ABSTRACT
BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).
Subject(s)
Antipsychotic Agents/therapeutic use , Dementia/psychology , Hallucinations/drug therapy , Piperidines/therapeutic use , Psychotic Disorders/drug therapy , Urea/analogs & derivatives , Aged , Aged, 80 and over , Dementia/drug therapy , Double-Blind Method , Female , Hallucinations/etiology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Parkinson Disease/drug therapy , Parkinson Disease/psychology , Proportional Hazards Models , Psychotic Disorders/etiology , Recurrence , Urea/therapeutic useABSTRACT
BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).
Subject(s)
Cardiac Myosins/metabolism , Cardiotonic Agents/therapeutic use , Heart Failure, Systolic/drug therapy , Urea/analogs & derivatives , Aged , Aged, 80 and over , Cardiac Myosins/drug effects , Cardiotonic Agents/adverse effects , Cardiotonic Agents/pharmacology , Cardiovascular Diseases/mortality , Female , Heart Failure, Systolic/metabolism , Heart Failure, Systolic/physiopathology , Humans , Male , Middle Aged , Myocardial Contraction/drug effects , Stroke Volume , Urea/adverse effects , Urea/pharmacology , Urea/therapeutic useABSTRACT
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 deathâ¯=â¯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 interactionâ¯=â¯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.
Subject(s)
Biomarkers , Heart Failure , Stroke Volume , Troponin I , Humans , Male , Double-Blind Method , Female , Heart Failure/drug therapy , Heart Failure/blood , Middle Aged , Aged , Troponin I/blood , Treatment Outcome , Stroke Volume/drug effects , Biomarkers/blood , Urea/analogs & derivatives , Urea/therapeutic use , Urea/pharmacology , Carbamates/therapeutic useABSTRACT
Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.
Subject(s)
Drug Therapy, Combination , Heart Failure , Ivabradine , Stroke Volume , Humans , Ivabradine/therapeutic use , Heart Failure/drug therapy , Heart Failure/physiopathology , Stroke Volume/drug effects , Stroke Volume/physiology , Cardiovascular Agents/therapeutic use , Cardiovascular Agents/pharmacology , Pyrimidines/therapeutic use , Urea/analogs & derivatives , Urea/therapeutic use , Benzazepines/therapeutic use , Benzazepines/pharmacology , Heterocyclic Compounds, 2-RingABSTRACT
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.
Subject(s)
Lysine , Positron Emission Tomography Computed Tomography , Prostate-Specific Antigen , Prostatic Neoplasms , Urea , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Aged , Prostate-Specific Antigen/blood , Lysine/analogs & derivatives , Urea/analogs & derivatives , Urea/therapeutic use , Middle Aged , Androgen Antagonists/therapeutic use , Recurrence , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate the effectiveness of desensitizing toothpastes in reducing post-bleaching tooth sensitivity. MATERIALS AND METHODS: A systematic review of randomized clinical trials was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Electronic searches were conducted in the PubMed/MEDLINE, Scopus, Web of Science, The Cochrane Library and Embase databases, using the following terms: (dentifrices OR toothpaste) AND (sensitive OR sensitivity OR dental sensitivity) AND (dental bleaching OR tooth bleaching OR dental whitening OR tooth whitening). RESULTS: Five studies involving 387 individuals undergoing in-office or at-home teeth bleaching were reviewed. Desensitizing toothpastes reduced sensitivity effectively after home bleaching with 22% carbamide peroxide and single-session in-office bleaching with 35% hydrogen peroxide. However, they were ineffective for home bleaching with 16% carbamide peroxide and in-office bleaching across two sessions with 35% or 38% hydrogen peroxide. CONCLUSION: Desensitizing toothpastes are effective for home bleaching with high concentration carbamide peroxide and single-session in-office bleaching with highly concentrated hydrogen peroxide, but ineffective for home bleaching with low concentration carbamide peroxide and two-session in-office bleaching with concentrated hydrogen peroxide.
Subject(s)
Carbamide Peroxide , Dentin Desensitizing Agents , Dentin Sensitivity , Hydrogen Peroxide , Tooth Bleaching Agents , Tooth Bleaching , Toothpastes , Humans , Dentin Sensitivity/prevention & control , Dentin Sensitivity/drug therapy , Tooth Bleaching/methods , Dentin Desensitizing Agents/therapeutic use , Urea/analogs & derivatives , Urea/pharmacology , Urea/therapeutic use , Peroxides/pharmacologyABSTRACT
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.
