Current Drug Targets - Volume 21, Issue 15, 2020

There is evidence that post-radical prostatectomy (post-RP) incontinence is not just the insufficiency of the external urethral sphincter mechanism. Up to a third of men with post-RP incontinence suffer from bladder dysfunction, namely overactive bladder (OAB). OAB is a complex symptom syndrome with poorly defined pathophysiology. It causes a significant burden to patients, negatively affects the quality of their life and its management might be difficult and challenging. The incidence of post-RP OAB ranges from 15.2 to 37.8%. The aetiology is multifactorial and includes the partial decentralization of the bladder, the detrusor underactivity, the bladder outlet obstruction and the co-existence with stress urinary incontinence (SUI). Post-RP SUI may lead to defunctionalized bladder and activation of urethrovesical reflex which further deteriorate post-RP continence. The diagnostic work-up of men with post-RP OAB should aim to identify potential aetiologic factors and personalize the treatment accordingly. Until now, there is no robust data from literature with regards to post-RP OAB management. It seems that anticholinergics and PDE5 inhibitors are effective in improving OAB parameters.

Intravesical Botox has become a widespread treatment for patients with refractory overactive bladder. Further to its acknowledged efficacy, both physicians and patients must be fully aware of possible complications, such as urinary tract infections, incomplete bladder emptying or even urinary retention and the possible need for intermittent self-catheterizations, fatigue, muscle weakness, transient hematuria and autonomic dysreflexia. Careful patient selection, particularly in terms of comorbidities, caution with technical aspects of the procedure such as the use of fine specifically designed injection needles, treatment of baseline UTIs or bacteriuria and avoidance of bladder overfilling could be the main measures, in addition to rigorous patient follow-up, to minimize the risk of post-Botox UTIs, hematuria, autonomic dysreflexia, and retention. Management of Botox failures is currently an unchartered area, starting with the definition of failure per se. Nevertheless, dose increase, particularly in neurogenic patients, increase of treatment frequency, switch to abobotulinumtoxinA, prolongation of injection intervals with add-on oral therapy, use of percutaneous tibial nerve stimulation or sacral neuromodulation and alleviation of risk factors for failure such as UTIs may be part of the management algorithm for Botox failures. As there is little evidence base to support such proposals and as the use of intravesical Botox is increasingly becoming a part of common urological practice, further research into the field of Botox failures and complications is needed so that both physicians and patients are granted with more solid, viable options.

Lower urinary tract symptoms (LUTS) secondary to benign prostate obstruction (BPO) afflict a very large part of the population on a global scale. Urologists confront patients with a diversity of BPH-related symptoms in their daily practice. For years, the cornerstone of obstructive BPH treatment consisted of mostly medical and to a lesser extent surgical therapies. However, while medical treatment has come to a standstill, over the last decade, new minimally invasive surgical therapies (MISTs) have emerged, conferring several possible advantages over conventional transurethral resection of the prostate (TURP). MISTs have also demonstrated the ability to better respect and preserve sexual function while providing safety and minimal morbidity. Their long-term efficacy and durability over drug therapy remain debatable, as is the need for secondary procedures. In the present paper, we aim to offer a narrative summary of the available literature, thus providing an indirect comparative assessment of drugs and MISTs for obstructive LUTS.

Between the end of 2005 and the beginning of 2006, several new target therapies have been introduced for the treatment of renal cell carcinoma. In this review, we aimed to explore and summarize the main findings of the use of systemic treatment and its effect on surgery in patients with renal cell carcinoma. We identified three different settings: neoadjuvant and adjuvant settings as well as the association of systemic therapy with surgery in the metastatic renal cell carcinoma patients. Neoadjuvant target therapy with tyrosine kinase inhibitor may facilitate the tumor resection and reduce the overall tumor diameter and its complexity. However, most of the evidence is from small phase I or II clinical trials and results are often conflicting without determining a relevant change in the main parameters investigated, such as tumor complexity. In the adjuvant setting, results from pivotal trials investigating the use of tyrosine kinase inhibitors for patients with non-metastatic RCC treated with surgery discourage this practice. Indeed, most of the evidence from single clinical trials and pooled results from meta-analysis failed to find a survival advantage with the use of adjuvant systemic treatment. To date, an improvement of clinical outcomes after systemic targeted therapies could be only found in the setting of cytoreductive nephrectomy. However, the CARMENA and SURTIME trials recently confirmed the evidence against a surgical treatment in patients with mRCC and poor prognosis. In the near future, significant changes may be introduced by the use of immunotherapies.

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

Kratom, or Mitragyna speciosa Korth., is a tropical plant prevalent in Southeast Asia, and it is utilized as a traditional remedy for symptomatic relief of various illnesses. It has been labeled as an atypical opioid with significant narcotic-like properties, capable of inducing kratom dependence among those who misuse or abuse it. The prevalence of kratom use has drastically increased worldwide, raising concerns among healthcare providers, particularly regarding the availability of efficacious treatment options for kratom dependence. This manuscript provides a comprehensive narrative review of literature focusing on the psychoactive alkaloids of kratom, the possible neurobiological and pathophysiological models underlying the occurrence of kratom dependence, and the clinical presentations and effective treatment options available for kratom dependence. The psychoactive alkaloids of kratom, such as mitragynine (MG) and 7-hydroxymitragynine (7-HMG), act as partial mu opioid agonists and induce kratom dependence. As a result, regular kratom use leads to withdrawal symptoms on abstinence, along with craving, tolerance, and cross-tolerance to morphine. The psychological withdrawal symptoms reported include depressed mood, anxiety, restlessness, irritability, and feeling tense, while the physical withdrawal symptoms are myalgia and body ache, joint pain, lacrimation, running nose, yawning, insomnia, diarrhea, feverish sensation, loss of appetite, tremors, itching over the body, loss of concentration, and chills. Neonatal withdrawal symptoms, such as oral intolerance, restlessness, irritability, and vomiting, are also reported in newborns of women who are on regular kratom use. Sublingual buprenorphine-naloxone (Suboxone) is reported as a promising treatment for detoxification and maintenance replacement therapy for kratom-dependent users. Alternative treatments for in-patient detoxification include intravenous clonidine and a combination of oral dihydrocodeine and lofexidine. We conclude by adding a note on the research gap concerning kratom dependence, which future studies should focus on.

