Current Pharmaceutical Design - Volume 25, Issue 30, 2019

Background: Opioids are the cornerstone of the management of cancer pain. However, the development of adverse effects may compromise the opioid response. They include nausea and vomiting, constipation, drowsiness, sleep disorders, cognitive dysfunction, myoclonus, pruritus, dysuria, dependence and the development of aberrant behaviors, respiratory depression, and some endocrine responses. Methods: The goal of this paper is to identify the most common opioid-related adverse effects, their pathophysiology, and proposing the possible treatments. This narrative review will describe how these adverse effects may develop and how to prevent or to treat. Conclusion: Intensity of adverse effects tend to decrease with continuous use. However, they may be persistent and may require symptomatic treatment or more complex treatment including alternative strategies for pain management.

Pain at the end of life is common in both malignant and non-malignant disease. It is feared by patients, their families and careers, and professionals. Effective pain control can be achieved for the majority of patients at the end of life using a multimodal approach. Pharmacological management relies predominantly on strong opioids. In spite of this, evidence suggests that under treatment of pain is common resulting in unnecessary suffering. Multiple barriers to use of opioids have been identified. Patient barriers include reluctance to report pain and to take analgesics. Professional barriers include inadequate pain assessment and lack of specialist knowledge and confidence in opioid therapy. Fear of side effects including respiratory depression affects patients and professionals alike. The impact of the “opioid epidemic”, with increasing prescribed and illicit opioid use around the world, has also led to increasingly stringent regulation and concern about under prescribing in palliative care. System barriers to use of opioids at the end of life result from limited opioid availability in some countries and also inconsistent and limited access to palliative care. Multiple interventions have been developed to address these barriers, targeted at patients, professionals and systems. There is increasing evidence to suggest that complex interventions combining a number of different approaches are most effective in optimising pain outcomes for patients at the end of life.

Background: Endogenous opioids are neuropeptides involved in pain-relieving processes. In the periphery, they are synthesised and stored in cells of the immune system. Objective: In the current study, we describe the influence of perioperative, intravenous (i.v.) lidocaine infusion in children on postoperative, serum endogenous opioid concentrations in children. Methods: Forty-four children undergoing major spinal surgery were enrolled in the cohort study. They were divided into two groups: group A (n = 21) generally anesthetised with fentanyl, propofol, rocuronium, a mixture of oxygen/air/sevoflurane and with analgetics and co-analgetics: morphine, acetaminophen, metamizole, gabapentin, dexamethason and group B (n = 23) where, in addition to the above-described general anesthesia, patients were given i.v. lidocaine as a co-analgesic. We also recruited 20 healthy age- and gender-matched children (group C). We measured endogenous opioid levels in serum using immunoenzymatic methods. We evaluated postoperative pain intensity using a numerical or visual pain scale and demand for morphine. Results: The levels of measured endogenous opioids were similar in the control and in the studied groups before surgery. We noted that group B patients had lower pain intensity when compared to group A subjects. In group B, the elevated serum concentrations of β -endorphin, enkephalin and dynorphin in the postoperative period were reported. We also observed that the levels of endogenous opioids negatively correlated with morphine requirements and positively correlated with lidocaine concentration. Conclusion: Multidrug pain management including lidocaine seems to be more efficient than models without lidocaine. The endogenous opioid system should be considered as a novel target for pain relief therapy in children.

Aim: To compare the effects of oral morphine and oxycodone and transdermal fentanyl and buprenorphine on quality of life (QoL) of cancer patients with severe pain. Patients and Methods: Cancer patients with severe pain (NRS 6-10) treated at home and in outpatient clinics who failed to respond to non-opioids and/or “weak” opioids were randomized to morphine, oxycodone, fentanyl, or buprenorphine treatment for 28 days. Immediate-release oral morphine was rescued analgesic and 10-ml lactulose twice daily was prophylaxis of constipation; no antiemetics were used for prophylaxis. Results: Above all, 62 patients participated and 53 patients completed the study. Good analgesia was obtained with all 4 opioids. Morphine was associated with the less negative impact of pain on the ability to walk and normal work, and tendency on activity (BPI-SF) and lower consumption of rescue morphine. All 4 opioids elicited similar adverse effects. According to ESAS, the intensity of nausea and drowsiness increased at the beginning but decreased as treatment continued. Appetite, well–being, anxiety, depression, and fatigue improved. No changes were seen in constipation, vomiting and dyspnea. Constipation was rarely observed with all opioids (BFI). Any opioids improved overall QoL and emotional functioning with tendency improving physical functioning (EORTC QLQ-C15-PAL). Activity improved (Karnofsky). Morphine induced greater improvement in physical functioning and trend in improvement mood (HADS). Conclusion: All opioids significantly improved patients’ QoL. Morphine induced less negative impact of pain on daily activities and greater improvement in physical functioning with trends of better mood and less intense fatigue.