Subject(s)
Cost-Benefit Analysis , Diabetic Foot , Skin Cream , Urea , Humans , Diabetic Foot/drug therapy , Diabetic Foot/economics , Female , Double-Blind Method , Male , Middle Aged , Urea/therapeutic use , Prospective Studies , Skin Cream/therapeutic use , Aged , Longitudinal Studies , Treatment OutcomeABSTRACT
OBJECTIVE: Screening and eradication of Helicobacter pylori help reduce disparities in the incidence of gastric cancer. We aimed to evaluate its acceptability and feasibility in the indigenous communities and develop a family index-case method to roll out this programme. DESIGN: We enrolled residents aged 20-60 years from Taiwanese indigenous communities to receive a course of test, treat, retest and re-treat initial treatment failures with the 13C-urea breath tests and four-drug antibiotic treatments. We also invited the family members of a participant (constituting an index case) to join the programme and evaluated whether the infection rate would be higher in the positive index cases. RESULTS: Between 24 September 2018 and 31 December 2021, 15 057 participants (8852 indigenous and 6205 non-indigenous) were enrolled, with a participation rate of 80.0% (15 057 of 18 821 invitees). The positivity rate was 44.1% (95% CI 43.3% to 44.9%). In the proof-of-concept study with 72 indigenous families (258 participants), family members of a positive index case had 1.98 times (95% CI 1.03 to 3.80) higher prevalence of H. pylori than those of a negative index case. The results were replicated in the mass screening setting (1.95 times, 95% CI 1.61 to 2.36) when 1115 indigenous and 555 non-indigenous families were included (4157 participants). Of the 6643 testing positive, 5493 (82.6%) received treatment. According to intention-to-treat and per-protocol analyses, the eradication rates were 91.7% (89.1% to 94.3%) and 92.1% (89.2% to 95.0%), respectively, after one to two courses of treatment. The rate of adverse effects leading to treatment discontinuation was low at 1.2% (0.9% to 1.5%). CONCLUSION: A high participation rate, a high eradication rate of H. pylori and an efficient rollout method indicate that a primary prevention strategy is acceptable and feasible in indigenous communities. TRIAL REGISTRATION NUMBER: NCT03900910.
Subject(s)
Helicobacter Infections , Helicobacter pylori , Stomach Neoplasms , Humans , Helicobacter Infections/diagnosis , Helicobacter Infections/drug therapy , Helicobacter Infections/epidemiology , Stomach Neoplasms/diagnosis , Stomach Neoplasms/epidemiology , Stomach Neoplasms/prevention & control , Urea/pharmacology , Urea/therapeutic use , Early Detection of Cancer/adverse effects , Anti-Bacterial Agents/pharmacology , Drug Therapy, Combination , Breath TestsABSTRACT
BACKGROUND: Previous studies have suggested that Helicobacter pylori (H. pylori) may act as a precipitating factor in gallstone formation, and the potential association between H. pylori infection and gallstone disease (GD) is still unclear and controversial. This study aimed to clarify the potential bidirectional relationship between H. pylori infection and GD. METHODS: This retrospective cohort study was performed in a population that underwent health checkups at the hospital between 2013 and 2018. H. pylori infection status was evaluated by urea breath test (UBT), and GD was diagnosed via ultrasound. Cox regression and propensity score matching (PSM) were used. RESULTS: Among 1011 participants without H. pylori infection at baseline, 134 participants were infected with H. pylori. Among 1192 participants without gallstones or cholecystectomy at baseline, 60 participants developed gallstones or cholecystectomy. The hazard ratio (HR) (95% CI) for incident H. pylori infection comparing the GD versus the no GD group was 1.84 (1.19, 2.85). The age- and sex-adjusted HR (95% CI) for incident GD comparing H. pylori-positive subjects to H. pylori-negative subjects was 1.74 (1.01, 2.98). Consistent results were also found with PSM and multivariate analysis. CONCLUSIONS: This cohort study demonstrated a potential bidirectional association between H. pylori infection and GD, which provides a basis for indicating the risk of GD and implementing the clinical strategies for GD. For the prevention and treatment of GD, H. pylori infection should be carefully considered and evaluated.
Subject(s)
Gallstones , Helicobacter Infections , Helicobacter pylori , Humans , Adult , Cohort Studies , Retrospective Studies , Helicobacter Infections/drug therapy , Breath Tests/methods , Urea/therapeutic useABSTRACT
Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.
