A Novel Strategy for the Discovery of Drug Targets: Integrating Clinical Evidence with Molecular Studies.

The mechanisms of several drugs remain unclear, limiting our understanding of how they exert their effects. Receptor affinities have not been comprehensively measured during drug development, and the safety investigations in humans are limited. Therefore, numerous unknown adverse and beneficial effects of drugs in humans persist. In this review, I highlight our achievements in identifying the unexpected beneficial effects of drugs through the analysis of real-world clinical data, which can contribute to drug repositioning and target finding. (1) Through the analysis of real-world data, we found that the anti-arrhythmic amiodarone induced interstitial lung disease, leading to fibrosis. Surprisingly, concurrent use of an anti-thrombin drug, dabigatran mitigated these adverse events. Pharmacological studies using animal models have mimicked this phenomenon and revealed the molecular mechanisms associated with the platelet-derived growth factor-alpha receptors. (2) The antidiabetic dipeptidyl-peptidase 4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid, which was reduced by the concomitant use of lisinopril. Pharmacological studies using human peripheral blood mononuclear cells have revealed that lisinopril suppressed the skin disorders by inhibiting the expression of cutaneous matrix metalloproteinase 9 in macrophages. (3) The antimicrobial fluoroquinolones increased the risk of tendinopathy, which was reduced by the concomitant use of dexamethasone. However, clinical guidelines have suggested that corticosteroid increases the risk of tendinopathy. Our investigation demonstrated that fluoroquinolones impaired tendon cells through DNA damage by generating reactive oxygen species. In contrast, dexamethasone exhibited an acute beneficial effect on tendon tissue by upregulating the expression of a radical scavenger, glutathione peroxidase 3.

Patellar tendinopathy: an overview of prevalence, risk factors, screening, diagnosis, treatment and prevention.

Patellar tendinopathy (PT), or jumper's knee, is an overuse injury that occurs in professional, as well as recreational, athletes. This condition is a noncontact injury, typically characterized by gradually increasing pain in the patellar tendon. It is prevalent in participants of several sports, but it occurs mostly in jumping sports. The diagnosis of PT is primarily clinical; however, imaging techniques can be useful as well. Risk factors differ between sexes, playing conditions, the kind of sport, playing level and personal characteristics. Screening is an essential tool to assess PT. This condition affects athletic performance and often persists for years. The use of preventative methods is imperative because of the persistence of this condition, especially in elite athletes who sometimes end their career after long and failed treatments. There are a wide variety of treatment and rehabilitation options available, the majority of which are non-operative, such as eccentric exercises, cryotherapy, platelet-rich plasma (PRP) injections, and anti-inflammatory strategies. If conservative treatment fails, surgery is the next most preferable step. Even though there are many surgical treatment methods, there is no clear evidence on what is the most effective approach to address PT. Taking this into consideration, as well as the extent of this clinical entity, novel therapeutic techniques, as well as screening and prevention methods, are expected to emerge in the near future.

Is Curcumine Useful in the Treatment and Prevention of the Tendinopathy and Myotendinous Junction Injury? A Scoping Review.

Physical activity in general and sports in particular, is a mechanism that produces stress and generates great force in the tendon and in the muscle-tendon unit, which increases the risk of injury (tendinopathies). Eccentric and repetitive contraction of the muscle precipitates persistent microtraumatism in the tendon unit. In the development of tendinopathies, the cellular process includes inflammation, apoptosis, vascular, and neuronal changes. Currently, treatments with oral supplements are frequently used. Curcumin seems to preserve, and even repair, damaged tendons. In this systematic review, we focus more especially on the benefits of curcumin. The biological actions of curcumin are diverse, but act around three systems: (a) inflammatory, (b) nuclear factor B (NF-κB) related apoptosis pathways, and (c) oxidative stress systems. A bibliographic search is conducted under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as a basis for reporting reliable systematic reviews to perform a Scoping review. After analysing the manuscripts, we can conclude that curcumin is a product that demonstrates a significant biological antialgic, anti-inflammatory, and antioxidant power. Therefore, supplementation has a positive effect on the inflammatory and regenerative response in tendinopathies. In addition, curcumin decreases and modulates the cell infiltration, activation, and maturation of leukocytes, as well as the production of pro-inflammatory mediators at the site of inflammation.

