Daily Dose Research Articles

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Up-titration of Guideline Directed Medical Therapy (GDMT) and the occurrence of side effects in Heart Failure with reduced Ejection Fraction (HFrEF)

Abstract Background The ESC Guidelines recommend early, full-dose use of heart failure (HF) medications to enhance survival, but real-world application often faces delays and inconsistencies. Clinicians often fear side effects during up-titration to the recommended target dose (TD), i.e. hypotension, bradycardia, renal impairment, and hyperkalemia (HK). The dependency of side effects during dose escalation from the severity of HF remains unclear. Purpose This study aimed to evaluate the relationship between the occurrence of side effects during up-titration of HF medication and HF severity reflected by N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods 425 patients with HFrEF and a complete data set of patient characteristics, medications and laboratory values at baseline (BL), 2 months (2M), and 6 months (6M) were included from our outpatient HF unit's prospective registry. Significant side effects were defined as: systolic blood pressure (SBP) <90mmHg, heart rate (HR) <50 beats per minute (bpm), potassium (K) >5.0mmol/l or K >5,5mmol/l and estimated glomerular filtration rate (eGFR) <30ml/min/1.73m2. Patients were categorized into three risk groups based on their NT-proBNP levels, i.e. low-risk with NT-proBNP <1000pg/ml, medium-risk with NT-proBNP 1000-2000pg/ml or high-risk with NT-proBNP >2000pg/ml. The occurrence of side effects was recorded and the development compared among the HF risk groups. Results Figure 1 shows up-titration of HF medication. Mean daily dosages of betablockers (BB), mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-system inhibitors (RASi) increased significantly during follow-up (BL vs 2M and BL vs 6M, p<0.001 for all). The majority of patients received ≥50% of the recommended TDs at 6M (89% for BB, 83% for MRA, 88% for RASi and 91% for total mean TDs ≥50%), and the achieved daily dosages at 6M were largely comparable across the HF risk groups at 6M, except for RASi (p=0.030). Figure 2 depicts the side effects. Side effects developed almost exclusively at short-term within 2M except for lower SBP (Figure 2A). Newly developed side effects occurring after up-titration (2B) were even more rare and predominantly occurred within the highest NT-proBNP group. The occurrence of hypotension and bradycardia was infrequent and comparable within the HF risk groups. Renal dysfunction (at 6M p=0,041) and HK occurred predominantly in higher risk patients (HK at 2M p=0,001 and at 6M p<0,001). Conclusions Up-titration of HF medications is highly feasible, particularly in low- and medium-risk patients. Despite rare side effects such as hyperkalemia and renal impairment, up-titration remains unimpeded, especially in patients with NT-proBNP levels below 2000pg/ml. These findings emphasize the safety of up-titration in HF.

South African Parents' and Grandparents' Perspectives on the Acceptability of Implant Delivery of Treatment to Young Children with HIV.

Children living with HIV (CLWH) face unique challenges with adherence to antiretroviral therapy. In South Africa, just over a third of children receiving antiretroviral therapy are virally suppressed. Long-acting, subcutaneous implants may improve outcomes in CLWH compared to current daily oral dosing regimens. Qualitative in-depth interviews and focus group discussions (FGD) were conducted with 50 caregivers of CLHW in Johannesburg, South Africa. Interviews and FGDs were audio-recorded and transcribed. Data were coded and analyzed using Dedoose v9 software and a thematic approach. Caregivers had generally positive impressions of the pediatric HIV treatment implant. They emphasized the advantages of a long-acting and discreet treatment option for CLWH. Cited advantages were perceived to have widespread impact on CLWH, their caregivers, and other social dynamics. Caregivers raised some concerns or uncertainties about the potential efficacy, side effects and safety of the implant. Future clinical testing and outreach efforts may address such concerns and mitigate potential misinformation about implants. This study indicates the need to develop long-acting, discreet, safe, and efficacious HIV treatment options for young children.

