Pimavanserin's Safety Profile: Insights from a Phase 3b Clinical Trial.

 The recent Alva et al. Phase 3b study on pimavanserin use in older adults with neurodegenerative diseases (NDDs), specifically including Alzheimer's disease, vascular dementia, Parkinson's disease (with or without dementia), frontotemporal dementia, and dementia with Lewy bodies, provides important new data on its safety for managing neuropsychiatric symptoms in this population. This commentary on the study further examines the findings within the broader context of antipsychotic therapy as it has evolved from chlorpromazine to pimavanserin in a continuous search for greater safety. Comparing pimavanserin's safety and efficacy profile with historical data and regulatory milestones provides a nuanced perspective for clinicians regarding the significance of the drug's known advantages over prior antipsychotic treatments. More research is needed to determine the full potential of pimavanserin to improve neuropsychiatric symptoms in older adults with NDDs.

Eligibility for omecamtiv mecarbil in a real-world heart failure population: Data from the Swedish Heart Failure Registry.

AIMS: We assessed eligibility for omecamtiv mecarbil (OM) in a real-world cohort with heart failure with reduced ejection fraction (HFrEF) according to the selection criteria of the GALACTIC-HF trial (trial scenario) and selected trial´s criteria more likely to impact real-world use (pragmatic scenario). METHODS AND RESULTS: We included 31,015 patients with HFrEF lasting ≥3 months and registered in the Swedish HF registry between 2000-2021. Trial eligibility was calculated by applying all the GALACTIC-HF selection criteria. The pragmatic scenario considered only the New York Heart Association class, history of worsening HF, N-terminal pro-B-type natriuretic peptides (NT-proBNP), blood pressure and renal failure criteria defined as in the trial. Eligibility for OM in chronic HFrEF was 21% and 36% in the trial and pragmatic scenarios, respectively. Eligibility was higher in those with EF<30% (trial: 27%, pragmatic: 44%), in-patients (trial:30%, pragmatic:57%), severe HF (trial: 35%, pragmatic: 60%), NYHA class III-IV (trial: 26%, pragmatic: 45%), and NT-proBNP≥5,000pg/mL (trial: 30%, pragmatic: 51%). The criteria that most limited eligibility were history of a recent worsening HF event (60% eligible in chronic HFrEF), elevated NT-proBNP (82% eligible), and deviating blood pressure (82% eligible). Overall, eligible patients were characterized by more severe HF and higher CV event-rates in both scenarios, and higher comorbidity burden in the pragmatic scenario. CONCLUSION: Approximately 21% of real-world chronic HFrEF patients would be eligible for OM according to the GALACTIC-HF selection criteria, and 36% according to the criteria more likely to affect OM use in clinical practice. Criteria in both scenarios identified a patient-group with severe HF and high CV event-rates.

Parkinson's Disease Psychosis and the Marketing of Pimavanserin.

In 2016, Nuplazid (pimavanserin) became the first FDA-approved treatment for Parkinson's Disease Psychosis (PDP). We explored the possibility that PDP was a term created to market Nuplazid. We examined trends in perceptions of psychosis in Parkinson's disease from the 1990s to 2020 through MEDLINE search term frequency, neurology textbooks, guidance from professional societies, Acadia annual reports, sponsored websites, and a sponsored meeting held by the National Institutes of Health (NIH). We analyzed continuing medical education (CME) activities on PDP and analyzed the connection between payments by the manufacturer of pimavanserin and prescriptions. Our analysis of nine sponsored CME activities reveals misleading themes, including: PDP is common, progressive, and not always drug-induced; there is no such thing as a benign hallucination, and psychotic symptoms always worsen; PDP increases mortality; and competing treatments are ineffective or dangerous while pimavanserin is safe and effective for treating PDP. Industry-sponsored CME was used to disseminate inaccurate and misleading marketing messages on psychosis related to Parkinson's disease. Some professional societies and some textbooks also resisted the PDP label. Reframing PDP as a unique condition is a typical example of condition branding. The establishment of PDP expanded the use of pimavanserin and is likely to have resulted in many avoidable deaths.

Initial [18F]DCFPyL PET/CT in treatment-naïve prostate cancer: correlation with post-ADT PSA outcomes and recurrence.