Knee Extensor Mechanism Tendinopathy: Evaluation, Treatment, and Prevention.

ABSTRACT: Knee extensor mechanism tendinopathy, including patellar and quadriceps tendinopathy, is common among athletes and those involved in jumping sports. It is largely a clinical diagnosis that presents as anterior knee pain and stiffness with associated tenderness over the affected tendon. Imaging modalities, including ultrasound and/or magnetic resonance imaging, may be helpful with the diagnosis of difficult cases or in the planning of interventional procedures. Focused and structured rehabilitation using eccentric or heavy slow resistance exercise in conjunction with load management is important for recovery. Adjuvant therapies (e.g., injections or surgery) may be necessary in recalcitrant cases or those with insufficient response to rehabilitation efforts. Prevention strategies focus on improving biomechanics, landing mechanism and lower-extremity balance, flexibility, and strength.

Interventions for prevention and in-season management of patellar tendinopathy in athletes: A scoping review.

INTRODUCTION: Patellar tendinopathy (PT) has a high prevalence in jumping athletes and presents a significant burden on athletes and clinicians due to its long-lasting duration and persistent symptoms. This scoping review aimed to map existing evidence on prevention and in-season management interventions for PT in athletes, evaluating intervention parameters and outcomes. METHODS: This scoping review was reported in accordance with the PRISMA-ScR. Databases searched included MEDLINE, CINAHL, AMED, EMBase, SPORTDiscus, and the Cochrane library (Controlled trials, Systematic reviews). All primary study designs investigating prevention or in-season management interventions for PT, while maintaining athletes in sport were considered for inclusion. RESULTS: 5987 articles were identified with 29 included in the review. Five studies investigated exercise-based prevention interventions on athletes at risk for PT, including two randomized controlled trials (RCTs), two cohort studies and one case-control study. 24 studies investigated in-season management or rehabilitation in athletes with PT, including 18 RCTs, three case reports, one cohort study, one case series, and one retrospective review. Of these 24 studies, 22 used various resistance training interventions, one used ESWT and one used patellar strapping and taping. The types of resistance training included eccentric, heavy-slow, isometric, inertial flywheel, blood-flow restriction, and isotonic training. Eccentric training was used in 9 studies, with single leg decline squats the most common exercise used in 7 studies. Outcome measures and intervention parameters were heterogenous throughout studies. CONCLUSION: Despite a dearth of studies on preventative interventions for athletes with PT, resistance training may be a useful prophylactic method. Eccentric, heavy slow and isometric resistance training have been found to be feasible and clinically beneficial in-season. There are a lack of studies showing that ESWT offers any additional benefit over resistance training in competing athletes. Patellar strapping and taping may offer short-term pain relief during training and competition. Systematic reviews are required to make definitive recommendations for PT.

Preventive effect of tailored exercises on patellar tendinopathy in elite youth athletes: A cohort study.

OBJECTIVE: To investigate the effects of an intervention with tailored exercises on the incidence of patellar tendinopathy (PT) in elite youth jumping athletes. DESIGN: Prospective crossover cohort. SETTING: One sport club facility. PARTICIPANTS: 271 elite youth basketball and volleyball player were followed in the first year of the study (Observation year) and 270 athletes were followed in the second year (intervention year). MAIN OUTCOME MEASURE: Incidence rates of PT per 1,000h of exposure. Cox survival analysis was used to verify the effects of the intervention (exercises implemented according to the findings of a preseason assessment) on PT incidence. RESULTS: The exercise prevention program significantly reduced the number of cases of PT, with athletes submitted to the intervention showing 51% less risk of developing PT. The overall PT incidence in the Observation year (5.9 per 1,000h of exposure) was significantly higher than that in the intervention year (2.8 per 1,000h of exposure) (P = .037). Twenty-six athletes developed PT in the observation year, whereas 13 athletes developed PT in the intervention year. CONCLUSIONS: A tailored preventive program may be able to reduce the incidence of patellar tendinopathy, especially in male youth volleyball athletes. Randomized controlled trials are encouraged to confirm these findings.

