Current Drug Targets - Volume 22, Issue 1, 2021

Our aim was to provide a narrative review regarding the prevalence, the associated pathophysiologic pathways and the potential management methods of sexual dysfunction related to ablative surgical techniques for Benign Prostatic Enlargement (BPE). Men suffering from BPE are at high risk of sexual dysfunction due to the disease itself, comorbidities, and pharmacological/surgical treatments. Transurethral resection of the prostate, as the gold standard treatment option for BPE, has historically been associated with relatively high rates of postoperative sexual dysfunction problems, mainly retrograde ejaculation but also erectile dysfunction. Ablative surgical techniques, including photoselective vaporization of the prostate (PVP), transurethral needle ablation (TUNA), Transurethral Microwave Therapy (TUMT), Convective Water Vapor Energy Ablation (Rezum®) and Aquablation®, have been proposed as treatment methods able to reduce treatment-related complications for BPE patients, including adverse effects on erectile and ejaculatory function, without compromising the efficacy rates for BPE. The neurovascular bundles can be damaged during TURP due to posterolateral capsular perforation. Ablative techniques and especially PVP theoretically seem to skip this hazard, as the distance created from the necrotic area to the capsule is generally larger compared to the distance induced after TURP. However, indirect thermal injury of erectile nerves, which could also be induced by the majority of available ablative techniques, could potentially lead to ED. Two special technical characteristics (physiological saline use for tissue ablation and real time penetration depth control) of Aquablation® could be proved beneficial with regard to the effect of the method on erectile function. In general, ablative techniques seem to have a minor impact on sexual function. However, low methodological quality characterizes most of the studies included in this review mainly due to the impossibility, in many cases, to perform blind randomization. Also, many studies did not have an erectile and ejaculatory function as primary outcomes limiting that way their statistical power to identify significant variations. Management of sexual dysfunction problems arising from ablative surgeries for BPE treatment could be divided into two levels. Firstly, intraoperatively the avoidance of manipulation of crucial structures regarding ejaculatory (bladder neck or ejaculatory ducts) and erectile function (neurovascular bundles) could possibly decrease the negative effect of these procedures on sexual function. Thus, in this direction, modifications of classic ablative techniques have been proposed resulting in encouraging outcomes regarding postoperative sexual function. Secondly, if EjD and/or ED are established, the already known treatment choices should be chosen in order for sexual function rehabilitation to be achieved. Thus, regarding ED: PDE5i daily or on-demand remains the gold standard first-line treatment choice followed by intracavernosal alprostadil injections in cases of failure, while penile prosthesis implantation must be kept as the final definitive solution when all the other methods have failed. Regarding ejaculation disorders (retrograde ejaculation or anejaculation): medical therapy with a-agonists (pseudoephedrine), sperm retrieval from the urine, bladder neck reconstruction, prostatic massage, electroejaculation, penile vibratory stimulation and surgical sperm retrieval are the available treatment options. Furthermore, high-quality studies are required to investigate the potential side effects of BPE surgery on sexual function and efficient treatment methods to manage them.

Aim: This study provides a critical literature review on state-of-the-art and novel strategies in the field of neoadjuvant treatments for muscle-invasive bladder cancer (MIBC). Methods: A nonsystematic literature review was performed using PubMed, Scopus and Clinical Trials.gov to retrieve papers related to neoadjuvant treatments for MIBC over the past 15 years. Prospective and retrospective studies were included. Results: Platinum-based treatment is the gold standard and mainly consists of a combination of cisplatin with vinblastine, methotrexate, doxorubicin, gemcitabine, adriamycin or even epirubicin. The 5- year absolute overall survival benefit of MVAC is 5% and the absolute disease-free survival improves by 9%. CMV treatment is associated with a 10-year overall survival improving from 30% to 36% and a 16% reduction in mortality. Gemcitabine and cisplatin regimen provides complete response in 20% of cases, with non-inferior oncological outcomes compared to MVAC regimen. Recent prospective trials investigating neoadjuvant immunotherapy show a high rate of complete response, from 29% with atezolizumab to 39.5% with pembrolizumab. The tyrosine kinase inhibitor pathway is being explored and could offer an interesting strategy to improve survival outcomes. Conclusion: Available evidence suggests better oncological outcomes for MIBC patients receiving neoadjuvant treatment before radical cystectomy. While MVAC remains the standard of care in cisplatin eligible patients, novel strategies are under development for cisplatin-ineligible patients, whereby immunotherapy seems to hold great promise.