PURPOSE: Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) targeting tracers has emerged as a valuable diagnostic tool for prostate cancer (PCa), androgen deprivation therapy (ADT) stands as the cornerstone treatment for advanced PCa, yet forecasting the response to hormonal therapy poses a significant clinical hurdle. METHODS: In a prospective cohort of 86 PCa patients undergoing short-term ADT, this study evaluated the prognostic potential of [18F]DCFPyL PET/CT scans. Comprehensive data encompassing clinical profiles, baseline prostate-specific antigen (PSA) levels, and imaging metrics were assessed. We developed predictive models for assessing decreases in PSA levels (PSA50 and PSA70) based on a combination of PET-related parameters and clinical factors. Kaplan-Meier survival analysis was utilized to ascertain the prognostic value of PET-based metrics. RESULTS: In this study, elevated [18F]DCFPyL uptake within the primary tumor, as indicated by a SUV ≥ 6.78 (p = 0.0024), and a reduction in the tumor volume (TV) of primary PSMA-avid tumor with PSMA-TV < 41.96 cm3 (p = 0.038), as well as an increased burden of metastatic PSMA-avid tumor, with PSMA-TV (PSMA-TV ≥ 71.39 cm3) (p = 0.012) were identified in association with diminished progression-free survival (PFS). PET and clinical parameters demonstrated constrained predictive capacity for PSA50 response as indicated by an area under the curve (AUC) of 0.442. CONCLUSION: Our study revealed that pretreatment [18F]DCFPyL uptake in primary or metastatic tumor sites is prognostically relevant in high-risk PCa patients undergoing ADT. Further research is needed to develop robust predictive models in this multifaceted landscape of PCa management.

Randomized Double-blind Cost-effectiveness Comparison of Two 10% Urea Creams in Patients with Diabetic Foot Syndrome.

OBJECTIVE: To evaluate the cost-effectiveness of two 10% urea creams in patients with diabetic foot syndrome. METHODS: This was a prospective, longitudinal, single-center, randomized, double-blind, prospective clinical trial that evaluated the skin quality of 20 feet belonging to 10 patients with diabetic foot syndrome after the application of two 10% urea creams purchased from pharmacies and supermarkets. RESULTS: At follow-up, 19 (95%) of the participants' feet showed improved skin quality, irrespective of the cream applied. On visual inspection, participants had a decreased presence of xerosis, hyperkeratosis, and preulcerative signs such as subkeratotic bruising and areas of redness on the dorsum of the toes. At the 3-month follow-up, nine (90%) of the participants stated that they had continued to apply the cream as a method of self-management to prevent complications. CONCLUSIONS: Creams containing 10% urea purchased in supermarkets improve foot skin quality in patients with diabetic foot syndrome, regardless of their cost. Based on these findings, the authors recommend creams containing 10% urea as a self-management tool for patients with diabetic foot syndrome.

Add-on effects of Chinese herbal medicine external application (FZHFZY) to topical urea for mild-to-moderate psoriasis vulgaris: Protocol for a double-blinded randomized controlled pilot trial embedded with a qualitative study.

Psoriasis vulgaris is a chronic dermatological disease with a high global prevalence. It significantly reduces patients' quality of life and is associated with a substantial economic burden. Conventional therapies for mild-to-moderate psoriasis are often associated with insufficient long-term symptomatic relief and side effects. Chinese herbal medicine (CHM) is commonly used for psoriasis management. A CHM formula, namely Fu zheng he fu zhi yang (FZHFZY), has shown promising treatment effects in clinical practice when used as a bath therapy. However, its efficacy and safety has not been evaluated by a rigorous randomized controlled trial (RCT). Therefore, we designed a double-blinded pilot RCT embedded with a qualitative study on CHM formula FZHFZY plus topical urea for mild-to-moderate psoriasis vulgaris to advance the evidence development and practice of CHM external application for psoriasis. This will be a mixed-method design consisting of a pilot RCT and a qualitative study. The pilot RCT is a two-arm, parallel, placebo-controlled, double-blinded trial. Sixty eligible participants will be randomized at a 1:1 ratio to receive eight weeks' treatment of either FZHFZY plus 10% urea cream, or placebo plus 10% urea cream, with 12-week follow-up visits after the treatment phase. The CHM or placebo will be administered externally as a bath therapy. Outcome measures include trial feasibility, efficacy and safety. The primary efficacy outcome will be Psoriasis Area Severity Index (PASI). Secondary efficacy outcomes include Physician Global Assessment, PASI-75, PASI-50, Body Surface Area, Dermatology Life Quality Index, Skindex-16, itch visual analogue scale and relapse. The qualitative study will be conducted to collect participants' feedback on CHM external application and their experience with the pilot RCT. This study will advance the evidence-based clinical practice of using CHM for psoriasis vulgaris and then to support translation of findings into clinical practice in the future. Trial registration number: ChiCTR2200064092.

