Pharmacological Treatment Research Articles

Mitochondrial elongation impairs breast cancer metastasis

Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.

EFFECT OF EXERCISE ON BURST FREQUENCY A MARKER OF SYMPATHETIC ACTIVITY IN HYPERTENSIVE INDIVIDUALS: A SYSTEMATIC REVIEW.

Background: Burst frequency is a factor that is used to know the relationship between sympathetic activity and blood pressure in individuals with hypertension. Various forms of exercise reduce the burst frequency among individuals with hypertension. This systematic review provides suggestion of exercise prescription for reducing blood pressure. Objective: To determine the effects of exercise training and its regulatory mechanisms on burst frequency (BF) a marker of muscle sympathetic nerve activity (MSNA) in hypertensive individuals. Methods: A systematic literature search of electronic databases such as PubMed, Web of Science and Scopus was conducted from inception to July 2024 included randomized controlled trials (RCTs), non-randomized experimental studies (non-RCTs) or pre-post experimental trials on hypertensive patients without associated metabolic disorders, with or without pharmacological treatment, aged between 18 and 70 years, both genders. Patients underwent at least 4 weeks of aerobic, resistance, or breathing exercises with BF as an outcome measure were included. The Revised Cochrane Risk of Bias tool (RoB 2) and Risk of Bias in Non-randomized Studies of Interventions tool (ROBINS-I) was used to evaluate the risk of bias. Results: Five trials were included. Four studies demonstrated a significant reduction in BF among exercise-trained hypertensive individuals, while one study reported no change in BF. Overall, two studies had "some concerns" about performance and attrition bias, one had "high RoB" for selection bias, one had “moderate RoB” due to expected confounding, and one had “serious RoB” due to uncontrolled confounding factors. Conclusion: These findings suggests that HIIT significantly reduces BF, while aerobic and breathing exercises offers lesser benefits, further research should focus on training dosages. Implications: It provides evidence to utilize tailored exercise programme that may reduce sympathetic overactivity in hypertensive patients for better blood pressure control and reduce cardiovascular risk.

Quercetin: A Promising Candidate for the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a chronic liver disease. The development of MASLD is influenced by a multitude of diseases associated with modern lifestyles, including but not limited to diabetes mellitus, hypertension, hyperlipidaemia and obesity. These conditions are often consequences of the adoption of unhealthy habits, namely a sedentary lifestyle, a lack of physical activity, poor dietary choices and excessive alcohol consumption. The treatment of MASLD is primarily based on modifying the patient’s lifestyle and pharmacological intervention. Despite the absence of FDA-approved pharmacological agents for the treatment of MASLD, several potential therapeutic modalities have demonstrated efficacy in reversing the histopathological features of the disease. Among the botanical ingredients belonging to the flavonoid group is quercetin (QE). QE has been demonstrated to possess a number of beneficial physiological effects, including anti-inflammatory, anticancer and antifungal properties. Additionally, it functions as a natural antioxidant. Preclinical evidence indicates that QE may play a beneficial role in reducing liver damage and improving metabolic health. Early human studies also suggest that QE may be an effective treatment for MASLD due to its antioxidant, anti-inflammatory, and lipid-regulating properties. This review aims to summarize the available information on the therapeutic effects of QE in MASLD.

"Pushed to Their Limits": Health Care Provider Perspectives on Barriers and Facilitators to Implementing a Mind-Body and Activity Program for Older Adults With Chronic Pain in a Community Clinic for the Underserved.

Older adults from underserved backgrounds experience chronic pain at a rate of 60% to 75%. Pharmacological treatments have limited efficacy and involve considerable risks. Mind-body interventions hold promise to improve pain outcomes but are typically not implemented in community clinics in which they are needed most, thus contributing to health disparities in chronic pain treatment. We conducted qualitative focus groups and interviews with 20 providers (eg, primary care doctors, nurses, administrators). We sought their perspectives on barriers and facilitators to implementing an evidence based mind-body activity program for older adults with chronic pain at an underserved community health clinic in Massachusetts. Subthemes were identified within 2 superordinate domains (barriers and facilitators) using a hybrid inductive-deductive thematic analysis approach following the Framework Method. Providers discussed facilitators (partner with clinic staff to facilitate referrals and buy-in, integrate referrals through the electronic medical record, offer groups in different languages, post and tailor advertisements) and barriers (limited staff bandwidth, scheduling challenges, inconsistent patient participation). These results will directly inform tailoring and subsequent effectiveness testing and implementation of the pain management program for older underserved adults with chronic pain in this community health care setting.

