Nilotinib-induced alterations in endothelial cell function recapitulate clinical vascular phenotypes independent of ABL1.

Nilotinib is a highly effective treatment for chronic myeloid leukemia but has been consistently associated with the development of nilotinib-induced arterial disease (NAD) in a subset of patients. To date, which cell types mediate this effect and whether NAD results from on-target mechanisms is unknown. We utilized human induced pluripotent stem cells (hiPSCs) to generate endothelial cells and vascular smooth muscle cells for in vitro study of NAD. We found that nilotinib adversely affects endothelial proliferation and migration, in addition to increasing intracellular nitric oxide. Nilotinib did not alter endothelial barrier function or lipid uptake. No effect of nilotinib was observed in vascular smooth muscle cells, suggesting that NAD is primarily mediated through endothelial cells. To evaluate whether NAD results from enhanced inhibition of ABL1, we generated multiple ABL1 knockout lines. The effects of nilotinib remained unchanged in the absence of ABL1, suggesting that NAD results from off- rather than on-target signaling. The model established in the present study can be applied to future mechanistic and patient-specific pharmacogenomic studies.

Ferroptosis in age-related vascular diseases: Molecular mechanisms and innovative therapeutic strategies.

Aging, an inevitable aspect of human existence, serves as one of the predominant risk factors for vascular diseases. Delving into the mystery of vascular disease's pathophysiology, the profound involvement of programmed cell death (PCD) has been extensively demonstrated. PCD is a fundamental biological process that plays a crucial role in both normal physiology and pathology, including a recently discovered form, ferroptosis. Ferroptosis is characterized by its reliance on iron and lipid peroxidation, and its significant involvement in vascular disease pathophysiology has been increasingly acknowledged. This phenomenon not only offers a promising therapeutic target but also deepens our understanding of the complex relationship between ferroptosis and age-related vascular diseases. Consequently, this article aims to thoroughly review the mechanisms that enable the effective control and inhibition of ferroptosis. It focuses on genetic and pharmacological interventions, with the goal of developing innovative therapeutic strategies to combat age-related vascular diseases.

Clinical evidence and rationale of mesoglycan to treat chronic venous disease and hemorrhoidal disease: a narrative review.

Chronic venous disease (CVD) and hemorrhoidal disease (HD) are among the most common vascular diseases in the world, with CVD affecting 22-41% of the population in Europe and HD having a point prevalence of 11-39%. The burden is substantial in terms of the effect of symptoms on patients' health-related quality of life (HRQoL) and direct/indirect medical costs. Treatment begins with lifestyle changes, compression in CVD and topical therapies in HD, and escalates as needed through oral therapies first and eventually to surgery for severe disease. CVD and HD share etiological features and pathological changes affecting the structure and function of the tissue extracellular matrix. Mesoglycan, a natural glycosaminoglycan (GAG) preparation composed primarily of heparan sulfate and dermatan sulfate, has been demonstrated to positively impact the underlying causes of CVD and HD, regenerating the glycocalyx and restoring endothelial function, in addition to having antithrombotic, profibrinolytic, anti-inflammatory, antiedema and wound-healing effects. In clinical trials, oral mesoglycan reduced the severity of CVD signs and symptoms, improved HRQoL, and accelerated ulcer healing. In patients with HD, mesoglycan significantly reduced the severity of signs and symptoms and the risk of rectal bleeding. In patients undergoing excisional hemorrhoidectomy, adding mesoglycan to standard postoperative care reduced pain, improved HRQoL, reduced incidence of thrombosis, and facilitated an earlier return to normal activities/work, compared with standard postoperative care alone. The clinical effects of mesoglycan in patients with CVD or HD are consistent with the agent's known mechanisms of action.

Research progress in the management of vascular disease with cannabidiol: a review.