Macrophages are one of the crucial mediators of the immune response in different physiological and pathological conditions. These cells have critical functions in the inflammation mechanisms that are involved in the inhibition or progression of a wide range of diseases including cancer, autoimmune diseases, etc. It has been shown that macrophages are generally divided into two subtypes, M1 and M2, which are distinguished on the basis of their different gene expression patterns and phenotype. M1 macrophages are known as pro-inflammatory cells and are involved in inflammatory mechanisms, whereas M2 macrophages are known as anti-inflammatory cells that are involved in the inhibition of the inflammatory pathways. M2 macrophages help in tissue healing via producing anti-inflammatory cytokines. Increasing evidence indicated that the appearance of different macrophage subtypes is associated with the fate of diseases (progression versus suppression). Hence, polarization of macrophages can be introduced as an important venue in finding, designing and developing novel therapeutic approaches. Albeit, there are different pharmacological agents that are used for the treatment of various disorders, it has been shown that several natural compounds have the potential to regulate M1 to M2 macrophage polarization and vice versa. Herein, for the first time, we summarized new insights into the pharmacological effects of natural compounds on macrophage polarization.

Background and Objectives: The 3’ repair exonuclease 1 (TREX1) gene is the major DNA-specific 3’–5 ’exonuclease of mammalian cells which reduces single- and double-stranded DNA (ssDNA and dsDNA) to prevent undue immune activation mediated by the nucleic acid. TREX1 is also a crucial suppressor of selfrecognition that protects the host from inappropriate autoimmune activations. It has been revealed that TREX1 function is necessary to prevent host DNA accumulating after cell death which could actuate an autoimmune response. In the manuscript, we will discuss in detail the latest advancement to study the role of TREX1 in autoimmune disease. Methods: As a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as an antiinflammatory molecule, the functional mechanisms of TREX1 were multifactorial. In this review, we will briefly summarize the latest advancement in studying the role of TREX1 in autoimmune disease, and discuss its potential as a therapeutic target for these diseases. Results: Deficiency of TREX1 in human patients and murine models is characterized by systemic inflammation and the disorder of TREX1 functions drives inflammatory responses leading to autoimmune disease. Moreover, much more studies revealed that mutations in TREX1 have been associated with a range of autoimmune disorders. But it is also unclear whether the mutations of TREX1 play a causal role in the disease progression, and whether manipulation of TREX1 has a beneficial effect in the treatment of autoimmune diseases. Conclusion: Integration of functional TREX1 biology into autoimmune diseases may further deepen our understanding of the development and pathogenesis of autoimmune diseases and provide new clues and evidence for the treatment of autoimmune diseases.

Repurposing already approved drugs as new anticancer agents is a promising strategy considering the advantages such as low costs, low risks and less time-consumption. Disulfiram (DSF), as the first drug for antialcoholism, was approved by the U.S. Food and Drug Administration (FDA) over 60 years ago. Increasing evidence indicates that DSF has great potential for the treatment of various human cancers. Several mechanisms and targets of DSF related to cancer therapy have been proposed, including the inhibition of ubiquitin-proteasome system (UPS), cancer cell stemness and cancer metastasis, and alteration of the intracellular reactive oxygen species (ROS). This article provides a brief review about the history of the use of DSF in humans and its molecular mechanisms and targets of anticancer therapy, describes DSF delivery strategies for cancer treatment, summarizes completed and ongoing cancer clinical trials involving DSF, and offers strategies to better use DSF in cancer therapies.