Influence of prior heart valve intervention on treatment and disease trajectory after diagnosis of heart failure with reduced ejection fraction

Abstract Background and aim Among patients with heart failure with reduced ejection fraction (HFrEF), knowledge is scarce on whether patients with prior valvular heart disease (VHD) intervention are distinct regarding clinical characteristics, treatment, and prognosis. Methods Using the Danish Heart Failure Registry and nationwide administrative registries, we identified patients with new-onset HFrEF from 2008 to 2021. Within this cohort, patients with a prior VHD intervention were identified and matched 1:5 on age-, sex-, in/outpatient presentation, and year of HFrEF diagnosis with remaining patients (controls). Outcomes were 1) baseline use and up-titration of guidelines-directed medical therapy (GDMT) and implementation of implantable cardioverter-defibrillator or cardiac resynchronization therapy with pacemaker/defibrillator (ICD/CRT-P/D) at 6 months follow-up, and 2) a composite of HF hospitalization or all-cause death at 3 years follow-up. The Kaplan-Meier estimator and Cox regression models, adjusted for HF severity, socioeconomic status, and major comorbidities, were used to compare the composite outcome, with patients without prior heart valve intervention as reference. Results The study cohort comprised 32,713 patients, of whom 1196 (3.6%) underwent a prior VHD intervention (median time since intervention 10 months). After matching, the study population were 1151 cases (median age 74 years, 82% men), and 3769 matched controls. Among cases and controls, median left ventricular ejection fraction was similar (30% vs. 30%) and the proportion in New York Heart Association (NYHA) class II was alike (82% vs 83%). At the time of HFrEF diagnosis, numerically more cases were on a beta-blocker (62% vs. 53%), ACEi/ARB/ARNI (48% vs. 44%), MRA (19% vs. 14%), and more had an implementation of (ICD/CRT-P/D) (17 % vs. 7%) (Figure 1). At 6 months, ≥ 50% of the daily target dose was achieved in (46% vs. 46%) for beta-blockers, (47% vs. 47%) for ACEi/ARBs/ARNI, (31% vs. 33%) for MRA, and implementation of ICD/CRT-P/D was attained in (28% vs. 18%), among cases and controls, respectively (Figure 1). The 3-year risk of HF hospitalization or all-cause death was 25% in cases and 24% in controls (Figure 2) with no significant differences (hazard ratio (HR) 0.95 , 95% confidence interval (CI) 0.84-1.08) compared to controls. Conclusions Patients with new-onset HFrEF and prior VHD interventions received more GDMT and had a higher implementation of ICD/CRT-P/D at the time of HFrEF diagnosis. However, following diagnosis, no major differences in GDMT initiation and up-titration, implementation of ICD/CRT-P/D, and the adjusted rates of HF hospitalization or all-cause death were observed among patients with and without prior heart valve intervention.Figure 1 Guideline-directed medicationFigure 2 Crude cumulative risk

Evaluation of Emulsification Techniques to Optimize the Properties of Chalcone Nanoemulsions for Antifungal Applications

Background/Objectives: Nanoemulsions (NEs) possess properties that enhance the solubility, bioavailability and therapeutic efficacy of drugs. Chalcones are compounds known for their antifungal properties. In this study, we evaluated different emulsification techniques to create alginate nanoemulsions containing chalcone (1E,4E)-1,5-bis (4-methoxyphenyl) penta-1,4-dien-3-one (DB4OCH3). Our goal was to develop an antifungal formulation targeting Candida albicans strains. Methods: Ultrasound and ultrasound combined with high-speed homogenization techniques were used to prepare alginate-stabilized nanoemulsions. Particle size, zeta potential and encapsulation efficiency were evaluated. Additionally, in vitro release studies were conducted. Results: The combined emulsification technique produced stable nanoparticles with high encapsulation efficiency and antifungal activity, with a minimum inhibitory concentration of 8.75 μg/mL for the nanoemulsions compared to 312 µg/mL for free DB4OCH3. NEs’ effectiveness can be attributed to their ability to form nanodroplets efficiently, facilitating the solubilization of the chalcone in the oily phase. The particle size varied between 195.70 ± 2.69 and 243.40 ± 4.49 nm, with an increase in chalcone concentration leading to larger particle sizes. The zeta potential showed values from −91.77 ± 5.58 to −76.90 ± 4.44 mV. The UHS-7 sample exhibited an encapsulation efficiency of 92.10% ± 0.77, with a controlled in vitro release of 83% after 34 h. Molecular docking simulations showed that the aromatic nature of DB4OCH3 resulted in the formation of apolar interactions with aromatic residues located in the active site of the TMK, as observed in their respective co-crystallized inhibitors, within an affinity energy range that enables optimum specificity of the ligand for these two pathways. Pharmacokinetic analyses indicated high passive cell permeability and low hepatic clearance, and phase I metabolism reduces its oral bioavailability and metabolic stability, suggesting a promising active ingredient as an oral drug with control of the daily oral dose administered. Conclusions: The combined nanoemulsification technique led to the formation of finely dispersed nanodroplets that favored the solubilization of the chalcone in the oil phase, which led to a better performance in the antifungal properties. DB4OCH3 shows promise as an oral drug with controlled dosing.

