Advances in GPCR-targeted drug development in dermatology.

Achieving the efficacy and specificity of G-protein-coupled receptor (GPCR) targeting-drugs in the skin remains challenging. Understanding the molecular mechanism underlying GPCR dysfunction is crucial for developing targeted therapies. Recent advances in genetic, signal transduction, and structural studies have significantly improved our understanding of cutaneous GPCR functions in both normal and pathological states. In this review, we summarize recent discoveries of pathogenic GPCRs in dermal injuries, chronic inflammatory dermatoses, cutaneous malignancies, as well as the development of potent potential drugs. We also discuss targeting of cutaneous GPCR complexes via the transient receptor potential (TRP) channel and structure elucidation, which provide new opportunities for therapeutic targeting of GPCRs involved in skin disorders. These insights are expected to lead to more effective and specific treatments for various skin conditions.

The Management of Knee Osteoarthritis in the Real World: An Italian National Survey.

Background: Knee osteoarthritis is a degenerative and inflammatory disease causing pain and worsening patients' quality of life. Various conservative treatment options exist, but a gap between scientific evidence and clinical practice is still present. The aim of this prospective multicenter observational study is to describe the real outpatient territorial management of patients with knee osteoarthritis and to analyze the correlation between the anthropometric and clinical characteristics of the population of patients suffering from symptomatic knee osteoarthritis who were screened in the national survey. Methods: The educational national project was divided into three modules: the first and the last through webinars; and the second held in daily practice. The participants had to register structured observations, which were then stored in a national database and analyzed in order to identify correlations. The subgroups were stratified by body composition, radiological severity of knee osteoarthritis, pain, and functional ability. Results: The project has been joined by 155 physicians, and 2.656 observations about real-world outpatients being treated for knee osteoarthritis in Italy were collected. Data relating to real-world pharmacological and rehabilitation therapies in correlation with body composition, the radiological severity of knee osteoarthritis, pain, and functional ability were reported. Conclusions: Currently, there are no standardized protocols using effective combinations of therapeutic exercises, physical agents, and medications to control the progression of knee osteoarthritis. This real-word national survey proved to be useful for describing the current state of the art of therapeutic management of knee osteoarthritis and for emphasizing the need to fill the gap between scientific evidence and clinical practice.

Application of virtual reality to enhance therapeutic Tai Chi for depression in elderly people.

The battle against depression in the elderly is crucial due to its significant impact on their quality of life, physical and cognitive health, increased risk of social isolation and suicide, as well as the associated higher healthcare costs. This research investigates the effects of traditional and augmented reality Tai Chi, using the virtual environment "Managed Tai Chi," on depression in elderly individuals. The study involved 300 participants aged over 60 from the Beijing Medical Center, with an experimental period lasting six months and sessions held once a week. The Geriatric Depression Scale (GDS) was utilized as a diagnostic tool at the pre-test and post-test stages. The findings revealed that the VR group exhibited a more substantial reduction in depression compared to the traditional and control groups (p ≤ 0.05), indicating the enhanced efficacy of Tai Chi with VR augmentation in treating depression in the elderly.

Surgical and pharmacological treatment of childhood obesity.

The increase in obesity prevalence has been slowing down in numerous countries recently. WHO Europe has organized surveillance of childhood obesity (Childhood Obesity Surveillance Initiative, COSI) since 2008, which observed the prevalence of overweight and obesity of 6-9-year-old children is followed during this study and proved this result. The study Children's Health 2016 showed that after a period of the global increase of obesity until 2011, there was in the Czech Republic a period of certain stabilization, in which there weren´t major changes in weight. Unfortunately, the covid pandemic changed this trend and the current data from 2021 showed in the Czech Republic a serious increase in childhood obesity. For these children will be necessary to use a new type of treatment of obesity as a surgical and pharmacological specific treatment.

HPV Infections-Classification, Pathogenesis, and Potential New Therapies.