The morbidity and mortality rates associated with vascular disease (VD) have been gradually increasing. Currently, the most common treatment for VD is surgery, with the progress in drug therapy remaining slow. Cannabidiol (CBD) is a natural extract of Cannabis sativa L. with sedative, analgesic, and nonaddictive properties. CBD binds to 56 cardiovascular-related receptors and exerts extensive regulatory effects on the cardiovascular system, making it a potential pharmacological agent for the management of VD. However, most CBD studies have focused on neurological and cardiac diseases, and research on the management of VD with CBD is still rare. In this review, we summarize the currently available data on CBD in the management of VD, addressing four aspects: the major molecular targets of CBD in VD management, pharmacokinetic properties, therapeutic effects of CBD on common VDs, and side effects. The findings indicate that CBD has anti-anxiety, anti-oxidation, and anti-inflammatory properties and can inhibit abnormal proliferation and apoptosis of vascular smooth muscle and endothelial cells; these effects suggest CBD as a therapeutic agent for atherosclerosis, stress-induced hypertension, diabetes-related vasculopathy, ischemia-reperfusion injury, and vascular damage caused by smoking and alcohol abuse. This study provides a theoretical basis for further research on CBD in the management of VD.

Reduction of lower-limb edema in patients with chronic venous disease by micronized purified flavonoid fraction: a systematic literature review and meta-analysis.

INTRODUCTION: The prevalence of lower limb edema is high among patients with chronic venous disease (CVD). Several clinical studies with various designs have assessed the effect of micronized purified flavonoid fraction (MPFF) on edema. The aim of this work was to provide a comprehensive and accurate evaluation of the reduction in ankle and calf circumference as an indicator of lower limb edema reduction in patients with CVD treated with MPFF by combining studies that use different designs in a single group meta-analysis. EVIDENCE ACQUISITION: We conducted a systematic literature review in April 2022 based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria to identify prospective studies investigating the effect of oral MPFF treatment 1000 mg/day on ankle and calf circumference in patients with CVD. Studies with population including at least one patient with an ulcer were excluded. All prospective studies irrespectively of design (i.e., interventional and non-interventional studies, randomized controlled trials (RCTs), non-randomized studies, studies without a control or reference treatment) were eligible. The Medline, Embase and Cochrane databases were searched. Endpoints were ankle and calf circumference measurements and their overall mean change from baseline estimated with random-effects meta-analysis methods. The evaluation criterion feeling of swelling was also analyzed as a standardized mean change (SMC) with 95% confidence intervals after combination of quantitative scales. EVIDENCE SYNTHESIS: Among 861 articles identified, eight studies (five RCTs including one placebo-controlled, three non-comparative studies) met the criteria. The overall population consisted of 1635 patients, predominantly female (89% ranging from 64% to 94%) with a mean age of 47 years ranging from 41 to 48 years. Mean reduction in ankle circumference was 6.0 mm (95%CI: 3.6 to 8.4; P<0.001) and 7.0 mm (95%CI: 0.9 to 13.1; P=0.024) after two and at least six months of treatment respectively. The results were similar when considering the study type RCTs and non-RCTs. Mean reduction in calf circumference was 5.7 mm (95%CI: 2.8 to 8.6; P<0.001) and 6.7 mm (95%CI: 5.2 to 8.1; P<0.001), at two months and at the last post-baseline evaluation respectively. Heterogeneity among studies was statistically significant (degree of consistency I2=93.5%; P<0.001 and I2=81.1%, P<0.01 for ankle and calf circumference, respectively). In the three studies reporting the effect on feeling of swelling a significant standardized mean change (SMC) reduction of 2.2 (95%CI: 0.2 to 4.2; P=0.028) on a quantitative scale was observed after two months of treatment with MPFF. CONCLUSIONS: MPFF appeared to be effective in reducing ankle and calf circumference as well as feeling of swelling irrespective of study design. The circumference reduction is present at short and long term, suggesting that benefit occurs early and is maintained overtime. Despite the observed heterogeneity among included studies, this meta-analysis supports the significant therapeutic efficacy of MPFF in reducing lower-limb edema in patients with CVD. The complete video presentation of the work is available online at www.minervamedica.it (Supplementary Digital Material 1: Supplementary Video 1, 5 min, 192 MB).