Blood pressure lowering efficacy of antihypertensive drugs and their combinations: a systematic review and meta-analysis of 500 randomised, double-blind placebo-controlled trials

Abstract Background Each 1 mmHg reduction in systolic blood pressure (SBP) reduces the risk of major cardiovascular disease events by about 2%. However, there are currently no tools to provide randomised trial-derived estimates of blood pressure (BP)-lowering efficacy of different antihypertensive regimens despite the vast number of possible drug-dose permutations. There has also been no attempt to classify efficacy of treatment regimens into low, moderate, and high intensity. Purpose We aimed to quantify the BP-lowering efficacy of the five major classes of antihypertensive drugs and their combinations. Methods We conducted a systematic review and meta-analysis of randomised double-blind placebo-controlled trials. CENTRAL, MEDLINE and Epistimonikos were searched from inception until December 2022 to identify trials, that compared angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, and diuretics versus placebo, for 4-26 weeks. Primary outcomes were reduction in SBP and diastolic blood pressure (DBP). Doses were classified into standard dose based on the World Health Organisation Defined Daily Dose. BP-lowering efficacy was estimated for each drug and dose using fixed-effects meta-analyses and meta-regressions, standardised to baseline SBP 154 mmHg. Treatment regimens were categorised into low, moderate, and high intensity according to estimated SBP-lowering efficacy of <10, 10-19 and ≥20 mmHg, respectively. Results A total of 500 trials (106,358 participants, 44% female) were included, which included 66 single antihypertensive drugs (monotherapy) and 89 two drug (dual) combinations. The mean baseline BP was 154/100 mmHg and mean follow-up was 8.6 weeks. Monotherapy at one standard dose reduced SBP by 8.5 (95% CI, 8.2-8.9) mmHg, with an additional 1.2 (1.0-1.5) mmHg reduction for each 10 mmHg higher pre-treatment SBP, and an additional 1.5 (1.2-1.8) mmHg reduction with each doubling in dose. There was significant heterogeneity between monotherapies, and 72% were classified as low intensity efficacy. Dual combinations at one standard doses of both the drugs reduced SBP by 15.2 (13.4-17.1) mmHg, and an additional 2.6 (1.4-3.8) mmHg reduction with doubling the doses of both the drugs. There was considerable heterogeneity between dual combinations and 59% were classified as moderate, and 11% as high intensity efficacy. The BP lowering efficacy of adding additional drug classes was confirmed to be additive after accounting for pre-treatment SBP. Triple combinations were classified as high intensity efficacy based on meta-regression analyses. Conclusions There is significant variability in the efficacy of different BP-lowering regimens. The present analyses, available in an online tool, can estimate the BP lowering efficacy for any combination of drug(s) and dose(s), and can classify treatment regimens into low, moderate or high intensity.