Therapeutic Controlled Release Strategies for Human Osteoarthritis.

Osteoarthritis is a progressive, irreversible debilitating whole joint disease that affects millions of people worldwide. Despite the availability of various options (non-pharmacological and pharmacological treatments and therapy, orthobiologics, and surgical interventions), none of them can definitively cure osteoarthritis in patients. Strategies based on the controlled release of therapeutic compounds via biocompatible materials may provide powerful tools to enhance the spatiotemporal delivery, expression, and activities of the candidate agents as a means to durably manage the pathological progression of osteoarthritis in the affected joints upon convenient intra-articular (injectable) delivery while reducing their clearance, dissemination, or side effects. The goal of this review is to describe the current knowledge and advancements of controlled release to treat osteoarthritis, from basic principles to applications in vivo using therapeutic recombinant molecules and drugs and more innovatively gene sequences, providing a degree of confidence to manage the disease in patients in a close future.

Epicardial Adipocytes in Cardiac Pathology and Healing.

Implications of epicardial adipose tissue (EAT) on the development of coronary artery disease (CAD) have garnered recent attention. Located between the myocardium and visceral pericardium, EAT possesses unique morphological and physiological contiguity to the heart. The transcriptome and secretome of EAT differ from that of other fat stores in the body. Physiologically, EAT protects the adjacent myocardium through its brown-fat-like thermogenic function and rapid fatty acid oxidation. However, EAT releases pro-inflammatory mediators acting on the myocardium and coronary vessels, thus contributing to the development and progression of cardiovascular diseases (CVD). Furthermore, EAT-derived mesenchymal stromal cells indicate promising regenerative capabilities that offer novel opportunities in cell-based cardiac regeneration. This review aims to provide a comprehensive understanding and unraveling of EAT mechanisms implicated in regulating cardiac function and regeneration under pathological conditions. A holistic understanding of the multifaceted nature of EAT is essential to the future development of pharmacological and therapeutic interventions for the management of CVD.

Long-term effectiveness of SBIRT by outreach visits on subsequent alcohol treatment utilization among inpatients from general hospital: a 36-months follow-up

Aim To investigate the long-term effect of Screening, Brief Intervention, and Referral to Treatment (SBIRT) on alcohol treatment utilization among general hospital inpatients. Methods This 36-month follow-up of a randomized controlled trial included general hospital inpatients who were screened using the Alcohol Use Disorder Identification Test (AUDIT). Patients with an AUDIT score of 8+ were included. Patients were randomized to either SBIRT (Relay) or treatment as-usual (TAU). Outcome was attendance at a specialized outpatient treatment institution or prescription of pharmacological alcohol treatment in general practice. Using the Danish Civil Registration System, patients were followed in the Danish National Patient Registry, Danish National Alcohol Treatment Register, and the Danish National Prescription Registry. Data was collected up to 36 months after discharge. Results The study population consisted of 258 patients in the Relay group and 303 patients in the TAU group. In the Relay group, 36 (14.0%) patients received treatment versus 23 (7.6%) in the TAU group. Patients in the Relay group had higher odds for receiving treatment compared to the TAU group (OR: 1.97, 95% CI: 1.1–3.4, p = 0.01). Significantly more patients in the Relay group scored 16+ on the AUDIT and had already tried to change their alcohol consumption (both p < 0.01). Adjusted for potential confounders, the effect of the Relay intervention was reduced (OR: 1.37, 95%CI: 0.7–2.5, p = 0.31). Conclusions This study did not find evidence that SBIRT is better than TAU at sustaining significant long-term alcohol treatment utilization after discharge among inpatients from general hospital.