Prevention of strain-induced impairments of patellar tendon micromorphology in adolescent athletes.

High-level patellar tendon strain may cause impairments of the tendon's micromorphological integrity in growing athletes and increase the risk for tendinopathy. This study investigated if an evidence-based tendon exercise intervention prevents high-level patellar tendon strain, impairments of micromorphology and pain in adolescent basketball players (male, 13-15 years). At three time points over a season (M1-3), tendon mechanical properties were measured using ultrasound and dynamometry, proximal tendon micromorphology with a spatial frequency analysis and pain and disability using VISA-P scores. The control group (CON, n = 19) followed the usual strength training plan, including sprint and change-of-direction drills. In the intervention group (INT, n = 14), three sessions per week with functional exercises were integrated into the training, providing repetitive high-magnitude tendon loading for at least 3 s per repetition. The frequency of high-level strain (ie, ≥9%) continuously decreased in INT, while tending to increase in CON since tendon force increased in both (p < 0.001), yet tendon stiffness only in INT (p = 0.004). In CON, tendon strain was inversely associated with tendon peak spatial frequency at all time points (p < 0.05), indicating impairments of tendon micromorphological integrity with higher strain, but not at M2 and M3 in INT. Descriptively, the fraction of asymptomatic athletes at baseline was similar in both groups (~70%) and increased to 100% in M3 in INT, while remaining unchanged in CON. We suggest that functional high-load tendon exercises could reduce the prevalence of high-level patellar tendon strain and associated impairments of its micromorphology in adolescent athletes, providing new opportunities for tendinopathy prevention.

Heel Complications.

Postoperative complications can be burdensome on both the patient and the surgeon. Attention in literature is often directed toward different forms of treatment and successful outcomes in surgery. The incentive of this article is to bring insight toward postoperative complications in rearfoot surgery, more specifically, the repair of the Achilles tendon with suture tape and suture anchors. This article directs attention to the recent reports on hypersensitivity reactions seen with the use of suture tape and nonabsorbable suture anchors and may encourage physicians to make patients aware of this potential complication when using these materials.

Proximal hamstring tendinopathy; expert physiotherapists' perspectives on diagnosis, management and prevention.

OBJECTIVES: To explore and summarise expert physiotherapists' perceptions on their assessment, management and prevention of proximal hamstring tendinopathy (PHT). METHODS: We conducted semi-structured interviews with expert physiotherapists until data saturation was met (n = 13). Interviews were transcribed verbatim and data were analysed systematically and organised into categories and sub-categories according to study aims. RESULTS: Experts report using a clinical reasoning-based approach, incorporating information from the patient interview and results of clinical load-based provocation tests, in the physical examination to diagnose PHT. Experts manage the condition through education and progressive loading targeting the hamstring unit and kinetic chain, avoiding provocative activities in positions of compression in early-mid stage rehab and a gradated and controlled return to sport. Passive therapies including injection therapies and surgery were believed to have limited utility. Prevention of recurrence primarily involved continuation of hamstring and kinetic chain strengthening programs and management of physical workload. CONCLUSION: Experts rely on a combination of information from the patient interview and a battery of pain provocation tests to diagnose PHT. Education and graded exercise of the hamstring group and synergists, minimising early exposure to hip flexion, were the foundation of management of the condition.

Effect of Metformin on Development of Tendinopathy Due to Mechanical Overloading in an Animal Model.