Pretreatment with dual antiplatelet therapy in acute myocardial infarction

Abstract Background Combined antithrombotic therapy prevents thrombus progression and its components embolization, and thus, it has an essential role in coronary microcirculation (re)perfusion in acute myocardial infarction (AMI). Pretreatment with P2Y12 inhibitors, on top of aspirin, before primary angioplasty has not been satisfactorily studied in STEMI. Purpose To investigate the impact of combined antiplatelet therapy on-treatment on the outcome of patients with STEMI. Methods Patients who suffered STEMI during the 7 years (1/2016-12/2022) were included. The analysis is based on population data from the National Health Information System (NHIS). Information on AMIs from the Intervention Module of the Registry of Cardiovascular Operations and Interventions was combined with prescription data from the Registry of Reimbursed Health Services 6 months before MI and identification of deceased patients from the Registry of Death Records. Data from the NHIS covers almost 100% of all cases in the population. Standard descriptive statistics and test were applied in the analysis. Multivariate logistic regression adjusted for clinical and procedural characteristics was adopted to analyze the influence of pretreatment on the risk of 1) out-of-hospital cardiac arrest (OHCA), 2) clinical condition at admission – need of mechanical ventilation and circulatory instability (Killip III,IV), 3) initial TIMI flow through the infarct-related coronary artery (IRA ), and 4) short term mortality. Results The study sample consisted of data from 40,383 STEMIs of which 1,601 patients were on dual antiplatelet therapy (DAPT) with aspirin plus iP2Y12 lasting 1 to 6 months before the event occurred. Patients on chronic oral anticoagulation (N 2101) were excluded. Patients on DAPT versus those without antiplatelet therapy or on aspirin at a daily dose of 100 mg were older, had higher comorbidity rates, and were at higher risk of mortality (Table). The multivariate logistic regression analysis showed that patients on DAPT at the time of MI onset and lasting for at least one month had a higher likelihood of preserved perfusion through the IRA (Odds ratio and 95% Confidence interval, OR (95% CI) 1. 193 (1.074; 1.326), p=0.001). However, the DAPT pretreatment did not reduce the risk of OHCA, the need for mechanical ventilation, or initial circulatory destabilization. It did not positively affect the prognosis of the patients (Figure ). Conclusion The significant benefit of the DAPT pretreatment on the preservation of infarct-related coronary artery flow did not translate into a positive effect on the prognosis of STEMI patients.

Consumption and expenditure of antidepressants and anxiolitycs in 14 European countries

Abstract Background Since the burden of depressive and anxiety disorders, assessing the use and spending of drugs commonly prescribed for treating such conditions is a valuable barometer of mental health assistance and healthcare services. The current research aims to evaluate the consumption of antidepressants and anxiolytics and the relative expenditure among 14 European countries (Austria, Czech Republic, Finland, Germany, Hungary, Italy, Latvia, Luxembourg, Norway, Portugal, Slovak Republic, Slovenia, Spain and Sweden). Methods A retrospective longitudinal study was assessed based on pooled time series analysis of secondary data over ten years (2012-2021). Defined Daily Doses (DDD) per 1,000 inhabitants and health expenditure per capita (current US$, computed on purchasing power parity) were considered. Linear and quadratic trends were calculated for defining relationships between the variables of interest. Results Prevailing patterns of consumption and spending show an increase in antidepressants and a decrease in anxiolytics. Noteworthy is the growth slope of antidepressant consumption in three selected countries, Portugal, Spain, and Sweden, by over two and a half times from 2012 to 2021. In addition, for a few countries, there is a pattern contrary to most countries for anxiolytics (Latvia, Spain) and discordant between consumption and expenditure for antidepressants (Austria, Hungary). Conclusions The widespread growth of antidepressant use deserves attention. As a public health issue, the prescription and use of antidepressants should be addressed by targeted policies for integrating multifaceted strategies. Key messages • Monitoring consumption and expenditure of antidepressant and anxiolytic drugs represents a valid tool for assessing the efficacy and availability of mental healthcare services among the population. • The growth in the consumption of antidepressants represents a relevant public health issue and deserves attention for the evaluation of an integrated approach of assistance.

Effectiveness and safety of levodopa-entacapone-carbidopa infusion in Parkinson disease: A real-world data study.

Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is a recently developed device-aided therapy for advanced Parkinson disease (PD) patients. The aim of this study was to report real-world evidence about the effectiveness, tolerability, and safety of LECIG in PD patients. A multicenter observational retrospective study of the first patients who initiated LECIG in Spain was performed. All neurologists with an experience of at least two patients treated until 30 March 2024 were invited to participate. Data about effectiveness and safety from the medical records (V0, pre-LECIG; V1, initiation of LECIG; V2, post-LECIG follow-up) with a total of 246 variables were collected. Seventy-three PD patients (61.6% males, 70.1 ± 9.1 years old) from 21 Spanish centers with a mean disease duration of 14.4 ± 6.3 years (range = 5-31) were included. Twenty-six patients (35.6%) were switched directly from levodopa-carbidopa intestinal gel. The mean exposure to LECIG was 177.3 ± 110.5 days (range = 7-476). The mean daily OFF time decreased from 5.2 ± 3 (pre-LECIG) to 1.9 ± 1.8 (post-LECIG; n = 66, p < 0.0001). Global improvement was observed in >85% of the patients. No significant change was detected in the levodopa equivalent daily dose from V0 to V2. Only 7% received 24-h infusion, and 24.7% required more than one cartridge per day at V2. Thirty-four patients (46.6%) had at least one adverse event related to LECIG and/or the device system. Five patients (6.8%) discontinued LECIG. LECIG was safe and effective in advanced PD patients.