Systematic literature review and expert meeting report on health-related quality of life in chronic venous disease.

INTRODUCTION: Chronic venous disease (CVD) can lead to considerable morbidity and impact health-related quality of life (HRQoL). The aim of this review was twofold: (i) to provide a deeper understanding of how CVD affects HRQoL (physical, psychological and social functioning), and (ii) to review the impact of evidence-based veno-active drugs (VADs) on HRQoL. EVIDENCE ACQUISITION: For the effect of CVD on HRQoL, information was gathered during an Expert Consensus Meeting, during which data were presented from both the patient and physician perspective assessed with validated quality-of-life measures. For the impact of VADs on HRQoL, a systematic literature review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases were searched for real world evidence or randomized-controlled trials (RCT) vs. placebo, reporting data on the influence of VADs on HRQoL in patients with CVD. EVIDENCE SYNTHESIS: CVD can negatively affect daily life in a number of areas related to pain, physical function and social activities. The impact of CVD on HRQoL begins early in the disease and for patients the emotional burden of the disease is as high as the physical burden. In contrast, physicians tend to overestimate the physical impact. The database search yielded 184 unique records, of which 19 studies reporting on VADs and HRQoL in patients with CVD met the inclusion criteria (13 observational and 6 RCTs). Micronized purified flavonoid fraction (MPFF) was the most represented agent, associated with 12/19 studies (2 RCTs and 10 observational). Of the 6 RCTs, only MPFF, aminaphthone and low-dose diosmin provided statistically significant evidence for improvement on HRQoL compared with placebo; for the other VADs improvements in HRQoL were not statistically different from placebo. MPFF was also associated with improvements in HRQoL in the observational studies, across all CEAP clinical classes, as monotherapy or in combination with other conservative therapy, and for all aspects of HRQoL: physical, psychological, and social. Real-world data for the other VADs were scarce. Ruscus extract, sulodexide and a semi-synthetic diosmin were each represented by a single observational study and these limited data were associated with statistically significant improvements compared with baseline in overall and subdomain scores across the range of CEAP clinical classes. CONCLUSIONS: CVD can impair patients' HRQoL significantly at all stages of the disease. MPFF has the greatest evidence base of clinical use in both RCT and real-world observational studies for effectiveness on HRQoL and is recognized by international guidelines. The complete video presentation of the work is available online at www.minervamedica.it (Supplementary Digital Material 1: Supplementary Video 1, 5 min, 194 MB).

Role of ascorbic acid in cardiac allograft vasculopathy.

PURPOSE OF THE REVIEW: Cardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long-term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post-transplant care. RECENT DATA: Recent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial. SUMMARY: CAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large-scale randomized control studies of ascorbic acid are needed to establish the role in routine post-transplant management.

Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy.

BACKGROUND: Gain-of-function mutations in STING1 (also known as TMEM173) which result in constitutive activation of STING, have been reported to cause STING-associated vasculopathy with onset in infancy (SAVI). Although a wider spectrum of associated manifestations and perturbations in disease onset have been observed since its description, the genotype-phenotype correlations are not definite, and there is no established treatment protocol for SAVI. CASE PRESENTATION: Herein, we report a kindred, heterozygous STING mutation (p.V155M) in which the 2-year-old proband suffered from severe interstitial lung disease (ILD) while her father was initially misdiagnosed with connective tissue disease associated with ILD at an adult age. Baricitinib was initiated after the diagnosis of SAVI in the proband combined with steroids, and during the 14-month follow-up, the respiratory symptoms were improved. However, as the improvement of laboratory indicators was limited, especially in autoimmune indices, and the lung CT images remained unaltered, it seems that JAK1/2 inhibition was unsatisfactory in completely controlling the inflammation of the disease in our study. CONCLUSIONS: Baricitinib was shown to elicit some effect on the ILD but failed to control the inflammation of the disease completely. Further exploration of JAK inhibitors or other therapeutic strategies are needed to more optimally treat this inflammatory disease.

