherence. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.Waterfall Plot of LDL-C (%) Reduction

Adverse Drug Reactions to β-Lactam Antibiotics: A Portuguese Pharmacovigilance Database Analysis

Abstract Background The β-lactam antibiotics are one of the most relevant drug classes globally. They accounted for the largest share of systemic antibiotics consumption in Portugal across both community and hospital settings. Due to their significance, continuous monitoring of adverse drug reactions (ADR) associated with β-lactams is fundamental. Aim To analyse and characterise cases related to β-lactam antibiotics received by the Portuguese National Pharmacovigilance System. Methods Retrospective analysis of cases containing at least one medicinal product classified as suspect under the Anatomical Therapeutic Chemical (ATC) code J01C or J01D, reported to the Portuguese Pharmacovigilance System between 2014 and 2023. Characterisation of cases considered patient demographics, reported suspected medicines, MedDRA Preferred Term (PT), seriousness and type of reporter. Results A total of 3557 cases were identified (54.0% females; median age = 42.0 years; interquartile range = 52.2), with 95.9% originating from spontaneous reporting and 93.5% being reported by healthcare professionals. The most frequently reported medicines were those belonging to ATC J01CR. Around 70% of cases were classified as serious, with 38.7% being related to situations of disability or other criteria of greater seriousness. Most frequently reported PTs were related to skin disorders. Anaphylactic reaction was the most reported Designated Medical Event term. The PTs “Drug ineffective” and “Off label use” were reported in 5.2% and 2.4% of the cases, respectively. Conclusions Despite the majority of cases are serious, most of the ADR identified are related to already known hypersensitivity reactions. To improve the knowledge regarding these medicines and to generate evidence to address emerging public health issues it is of paramount importance to strength the Portuguese Pharmacovigilance System. This can be achieved through enhancing spontaneous reporting and implementing active pharmacovigilance programs. Key messages • Monitoring the efficacy and safety profile of β-lactams in a real-world context is crucial to mitigate the impact in public health and associated economic burden. • Enhancing the surveillance systems improves data collection and evidence generation, supporting tailoring treatment approaches and implementation of public health policies.