To date, more than 400 types of human papillomavirus (HPV) have been identified. Despite the creation of effective prophylactic vaccines against the most common genital HPVs, the viruses remain among the most prevalent pathogens found in humans. According to WHO data, they are the cause of 5% of all cancers. Even more frequent are persistent and recurrent benign lesions such as genital and common warts. HPVs are resistant to many disinfectants and relatively unsusceptible to external conditions. There is still no drug available to inhibit viral replication, and treatment is based on removing lesions or stimulating the host immune system. This paper presents the systematics of HPV and the differences in HPV structure between different genetic types, lineages, and sublineages, based on the literature and GenBank data. We also present the pathogenesis of diseases caused by HPV, with a special focus on the role played by E6, E7, and other viral proteins in the development of benign and cancerous lesions. We discuss further prospects for the treatment of HPV infections, including, among others, substances that block the entry of HPV into cells, inhibitors of viral early proteins, and some substances of plant origin that inhibit viral replication, as well as new possibilities for therapeutic vaccines.

Clinical Intervention Strategies and Family Dynamics in Adolescent Eating Disorders: A Scoping Review for Enhancing Early Detection and Outcomes.

Background: This systematic review investigated the impact of familial factors on individuals aged 10-17 who have clinical signs or symptoms of eating disorders. Simultaneously, it scrutinized the involvement of the family in therapy, as well as other forms of intervention. Methods: The PsycINFO, PubMed, and Scopus databases were used to search for research material comprehensively. After applying specific criteria, 46 articles were deemed suitable and included in the systematic review. The study comprised a cohort of 4794 adolescents who received a diagnosis of either Anorexia Nervosa (AN), Bulimia Nervosa (BN), or Binge-Eating Disorder (BED). In addition, controls were utilized for 1187 adolescents, 1563 parents, 1809 siblings, and 11 other relatives. Results: The connection between family factors and eating disorders is primarily determined by the families' level of functioning, satisfaction with the family dynamic, parents' attitudes toward their children, and the role of food within the family system. Family Therapy was the most used psychotherapeutic approach in the treatment of AN. The incidence of reports in BN closely paralleled that of Cognitive-Behavioral Therapy (CBT) models. Articles about (Enhanced) CBT were exclusively associated with BED. Conclusions: Family-based approaches are crucial in comprehending, preventing, and addressing eating disorders in adolescents. Incorporating the study of family dynamics and actively engaging families in the treatment process can significantly enhance recovery rates and decrease the occurrence of relapses.

Lipid nanoparticle: advanced drug delivery systems for promotion of angiogenesis in diabetic wounds.

Diabetic wound is one of the most challenge in healthcare, requiring innovative approaches to promote efficient healing. In recent years, lipid nanoparticle-based drug delivery systems have emerged as a promising strategy for enhancing diabetic wound repair by stimulating angiogenesis. These nanoparticles offer unique advantages, including improved drug stability, targeted delivery, and controlled release, making them promising in enhancing the formation of new blood vessels. In this review, we summarize the emerging advances in the utilization of lipid nanoparticles to deliver angiogenic agents and promote angiogenesis in diabetic wounds. Furthermore, we provide an in-depth exploration of key aspects, including the intricate design and fabrication of lipid nanoparticles, their underlying mechanisms of action, and a comprehensive overview of preclinical studies. Moreover, we address crucial considerations pertaining to safety and the translation of these innovative systems into clinical practice. By synthesizing and analyzing the available knowledge, our review offers valuable insights into the future prospects and challenges associated with utilizing the potential of lipid nanoparticle-based drug delivery systems for promoting robust angiogenesis in the intricate process of diabetic wound healing.

Comparative effectiveness of non- pharmacological treatments in patients with persistent postural-perceptual dizziness: a systematic review and effect sizes analyses.

