Emerging Biomarker-Guided Therapies in Prostate Cancer

Prostate cancer remains one of the leading causes of cancer death in men worldwide. In the past decade, several new treatments for advanced prostate cancer have been approved. With a wide variety of available drugs, including cytotoxic agents, androgen receptor axis-targeted therapies, and alpha-emitting radiation therapy, identifying their optimal sequencing remains a challenge. Progress in the understanding of the biology of prostate cancer has provided an opportunity for a more refined and personalized treatment selection process. With the advancement of molecular sequencing techniques, genomic precision through the identification of potential treatment targets and predictive biomarkers has been rapidly evolving. In this review, we discussed biomarker-driven treatments for advanced prostate cancer. First, we presented predictive biomarkers for established, global standard treatments for advanced diseases, such as chemotherapy and androgen receptor axis-targeted agents. We also discussed targeted agents with recent approval for special populations, such as poly ADP ribose polymerase (PARP) inhibitors in patients with metastatic castrate-resistant prostate cancer with homologous recombination repair-deficient tumors, pembrolizumab in patients with high levels of microsatellite instability or high tumor mutational burden, and prostate-specific membrane antigen (PSMA) directed radioligand theragnostic treatment for PSMA expressing tumors. Additionally, we discussed evolving treatments, such as cancer vaccines, chimeric antigen receptor T-cells (CAR-T), Bispecific T-cell engagers (BiTEs), other targeted agents such as AKT inhibitors, and various combination treatments. In summary, advances in molecular genetics have begun to propel personalized medicine forward in the management of advanced prostate cancer, allowing for a more precise, biomarker-driven treatment selection with the goal of improving overall efficacy.     

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.     

Inhibition by the putative potassium channel opener pinacidil of the electrically-evoked release of endogenous dopamine and noradrenaline in the rat vas deferens

Summary The effect of pinacidil on the release of endogenous noradrenaline and dopamine from the sympathetic innervation of the rat vas deferens was examined. Amine release was evoked by electrical stimulation (1, 2, 5 and 10 Hz) or by depolarization with high potassium (75 mmol/l) in the medium. Dopamine and noradrenaline were measured by means of high pressure liquid chromatography with electrochemical detection.Pinacidil (1, 5, 10 and 50 mol/l) produced a concentration-dependent inhibition of the electrically stimulated (2 Hz) overflow of noradrenaline and dopamine. Only pinacidil 50 mol/l increased the spontaneous loss of dopamine and noradrenaline. The inhibitory effects of pinacidil (5 mol/l) on amine overflow were also observed at other frequencies of stimulation (1, 5 and 10 Hz). The magnitude of the inhibitory effect on noradrenaline release was approximately the same at all frequencies (63% to 56% reduction); for dopamine, the higher the frequency of stimulation, the greater the inhibitory effect of pinacidil (up to 73% reduction). When the preparations were continuously stimulated for 70 min at 2 Hz, pinacidil (5 mol/l) reduced the overflow of dopamine and noradrenaline during the first 40 or 30 min of stimulation only. The addition of phentolamine (1 mol/l) to the perifusion medium slightly reduced the inhibitory effect of pinacidil on amine overflow, but the inhibition by pinacidil remained statistically significant. Tetraethylammonium (10 mmol/l) completely abolished the inhibitory effect of pinacidil (10 mol/l). Pinacidil (5 mol/l) did not reduce the potassium-evoked release of the amines.The results demonstrate that pinacidil impairs transmitter release from the sympathetic innervation of the rat vas deferens, probably as a consequence of the opening of potassium channels. Send offprint request to P. Soares-da-Silva at the above adress     