Cardiovascular Insights for the Appropriate Management of Chronic Venous Disease: A Narrative Review of Implications for the Use of Venoactive Drugs.

Evidence suggests that chronic venous disease (CVD) may be a cardiovascular disorder, as patients with CVD are prone to developing arterial (atherosclerosis) and venous (thromboembolism) diseases. This may be partly explained by shared risk factors. Thus, patients with CVD or cardiovascular disease require careful history-taking and physical assessment to identify coexisting pathologies and risk factors. This article summarises a symposium at the XIX World Congress of the International Union of Phlebology held in Istanbul, Turkey, in September 2022. Common pathophysiological features of CVD and cardiovascular disease are endothelial injury, hypercoagulability and systemic inflammation. In CVD, inflammation primarily affects the microcirculation, with changes in capillary permeability, vein wall and valve remodelling and increase in oxidative stress. Once patients develop symptoms/signs of CVD, they tend to reduce their physical activity, which may contribute to increased risk of cardiovascular disease. Data show that the presence of CVD is associated with an increased risk of cardiovascular disease, including peripheral arterial disease and heart failure (HF), and the risk of adverse cardiovascular events increases with CVD severity. In addition, patients with cardiovascular disease, particularly those with HF, are at increased risk of venous thromboembolism (VTE) and should be assessed for VTE risk if they are hospitalised with cardiovascular disease. Therefore, CVD management must include a multi-specialty approach to assess risk factors associated with both the venous and arterial systems. Ideally, treatment should focus on the resolution of endothelial inflammation to control both CVD and cardiovascular disease. International guidelines recommend various conservative treatments, including venoactive drugs (VADs), to improve the symptoms/signs of CVD. Micronized purified flavonoid fraction (MPFF) is a VAD, with high-quality evidence supporting its use in relieving symptoms/signs of CVD and improving quality of life. Moreover, in large-scale observational studies, MPFF has shown superior effectiveness in real-world populations compared with other VADs. Video Abstract. (MP4 97173 kb).

Blood vessel disease can affect both arteries and veins; when it affects arteries, it is called cardiovascular disease, and when it affects veins, it is called chronic venous disease (CVD). In most cases, the underlying disease process is similar, irrespective of the type of blood vessels affected, and the risk of both CVD and cardiovascular disease is increased by age, smoking, overweight/obesity and diabetes. If cardiovascular disease affects arteries in the legs, the symptoms can be similar to that of CVD, with pain, feelings of leg heaviness or tiredness and skin changes. CVD and cardiovascular disease are usually treated by different specialists. A symposium was held at the XIX World Congress of the International Union of Phlebology in Istanbul, Turkey, in September 2022, to raise awareness of the relationship between the two conditions. The speakers described the common disease processes in CVD and cardiovascular disease, and how patients with CVD are at increased risk of cardiovascular disease, and vice versa. They reiterated the importance of thoroughly assessing patients with either cardiovascular disease or CVD to see if both arterial and venous disease were present. When patients have CVD, international treatment guidelines recommend various conservative treatments, including venoactive drugs, to improve symptoms and signs. There is high-quality evidence to support the use of the venoactive drug, micronized purified flavonoid fraction (MPFF), to improve quality of life and relieve a broad range of CVD symptoms/signs. Large-scale observational studies support the effectiveness of MPFF in a real-world population of patients with CVD compared with other venoactive drugs.

VEIN STEP: A Prospective, Observational, International Study to Assess Effectiveness of Conservative Treatments in Chronic Venous Disease.