BACKGROUND: Tendinopathy is a debilitating tendon disorder that affects millions of Americans and costs billions of health care dollars every year. High mobility group box 1 (HMGB1), a known tissue damage signaling molecule, has been identified as a mediator in the development of tendinopathy due to mechanical overloading of tendons in mice. Metformin (Met), a drug approved by the Food and Drug Administration used for the treatment of type 2 diabetes, specifically inhibits HMGB1. This study tested the hypothesis that Met would prevent mechanical overloading-induced tendinopathy in a mouse model of tendinopathy created by intensive treadmill running (ITR). METHODS: C57BL/6J mice (female, 3 months old) were equally separated into 4 groups and treated for 24 weeks as follows: group 1 had cage control activities, group 2 received a single intraperitoneal injection of Met (50 mg/kg body weight) daily, group 3 underwent ITR to induce tendinopathy, and group 4 received daily Met injection along with ITR to inhibit HMGB1. Tendinopathic changes were assessed in Achilles tendons of all mice using histology, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: ITR induced HMGB1 release into the tendon matrix and developed characteristics of tendinopathy as evidenced by the expression of macrophage marker CD68, proinflammatory molecules (COX-2, PGE2), cell morphological changes from normal elongated cells to round cells, high levels of expression of chondrogenic markers (SOX-9, collagen type II), and accumulation of proteoglycans in tendinopathic tendons. Daily injection of Met inhibited HMGB1 release and decreased these degenerative changes in ITR tendons. CONCLUSIONS: Inhibition of HMGB1 by injections of Met prevented tendinopathy development due to mechanical overloading in the Achilles tendon in mice. CLINICAL RELEVANCE: Met may be able to be repurposed as a therapeutic option for preventing the development of tendinopathy in high-risk patients.

Controlled trial to compare the Achilles tendon load during running in flatfeet participants using a customized arch support orthoses vs an orthotic heel lift.

BACKGROUND: Achilles tendinopathy is one of the most common overuse injuries in running, and forefoot pronation, seen in flatfeet participants, has been proposed to cause additional loading across the Achilles tendon. Foot orthoses are one of the common and effective conservative treatment prescribed for Achilles tendinopathy, it works by correcting the biomechanical malalignment and reducing tendon load. Previous studies have shown reduction of Achilles Tendon load (ATL) during running by using customized arch support orthosis (CASO) or an orthotic heel lift (HL). However, there are still little biomechanical evidence and comparative studies to guide orthotic prescriptions for Achilles tendinopathy management. Therefore, this study seeks to investigate the two currently employed orthotic treatment options for Achilles tendinopathy: CASO and HL for the reduction of ATL and Achilles tendon loading rate (ATLR) in recreational runners with flatfeet. METHODS: Twelve participants were recruited and run along the runway in the laboratory for three conditions: (1) without orthoses, (2) with CASO (3) with HL. Kinematic and kinetic data were recorded by 3D motion capturing system and force platform. Ankle joint moments and ATL were computed and compared within the three conditions. RESULTS: Participants who ran with CASO (p = 0.001, d = 0.43) or HL (p = 0.001, d = 0.48) associated with a significant reduction in ATL when compared to without orthotics while there was no significant difference between the two types of orthoses, the mean peak ATL of CASO was slightly lower than HL. Regarding the ATLR, both orthoses, CASO (p = 0.003, d = 0.93) and HL (p = 0.004, d = 0.78), exhibited significant lower value than the control but similarly, no significant difference was noted between them in which the use of CASO yielded a slightly lower loading rate than that of HL. CONCLUSIONS: Both CASO and HL were able to cause a significant reduction in peak ATL and ATLR comparing to without orthotics condition. There were subtle but no statistically significant differences in the biomechanical effects between the two types of orthoses. The findings help to quantify the effect of CASO and HL on load reduction of Achilles tendon and suggests that foot orthoses may serve to prevent the incidence of Achilles tendon pathologies. TRIAL REGISTRATION: NCT04003870 on clinicaltrials.gov 1 July 2019.

High cholesterol inhibits tendon-related gene expressions in tendon-derived stem cells through reactive oxygen species-activated nuclear factor-κB signaling.