Pancreatic ductal adenocarcinoma (PDA) has one of the worst prognosis and higher mortality among most cancers. The diagnosis of PDA is frequently delayed due to a lack of specific biomarkers, and the efficacy of current chemotherapeutic drugs is limited. Moreover, chemotherapy is generally applied in advanced stages, where metastatic spread has already occurred. Nanotechnologybased systems are allowing to advance in the diagnosis and treatment of PDA. New nanoformulations have shown to improve the activity of conventional chemotherapeutic agents, such as gemcitabine, and new antitumor drugs, protecting them from degradation, improving their selectivity, solubility and bioavailability, and reducing their side effects. Moreover, the design of nanocarriers represents a new way to overcome drug resistance, which requires a comprehensive understanding of the tumor microenvironment of PDA. This article reviews the current perspectives, based on nanomedicine, to address the limitations of pancreatic cancer treatment, and the futures lines of research to progress in the control of this disease.

Schizophrenia is a multifactorial, highly complex behavioral and cognitive disorder caused by disruptions of neurotransmitters in the brain, consequently affecting its functioning. The disorder is known to affect approximately 1% of the adult population worldwide. Antipsychotics used in the treatment have considerable drawbacks as they primarily aim to alleviate the positive symptoms of different aspects of the disorder and fail to treat the negative and cognitive symptoms. Considering the poor functional outcome of conventional antipsychotic therapy, the recent development of effective targets is of clinical importance. In this review, we summarize perspective on recent approaches and advances on schizophrenia. New therapeutically potential compounds for the treatment of schizophrenia act on metabotropic glutamate receptor, Matrix metalloproteinase, endocannabinoid receptor, nicotinic acetylcholine receptor, muscarinic acetylcholine cholinergic receptor and Dynorphin /Kappa Opioid receptor systems. This review explores the functions of different receptors other than dopaminergic systems to treat and manage schizophrenia effectively. The article would provide readers guidance on newer targets related to schizophrenia.

Malignant pleural mesothelioma (MPM) is a remarkably aggressive thoracic malignancy with a limited survival of only 5-12 months. However, MPM still remains unresponsive to conventional standards of treatment, including pleurectomy and decortication, extrapleural pneumonectomy for resectable disease with or without chemotherapy, and/or radiation therapy. The mechanism of carcinogenesis has not been fully elucidated, although approximately 80% of cases can still be linked to asbestos exposure. The tumor immune microenvironment (TME) has been proven to play an important role in MPM pathogenesis and treatment outcomes. Several molecular pathways have been implicated in the MPM tumor microenvironment, such as angiogenesis, apoptosis, cell cycle regulation, and stromal processes. Immunotherapy has already shown promising results in other thoracic solid tumors, such as non-small-cell lung cancer (NSCLC). However, immunotherapy has shown less convincing results in MPM than in melanoma and NSCLC. A multicenter, randomized trial (DETERMINE) proved that immune checkpoint inhibition using tremelimumab, an anti-cytotoxic T lymphocyteassociated protein 4 (CTLA-4) antibody, failed to improve median overall survival. Therefore, it is important to explore the relationship between the characteristics of the tumor microenvironment and immunotherapy. Here, we review the heterogeneity of the TME and the progress in the understanding of the immune microenvironment and immunotherapy in MPM to explore the mechanisms of resistance to immunotherapy.

Natural polymers, particularly polysaccharide, have been used as drug delivery systems for a variety of therapeutic agents such as peptides, proteins, vaccines, DNA, and drugs for parenteral and non-parenteral administration. Chitosan, the second most abundant naturally occurring polysaccharide after cellulose, is a biocompatible and biodegradable mucoadhesive polymer that is extensively used in the preparation of nanoparticles (NPs). Chitosan NPs loaded with drugs were found to be stable, permeable and bioactive. In this review, the importance of chitosan and its derivatives in drug delivery is illustrated, different methods of preparation of chitosan and chitosan derivatives NPs and their physio- chemical properties are addressed. Moreover, the desirable characteristics of successful NPs based drug delivery systems, as well as the pharmaceutical applications of these NPs are also clearly explored.

Pathologies linked to the renin-angiotensin system are frequent, and the drugs used in them are numerous and show great variability in therapeutic effects and adverse reactions. Genetic variants have been detected in the angiotensinogen gene (6), angiotensin-converting enzyme (9), angiotensinconverting enzyme 2 (1), and angiotensin receptor Type 1 (4) among others. However, the large number of studies that have analyzed each of them makes it complex and almost impossible to consider all the existing information. This manuscript aims to review the effects of the different known variants on the expected response of different drugs as a basis for the future development of therapeutic guidelines that seek to implement therapeutic individualization strategies on the renin-angiotensin system.