Background: Many diseases can be treated with metformin. People with serum thyrotropin (TSH) levels higher than 10 mIU/L are at a risk of cardiovascular events. Some studies have suggested that metformin can lower serum TSH levels to a subnormal level in patients with hyperthyrotropinaemia or hypothyroidism. Objective: The objective of this analysis is to evaluate the effect of metformin treatment on serum TSH, free triiodothyronine (FT3), and free thyroxine (FT4) levels and other associated physiological indices. Methods: A comprehensive search using the PubMed, EMBASE, Web of Science and Cochrane Central databases was undertaken for controlled trials on the effect of metformin on serum TSH, FT3, and FT4 levels and associated physiological indices. The primary outcome measures were serum TSH, FT3 and FT4 levels, thyroid size, thyroid nodule size, blood pressure, heart rate, body weight, and body mass index (BMI). The final search was conducted in April 2019. Results: Six RCTs were included. A total of 494 patients met the inclusion criteria. Metformin treatment did not significantly lower the serum TSH levels at 3 or 6 months but did at 12 months. Moreover, forest plots also suggested that metformin can significantly lower the serum TSH levels in patients with normal thyroid function but cannot statistically change the serum TSH levels in patients with abnormal thyroid function. In addition, metformin treatment clearly lowered the serum FT3 levels and had no significant effect on serum FT4 levels. Lastly, metformin cannot significantly change the systolic blood pressure (SBP) or BMI but can clearly increase the diastolic blood pressure (DBP). Conclusion: Metformin treatment can significantly lower the serum TSH levels, and this effect was much clearer after a 12-month treatment duration and in people with normal thyroid function. However, metformin cannot significantly change the serum FT4 levels or lower serum FT3 levels in people with non-thyroid cancer diseases. In addition, metformin can significantly increase DBP, but it has no clear effect on SBP or BMI.

Background: The findings of trials investigating the effects of L-carnitine administration on serum lipids are inconsistent. This meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effects of L-carnitine intake on serum lipids in patients and healthy individuals. Methods: Two authors independently searched electronic databases including MEDLINE, EMBASE, Cochrane Library, Web of Science, PubMed and Google Scholar from 1990 until August 1, 2019, in order to find relevant RCTs. The quality of selected RCTs was evaluated using the Cochrane Collaboration risk of bias tool. Cochrane’s Q test and I-square (I2) statistic were used to determine the heterogeneity across included trials. Weight mean difference (SMD) and 95% CI between the two intervention groups were used to determine pooled effect sizes. Subgroup analyses were performed to evaluate the source of heterogeneity based on suspected variables such as, participant’s health conditions, age, dosage of L-carnitine, duration of study, sample size, and study location between primary RCTs. Results: Out of 3460 potential papers selected based on keywords search, 67 studies met the inclusion criteria and were eligible for the meta-analysis. The pooled results indicated that L-carnitine administration led to a significant decrease in triglycerides (WMD: -10.35; 95% CI: -16.43, -4.27), total cholesterol (WMD: -9.47; 95% CI: - 13.23, -5.70) and LDL-cholesterol (LDL-C) concentrations (WMD: -6.25; 95% CI: -9.30, -3.21), and a significant increase in HDL-cholesterol (HDL-C) levels (WMD: 1.39; 95% CI: 0.21, 2.57). L-carnitine supplementation did not influence VLDL-cholesterol concentrations. When we stratified studies for the predefined factors such as dosage, and age, no significant effects of the intervention on triglycerides, LDL-C, and HDL-C levels were found. Conclusion: This meta-analysis demonstrated that L-carnitine administration significantly reduced triglycerides, total cholesterol and LDL-cholesterol levels, and significantly increased HDL-cholesterol levels in the pooled analyses, but did not affect VLDL-cholesterol levels; however, these findings were not confirmed in our subgroup analyses by participant’s health conditions, age, dosage of L-carnitine, duration of study, sample size, and study location.

Background: Adenocarcinoma of colon and rectum are one of the most common cancers worldwide, responsible for over 1,300,000 people diagnosed. Also, they are responsible for metastasis, which leads to death in less than 5 years. Methods: In this study, we developed, characterized, and pre-clinically tested a new nano-radiopharmaceutical for early and differential detection of adenocarcinoma of colon and rectum. Results and Conclusion: Results demonstrated the specificity of the developed nanosystem and the ability to reach the tumor with very specific targeting. Also, the imaging data support the use of this nano-agent as a nanoimaging- guided-radiopharmaceutical.