Effects of remifentanil on human C20 microglial pro-inflammatory activation

OBJECTIVE: Remifentanil (RF) is a potent short-acting μ-opioid receptor agonist. Although preferred for its unique pharmacokinetics, the clinical use may be limited by hyperalgesia. Preclinical studies have shown a potential role of microglia on the development of hyperalgesia, with limited and conflicting evidence on RF. Considering the role of microglia in the initiation and maintenance of brain inflammation and their different responses among species, we aimed at characterizing RF effects on human adult microglia in vitro. MATERIALS AND METHODS: RF was tested at clinically relevant concentrations on the human microglial C20 cell line. Expression and release of interleukin-6 (IL-6) and brain derived neurotrophic factor (BDNF) were assessed under basal and inflammatory conditions. RESULTS: The expression and secretion of IL-6 significantly increased in C20 cells in response to pro-inflammatory cytokines. RF did not modify this response neither under basal nor under inflammatory conditions. No toxicity due to RF was detected. The drug displayed a modest stimulatory effect on the production of BDNF. CONCLUSIONS: Although RF does not exert direct pro-inflammatory actions on human adult microglia, its effects on BDNF, a crucial mediator of pain transmission, suggest a possible role on neuroinflammation and pain perception

Epidemiology of renal colic in a district general hospital

BACKGROUND/AIMS: To assess the incidence of renal colic and the results of emergency management. METHODS: During a 12 month period data of patients with symptoms of renal colic were collected. RESULTS: A total of 495 visits were registered. The M/F was 2.19. Mean age was higher in males (45.5+/-13.0 vs 42.5+/-15.5 years, P=0.025). Three patients were hospitalised for immediate urinary diversion due to anuria or sepsis. Fifty-three patients recovered without performing any pharmacological treatment. Analgesic treatment (mainly NSAID) was offered to 439 patients. After a 6 hour period 36 patients were admitted to the hospital owing to persistent pain. Pain was reduced in 403 patients (91.8%) who were offered outpatient renal ultrasound within 48 hours. Twenty-five patients (6.2%) required deferred hospitalisation. Follow up with renal ultrasound was obtained in 213. CONCLUSION: Renal colics accounted for 0.9% of ambulatory care visits to our emergency departments with an annual rate of 0.158 visits per 100 in the general population. NSAIDs were efficacious in the management of colic. Diagnostic work up was able to demonstrate the presence of a stone in 56% of the subjects presenting with renal colic whereas alternative diagnoses were demonstrated in 12%

LAT1, a novel pharmacological target for the treatment of glioblastoma

The L-Type Amino Acid transporter, LAT1 (SLC7A5), has a crucial role in mediating amino acid uptake into the cells, thus modulating cell growth and proliferation as well as other intracellular functions. Different studies have reported a central role of LAT1 in glioblastoma development and progression, suggesting that the modulation of its activity could be a novel therapeutic strategy. LAT1 also has an important role in the peripheral immune system, by regulating the activation status of several immune cells through modulation of the mechanistic target of rapamycin kinase. In glioblastoma (GBM), the blood–brain barrier is disrupted, which allows the recruitment of peripheral immune cells to the tumour site. These cells, together with resident microglia, contribute to cancer growth and progression. Currently, little is known about the function of LAT1 in the reprogramming of the immune component of the tumour microenvironment in the context of GBM. In this article, we review the available data on the role of LAT1 in the regulation of GBM biology, including its potential role in the tumour microenvironment, particularly in infiltrating-peripheral immune cells and resident microglial cells. In addition, we review the available data on the main pharmacological inhibitors of LAT1, aiming to evaluate their possible role as novel therapeutics for GBM

A comparison between the assessments of progression-free survival by local investigators versus blinded independent central reviews in phase III oncology trials

Purpose: In this study, we compared the assessments of progression-free survival (PFS) carried out by the local investigator or by a blinded independent central review in the framework of phase III registration randomized controlled trials (RCT) in oncology. Methods: We carried out a search in the clinicatrials.gov database, looking at the RCTs reporting the results of both independently assessed and investigator-assessed PFS. The hazard ratios (HRs) of investigator-assessed PFS and independently assessed PFS were recorded, and a discrepancy index was obtained by calculating the ratio of their respective HRs. Moreover, we investigated possible factors of discrepancy by analyzing the trials in different groups (by year, by tumor type, by drug type, by study design). Results: We analyzed 28 RCTs meeting the search criteria. The estimated mean discrepancy index was 0.98 (confidence interval 0.927\u20131.032 (n = 32)). Subgroup analysis showed that the confidence intervals in all cases included the value 1, except in the subgroup of studies started in the period 2003\u20132006. Conclusion: In phase III oncology trials, we found no significant differences between the hazard ratios estimated by local investigators and those estimated by blinded independent central reviews. A relatively higher variability, in terms of large CI, was found in trials with biological agents

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials

The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was \u201cmore optimistic,\u201d whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies

The emerging role of the BDNF-TrkB signaling pathway in the modulation of pain perception

The brain derived neurotrophic factor (BDNF) is a crucial neuromodulator in pain transmission both in peripheral and central nervous system (CNS). Despite evidence of a pro-nociceptive role of BDNF, recent studies have reported contrasting results, including anti-nociceptive and anti-inflammatory activities. Moreover, BDNF polymorphisms can interfere with BDNF role in pain perception. In Val66Met carriers, the Met allele may have a dual role, with anti-nociceptive actions in normal condition and pro-nociceptive effects during chronic pain. In order to elucidate the main effects of BDNF in nociception, we reviewed the main characteristics of this neurotrophin, focusing on its involvement in pain

The mTOR kinase inhibitor rapamycin enhances the expression and release of pro-inflammatory cytokine interleukin 6 modulating the activation of human microglial cells.

Emerging evidence suggests the potential use of rapamycin in treatment of several neurological disorders. The drug readily crosses the blood brain barrier and may exert direct immunomodulatory effects within the brain. Microglia are the main innate immune cells of the brain, thus critically involved in the initiation and development of inflammatory processes at this level. However, there are conflicting data from rodent studies about the pharmacological effects of rapamycin on microglial inflammatory responses. Considering that rodent microglia display relevant biochemical and pharmacological differences compared to human microglia, in the present study we studied the effects of rapamycin in an experimental model of human microglia, the human microglial clone 3 (HMC3) cell line. Rapamycin was tested in the nM range both under basal conditions and in cells activated with a pro-inflammatory cytokine cocktail, consisting in a mixture of interferon-\u3b3 and interleukin-1\u3b2 (II). The drug significantly increased II stimulatory effect on interleukin-6 (IL-6) expression and release in the HMC3 cells, while reducing the production of free oxygen radicals (ROS) both under basal conditions and in cells activated with II. Consistently with its known molecular mechanism of action, rapamycin reduced the extent of activation of the so-called 'mechanistic' target of rapamycin complex 1 (mTORC1) kinase and the total amount of intracellular proteins. In contrast to rodent cells, rapamycin did not alter human microglial cell viability nor inhibited cell proliferation. Moreover, rapamycin did not exert any significant effect on the morphology of the HMC3 cells. All together these data suggest that the inhibition of mTORC1 in human microglia by rapamycin results in complex immunomodulatory effects, including a significant increase in the expression and release of the pro-inflammatory IL-6