Subject(s)
Heart Failure/drug therapy , Heart Failure/physiopathology , Stroke Volume , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds/therapeutic use , Clinical Trials, Phase III as Topic , Drug Combinations , Drug Development , Enzyme Activators/therapeutic use , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Models, Biological , Natriuretic Peptides/metabolism , Neprilysin/antagonists & inhibitors , Pyrimidines/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Soluble Guanylyl Cyclase/metabolism , Urea/analogs & derivatives , Urea/therapeutic use , Valsartan/therapeutic use , Ventricular Remodeling/drug effects , Ventricular Remodeling/physiologyABSTRACT
PURPOSE: To present the potential mechanisms by which landiolol enhances a positive inotropic response in critically ill patients. METHODS: Analysis of preclinical, animal, and clinical data to provide novel knowledge and translate research findings into potential clinical application. RESULTS: The super-selective ß1-antagonist landiolol may increase inotropy and may be associated with positive outcomes in critically ill patients with acute decompensated heart failure or sepsis. CONCLUSION: This review sheds light on the potential mechanisms by which landiolol enhances a positive inotropic response, potentially alleviating the long-held concern over possible negative hemodynamic effects in critically ill patients.
Subject(s)
Adrenergic beta-Antagonists , Heart Failure , Animals , Humans , Heart Rate , Critical Illness , Urea/pharmacology , Urea/therapeutic use , Heart Failure/drug therapy , Critical CareABSTRACT
BACKGROUND: Multikinase inhibitors (MKIs) treatment has been proven as a powerful strategy in cancer therapy. However, it is greatly hampered by its common adverse effect known as hand-foot skin reaction (HFSR), especially in patients with moderate-to-severe HFSR. OBJECTIVE: To investigate the clinical characteristics, histopathological features, treatment response, and bio-indicators of HFSR. METHODS: We retrospectively reviewed the medical records of 102 patients with moderate-to-severe HFSR resulting from MKIs therapy. RESULTS: The median time to development of moderate-to-severe HFSR was 18 days, which would be significantly affected by the type of MKIs and the history of HFSR. Notably, we found that HFSR was classified into three consecutive stages: erythematous lesion, yellow hyperkeratotic lesion with surrounding erythema, and hyperkeratotic lesion. Inflammation was observed in the first two stages of HFSR, but disappeared in the third stage; in contrast, the hyperkeratosis gradually became thicker from stage one to stage three. Moreover, topical medications were demonstrated as an effective therapy for HFSR, among which, the topical steroids and urea ointment treatment response rate was 37.14%, the Shouzu Ning Decoction (SND) treatment response rate was 65%, and the SND in combination with urea ointment treatment response rate was 75%, meanwhile, systemic therapies did not improve the therapeutic efficacy of topical medications alone. In addition, the serum levels of HMGB1 were found to be a potential indicator for tracking the healing process as well as predicting the prognosis of HFSR. CONCLUSION: This study revealed the potential factors affecting the development of HFSR, evaluated the therapeutic response towards different strategies for treating HFSR, and identified a potential prognostic indicator of HFSR.
Subject(s)
Hand-Foot Syndrome , Protein Kinase Inhibitors , Humans , Retrospective Studies , Ointments/therapeutic use , Protein Kinase Inhibitors/adverse effects , Treatment Outcome , Prognosis , Urea/therapeutic use , Hand-Foot Syndrome/drug therapy , Phenylurea Compounds/adverse effectsABSTRACT
OBJECTIVE: Assess the effects of activated charcoal-based products on whitening and changes on dental enamel surface. MATERIAL AND METHODS: Fifty-two blocks of bovine dental enamel were randomly distributed in four groups (n = 13): brushing with activated charcoal-based powder (PW); brushing with activated charcoal-based dentifrice (AC); brushing with a conventional dentifrice containing 1450 ppm of fluoride (CD); and whitening with 10% carbamide peroxide (CP). Color, microhardness, and surface alteration were analyzed at baseline and after 14 days of treatment. Three samples per group were randomly selected and examined using scanning electron microscopy (SEM) to analyze the morphology. RESULTS: PW exhibited greater color change for the ΔE00 , ΔWID, Δb* and ΔL* parameters than other groups (p < 0.05). After treatment, microhardness decreased in AC and CP groups (p < 0.05). Also, PW and AC groups showed more surface alteration than CD and CP (p < 0.001). Changes in the morphology of dental enamel were observed by SEM in PW and AC groups. CONCLUSION: Activated charcoal-based products showed a lower whitening effect than 10% carbamide peroxide. These products also influenced dental enamel microhardness, resulting in greater surface alteration. CLINICAL SIGNIFICANCE: Activated charcoal-based products promoted minimum whitening effects with significant enamel surface alteration. The 10% carbamide peroxide was more effective for whitening and caused slight enamel surface alteration.