Background: Kidney stones are one of the longest known and most common diseases in the urinary tract, with a prevalence that ranges from 1% to 20%. Many phytotherapeutic and herbal medicines have been described for the treatment and prevention of kidney stones. Objective: The aim of this study was to perform a comprehensive review of publications on various phytotherapeutic and herbal medicines, including both clinical and animal studies. Results: Phytotherapy may influence the risk of recurrence of calcium oxalate and uric acid stones. The most solid evidence relates to Phyllanthus niruri, one of the most studied phytotherapeutics; findings suggest that it interferes with calcium oxalate crystallization, reduces hyperoxaluria and hyperuricosuria, and increases the efficacy of shock wave lithotripsy due to reduced crystallization, without significant adverse effects. Theobromine has been shown to reduce the crystallization of uric acid in patients and appears to be a promising supplement to treat such stones. Conclusion: Many phytotherapeutic and herbal agents have been studied for the treatment of urolithiasis, most of them only in a small number of patients or in animal models. Further randomized clinical trials are needed to evaluate the effects of these agents on kidney stones.

Background: Phosphodiesterase 5 inhibitors (PDE5I) represent the first-line treatment in the management of post-operative erectile dysfunction (ED) after pelvic oncological surgery. The aim of our study is to evaluate the available evidence on the efficacy of PDE5Is, including new formulations and penile rehabilitation post-pelvic surgery. Evidence Acquisition: A systematic review of the literature was performed until May 2020. The following databases were searched: Scopus, Medline and Web of Science. The MeSH search was conducted by combining the following terms: ‘erectile dysfunction’, ‘radical prostatectomy’ ‘pelvic’ ‘bladder’ ‘phosphodiesterase’ inhibitors’ ‘avanafil’ ‘sildenafil’ ‘tadalafil’ ’lodenafil’ ‘mirodenafil’ ‘udenafil’ ‘vardenafil’ ‘sublingual’ ‘orodispersible’ ‘penile’ ‘rehabilitation’. Evidence Synthesis: Sildenafil, Tadalafil, vardenafil and Avanafil improve EF compared with placebo in men with all levels of ED severity after radical prostatectomy with good tolerability. No specific recommendations can be suggested regarding the superiority of a drug over the other. The optimal dose, continuous vs. on-demand and duration of treatment, is still under investigation. In vitro and preclinical studies suggest the possible role for lodenafil, mirodenafil and oro-dispersible formulations in patients undergoing oncological pelvic surgery. Few studies demonstrated the efficacy of udenafil in improving ED after rectal surgery or radical prostatectomy. Complete recovery of EF after surgery is still an unmet need in the field of penile rehabilitation after pelvic surgery. Conclusion: PDE5Is have a crucial role in the management of post pelvic surgery of ED. New drugs and new formulations have shown excellent results in patients with ED; however, data in patients after surgery is still scarce. Further well designed RCT should clarify the role of these new compounds and oro-dispersible formulations in the management of ED in patients undergoing pelvic surgery.

Abl1 tyrosine kinase is a validated target for the treatment of chronic myeloid leukemia. It is a form of cancer that is difficult to treat and much research is being done to identify new molecular entities and to tackle drug resistance issues. In recent years, drug resistance of Abl1 tyrosine kinase has become a major healthcare concern. Second and third-generation TKI reported better responses against the resistant forms; still they had no impact on long-term survival prolongation. New compounds derived from natural products and organic small molecule inhibitors can lay the foundation for better clinical therapies in the future. Computational methods, experimental and biological studies can help us understand the mechanism of drug resistance and identify novel molecule inhibitors. ADMET parameters analysis of reported drugs and novel small molecule inhibitors can also provide valuable insights. In this review, available therapies, point mutations, structure-activity relationship and ADMET parameters of reported series of Abl1 tyrosine kinase inhibitors and drugs are summarised. We summarise in detail recent computational and molecular biology studies that focus on designing drug molecules, investigation of natural product compounds and organic new chemical entities. Current ongoing research suggests that selective targeting of Abl1 tyrosine kinase at the molecular level to combat drug resistance in chronic myeloid leukemia is promising.