Clinical studies have indicated that increased serum cholesterol levels raised the risk of tendinopathy in hypercholesterolemia, but the effect of cholesterol on tendon-derived stem cells (TDSCs) and its underlying mechanism have not been studied. The purpose of this study is to investigate the association between cholesterol and tendinopathy in vitro and in vivo, and its underlying molecular mechanism as well. In TDSCs, the effect of cholesterol was assessed by quantitative polymerase chain reaction, western blot analysis, and immunofluorescence staining. Intracellular levels of reactive oxygen species (ROS) was detected, using flow cytometry. The link between nuclear factor (NF)-κB signaling and the effect of cholesterol was evaluated using a representative IκB kinase (IKK) inhibitor, BAY 11-7082. In addition, Achilles tendons from apolipoprotein E mice fed with a high-fat diet were histologically assessed using hematoxylin and eosin staining and immunohistochemistry. We found that high cholesterol apparently lowered the expression of tendon cell markers (collagen 1, scleraxis, tenomodulin), and elevated ROS levels via the NF-κB pathway both in vitro and in vivo. The ROS scavenger N-acetylcysteine (NAC) and BAY 11-7082 reversed the inhibiting effect of cholesterol on the tendon-related gene expressions of TDSCs. Moreover, NAC blocked cholesterol-induced phosphorylation of IκBα and p65. Significant histological alternation in vivo was shown in Achilles tendon in the hypercholesterolemic group. These results indicated that high cholesterol may inhibit the tendon-related gene expressions in TDSCs via ROS-activated NF-кB signaling, implying pathogenesis of tendinopathy in hypercholesterolemia and suggesting a new mechanism underlying hypercholesterolemia-induced tendinopathy.

The effects of hyperlipidemia on rotator cuff diseases: a systematic review.

BACKGROUND: Rotator cuff disease is a common condition that causes shoulder pain and functional disability. Recent studies suggested that hyperlipidemia might be associated with the development of rotator cuff disease. The objective of this study was to explore the relationship of hyperlipidemia and rotator cuff diseases. METHODS: A computerized search using relevant search terms was performed in the PubMed, EMBASE, and Cochrane Library databases, as well as a manual search of reference and citation lists of the included studies. Searches were limited to studies that explored the association of hyperlipidemia and rotator cuff diseases. RESULTS: Sixteen studies were included in this systematic review. Ten of sixteen included studies suggested an association between dyslipidemia and rotator cuff diseases, while the other six studies did not find an association. Two studies demonstrated there were an association between statins and reduced risk of developing rotator cuff diseases or decreased incidence of revision after rotator cuff repair. CONCLUSION: The current study suggested that there was an association between hyperlipidemia and rotator cuff diseases. Furthermore, current evidence suggested that use of statins could decrease the risk of developing rotator cuff diseases and the incidence of revision after rotator cuff repair. Future high-quality studies are highly needed to confirm these findings.

Effectiveness of foot orthoses for the prevention of lower limb overuse injuries in naval recruits: a randomised controlled trial.

OBJECTIVES: To evaluate the effectiveness of prefabricated foot orthoses for the prevention of lower limb overuse injuries in naval recruits. METHODS: This study was a participant-blinded and assessor-blinded, parallel-group randomised controlled trial. Three-hundred and six participants aged 17-50 years who undertook 11 weeks of initial defence training at the Royal Australian Navy Recruit School (Cerberus, Australia) were randomised to a control group (flat insoles, n=153) or an intervention group (contoured, prefabricated foot orthoses, n=153). The combined incidence of medial tibial stress syndrome, patellofemoral pain, Achilles tendinopathy and plantar fasciitis/plantar heel pain during the 11-week training period were compared using incidence rate ratios (IRR). Data were analysed using the intention-to-treat principle. RESULTS: Sixty-seven injuries (21.9%) were recorded. The control and intervention group sustained 40 (26.1%) and 27 (17.6%) injuries, respectively (IRR 0.66, 95% CI 0.39 to 1.11, p=0.098). This corresponds to a 34% reduction in risk of developing medial tibial stress syndrome, patellofemoral pain, Achilles tendinopathy or plantar fasciitis/plantar heel for the intervention group compared with the control group. Participants in the prefabricated orthoses group were more likely to report at least one adverse event (20.3% vs 12.4%; relative risk (RR) 1.63, 95% CI 0.96 to 2.76; p=0.068; number needed to harm 13, 95% CI 6 to 253). The most common adverse events were foot blisters (n=20, 6.6%), arch pain (n=10, 3.3%) and shin pain (n=8, 2.6%). CONCLUSION: Prefabricated foot orthoses may be beneficial for reducing the incidence of lower limb injury in naval recruits undertaking defence training. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12615000024549.