The Bidirectional Relationship Between Cardiovascular Medications and Oral and Gut Microbiome Health: A Comprehensive Review

Cardiovascular diseases (CVDs) are a leading cause of widespread morbidity and mortality. It has been found that the gut and oral microbiomes differ in individuals with CVDs compared to healthy individuals. Patients with CVDs often require long-term pharmacological interventions. While these medications have been extensively studied for their cardiovascular benefits, emerging research indicates that they may also impact the diversity and composition of the oral and gut microbiomes. However, our understanding of how these factors influence the compositions of the oral and gut microbiomes in individuals remains limited. Studies have shown that statins and beta-blockers, in particular, cause gut and oral microbial dysbiosis, impacting the metabolism and absorption of these medications. These alterations can lead to variations in drug responses, highlighting the need for personalized treatment approaches. The microbiome’s role in drug metabolism and the impact of CVD medications on the microbiome are crucial in understanding these variations. However, there are very few studies in this area, and not all medications have been studied, emphasizing the necessity for further research to conclusively establish cause-and-effect relationships and determine the clinical significance of these interactions. This review will provide evidence of how the oral and gut microbiomes in patients with cardiovascular diseases (CVDs) interact with specific drugs used in CVD treatment.

Physical activity in the treatment-resistant depression and non-remitted depression: a systematic review of randomized controlled trials

Background The objective of this systematic review was to analyze the effects of physical activity (PA) intervention as an adjuvant strategy to pharmacological treatment in people with treatment-resistant depression (TRD) and non-remitted depression (NRD). Methods A search strategy was realized from five databases: PubMed, Cochrane Central Register of Controlled Trials, Scopus, SPORTDiscus, and Web of Science. The Physiotherapy Evidence Database and Oxford’s Evidence Levels were used to classify the quality appraisal. Results Of the 10777 records, 11 randomized controlled studies attained the inclusion criteria. The more significant outcome for this analysis was the improvement of depression by PA or exercise in TRD and NRD. According to the FITT (Frequency, Intensity, Time, and Type) principle, there was some variability in the PA intervention, and except for one article, they all were classified as excellent in terms of quality description. Conclusions This review highlights the potential of PA intervention as an adjuvant program to improve different traits of TRD and NRD. The remission of depression seems to be higher after PA intervention, showing improvements in quality of life, sleep quality, executive function, and vitality.

Comparative Efficacy of Different Pharmacological Treatments for Pityriasis Rosea: A Network Meta-Analysis

Background/Objectives: Pityriasis rosea (PR) is a self-limiting exanthematous disease associated with the endogenous reactivation of human herpesviruses (HHV)-6 and HHV-7. Classically, the lesions gradually resolve, leaving no sequelae. Therefore, the best treatment is reassuring the patient and suggesting a resting period. However, atypical PR cases characterized by extensive, persistent lesions and systemic symptoms may impact the patient’s quality of life, and, therefore, a treatment can be prescribed. There is limited evidence on the comparative effectiveness of pharmacological treatments for PR; therefore, we performed a network meta-analysis to compare these interventions. Methods: Overall, 12 randomized control trials (RCTs) were identified. The outcomes were itch resolution and rash improvement. Results were expressed as risk ratio (RR) and 95% confidence interval (CI). We also calculated the relative ranking of the interventions for achieving the aforementioned outcomes as their surface under the cumulative ranking (SUCRA). Results: On network meta-analysis, only oral steroids and the combination of oral steroids+antihistamine resulted significantly superior to the placebo in terms of itch resolution (RR 0.44, CI 0.27–0.72 and RR 0.47, CI 0.22–0.99). Oral steroids resulted in the best treatment (SUCRA 0.90) for itch resolution. In terms of rash improvement, only acyclovir and erythromycin resulted significantly superior to placebo (RR 2.55, CI 1.81–3.58; and RR 1.69, CI 1.23–2.33), and acyclovir outperformed all the other tested interventions. Consequently, acyclovir ranked as the best intervention (SUCRA score 0.92). Conclusions: Acyclovir represents the best option for patients with PR that have extensive, persistent lesions or systemic symptoms. Steroids and antihistamines seemed the best treatment for itch resolution.

TRATAMENTO FARMACOLÓGICO COMO PROFILAXIA DA CEFALEIA PRIMÁRIA DO TIPO MIGRÂNEA: UMA ANÁLISE DA EFICÁCIA DOS MEDICAMENTOS

INTRODUCTION: Migraine headache is a neurological problem, varying in form and intensity, being a disruptive factor in the lives of those affected. OBJECTIVE: To present the main prophylactic pharmacological treatments for migraine, evaluating their effects and safety in comparison to other treatments. METHODS: The search was carried out through the VHL in the MEDLINE and LILACS databases, using studies from the last 5 years and with full text available in English and Portuguese. Of the 200 articles initially evaluated, 61 were selected to compose the final corpus of the study. RESULTS: 32 treatments were found available for migraine prophylaxis, with emphasis on monoclonal antibodies to the peptide related to the calcitonin gene, which reduce the frequency, duration and intensity of migraine attacks, providing a comparative improvement in relation to conventional therapies. Medications such as beta-blockers, angiotensin II antagonists, antiepileptics and onabotulinumtoxinA have also demonstrated efficacy in obtaining positive responses to migraine treatment. CONCLUSION: Evidence suggests that, due to the multiple therapeutic approaches to migraine, personalized treatment is necessary, considering the individual response to the intervention and the risk of damage in the care plan.