Introduction: The patho-psychological mechanisms of persistent postural-perceptual dizziness (PPPD) appear to be very complex, and a multimodal, multidisciplinary approach is suggested for treating patients with PPPD. The aim of this review was to provide a comprehensive overview of non-pharmacological treatments and their comparative effectiveness in patients with PPPD. Methods: Scopus, Web of Science, PsycINFO, Medline, Embase, CINAHL, Cochrane Library and ClinicalTrials.gov were searched in April 2022 with a search update in August 2023. Only randomized controlled trials (RCTs) were included. There was no restrictions regarding publication date. Two reviewers independently identified eligible trials, extracted data, double-checked all extracted information from the included articles and assessed the risk of bias using the Cochrane risk of bias tool. A qualitative synthesis was performed, considering methodological heterogeneity between trials. Finally, an effect size analysis was performed for each treatment comparison. The standardized mean differences (SMD) and their corresponding 95% confidence intervals (95%CI) were calculated for each trial using Review Manager 5.4. Results: Thirteen RCTs (618 patients with moderate or mild dizziness) out of 1,362 references describing seven different non-pharmacological comparisons were selected. Nine trials included patients with PPPD, and four trials included patients with functional dizziness. The trials used different interventions that were classified as: (1) psychotherapeutic interventions (cognitive behavioral therapy, patient education), (2) physiotherapeutic interventions/training (vestibular rehabilitation, optokinetic stimulation), (3) stimulation procedures (vagus nerve stimulation, transcranial direct current stimulation) and (4) device application (visual desensitization using personalized glasses). However, most of the trials investigated the effects of single interventions, rather than multimodal interdisciplinary treatment of patients with PPPD. The SMD for dizziness handicap and severity was between 0.04 and 0.52 in most trials. In one trial using visual desensitization, the SMD was 1.09 (strong effect on the severity of dizziness) and 1.05 (strong effect on dizziness handicap). Discussion: Several individual interventions have shown benefits in the treatment of patients with PPPD with small to moderate effects. However, the multimodal treatment or a combination of vestibular rehabilitation with visual desensitization, cognitive behavioral therapy including patient education, and medication support should be further investigated. Future trials should include a large sample size with severe dizziness, and provide a longer follow-up period. Clinical trial registration: PROSPERO CRD42022320344.

In Silico TRials guide optimal stratification of ATrIal FIbrillation patients to Catheter Ablation and pharmacological medicaTION: the i-STRATIFICATION study.

AIMS: Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for secondary treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in silico trials. METHODS AND RESULTS: A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low-voltage areas, LVAs), was developed and validated against clinical data from ionic currents to electrocardiogram. Virtual patients presenting AF post-PVI underwent 12 secondary treatments. Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in the small right atria (<60 mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-PLAN sufficed (66% efficacy) for the small left atria (<90 mL). For the bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVAs greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVAs, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient's ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant. CONCLUSION: In silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool.

Oral ß-RA induces metabolic rewiring leading to the rescue of diet-induced obesity.

Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome. This potential intervention could involve the modulation of endogenous CoQ biosynthesis by the use of analogs of the precursor of its biosynthesis, such as ß-resorcylic acid (ß-RA). Here, we show that oral supplementation with ß-RA, incorporated into the diet of diet-induced obese (DIO) mice, leads to substantial weight loss. The anti-obesity effects of ß-RA are partially elucidated through the normalization of mitochondrial CoQ metabolism in white adipose tissue (WAT). Additionally, we identify an HFN4α/LXR-dependent transcriptomic activation of the hepatic lipid metabolism that contributes to the anti-obesity effects of ß-RA. Consequently, ß-RA mitigates WAT hypertrophy, prevents hepatic steatosis, counteracts metabolic abnormalities in WAT and liver, and enhances glucose homeostasis by reducing the insulin/glucagon ratio and plasma levels of gastric inhibitory peptide (GIP). Moreover, pharmacokinetic evaluation of ß-RA supports its translational potential. Thus, ß-RA emerges as an efficient, safe, and translatable therapeutic option for the treatment and/or prevention of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD).

[Neuromodulatory pharmacotherapy individualization in prolonged and chronic consciousness disorders after severe traumatic brain injury]. / K probleme individualizatsii neiromodulyatornoi farmakoterapii pri prolongirovannykh i khronicheskikh narusheniyakh soznaniya vsledstvie tyazheloi cherepno-mozgovoi travmy.

One of the most probable causes of effective therapy for post-comatose disorders of consciousness is the lack of individualization of drug prescriptions. In this observational study, we analyzed 48 courses of neuromodulatory therapy in 28 patients with prolonged and chronic disorders of consciousness following severe traumatic brain injury. Comparison of 24 effective and 24 ineffective courses demonstrated higher effectiveness of pharmacotherapy through its individualization, i.e. the choice of a drug whose neuromodulatory spectrum would correspond to neurological syndromes of neurotransmitter dysfunction. In this approach, 74% of therapy courses were effective while opposite management resulted only 34% of effective courses.