Background: It becomes increasingly evident that the SARS-CoV-2 infection is not limited to the respiratory system. In addition to being a target of the virus, the kidney also seems to have a substantial influence on the outcomes of the disease. Methods: Data was obtained by a comprehensive and non-systematic search in the PubMed, Cochrane, Scopus and SciELO databases, using mainly the terms “SARS-CoV-2”, “COVID-19”, “chronic kidney disease”, “renal transplantation”, acute kidney injury” and “renal dysfunction” Discussion: The membrane-bound angiotensin-converting enzyme 2 is the receptor for SARS-CoV- -2, and this interaction may lead to an imbalance of the Renin-Angiotensin System (RAS), associated with worse clinical presentations of COVID-19, including acute pulmonary injury, hyperinflammatory state and hematological alterations. In the framework of renal diseases, the development of acute kidney injury is associated mostly with immune alterations and direct cytopathic lesions by the virus, leading to higher mortality. As for chronic kidney disease, the patients at a non-terminal stage have a worse prognosis, while the hemodialysis patients appear to have mild courses of COVID-19, probably due to lower chances of being affected by the cytokine storm. Furthermore, the current scenario is unfavorable to kidney donation and transplantation. The relationship between COVID-19 and immunosuppression in kidney transplantation recipients has been greatly discussed to determine whether it increases mortality and how it interacts with immunosuppressive medications. Conclusion: The kidney and the RAS exert fundamental roles in the SARS-CoV-2 infection, and more research is required to have a complete understanding of the repercussions caused by COVID-19 in renal diseases.

Prostate cancer (PCa) is a hormone-dependent disease, including several different patterns from indolent and clinically meaningless to aggressive and lethal disease. Among non -metastatic PCa, high-risk disease represents a therapeutical challenge, given the unfavorable oncological outcomes after exclusive local therapy. Deprivation therapy in the neoadjuvant setting is not recommended prior to radical prostatectomy since it did not provide any survival advantage, although reducing tumor volume, surgical margins rate, local and nodal stage. However, in the few recent years, new hormonal treatments for metastatic PCa emerged and showed a relevant increase of overall survival concerning standard androgen deprivation therapy (ADT). Thus, neo-adjuvant regimens of ADT based on these novel molecules are now under investigation and the results of ongoing clinical trials are expected in order to provide a definitive answer on the real role of neoadjuvant hormonal therapy in the treatment of high-risk localized prostate cancer. In this narrative review, we underline the role of neoadjuvant therapy before radical prostatectomy in high-risk PCa patients considering the impact of the new available hormonal agents.

Bone is one of the dynamic tissues in the human body that undergoes continuous remodelling through subsequent actions of bone cells, osteoclasts, and osteoblasts. Several signal transduction pathways are involved in the transition of mesenchymal stem cells into osteoblasts. These primarily include Runx2, ATF4, Wnt signaling and sympathetic signalling. The differentiation of osteoclasts is controlled by M-CSF, RANKL, and costimulatory signalling. It is well known that bone remodelling is regulated through receptor activator of nuclear factor-kappa B ligand followed by binding to RANK, which eventually induces the differentiation of osteoclasts. The resorbing osteoclasts secrete TRAP, cathepsin K, MMP-9 and gelatinase to digest the proteinaceous matrix of type I collagen and form a saucer-shaped lacuna along with resorption tunnels in the trabecular bone. Osteoblasts secrete a soluble decoy receptor, osteoprotegerin that prevents the binding of RANK/RANKL and thus moderating osteoclastogenesis. Moreover, bone homeostasis is also regulated by several growth factors like, cytokines, calciotropic hormones, parathyroid hormone and sex steroids. The current review presents a correlation of the probable molecular targets underlying the regulation of bone mass and the role of essential metabolic elements in bone remodelling. Targeting these signaling pathways may help to design newer therapies for treating bone diseases.

Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review the current insights on aspirin’s anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting the immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant for aspirin’s anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investigations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.

Background: Surgery is considered a cornerstone of inflammatory bowel disease (IBD) treatment. In the last years, robotic surgery has seen an increase in adoption rates for both benign and malignant diseases. Objective: This work aims to review the current applications of robotic surgery in IBD. Discussion and Conclusion: Minimally-invasive techniques have been applied to the treatment of IBD for more than 20 years. Investments in surgical digital and robotic platforms are increasingly arising, with an estimate of getting doubled within the next 5 years. Robotic surgery represents the newest technology available to reduce the impact of surgery on patients affected by IBD, and may theoretically be even more effective than other minimally-invasive techniques given the lower rate of conversion to open surgery as compared to laparoscopy according to many large retrospective series. Data on robotic surgery applied to IBD are still scarce and initial experiences in high-volume centers from retrospective series suggested that robotic surgery may achieve similar results when compared to laparoscopy. A new wave of robotics incorporating artificial intelligence is awaited to empower the capability of IBD surgeon in terms of intraoperative decision-making beyond technical skill enhancement.

Background: The management of chronic conditions, above all rheumatic disease and diabetes, now incorporates a "treat to target" strategy where treatment aims to achieve objective outcomes. This is applicable in ulcerative colitis (UC) as well. Targets are demonstrated to prevent endorgan dysfunction, specifically bowel damage and its complications, and lastly colorectal cancer. Recently, the scientific community has tried to define further targets beyond those currently recommended, namely mucosal healing and clinical remission. Studies that prospectively investigated this approach in UC are scanty and a treat-to-target (T2T) algorithm is not routinely used in daily clinical practice. Objective: We aim to review current evidence on T2T in UC and discuss its adoption in routine clinical practice as well as in clinical trials. Methods: A PubMed search was conducted in February 2020 to identify published papers investigating targets’ achievement rates in UC. Results: Different targets can be achieved through approved drugs for mild to moderate UC; histological remission is emerging as a robust target with respect to long-term outcomes. Conclusion: Further studies to compare a T2T strategy with the traditional care are needed, particularly in the mild to moderate spectrum of disease.

Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis. The interaction between inflammation and coagulation has extensively been studied. It is well-known that some drugs can influence the haemostatic system, but several concerns on the association between therapies and increased risk of thrombosis remain open. While biologics seem to have a protective role against thrombosis via their anti-inflammatory effect, some concerns about an increased risk of thrombosis with JAK inhibitors have been raised. We conducted a literature review to assess the association between biologics/small molecules and venous/arterial thrombotic complications. An increased risk of venous and arterial thrombosis was found in patients treated with corticosteroids, whereas anti-TNFα were considered protective agents. No thromboembolic adverse event was reported with vedolizumab and ustekinumab. In addition, thromboembolic events rarely occurred in patients with ulcerative colitis (UC) after therapy with tofacitinib. The overall risk of both venous and arterial thrombosis was not increased based on the available evidence. Finally, in the era of JAK inhibitors, the treatment should be individualized by evaluating the pre-existing potential thrombotic risk balanced with the intrinsic risk of the medication used.

Colitis-associated colorectal cancer (CAC) remains a critical complication of ulcerative colitis (UC) with a mortality of approximately 15%, which makes early CAC diagnosis crucial. The current standard of surveillance, with repetitive colonoscopies and histological testing of biopsied mucosa samples, is burdensome and expensive, and therefore less invasive methods and reliable biomarkers are needed. Significant progress has been made, thanks to continuous extensive research in this field, however, no clinically relevant biomarker has been established so far. This review of the current literature presents the genetic and molecular differences between CAC and sporadic colorectal cancer and covers progress made in the early detection of CAC carcinogenesis. It focuses on biomarkers under development, which can easily be tested in samples of body fluids or breath and, once made clinically available, will help to differentiate between progressors (UC patients who will develop dysplasia) from non-progressors and enable early intervention to decrease the risk of cancer development.