The effect of Glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in type 2 diabetes mellitus patients with coronary artery disease

Abstract Background Cardiovascular disease is the primary cause of mortality in patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCT) have shown that Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve cardiovascular outcomes in T2DM patients, with greater therapeutic benefits observed in patients with established atherosclerotic cardiovascular disease. However, the effect of GLP1-RA therapy on cardiovascular outcomes has been inconsistent and the RCT have not been sufficiently powered to examine the effect of GLP1-RA on mortality or their therapeutic effect in different subgroups of T2DM patients. Purpose This study aimed to examine the effect of GLP1-RA therapy on cardiovascular outcomes and mortality in a real-world cohort of T2DM patients with coronary artery disease (CAD). Methods This study included T2DM patients with CAD who were treated with metformin at a daily dose of ≥ 1g for a period of ≥ 180 days. CAD was defined as ≥ 50% luminal stenosis in any coronary artery segment according to a nationwide angiography and angioplasty registry. We performed sequential emulated target trials at monthly intervals between January 1, 2013 and December 31, 2020 to examine the effect of GLP1-RA therapy on major adverse cardiovascular outcomes (MACE), a composite of myocardial infarction, ischemic stroke and all-cause mortality. Secondary outcomes included the individual components of MACE. Marginal structural models were used to compute pooled effect estimates. This was an intention-to-treat analysis with 5 years of follow-up for each emulated target trial. Inverse probability of treatment weighting was used to adjust for confounding due to differences in patient demographics at baseline. Results This study consisted of 26,746 individuals who were treated with GLP1-RA and 74,638 controls. The 5-year cumulative risk of MACE was 27.7 % in the GLP1-RA group and 32.7 % in the control group (risk ratio 0.85 [95% confidence interval 0.82 – 0.88]). GLP1-RA therapy was associated with a lower risk of all-cause mortality (risk ratio 0.76 [95% confidence interval 0.72 – 0.79]) and myocardial infarction (risk ratio 0.95 [95% confidence interval 0.89 – 1.00]). We found little or no effect of GLP1-RA therapy on the risk of ischemic stroke (risk ratio 1.13 [95% confidence interval 0.97 – 1.27]). Conclusions In this large real-world cohort of T2DM patients with established CAD, we observed that GLP1-RA therapy was associated with a lower risk of MACE, myocardial infarction and all-cause mortality.

Estimating the Prevalence of Primary Hypothyroidism in Karbala City, and Modulation of Clinical Manifestations Among Patients Receiving Levothyroxine; A Single Center Study

Background: Hypothyroidism has a wide range of clinical manifestations and general symptoms, including but not limited to obesity, tiredness, poor concentration, depression, widespread muscle soreness, menstruation abnormalities, and constipation. The administration of a daily dosage of levothyroxine is sufficient for the successful management of hypothyroidism, as it facilitates the restoration of serum thyroid stimulating hormone (TSH) levels to their normal range. Several factors can influence the absorption of levothyroxine in the human body, including age, weight, the presence of other medical problems, and dietary intake. The aim of this study was to assess the prevalence of primary hypothyroidism and alteration in clinical presentation associated with replacement therapy. Methods: This was a cross-sectional, observational study conducted over at Al Hassan Metabolism, Endocrine, and Diabetes Center (HMEDC) in Karbala city. The study team created a questionnaire, and data was collected from face-to-face patient interviews, which included various sociodemographic variables, TSH and ferritin levels, drug interactions, as well as signs and symptoms exhibited both prior to and following treatment. Additionally, the patient treatment regimen and the specific doses of levothyroxine administered are also recorded. Results: the total number of cases visited Al Hassan Metabolism, Endocrine, and Diabetes Center (HMEDC) during the study period was (10800). The prevalence of thyroid diseases was 300 (2.8%). The rate of primary hypothyroidism out of the total number of hypothyroid cases was 85.1%. (61%) of the patients had normal levels of TSH whereas (42%) of the patients were found to be undertreatment. A total of (84%) of the patients exhibited normal levels of ferritin. The patients exhibited a reduction in their signs and symptoms following the administration of therapy. Conclusion: treatment with levothyroxine improved sluggish speech, constipation, lack of appetite, cold sensitivity, weight gain, and weariness. There is no observed correlation between the dosage of levothyroxine and the manifestation of signs and symptoms.