Subject(s)
Dentifrices , Tooth Bleaching , Animals , Cattle , Carbamide Peroxide , Charcoal/pharmacology , Dental Enamel , Dentifrices/pharmacology , Dentifrices/therapeutic use , Peroxides/pharmacology , Peroxides/therapeutic use , Tooth Bleaching/methods , Urea/pharmacology , Urea/therapeutic useABSTRACT
BACKGROUND: Nowadays bleaching procedures have gained popularity in orthodontic patients. Peroxide and Carbamide acids are the common agents which are used in in-office and at home bleaching techniques. Consequently, the Bonding adhesion to the enamel can be influenced by the orthodontic phase and the residual peroxide might interfere with the polymerization and the adhesion of the brackets. Frequent debonding of the brackets from teeth after the bleaching procedure could cause the lengthening of the therapy and promote irregularities on enamel surface derived from an additional bonding phase of the brackets. The aim of this systematic review is to appraise the influence regarding the effect of the bleaching procedure on the bond strength of orthodontic brackets. METHODS: An electronic database search was performed. Search terms included: bleaching, brackets, adhesion; data were extracted and summarized. Risk of bias was assessed using the Chocrane risk of bias tool, adapted for in vitro studies. RESULTS: A total of 8689 articles were screened and 11 studies met the inclusion criteria of this systematic review. 1000 teeth of human and bovine origin were analyzed for the shear bond strength (SBS) of stainless and ceramic brackets after the bleaching treatments. All the authors divided the groups in different subgroups with different bleaching agents and in different concentration. The SBS value allowed to demonstrate the necessity to delay the bonding of the brackets for two weeks after a bleaching treatment and its improvement when tooth mousse or antioxidants agents are used. CONCLUSIONS: The SBS values and the delay of the bonding procedure must be considered in dental practice and clinical strategies are necessary in order to avoid drawbacks which could cause the debonding of the brackets after bleaching due to the alterations of the dental substrate, thus interfering with the orthodontic treatments.
Subject(s)
Dental Bonding , Orthodontic Brackets , Tooth Bleaching , Humans , Animals , Cattle , Tooth Bleaching/adverse effects , Orthodontic Brackets/adverse effects , Dental Bonding/methods , Peroxides/therapeutic use , Peroxides/chemistry , Urea/therapeutic use , Urea/chemistry , Shear Strength , Dental Stress Analysis , Materials TestingABSTRACT
AIM: To study the efficiency of pre-administration of a peptide mimicking the spatial structure of erythropoietin -chain B in modeling experimental post-contrast acute kidney injury. MATERIALS AND METHODS: In this study, an experimental model of post-contrast acute kidney injury was created using a non-steroidal anti-inflammatory drug, a nitric oxide synthase inhibitor, and injection of iopromide to mature male mice. After 48 hours, a comprehensive assessment of the concentration of creatinine, urea, glomerular filtration rate, the ratio of urea/albumin in the serum, as well as the level of proteinuria and interleukin 6 in the urine was carried out. RESULTS: A peptide mimicking the spatial structure of erythropoietin -chain B, administered at a dose of 100 g/kg 30 minutes before modeling of pathologic process, contributes to a significant decrease in creatinine and urea concentrations by 2.5 and 1.8 times, respectively, with an increase in glomerular filtration rate 4.4 times. In addition, in the group with pharmacological correction, there was a significant decrease in the ratio of urea/albumin by 2.2 times, a decrease in the level of proteinuria by 61.9% and a decrease in the concentration of pro-inflammatory interleukin-6 in the urine by 2.1 times. CONCLUSION: Thus, the preliminary administration of a peptide that mimics the spatial structure of the erythropoietin -chain B helps to reduce the severity of post-contrast acute kidney injury in the experiment, due to anti-inflammatory properties.
Subject(s)
Acute Kidney Injury , Erythropoietin , Male , Mice , Animals , Creatinine/therapeutic use , Erythropoietin/pharmacology , Erythropoietin/therapeutic use , Acute Kidney Injury/chemically induced , Peptides/therapeutic use , Proteinuria/pathology , Urea/therapeutic use , Albumins/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Kidney/pathologyABSTRACT
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are common heart muscle disorders that are caused by pathogenic variants in sarcomere protein genes. HCM is characterized by unexplained cardiac hypertrophy (increased chamber wall thickness) that is accompanied by enhanced cardiac contractility and impaired relaxation. DCM is defined as increased ventricular chamber volume with contractile impairment. In this review, we discuss recent analyses that provide new insights into the molecular mechanisms that cause these conditions. HCM studies have uncovered the critical importance of conformational changes that occur during relaxation and enable energy conservation, which are frequently disturbed by HCM mutations. DCM studies have demonstrated the considerable prevalence of truncating variants in titin and have discerned that these variants reduce contractile function by impairing sarcomerogenesis. These new pathophysiologic mechanisms open exciting opportunities to identify new pharmacological targets and develop future cardioprotective strategies.