SEMAGLUTIDE : A THERAPEUTIC REVOLUTION IN THE MANAGEMENT OF OBESITY AND OVERWEIGHT IN TYPE 2 DIABETICS

Introduction: Obesity is a public health condition that results in adverse health impacts and, together with overweight, is one of the main risk factors for the development of type 2 diabetes mellitus. Semaglutide , an analogue of glucagon-like peptide 1 (GLP-1) , has emerged as a promising therapeutic option in the management of obesity, since it can be prescribed for both glycemic control and weight reduction.Methodology: An integrative review was carried out in the databases indexed by the Virtual Health Library (VHL), using as inclusion criteria primary articles published in 2024 in English, with 8 works selected. Results and discussion: Semaglutide has been shown to be an effective pharmacological treatment for patients with type 2 Diabetes Mellitus. Both its weekly subcutaneous and daily oral presentation were able to reduce the average weight and BMI of patients with a variation between 3% and 6% in 3 to 12 months, with the reduction being proportional to the dosage. However, adverse effects were frequent in patients, mostly mild and involving nausea, diarrhea, and constipation, sometimes sufficient to impair adherence. Conclusion : Semaglutide is a safe and effective pharmacological option for the treatment of obesity and overweight in type 2 diabetics.

Natural forgetting reversibly modulates engram expression

Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. However, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, through behavioral and pharmacological interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we showed that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting may be an adaptive form of engram plasticity which allows engrams to switch from an accessible state to an inaccessible state.

Natural forgetting reversibly modulates engram expression.

Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. However, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, through behavioral and pharmacological interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we showed that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting may be an adaptive form of engram plasticity which allows engrams to switch from an accessible state to an inaccessible state.

Burden of disease and cost of illness of overweight and obesity in Portugal.

The prevalence of overweight and obesity has increased in the last decades, posing significant health and economic impacts globally. These conditions are related to several non-communicable diseases, including cardiovascular disease, type II diabetes and cancer. This study estimated the disease burden and healthcare costs associated with overweight and obesity in the adult population in mainland Portugal, in 2018. Burden of disease was measured in disability-adjusted life years (DALY) following Global Burden of Disease (GBD) methodology. DALY were calculated as the sum of years of life lost (YLL) and years lived with disability (YLD). The analyses included morbidity, mortality and related costs directly related to overweight and obesity, as well as the attributable morbidity, mortality and related costs of of 25 selected diseases related to obesity (DrO). A prevalence-based cost analysis was conducted a from the perspective of the public National Health Service, including costs related to inpatient, outpatient care and pharmacological treatment. In 2018, total DALY amounted to 260,943, with 75% due to premature death (196,438 YLL) and 25% due to disability (64,505 YLD). The economic burden of overweight and obesity was estimated at approximately € 1,148 million. Of these, approximately € 13.3 million (1%) were costs related to the treatment of obesity, and the remaining were costs of DrO attributed to overweight and obesity. Outpatient care corresponded to 43% of total costs, pharmacological treatment 38%, and inpatient care 19%. Cardiovascular and cerebrovascular diseases were the largest contributor to total costs (38%), followed by type II diabetes (34%). Overweight and obesity incur a large disease and economic burden to the public healthcare sector, representing approximately 0.6% of the country´s gross domestic product and 5.8% of public health expenditures.