INTRODUCTION: VEIN STEP was conducted to collect international data on the management of chronic venous disease (CVD) and to assess the effectiveness of conservative treatments for the relief of CVD signs and symptoms. METHODS: This international, observational, prospective, longitudinal, cohort study recruited adult outpatients consulting for symptomatic CVD. The primary objective was the effectiveness of conservative treatments on symptoms, signs and quality of life in a real-life setting assessed using a range of patient-reported outcome measures: 10-cm Visual Analog and Patient Global Impression of Change scales for symptoms; Venous Clinical Severity Score for physician assessment of signs; and 14-item ChronIc Venous Insufficiency Questionnaire (CIVIQ-14) for quality of life. At inclusion, patients were prescribed conservative treatment according to the physicians' usual practice. Follow-up visits took place at weeks 2 and 4, with an optional week 8 visit. RESULTS: The analysis set comprised 6084 subjects (78% female) from nine countries with a mean age of 50.6 ± 13.8 years and BMI of 28.0 ± 4.9 kg/m2. The most common CEAP classifications were C1 (23.0%), C2 (31.6%), and C3 (30.7%). Conservative therapy consisted of oral venoactive drugs (VADs; 95.8% of subjects) including micronized purified flavonoid fraction (MPFF 75.5%) and diosmin (18.8%), compression (52.0%), and topicals (31.5%). Conservative therapy led to global symptom improvement in 89% of patients after 2 weeks and 96% at 4 weeks. Pain, leg heaviness, cramps, and sensation of swelling were improved in 82%, 71%, 45.5%, and 46% of patients, respectively. Conservative therapy was associated with a decrease over time in patient-assessed global symptom intensity: - 2.37 ± 1.73 (P < 0.001) and physician-assessed disease severity - 1.83 ± 2.82 (P < 0.001). Among the VADs, MPFF-based conservative therapy was associated with the greatest reduction in symptom and sign intensity. Improvements in CIVIQ-14 were observed with all treatments but were greatest for MPFF. CONCLUSION: In this prospective study conducted in the real-world setting, treatment with conservative therapy, in particular MPFF, was associated with meaningful improvements in the clinical signs and symptoms of disease as well as in quality of life in patients with CVD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04574375.

STUDY AIM: The VEIN STEP study aimed to gather global data on managing chronic venous disease (CVD) and evaluate the usefulness of conservative (non-surgical) treatments for improving CVD signs and symptoms. METHODS: Persons included in the study group had symptomatic CVD and were visiting outpatient clinics. The main aim was to measure how well treatments improved symptoms, physical signs of the illness, and quality of life. Different methods were used to measure these aspects, such as rating symptoms on a 10-point scale and using questionnaires completed by patients and doctors. STUDY FINDINGS: 6084 participants from nine countries joined the study. They were mostly women (78%) with an average age of around 50. Common symptoms included leg pain and leg heaviness. Treatments consisted mainly of drugs active on vein function, like MPFF and diosmin, along with compression stockings and creams. Conservative treatment led to symptom improvement in 89% of patients after 2 weeks and 96% at 4 weeks. Pain and leg heaviness improved in most patients (82% and 71% over the same period) while cramps, and swelling showed improvement in 45.5% and 46% of patients, respectively. Patients reported a significant decrease in symptom intensity, and doctors observed a reduction in disease severity. MPFF was associated with the highest reduction in symptom intensity. Improvements in quality of life were observed with all treatments but were greatest for MPFF. CONCLUSION: The study highlights that conservative treatments, especially MPFF, are associated with significant improvements in the clinical signs and symptoms of patients with CVD as well as in their quality of life.

E3 Ubiquitin Ligases in Endothelial Dysfunction and Vascular Diseases: Roles and Potential Therapies.

ABSTRACT: Ubiquitin E3 ligases are a structurally conserved family of enzymes that exert a variety of regulatory functions in immunity, cell death, and tumorigenesis through the ubiquitination of target proteins. Emerging evidence has shown that E3 ubiquitin ligases play crucial roles in the pathogenesis of endothelial dysfunction and related vascular diseases. Here, we reviewed the new findings of E3 ubiquitin ligases in regulating endothelial dysfunction, including endothelial junctions and vascular integrity, endothelial activation, and endothelial apoptosis. The critical role and potential mechanism of E3 ubiquitin ligases in vascular diseases, such as atherosclerosis, diabetes, hypertension, pulmonary hypertension, and acute lung injury, were summarized. Finally, the clinical significance and potential therapeutic strategies associated with the regulation of E3 ubiquitin ligases were also proposed.