Effect of d-amphetamine repeated administration on rat antioxidant defences

The purpose of this study was to evaluate rat tissue antioxidant status after repeated administration of d-amphetamine. Three groups of four rats each were used: control, d-amphetamine sulphate dosed (s.c., 20 mg/kg per day), and pair-fed. After 14 days of d-amphetamine daily administration, superoxide dismutase (CuZnSOD and MnSOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GRed), glutathione-S-transferase (GST), glutathione (GSH), cysteine and thiobarbituric acid reactive substances (TBARS) were measured in liver, kidney, and heart. Various serum and urine parameters were also analysed. d-Amphetamine treatment induced an increase of liver GSH, as well as a decrease of cysteine and MnSOD levels in this organ. A small increase in serum transaminases was also observed in comparison to the pair-fed group. Hepatic levels of TBARS, GPx, GRed and CuZnSOD were found to be similar among the three groups of rats. d-Amphetamine treatment induced an increase of kidney GST, GRed and catalase levels, and an elevation of N-acetyl-β-d-glucosaminidase efflux to the urine, accompanied by a decrease in urinary creatinine, compared to the pair-fed group. In d-amphetamine treated animals, heart cysteine levels were significantly depleted when compared to the pair-fed group, but all three groups of rats were found to have similar heart antioxidant enzyme levels. These results indicate that repeated administration of d-amphetamine caused a certain degree of stress in liver and kidney, which was followed by adaptations of antioxidant defences. The mechanisms involved in d-amphetamine-induced toxicity may explain the different adaptations observed for the studied organs. Received: 19 October 1998 / Accepted: 11 January 1999     

Opioid-based micro and nanoparticulate formulations: alternative approach on pain management

Context Opioids have been used as the reference treatment on chronic pain. However, they are related to serious adverse effects which affect the patient compliance to treatment, as well as, his quality of life. Particulate formulations have been investigated as an alternative to improve opioid efficacy and safety. Objective Summarise the available studies concerning micro and nanoencapsulated opioid formulations discussing their biopharmaceutical characteristics, such as composition, size, in vitro release, pharmacokinetic and antinociceptive profile. Methods Papers available in 1995–2015 at Medline, Science Direct and Web of Science databases were collected and assessed. Searches were performed using varied combinations of the keywords of this work. Results Opioid-loaded particles showed prolonged drug release with maintenance of serum therapeutic concentrations and extended analgesia when compared with the free drugs. The side effects incidences were reduced or maintained the same. Conclusion Particulate formulations can significantly increase both potency and safety profiles of opioids.     

Antagonism between perazine and flavine on the NAD-kinases of rat brain and liver

Summary The effect of perazine and the flavines FAD, FMN and riboflavine on the NAD-kinase of rat brain and the NAD-kinase of rat liver was studied.The flavine derivatives inhibited both enzymes. The inhibition mechanism was found to be non-competitive with rat liver NAD-kinase.Perazine, added simultaneously, restored the enzyme activity. The mechanism of interaction was elucidated by the use of the pA_¯x-method and found to be competitive with rat liver NAD-kinase. The antagonism described occured with the rat brain enzyme too, but with the method used the mechanisms of inhibition and interaction could not be investigated.     

The correction of aphakia in infants with hydrogel extended-wear contact lenses. Corneal studies

Although hydrogel extended-wear contact lenses (EWCLs) have been used extensively in the correction of aphakia in neonates, little is known about the effects of these lenses on infant corneas. Recent studies have demonstrated that long-term contact lenses can induce endothelial morphometric changes, including an increased coefficient of variation (CV) of mean endothelial cell area. Using wide-field specular microscopy, the authors studied 11 eyes of 10 patients, 1 to 3 years of age who, after lensectomy for congenital cataracts, wore EWCLs for the correction of aphakia. Except for two corneas in which increased pachometric readings and CV developed after repeated episodes of lens loss and inflammation, the EWCL were well tolerated and associated with few complications in this study.     

Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma

While surgical resection has remained the mainstay of treatment in early-stage renal cell carcinoma (RCC), therapeutic options in the advanced setting have remarkably expanded over the last 20 years. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGF-TKIs) and anti-programmed cell death 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have become globally accepted options in the upfront metastatic setting, with different ICI-based combination strategies improving overall survival compared to single-agent Sunitinib. Although some patients benefit from long-term responses, most eventually develop disease progression. Ongoing efforts to better understand the biology of RCC and the different mechanisms of acquired resistance have led to the identification of promising therapeutic targets. Belzutifan, a novel agent targeting the angiogenic pathway involving hypoxia-inducible factors (HIFs), has already been approved for the treatment of early-stage tumors associated with VHL disease and represents a very promising therapy in advanced RCC. Other putative targets include epigenetic regulation enzymes, as well as several metabolites such as adenosine, glutaminase and tryptophan, which are critical players in cancer cell metabolism and in the tumor microenvironment. Different methods of immune regulation are also being investigated, including CAR-T cell therapy and modulation of the gut microbiome, in addition to novel agents targeting the interleukin-2 (IL-2) pathway. This review aims to highlight the emergent novel therapies for RCC and their respective completed and ongoing clinical trials.