The challenge of pharmacotherapy for musculoskeletal pain: an overview of unmet needs.

Musculoskeletal disorders are characterized by several impairments, including pain, affecting muscles, bones, joints and adjacent connective tissue, resulting in temporary or permanent functional limitations and disability. Musculoskeletal pain is particularly prevalent worldwide and greatly impacts the quality of life, social participation and economic burden. To date, several issues persist about the classification of musculoskeletal pain and its management strategies and resources. The treatment of musculoskeletal pain conditions is complex and often requires a multimodal approach, including pharmacological and non-pharmacological therapy that might be ineffective in many cases, resulting in poor patient satisfaction and controversial expectations about the potential benefits of available interventions. This manuscript provides an overview of unmet needs in managing musculoskeletal pain, particularly focusing on pharmacotherapeutic pitfalls in this context.

4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease.

Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.

Obesity in Prediabetic Patients: Management of Metabolic Complications and Strategies for Prevention of Overt Diabetes.

Obesity and prediabetes affect a substantial part of the general population, but are largely underdiagnosed, underestimated, and undertreated. Prediabetes differs from diabetes only in the degree of hyperglycaemia consequent to the progressive decline in residual beta-cell function. Both prediabetes and diabetes occur as a consequence of insulin resistance that starts several years before the clinical onset of overt diabetes. Macrovascular complications in patients with diabetes are mainly caused by insulin resistance. This is why in prediabetes, the overall cardiovascular risk is, by all means, similar to that in patients with diabetes. It is important, therefore, to identify prediabetes and treat patients not only to prevent or delay the onset of diabetes, but to reduce the cardiovascular risk associated with prediabetes. This review provides an overview of the pathophysiology of prediabetes in patients with obesity and the progression toward overt diabetes. We have reviewed nutritional and pharmacological approaches to the management of obesity and reduced glucose tolerance, and the treatment of the major comorbidities in these patients, including hypertension, dyslipidaemia, and Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), has also been reviewed. In patients with obesity and prediabetes, the nutritional approach is similar to that adopted for patients with obesity and diabetes; treatments of dyslipidaemia and hypertension also have the same targets compared to patients with diabetes. MASLD is a critical issue in these patients; in the prediabetic state, MASLD rarely progresses into fibrosis. This highlights the importance of the early recognition of this pathological condition before patients become diabetic when the risk of fibrosis is much higher. It is necessary to raise awareness of the clinical relevance of this pathological condition in order to prompt early intervention before complications occur. The single most important therapeutic goal is weight loss, which must be early and persistent.

TaKeTiNa Music Therapy for Outpatient Treatment of Depression: Study Protocol for a Randomized Clinical Trial.

BACKGROUND/OBJECTIVES: Depression is a prevalent and debilitating illness that significantly affects psychological and physical well-being. Apart from conventional therapies such as psychotherapy and medication, individuals with depression often lack opportunities for activities that are generally perceived as enjoyable, such as music, meditation, and arts, which have demonstrated therapeutic effectiveness. TaKeTiNa music therapy has been employed as a therapeutic intervention for more than two decades. However, there is a notable absence of well-designed clinical trials investigating its antidepressant effects, a gap we aim to address in our current study. Furthermore, shifts in the progression of depression may manifest both psychologically, by influencing emotional states, and physiologically, by leading to alterations in lipid and sphingolipid metabolism, cortisol levels, and immune system function. Our study seeks to analyze the impact of TaKeTiNa music therapy on both levels. METHODS: This is a prospective monocentric randomized waitlist-controlled clinical trial. It investigates the influence of TaKeTiNa music therapy on patients with major depression in an outpatient setting. Therefore, interested persons are randomly assigned to two groups, an intervention group or a control group, after completing a screening procedure. The intervention group starts with an eight-week TaKeTiNa music therapy intervention. The waiting group receives the same therapy program after completing the follow-up period. Blood and saliva sampling as well as responses to questionnaires are obtained at specific time points. DISCUSSION: Our study investigates the effects of TaKeTiNa music therapy, a non-pharmacological antidepressant treatment option, on depressive symptoms. We also address functional and causal immunological changes; hormonal changes, such as changes in cortisol levels; and metabolic changes, such as changes in serum lipids and sphingolipids, during the course of depression. We expect that this study will provide evidence to expand the range of treatment options available for depression.