Efficacy and safety of baricitinib in Japanese patients with autoinflammatory type I interferonopathies (NNS/CANDLE, SAVI, And AGS).

BACKGROUND: This study evaluated the efficacy and safety of baricitinib (Janus kinase-1/2 inhibitor), in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS). METHODS: A Phase 2/3, multicenter, open-label study (NCT04517253) was conducted across 52 weeks. Primary efficacy endpoint assessed the change in mean daily diary score (DDS) from baseline to the end of primary treatment period. Other efficacy endpoints included change in mean DDS to the end of maintenance period, daily corticosteroid use, Physician's Global Assessment of Disease Activity (PGA) scores, and daily symptom-specific score (DSSS) from baseline to primary and maintenance treatment periods. All treatment-emergent adverse events (TEAEs) that occurred postdosing were recorded. RESULTS: Overall, 9 patients (5 with NNS, 3 with SAVI, and 1 with AGS) were enrolled; 55.6% were females, mean age was 26 years, and mean corticosteroid use/weight was 0.2 mg/kg. At the end of primary treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.22) and SAVI (0.21) and increased in the patient with AGS (0.07). At the end of maintenance treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.18) and SAVI (0.27) and increased in the patient with AGS (0.04). Mean percent corticosteroid use decreased by 18.4% in 3 out of 5 patients with NNS/CANDLE and 62.9% in 1 out of 3 patients with SAVI. Mean PGA score decreased from baseline in patients with NNS/CANDLE (1.60), SAVI (1.33), and AGS (1.0), and mean DSSS improved from baseline. All patients reported ≥ 1 TEAE. Frequently reported AEs included BK polyomavirus detection (3; 33.3%), increased blood creatine phosphokinase (2; 22.2%), anemia (2; 22.2%), and upper respiratory tract infection (2; 22.2%). Three (33.3%) patients reported serious adverse events, 1 of which was related to study drug. One patient with SAVI died due to intracranial hemorrhage, which was not related to study drug. CONCLUSION: Baricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities. TRIAL REGISTRATION: NLM clinicaltrials.gov, NCT04517253 . Registered 18 August 2020.

Strategies for Avoiding Typical Drug-Drug Interactions and Drug-Related Problems in Patients with Vascular Diseases.

Background and objectives: Drug-drug interactions and drug-related problems in patients with vascular diseases are common. To date, very few studies have focused on these important problems. The aim of the present study is to investigate the most common drug-drug interactions and DRPs in patients with vascular diseases. Materials and Methods: The medications of 1322 patients were reviewed manually in the time period from 11/2017 to 11/2018; the medications of 96 patients were entered into a clinical decision support system. Potential drug problems were identified, and a read-through consensus was reached between a clinical pharmacist and a vascular surgeon during the clinical curve visits; possible modifications were implemented. The focus was on additional dose adjustment and drug antagonization on drug interactions. Interactions were classified as contraindicated/high-risk combination (drugs must not be combined), clinically serious (interaction can be potentially life-threatening or have serious, possibly irreversible consequences), or potentially clinically relevant and moderate (interaction can lead to therapeutically relevant consequences). Results: A total of 111 interactions were observed. Of these, 6 contraindicated/high-risk combinations, 81 clinically serious interactions, and 24 potentially clinically relevant and moderate interactions were identified. Furthermore, 114 interventions were recorded and categorized. Discontinued use of the drug (36.0%) and drug dose adjustment (35.1%) were the most common interventions. Mostly, antibiotic therapy was continued unnecessarily (10/96; 10.4%), and the adjustment of the dosage to kidney function was overlooked in 40/96; 41.7% of the cases. In the most common cases, a dose reduction was not considered necessary. Here, unadjusted doses of antibiotics were found in 9/96, 9.3% of the cases. Notes for medical professionals summarized information that did not require direct intervention but rather increased attention on the part of the ward doctor. It was usually necessary to monitor laboratory parameters (49/96, 51.0%) or the patients for side effects (17/96, 17.7%), which were expected with the combinations used. Conclusions: This study could help identify problematic drug groups and develop prevention strategies for drug-related problems in patients with vascular diseases. A multidisciplinary collaboration between the different professional groups (clinical pharmacists and surgeons) might optimize the medication process. Collaborative care could have a positive impact on therapeutic outcomes and make drug therapy safer for patients with vascular diseases.