Safety of an Accelerated Ferric Gluconate Inpatient Infusion Regimen

Background: Inpatient use of intravenous iron has been increasing. Ferric gluconate is traditionally given once daily. Twice-daily dosing provides faster iron repletion, but there are limited data to support the safety of twice-daily dosing. Objective: The aim of this study was to investigate the safety of twice-daily dosing for ferric gluconate compared with daily dosing. Methods: This was an institutional review board-approved retrospective observational study of hospitalized adult patients who received intravenous ferric gluconate 250 mg daily or twice daily between January 1 and April 3, 2022. The primary composite safety outcome included hypotension, infusion reaction, rapid response alert, or escalation in level of care. Secondary outcomes included total amount of iron received, hospital length of stay, and changes in laboratory values. Results: A total of 126 patients were included in this study, with 63 patients in each group. The primary outcome occurred in 29 patients (46%) in the twice-daily group compared with 36 patients (57.1%) in the daily group (relative risk = 0.81; 95% CI, 0.57-1.13; P = 0.212). Changes in iron, hemoglobin, and transferrin saturation were similar between the 2 groups. Median length of stay was statistically shorter in the twice-daily group (7.79 days) compared with the daily group (12.9 days; p = 0.006). Conclusions: In this retrospective single-center study of hospitalized adult patients, those who received intravenous ferric gluconate twice daily did not experience an increased rate of a composite safety outcome of hypotension, infusion reactions, or escalation in level of care compared with those with daily dosing.

Switching from Premixed Insulin to Insulin Degludec/Insulin Aspart for the Management of Type 2 Diabetes Mellitus: Implications of a Real-World Study on Insulin Degludec Dosing.

When switching from premixed insulin to insulin degludec/aspart (IDegAsp), IDegAsp usually starts at the same dose as the premixed insulin according to limited clinical experience or at a dose according to clinician discretion. The dose of insulin degludec used in the real world after switching has been poorly investigated. A retrospective analysis was conducted on patients with type 2 diabetes who switched from premixed insulin to IDegAsp from October 2016 to December 2023. Repeated measures analysis of variance was used to compare changes in insulin dose, glycated hemoglobin (HbA1c), fasting blood glucose (FBG), and postprandial blood glucose (PBG) before and after switching. Sixty-six patients with prior low-ratio premixed insulin and 22 with prior mid-ratio premixed insulin were included. Among the low-ratio insulin users, the total daily dose of insulin degludec (IDeg) decreased by 21.43% and 19.05% at 3 and 6months, respectively, after switching, compared with prior basal insulin dose (both p < 0.001). Conversely, among mid-ratio insulin users, the IDeg daily dose increased by 10.71% and 32.14% at 3 and 6months, respectively, after switching, compared with prior basal insulin dose (both p < 0.001). In all patients, HbA1c levels decreased by 0.70%, FBG decreased by 1.00mmol/l, and PBG decreased by 1.61mmol/l after 6months of switching (all p < 0.05); the total daily insulin dose and injection frequency significantly decreased after switching (both p < 0.05); age and disease duration did not affect IDegAsp effects on HbA1c reduction. In the setting of transition to IDegAsp from premixed insulin, the dose of basal insulin in the premixed formulation can be a valuable reference for adjusting insulin degludec dose. IDegAsp is superior to premixed insulin in blood glucose control with reduced total daily dose and injection frequency. IDegAsp could be the best choice for the management of diabetes in elderly patients.

Changes in serum uric acid, glutathione, and amyloid-β1-42 levels in Parkinson’s disease patients and their association with disease progression and cognitive decline