Beyond Pharmacology: The Biological Mechanisms of Remote Ischemic Conditioning in Cerebrovascular Disease

Cerebrovascular diseases (CVDs), comprising predominantly ischemic stroke and chronic cerebral hypoperfusion (CCH), are a significant threat to global health, often leading to disability and mortality. Remote ischemic conditioning (RIC) has emerged as a promising, non-pharmacological strategy to combat CVDs by leveraging the body’s innate defense mechanisms. This review delves into the neuroprotective mechanisms of RIC, categorizing its effects during the acute and chronic phases of stroke recovery. It also explores the synergistic potential of RIC when combined with other therapeutic strategies, such as pharmacological treatments and physical exercise. Additionally, this review discusses the pathways through which peripheral transmission can confer central neuroprotection. This review concludes by addressing the challenges regarding and future directions for RIC, emphasizing the need for standardized protocols, biomarker identification, and expanded clinical trials to fully realize its therapeutic potential.

Limited Potential of Repetitive Transcranial Magnetic Stimulation for Treatment of Essential Tremor: A Systematic Review

Essential tremor (ET) is a prevalent movement disorder characterized by action tremors, predominantly affecting the upper limbs. While various pharmacological and non-pharmacological interventions have shown efficacy in managing ET, the therapeutic role of repetitive transcranial magnetic stimulation (rTMS) remains uncertain. This systematic review synthesizes evidence from clinical trials investigating rTMS as a treatment for ET. Despite some open-label trials reporting reductions in tremor severity, double-blinded studies revealed no significant difference between active and sham rTMS, suggesting a strong placebo effect. The findings indicate that while rTMS can reduce tremor scores, its therapeutic efficacy in ET remains unproven. Future research should focus on improving sham designs and conducting larger, rigorously controlled trials to clarify rTMS’s role in ET management. Current evidence supports considering alternative treatments, such as deep brain stimulation, over rTMS for ET.

Strategies for applying noninvasive brain stimulation techniques to treat psychiatric disorders

With the continuous development of science and technology, medical science, and bioengineering technology, various neuromodulation techniques, such as electrical, magnetic, acoustic, and optical modalities, are rapidly emerging in the therapeutic regime of psychiatric disorders. How to choose the appropriate noninvasive brain stimulation techniques for different psychiatric disorders and their clinical features is becoming a practical dilemma in clinical setting. In this paper, by describing the complex pathogenesis of psychiatric disorders and the limitations of existing therapeutic approaches on psychiatric disorders, combining with the characteristics of different neuromodulation techniques, we propose a new strategy of combined noninvasive brain stimulation to intervene in psychiatric disorders: high-intensity stimulation modulating the whole brain without inducing epilepsy should be as the basic treatment of psychiatric disorders, applying low-intensity stimulation with the advantage of specific targets/brain regions to modulate the residual symptoms or/and single symptom, and for refractory and acute psychiatric disorders, ECT/MECT is preferred for rapid symptom control; different noninvasive brain stimulation techniques can be combined with pharmacological and psychotherapeutic treatments, which will provide a new idea for the future development of this field.

Pathophysiology of vascular ageing and the effect of novel cardio-renal protective medications in preventing progression of chronic kidney disease in people living with diabetes.

Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio-renal complications and guide treatment interventions in people with diabetes. We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon-like peptide-1 (GLP-1) receptor agonists. Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney-derived anti-ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT-2 inhibitors and GLP-1 receptor agonists all influence pathways involved in vascular ageing. A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio-renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes.

Worsening sleep predicts next-week suicidal ideation in a high-risk adolescent outpatient treatment sample.

Suicidal thoughts and behaviors often onset during adolescence, constituting a major public health concern. Despite rising rates in youth, psychotherapeutic and pharmacological treatment outcomes remain meager, indicating a need to identify modifiable risk factors. Experts suggest sleep may serve as a promising clinical indicator of risk and treatment progress, yet few studies have examined acute temporal associations between sleep and suicidal ideation. Participants were depressed and suicidal adolescents (age 13-19, n = 311) attending an intensive outpatient program (IOP). Patients completed weekly self-report assessments of sleep, depression, and suicidal ideation throughout IOP, with an average of 5 assessments over 30 days. Greater overall sleep difficulties, as well as within-person increases in sleep difficulties, were predictive of greater depression severity and suicidal ideation at subsequent assessments, above and beyond previous levels of symptoms. The reverse associations were not found. Inclusion of within-person changes in sleep difficulties significantly improved model fit compared to inclusion of overall sleep difficulties alone. This study provides additional evidence for a prospective relationship between worsening sleep difficulties and suicidal ideation in an IOP youth sample. Worsening sleep may be an important clinical indicator of subsequent depression and suicide risk among adolescents in treatment.