Subject(s)
Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Hypertrophic/genetics , Connectin/genetics , Myocardial Contraction/genetics , Sarcomeres/genetics , Benzylamines/therapeutic use , Cardiac Myosins/genetics , Cardiac Myosins/metabolism , Cardiomyopathy, Dilated/drug therapy , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/metabolism , Cardiotonic Agents/therapeutic use , Carrier Proteins/genetics , Carrier Proteins/metabolism , Connectin/metabolism , Gene Expression , Humans , Mutation , Myocardial Contraction/drug effects , Myocardium/metabolism , Myocardium/pathology , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Sarcomeres/drug effects , Sarcomeres/metabolism , Sarcomeres/pathology , Troponin T/genetics , Troponin T/metabolism , Uracil/analogs & derivatives , Uracil/therapeutic use , Urea/analogs & derivatives , Urea/therapeutic useABSTRACT
BACKGROUND: Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. MATERIALS AND METHODS: A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [177Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [177Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. RESULTS: Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [177Lu]Lu-PSMA I&T and five (9.1%) for [177Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [177Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [177Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [177Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). CONCLUSION: In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Dipeptides/therapeutic use , Heterocyclic Compounds, 1-Ring/therapeutic use , Humans , Lutetium/therapeutic use , Male , Matched-Pair Analysis , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/pathology , Treatment Outcome , Urea/analogs & derivatives , Urea/therapeutic useABSTRACT
The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC50 value of 0.03 ± 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.
Subject(s)
Enzyme Inhibitors , Epoxide Hydrolases , Animals , Benzamides/pharmacology , Benzamides/therapeutic use , Enzyme Inhibitors/chemistry , Pain , Rats , Structure-Activity Relationship , Urea/pharmacology , Urea/therapeutic useABSTRACT
Targeted delivery of drugs into specific cancer cells is an effective way to enhance the efficacy and minimize the side effects of therapy. Prostate malignant cells overexpress the prostate-specific membrane antigen (PSMA), a membrane protein that may be a valid target for selective drug administration. To target prostate cancer cells, a ß-cyclodextrin perfunctionalised with dipeptide-like urea arms, a well-established mimic of a selective ligand against PSMA, is herein reported, to develop a multivalent drug delivery and targeting system. Firstly, fluorescein was used to validate the system on cells that express high levels of PSMA (prostate tumoral cells, LNCap) or very low levels of PSMA (non-tumoral cells, Hek293T). Then, the antineoplastic agent doxorubicin complexed with ß-cyclodextrin functionalized with PSMA-like ligand takes less time to induce cytotoxicity on LNCap cells compared to doxorubicin alone. This might represent a promising drug-delivery approach to selectively target prostate cancer cells.
Subject(s)
Prostatic Neoplasms , beta-Cyclodextrins , Antigens, Surface/metabolism , Cell Line, Tumor , Doxorubicin/pharmacology , Glutamate Carboxypeptidase II/metabolism , HEK293 Cells , Humans , Ligands , Male , Prostatic Neoplasms/pathology , Urea/pharmacology , Urea/therapeutic useABSTRACT
Post-stroke antiplatelet therapy has been proved to reduce the risk of recurrent stroke; however, it may also increase the incidence of intracranial hemorrhage that could offset any benefits. Therefore, the balance between the benefits and risks of antiplatelet drugs is a critical issue to consider. In the present study, we have compared the effects of post-stroke administration of antiplatelet agents on functional outcomes in the stroke-prone spontaneously hypertensive rat (SHRSP), an established animal model that mimics human lacunar stroke and cerebral small vessel disease. We confirmed that a potent phosphodiesterase 3 (PDE3) inhibitor, K-134, significantly improved post-stroke survival rate and survival time, attenuated stroke-induced neurological deficits, and decreased the incidence of cerebral lesion caused by intracerebral hemorrhage and softening. Similarly, cilostazol showed beneficial effects, though to a lower extent with respect to the survival outcome and neurological symptoms. On the other hand, a P2Y12 inhibitor, clopidogrel significantly improved survival outcomes at the higher dose but caused massive bleeding in the brain at both low and high doses. In contrast, no hemorrhagic lesion was observed in K-134-treated SHRSPs despite its antiplatelet activity. Our findings indicate that K-134 may have a superior post-stroke therapeutic outcome in comparison to other antiplatelet drugs.