"One a Day Keeps the Prison Away": Understanding the Experiences of Individuals Convicted of Sexual Offences Receiving Anti-Androgens for the Treatment of Problematic Sexual Arousal.

Problematic sexual arousal (PSA) is an umbrella term to describe a range of clinical presentations related to excessive sexual thinking (e.g., sexual preoccupation) and sexual behavior (e.g., hypersexuality). Although such concepts are known to affect sexual recidivism among individuals convicted of sexual offences, PSA is not routinely or directly targeted in offending behavior programs in England and Wales. However, in recent years, there have been moves to incorporate pharmacological interventions for addressing this among people with sexual offence histories. Although some work to understand the experiences of those taking SSRI medication for this purpose has emerged, little is known about the experiences of service users taking anti-androgen medication. In this study, we interviewed all individuals in prison taking anti-androgens for the treatment of problematic sexual arousal following convictions for sexual offences in England at the time of data collection (N = 10). Using a phenomenologically oriented thematic analysis, we established themes pertaining to "Differing needs: Motivations for treatment," "Medication as a risk management strategy," and how the medication helped the men in their pursuit of "Discovering a 'new me'." This work contributes important knowledge to inform the development of ethical and effective prescribing of anti-androgen medication with this population and offer recommendations for both future research and the development of clinical practice.

The Effect of Thiazolidinediones in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterised by insulin resistance and is a risk for type 2 diabetes mellitus (T2DM). The aim of this study was to review the literature on the effect of pioglitazone and rosiglitazone in women with PCOS. METHODS: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science in April 2020 and updated in March 2023. Studies were deemed eligible if they were randomised controlled trials (RCTs) reporting the effect of pioglitazone and rosiglitazone in PCOS. The study follows the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: Out of 814 initially retrieved citations, 24 randomised clinical trials (RCTs) involving 976 participants were deemed eligible. Among women with PCOS, treatment with rosiglitazone compared to metformin resulted in a significant increase in the mean body weight (mean difference (MD) 1.95 kg; 95% CI 0.03-3.87, p = 0.05). Metformin treatment was associated with a reduction in mean body mass index (BMI) compared to pioglitazone (MD 0.85 kg/m2; 95% CI 0.13-1.57, p = 0.02). Both pioglitazone compared to placebo (MD 2.56 kg/m2; 95% CI 1.77-3.34, p < 0.00001) and rosiglitazone compared to metformin (MD 0.74 kg/m2; 95% CI 0.07-1.41, p = 0.03) were associated with a significant increase in BMI. Treatment with pioglitazone compared to placebo showed a significant reduction in triglycerides (MD - 0.20 mmol/L; 95% CI - 0.38 to - 0.03, p = 0.02) and fasting insulin levels (MD - 11.47 mmol/L; 95% CI - 20.20, - 2.27, p = 0.01). Rosiglitazone compared to metformin was marginally significantly associated with a reduction in the luteinising hormone (LH) (MD - 0.62; 95% CI - 1.25-0.00, p = 0.05). CONCLUSION: Both pioglitazone and rosiglitazone were associated with significant increases in body weight and BMI when compared with metformin or placebo. Pioglitazone significantly reduced triglycerides and fasting insulin when compared with placebo while rosiglitazone showed a modest reduction of LH when compared with metformin. PROSPERO REGISTRATION NO: CRD42020178783.

[Clinical management of treatment-resistant depression]. / Klinisches Management der therapieresistenten Depression.

Treatment-resistant depression (TRD) is a complex disorder. Although no standardized definition has been established to date, there are promising and well-established treatment options for the condition. Looking at the current pharmacological and neuromodulatory strategies, there is an urgent need for fast-acting and well-tolerated treatment options. The search for new mechanisms of action goes beyond the monoamine hypothesis. For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have a favorable side-effect profile.