Improving venous symptoms in C0s-C1s patients after multicomponent diosmin-based preparation: Initial experience.

The use of drug therapies in patients with chronic venous disease (CVD) remains a topic of debate regarding safety, compliance, and effectiveness. Although the beneficial effects of molecules like diosmin have been established in patients with chronic venous insufficiency (CVI) of C3-C6 classes, the evidence for its use in C0-C1 patients is not well documented. This report aims to describe and analyze the positive impact of a new diosmin-based drug therapy on a population of C0-C1 patients in terms of relief of venous symptoms.

Endothelial dysfunction in ME/CFS patients.

OBJECTIVE: A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS. STUDY DESIGN: The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures. RESULTS: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline. CONCLUSIONS: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.

Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics.

Senescence compromises the essential role that the endothelium plays in maintaining vascular homeostasis, so promoting endothelial dysfunction and the development of age-related vascular diseases. Their biological and clinical significance calls for strategies for identifying and therapeutically targeting senescent endothelial cells. While senescence and endothelial dysfunction have been studied extensively, distinguishing what is distinctly endothelial senescence remains a barrier to overcome for an effective approach to addressing it. Here, we review the mechanisms underlying endothelial senescence and the evidence for its clinical importance. Furthermore, we discuss the current state and the limitations in the approaches for the detection and therapeutic intervention of target cells, suggesting potential directions for future research.

Therapeutic Implications of Curcumin in the Treatment of Inflammatory Eye Diseases: A Review.

Curcumin is the main active constituent of the medicinal plant Curcuma longa L., used traditionally as a medicinal spice in several ancient civilizations. Different preclinical and clinical studies support the anti-inflammatory properties of curcumin in various inflammatory diseases. As inflammation has an essential role in the pathophysiology of many ocular diseases, curcumin has been suggested as a promising therapeutic agent with anti-inflammatory properties. Based on the extent of experimental and clinical evidence, curcumin can exert protective effects against the corneal, uveal, retinal, optic nerve, orbital, and lacrimal gland inflammatory disorders. Herein, the available literature on the beneficial effects of curcumin in inflammatory eye diseases is reviewed. The limitations and future directions of these investigations are also discussed.

Repurposing Metformin for Vascular Disease.

Metformin has been used as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom Prospective Diabetes Study (UKPDS), metformin use rapidly increased and today is the first-choice anti-hyperglycaemic drug for patients with type 2 diabetes (T2D). Metformin is in daily use by an estimated 150 million people worldwide. Historically, the benefits of metformin as an anti-diabetic and cardiovascular-protective drug have been linked to effects in the liver, where it acts to inhibit gluconeogenesis and lipogenesis, as well as reduce insulin resistance and enhance peripheral glucose utilization. However, direct protective effects on the endothelium and effects in the gut prior to metformin absorption are now recognized as important. In the gut, metformin modulates the glucagon-like peptide- 1 (GLP-1) - gut-brain axis and impacts the intestinal microbiota. As the apparent number of putative tissue and cellular targets for metformin has increased, so has the interest in re-purposing metformin to treat other diseases that include polycystic ovary syndrome (PCOS), cancer, neurodegenerative diseases, and COVID-19. Metformin is also being investigated as an anti-ageing drug. Of particular interest is whether metformin provides the same level of vascular protection in individuals other than those with T2D, including obese individuals with metabolic syndrome, or in the setting of vascular thromboinflammation caused by SARS-CoV-2. In this review, we critically evaluate the literature to highlight clinical settings in which metformin might be therapeutically repurposed for the prevention and treatment of vascular disease.