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies.

The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD+ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.

Parkinson's disease psychosis management: an evidence based, experience informed, pragmatic approach.

INTRODUCTION: Psychotic symptoms in people with Parkinson's disease (PD) have attracted increasing. Recommendations on treating psychosis often fail to take into account what psychotic symptoms require treatment, which has been complicated by the increasing number of reports documenting the frequency of 'minor' hallucinations. AREAS COVERED: This article focuses both on the phenomenology of psychotic symptoms and their management. EXPERT OPINION: Understanding the nature and implications of the types of psychotic symptoms in PD is the key to proper treatment. Evidence and experience-based data on the effect of anti-psychotic medications will be reviewed and how the various clinical settings should determine the treatment approach. The evidence base consists of all reported blinded trials recorded in PubMed and the experience-based studies are those chosen by the author from PubMed as illustrative. Specific recommendations for the treatment of psychosis will be listed for specific situations. Pimavanserin is the first-line choice for mild symptoms; quetiapine for symptoms that require improvement in a short period and clozapine for urgent problems or those which fail the other approaches.

Psychotic symptoms are common in PD, affecting the majority of patients by the time of death. 'Minor hallucinations' rarely require treatment but formed hallucinations and delusions often do. The vast majority of patients requiring treatment are on medications for PD motor problems. Some patients can be treated with reduction of psychoactive medications that are unrelated to PD, and some may tolerate reductions in PD medications without intolerable worsening of motor function. The remainder require treatment with medications that reduce psychotic symptoms, which include cholinesterase inhibitors, clozapine, pimavanserin, and possibly quetiapine and electroconvulsive therapy. Only clozapine and pimavanserin have unequivocal evidence for efficacy and motor tolerance. Data will be reviewed in support of each of these medications will be reviewed and pragmatic suggestions based on a large experience on when each might be used, and in what order they may be tried if initial approaches fail.

Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

Efectividad de la administración de urea para el tratamiento de la hiponatremia en la insuficiencia cardiaca / Effectiveness of urea administration for the treatment of hyponatremia in heart failure

Objetivos Valorar la eficacia y la seguridad de la urea en pacientes con hiponatremia e insuficiencia cardiaca (IC). Métodos y resultados Se trata de un estudio observacional retrospectivo analítico de pacientes con IC e hiponatremia (Na+ <135mmol/l). Se incluyeron 49 pacientes tratados con urea y 47 pacientes que no recibieron urea, todos ellos bajo tratamiento estándar (según práctica clínica habitual) de la IC, con seguimiento en el hospital Álvaro Cunqueiro de Vigo entre enero de 2013 y mayo de 2022. En el estudio se evaluó la normalización de los niveles de sodio (Na >135mmol/l). La natremia al inicio del tratamiento con urea oral era de 127±5,22mmol/l, a las 24horas el sodio era de 128±2,47 (p<0,009) y la media el día de la normalización fue de 135,19±4,23mmol/l (p<0,005). Los días de media para conseguir la normalización del sodio fueron 5,03±2,37. La uremia al inicio del tratamiento con urea era de 73±46,93mg/dl y la media el día de la normalización del Na+ fue de 116,05±63,64mg/dl (p<0,002). La dosis media de urea oral fue 22,5g/día. No se observaron efectos adversos relevantes, ni cambios en cuanto a las cifras de creatinina. Conclusiones El tratamiento con urea oral añadido al tratamiento estándar, durante cortos periodos de tiempo, es seguro y eficaz para corregir la natremia en pacientes con IC hipervolémica con hiponatremia.

Objectives To assess the efficacy and safety of urea in patients with hyponatremia and heart failure (HF). Methods and results This is a retrospective observational analytical study of patients with HF and hyponatremia (Na+ <135mmol/L). Forty-nine patients treated with urea and 47 patients who did not receive urea, all under standard treatment (according to usual clinical practice) for HF, were included and followed up at Álvaro Cunqueiro Hospital in Vigo (Spain) between January 2013 and May 2022. The study evaluated the normalization of sodium levels (Na >135mmol/L). The initial natremia at the start of oral urea treatment was 127±5.22 mmol/L, at 24h the sodium level was 128±2.47 (P<.009), and the mean on the day of normalization was 135.19±4.23mmol/L (P<.005). The average number of days to achieve sodium normalization was 5.03±2.37 days. The initial uremia at the start of urea treatment was 73±46.93mg/dL, and the mean on the day of Na+ normalization was 116.05±63.64mg/dL (P<.002). The average oral urea dose was 22.5g/day. No relevant adverse effects were observed, nor were there significant changes in creatinine levels. Conclusions Oral urea treatment, when added to standard treatment for short periods of time, is safe and effective in correcting natremia in patients with hypervolemic HF with hyponatremia. (AU)

Pharmacological Treatment of Heart Failure: Recent Advances.