Objective This study aims to evaluate the diagnostic significance of serum uric acid (UA), glutathione (GSH), and amyloid-β1-42 (Aβ1-42) levels in relation to disease progression and cognitive impairment in patients with Parkinson’s disease (PD). Methods A total of 209 PD patients with disease duration ranging from 4.0 to 6.8 years were enrolled. Based on the Hoehn-Yahr staging system, patients were classified into Early (n = 67), Medium-term (n = 70), and Advanced (n = 72) stages. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), dividing the cohort into CD (cognitive dysfunction, n = 94) and NO-CD (no cognitive dysfunction, n = 115) groups. Serum UA, GSH, and Aβ1-42 levels were analyzed for correlations with clinical data. Independent risk factors and diagnostic value were determined through multivariable logistic regression models and receiver operating characteristic curve analysis. Results Serum UA and GSH levels progressively declined with advancing disease stage, while Aβ1-42 increased. Compared to the NO-CD group, the CD group showed lower serum UA and GSH levels, and higher Aβ1-42 levels. Serum UA and GSH were inversely correlated with disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale scores, while Aβ1-42 showed positive correlations. UA (p = 0.006), GSH (p < 0.001), and Aβ1-42 (p = 0.040) were independent predictors of disease stage. Similarly, UA (p = 0.003), GSH (p < 0.001), and Aβ1-42 (p < 0.001) were independent predictors of cognitive dysfunction. The combined assessment of these markers demonstrated a higher area under the curve (AUC) than individual markers for disease and cognitive decline identification. Conclusions Serum UA, GSH, and Aβ1-42 are independent predictors of disease progression and cognitive decline in PD patients. Their combined use offers enhanced diagnostic accuracy for disease staging and cognitive impairment in PD.

Efficacy of Streptococcus salivarius Blis K12 in the Prevention of Upper Respiratory Tract Infections in Physically Active Individuals: A Randomized Controlled Trial

This study investigates the efficacy of Streptococcus salivarius K12 in preventing upper respiratory tract infections (URTIs) in healthy adults. URTIs are a common issue, particularly in physically active individuals, leading to significant disruptions in daily life. Probiotics, such as S. salivarius K12, have emerged as a potential preventive strategy for these infections. This research was conducted as a randomized, double-blind, placebo-controlled trial involving 112 participants aged between 19 and 25. Participants were randomly divided into two groups: one group received a daily dose of S. salivarius K12, marketed as Bactoblis®, while the other received a placebo. The trial lasted for four months, during which adherence to the treatment protocol was closely monitored. The primary goal was to measure the incidence of URTIs using the Jackson Scale and the Wisconsin Upper Respiratory Symptom Survey (WURSS-11). The results indicated that higher adherence to the S. salivarius K12 treatment was associated with an increased number of days without URTI symptoms. Although the overall severity of symptoms did not differ significantly between the treatment and control groups, those with high adherence to S. salivarius K12 (greater than 90%) reported more days free from illness. In conclusion, S. salivarius K12 demonstrated potential as a preventive measure against URTIs, especially in individuals who adhered strictly to the treatment regimen. However, further research involving larger populations and longer follow-up periods is needed to fully confirm these findings and better understand the role of S. salivarius K12 in preventing respiratory infections.

Bempedoic Acid, the First-in-Class Oral ATP Citrate Lyase Inhibitor with Hypocholesterolemic Activity: Clinical Pharmacology and Drug–Drug Interactions

Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug–drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid–CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid–CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein–cholesterol (LDL-C) (20–25%), non-high-density lipoprotein–cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid–glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications.

Silexan in anxiety, depression, and related disorders: pharmacological background and clinical data.

We present a narrative review of clinical trials investigating the anxiolytic and antidepressant effects of silexan, an active substance derived from lavender oil and summarize nonclinical findings from pharmacological studies supporting its therapeutic use. Six studies investigated the efficacy of the lavender oil in patients with subthreshold and generalized anxiety disorders as well as in mixed anxiety and depressive disorder (MADD). Furthermore, we present data indicating that silexan may influence sleep quality as well as anxiety or depressive disorders in individuals with post-COVID-19. Silexan taken orally at a daily dose of 80mg for 10 weeks was significantly superior to placebo in reducing psychic and somatic symptoms of anxiety and was as effective as 0.5mg/d lorazepam and 20mg/d paroxetine. In patients with mild or moderate major depression, silexan was superior to placebo and comparably effective to 50mg/d sertraline. Significant antidepressant effects were also observed in MADD and depression co-morbid with anxiety. The herbal product had a beneficial effect on activities of daily living and health-related quality of life. Adverse events associated with silexan in clinical trials were limited to eructation and mild, transient gastrointestinal complaints. The herbal product was not associated with drug interactions, sedation, sleep disturbance, dependence and abuse potential, sexual dysfunction, weight gain or withdrawal symptoms. Silexan was therefore safe and effective in subthreshold and syndromal anxiety disorders and in major depression.