The effect of load on Achilles tendon structure in novice runners.

OBJECTIVES: To observe the changes in Achilles tendon structure in novice runners, with loading prescriptions of 100% body weight compared to 20% body weight. DESIGN: Randomised crossover. METHODS: Twenty novice runners participated in two separate running bouts spaced 14days apart, one of high load at 100% body weight, and one of low load at 20% body weight. Tendon structure was measured by ultrasonographic tissue characterisation on 6 occasions; immediately prior to each run, 2 and 7days after each run. RESULTS: The interaction effect of time and condition was not found to be significant for echotypes I-IV [Wald chi-square=2.8, d.f.=2, P=0.247; Wald chi-square=2.888, d.f.=2, P=0.236; Wald chi-square=1.385, d.f.=2, P=0.5; Wald chi-square=4.19, d.f.=2, P=0.123], respectively. A significant effect of time was found for echotypes III [Wald chi-square=6.785, d.f.=2, P=0.0.034] and IV [Wald chi-square=7.491, d.f.=2, P=0.0.024]. CONCLUSIONS: The decrease in echotypes III and IV suggest that moderate loads can be applied to the Achilles tendon without compromising tendon structure. Low to moderate loads may be beneficial in the management of Achilles tendinopathy. Further studies should focus on protocols with higher loading and/or repetitive loading in athletic populations with and without Achilles tendinopathy to assess any differences in tendon structure.

Tendinite: Tudo sobre a típica lesão do esforço repetitivo, que afeta ombro, pulso, joelho…

Conheça detalhes da tendinite nesse artigo completo e saiba por que a inflamação do tendão pode se tornar séria sem tratamento, e exigir até mesmo cirurgia

[Running and causes of running-related injuries].

Running is one of the most popular sports among the adult Danish population. Overuse injuries of the knee, such as runners knee, jumpers knee, patello-femoral pain syndrome and patello-femoral pre-arthrosis, are common and cause reduction of the health beneficial physical activity. Treatment should primarily focus on adjustment of training habits and physiotherapeutic guided rehabilitation. Other treatment options include changing landing pattern during running, corticosteroid injections, non-steroid anti-inflammatory drugs and ultimately surgery.

Rehabilitation and Prevention of Proximal Hamstring Tendinopathy.

Proximal hamstring tendinopathy (PHT) comprises a small but significant portion of hamstring injuries in athletes, especially runners. PHT is a chronic condition that is clinically diagnosed but can be supported with imaging. The main presenting complaint is pain in the lower gluteal or ischial region that may or may not radiate along the hamstrings in the posterior thigh. There is little scientific evidence on which to base the rehabilitation management of PHT. Treatment is almost always conservative, with a focus on activity modification, addressing contributing biomechanical deficiencies, effective tendon loading including eccentric training, and ultrasound-guided interventional procedures which may facilitate rehabilitation. Surgery is limited to recalcitrant cases or those involving concomitant high-grade musculotendinous pathology. The keys to PHT management include early and accurate diagnosis, optimal rehabilitation to allow for a safe return to preinjury activity level, and preventative strategies to reduce risk of reinjury.