BACKGROUND: Heart failure is a clinical condition with high mortality and morbidity that occurs when the heart is unable to pump enough blood to meet the metabolic demands of the body. The pharmacological management of heart failure has been revolutionized over the past decade with novel treatments. OBJECTIVE: The aim of the review is to highlight the recent pharmacological advances in the management of heart failure. RESULTS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i), iron carboxymaltose, finerenone, omecamtiv mecarbil, and vericiguat have been shown to reduce hospitalization for heart failure. However, only SGLT2i, vericiguat, and omecamtiv mecarbil have been shown to reduce cardiovascular death. Finerenone has been shown to reduce cardiovascular events and renal adverse outcomes in patients with diabetes and kidney disease. Currently, only SGLT2i has been studied in patients beyond the heart failure with reduced ejection fraction population. CONCLUSION: The current quadruple therapy in the treatment of heart failure has demonstrated a reduction in the hospitalization of patients and a decrease in mortality associated with the condition. Individualized heart failure therapy research have shown some benefit in select heart failure patients. Further research on novel therapies will help improve heart failure patient outcomes.

Efectividad de la administración de urea para el tratamiento de la hiponatremia en la insuficiencia cardiaca / Effectiveness of urea administration for the treatment of hyponatremia in heart failure

Objetivos Valorar la eficacia y la seguridad de la urea en pacientes con hiponatremia e insuficiencia cardiaca (IC). Métodos y resultados Se trata de un estudio observacional retrospectivo analítico de pacientes con IC e hiponatremia (Na+ <135mmol/l). Se incluyeron 49 pacientes tratados con urea y 47 pacientes que no recibieron urea, todos ellos bajo tratamiento estándar (según práctica clínica habitual) de la IC, con seguimiento en el hospital Álvaro Cunqueiro de Vigo entre enero de 2013 y mayo de 2022. En el estudio se evaluó la normalización de los niveles de sodio (Na >135mmol/l). La natremia al inicio del tratamiento con urea oral era de 127±5,22mmol/l, a las 24horas el sodio era de 128±2,47 (p<0,009) y la media el día de la normalización fue de 135,19±4,23mmol/l (p<0,005). Los días de media para conseguir la normalización del sodio fueron 5,03±2,37. La uremia al inicio del tratamiento con urea era de 73±46,93mg/dl y la media el día de la normalización del Na+ fue de 116,05±63,64mg/dl (p<0,002). La dosis media de urea oral fue 22,5g/día. No se observaron efectos adversos relevantes, ni cambios en cuanto a las cifras de creatinina. Conclusiones El tratamiento con urea oral añadido al tratamiento estándar, durante cortos periodos de tiempo, es seguro y eficaz para corregir la natremia en pacientes con IC hipervolémica con hiponatremia.

Objectives To assess the efficacy and safety of urea in patients with hyponatremia and heart failure (HF). Methods and results This is a retrospective observational analytical study of patients with HF and hyponatremia (Na+ <135mmol/L). Forty-nine patients treated with urea and 47 patients who did not receive urea, all under standard treatment (according to usual clinical practice) for HF, were included and followed up at Álvaro Cunqueiro Hospital in Vigo (Spain) between January 2013 and May 2022. The study evaluated the normalization of sodium levels (Na >135mmol/L). The initial natremia at the start of oral urea treatment was 127±5.22 mmol/L, at 24h the sodium level was 128±2.47 (P<.009), and the mean on the day of normalization was 135.19±4.23mmol/L (P<.005). The average number of days to achieve sodium normalization was 5.03±2.37 days. The initial uremia at the start of urea treatment was 73±46.93mg/dL, and the mean on the day of Na+ normalization was 116.05±63.64mg/dL (P<.002). The average oral urea dose was 22.5g/day. No relevant adverse effects were observed, nor were there significant changes in creatinine levels. Conclusions Oral urea treatment, when added to standard treatment for short periods of time, is safe and effective in correcting natremia in patients with hypervolemic HF with hyponatremia. (AU)