Tuberculous Pleurisy in a Patient with a History of Breast Cancer: Diagnostic Challenges and Management Options

Background: Tuberculosis (TB) and cancer are increasingly prevalent diseases that can be challenging to diagnose due to similarities in clinical and radiological findings. This case report describes a 46-year-old woman with a history of breast cancer who developed tuberculous pleurisy (TP). Case presentation: A 46-year-old woman who underwent mastectomy and chemotherapy for BC in 2023 had hypertension, but no history of TB. The patient presented with dry cough, fever, and stomach discomfort, with an oxygen saturation level of 60%, but no respiratory distress before their appointment. Microscopy and culture tests were negative for Mycobacterium TB, A positive result was observed with an IFN-γ level of 0.35 IU/ml and 26% of the negative control after TB antigen stimulation. Histological analysis using hematoxylin and eosin staining showed Langhans giant cells, epithelioid cell granulomas, caseous necrosis, and necrotic foci. These findings indicate granulomatous inflammation with no signs of malignancy. Following the diagnosis, the patient received a daily dose of 300 mg isoniazid, 600 mg rifampin, 1500 mg pyrazinamide, and 10 mg pyridoxine for six months without any adverse effects. Conclusion: Physicians must employ a combination of diagnostic techniques, including morphological and microbiological confirmation, to accurately diagnose pleural effusion in this patient population.

Efficacy and pharmacodynamics of herbal medicine in patients with metabolic phenotype of osteoarthritis

High prevalence of the metabolic phenotype of osteoarthritis (MPOA) and unsatisfactory methods of its treatment necessitate the development of novel therapeutic approaches for this phenotype of OA. Turmeric preparations have a wide range of biological activity; their use in patients with MPOA can be effective and reduce the drug burden. In the present paper, we review our own published research findings on the effectiveness and pharmacodynamics of turmeric preparations in patients with MPOA. In the two studies, we evaluated the effects of two curcumin-containing parapharmaceuticals: Epigenorm Antivir (EA) and Curcumin. Forty-one women with MFOA were included in both studies. Twenty-three patients received EA at a daily dose of 1000 mg for 12 weeks, and 18 patients received curcumin from Evalar at a dose of 1000 mg for 8 weeks. The endpoints for both studies were VAS pain, dysfunction and other symptoms of OA measured using the KOOS scale. After 12 weeks of EA treatment, there was a 2.5-fold decrease pain levels. The decrease in pain was associated with an improvement in the patient’s daily and sports activities and quality of life. These effect sizes were classified as moderate to large according to Cohen. No adverse events were observed during the period of taking EA. Clinical improvement was associated with a decrease in the content of MS individual components: low-density lipoprotein cholesterol and triglycerides. The treatment caused a decrease in the level of systemic inflammation, as evidenced by a decrease in the concentration of TNFα, histamine, IL-18, C-reactive protein, and neopterin. The concentrations of IL-10 and adiponectin increased after treatment. In another study, treatment with curcumin for 4 weeks had an analgesic effect, improved measures of function and quality of life. Clinical improvement was associated with the reductions in serum levels of a number of proinflammatory cytokines, C-reactive protein, and lipids. Thus, the results of the pilot studies evaluating efficacy, safety, and pharmacodynamics of parapharmaceuticals EA and Curcumin in patients with MFOA indicate pleiotropic effects of the interventions. The findings provide a rationale for conducting larger, controlled, blind, randomized clinical trials.

The Effect of Dysautonomia on Motor, Behavioral, and Cognitive Fluctuations in Parkinson's Disease.

Motor and nonmotor fluctuations adversely impact the quality of life in Parkinson's disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations. We sought to evaluate the effect of dysautonomia on motor and nonmotor fluctuations in PD. Two hundred subjects with PD were evaluated in both on and off dopamine states to assess changes in symptoms related to dopaminergic fluctuations. Multivariable logistic regression was performed to assess the association of dysautonomia with motor, cognitive, and psychiatric worsening from on to off states with adjustment for disease duration, levodopa equivalent daily dosage (LEDD), and dopamine-agonist LEDD. Subjects with dysautonomia had greater odds of clinically meaningful change in motor features (odds ratio [OR]: 3.0), cognition (OR: 3.4), and anxiety (OR: 4.3) compared to those without dysautonomia. Dysautonomia may be a contributory mechanism behind fluctuations in PD. The exact nature of this relationship deserves further evaluation. © 2024 International Parkinson and Movement Disorder Society.