Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials.

Chronic pain is a major source of morbidity for which there are limited effective treatments. Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide, has demonstrated utility in the treatment of neuropathic and inflammatory pain. Emerging reports have supported a possible role for its use in the treatment of chronic pain, although this remains controversial. We undertook a systematic review and meta-analysis to examine the efficacy of PEA as an analgesic agent for chronic pain. A systematic literature search was performed, using the databases MEDLINE and Web of Science, to identify double-blind randomized controlled trials comparing PEA to placebo or active comparators in the treatment of chronic pain. All articles were independently screened by two reviewers. The primary outcome was pain intensity scores, for which a meta-analysis was undertaken using a random effects statistical model. Secondary outcomes including quality of life, functional status, and side effects are represented in a narrative synthesis. Our literature search identified 253 unique articles, of which 11 were ultimately included in the narrative synthesis and meta-analysis. Collectively, these articles described a combined sample size of 774 patients. PEA was found to reduce pain scores relative to comparators in a pooled estimate, with a standard mean difference of 1.68 (95% CI 1.05 to 2.31, p = 0.00001). Several studies reported additional benefits of PEA for quality of life and functional status, and no major side effects were attributed to PEA in any study. The results of this systematic review and meta-analysis suggest that PEA is an effective and well-tolerated treatment for chronic pain. Further study is warranted to determine the optimal dosing and administration parameters of PEA for analgesic effects in the context of chronic pain.

The Effect of Smoking Cessation on Acute Pain: A Systematic Review.

Smoking is a known risk factor for developing various pain-related disorders. However, acute pain often triggers the craving for cigarette consumption, resulting in a positive feedback mechanism. In addition, there is evidence of decreased pain tolerance during the early stages of abstinence. Therefore, in this study, we aimed to investigate whether a period of decreased pain tolerance and increased pain intensity occurs during smoking cessation. A systematic literature search was conducted through PubMed and Web of Science databases for controlled studies investigating the influence of smoking cessation on acute (defined as pain presentation of < 3 months) and postoperative pain. The outcomes of interest included pain perception threshold, pain tolerance, pain intensity, and postoperative opioid requirements. The search strategy yielded 1478 studies, of which 13 clinical studies met our inclusion criteria. The included studies collectively represented data from 1721 participants from four countries. Of these, 43.3% of the included individuals were females. The mean age of the included subjects was 44.2 ± 8.2 years. The duration of smoking cessation varied considerably. The shortest duration was 2 h; others investigated the effect after more than 1 month of smoking cessation. Smokers had a history of 14.6 ± 9.9 years of nicotine abuse. The mean number of daily smoked cigarettes was 17.5 ± 10.3. Most studies examined in this systematic review show a negative influence of smoking cessation on acute pain. However, the affected pain modalities, the duration of the altered pain perception, and whether male and female smokers are equally affected could not be ascertained due to high heterogeneity and few available studies.

Carbon-Source Dependent Interplay of Copper and Manganese Ions Modulates the Morphology and Itaconic Acid Production in Aspergillus terreus.

The effects of the interplay of copper(II) and manganese(II) ions on growth, morphology and itaconic acid formation was investigated in a high-producing strain of Aspergillus terreus (NRRL1960), using carbon sources metabolized either mainly via glycolysis (D-glucose, D-fructose) or primarily via the pentose phosphate shunt (D-xylose, L-arabinose). Limiting Mn2+ concentration in the culture broth is indispensable to obtain high itaconic acid yields, while in the presence of higher Mn2+ concentrations yield decreases and biomass formation is favored. However, this low yield in the presence of high Mn2+ ion concentrations can be mitigated by increasing the Cu2+ concentration in the medium when D-glucose or D-fructose is the growth substrate, whereas this effect was at best modest during growth on D-xylose or L-arabinose. A. terreus displays a high tolerance to Cu2+ which decreased when Mn2+ availability became increasingly limiting. Under such conditions biomass formation on D-glucose or D-fructose could be sustained at concentrations up to 250 mg L-1 Cu2+, while on D-xylose- or L-arabinose biomass formation was completely inhibited at 100 mg L-1. High (>75%) specific molar itaconic acid yields always coincided with an "overflow-associated" morphology, characterized by small compact pellets (<250 µm diameter) and short chains of "yeast-like" cells that exhibit increased diameters relative to the elongated cells in growing filamentous hyphae. At low concentrations (≤1 mg L-1) of Cu2+ ions, manganese deficiency did not prevent filamentous growth. Mycelial- and cellular morphology progressively transformed into the typical overflow-associated one when external Cu2+ concentrations increased, irrespective of the available Mn2+. Our results indicate that copper ions are relevant for overflow metabolism and should be considered when optimizing itaconic acid fermentation in A. terreus.

Manganese Deficiency Is Required for High Itaconic Acid Production From D-Xylose in Aspergillus terreus.

Itaconic acid is used as a bio-based, renewable building block in the polymer industry. It is produced by submerged fermentations of the filamentous fungus Aspergillus terreus from molasses or starch, but research over the efficient utilization of non-food, lignocellulosic plant biomass is soaring. The objective of this study was to test whether the application of two key cultivation parameters for obtaining itaconic acid from D-glucose in high yields - Mn2+ ion deficiency and high concentration of the carbon source - would also occur on D-xylose, the principal monomer of lignocellulose. To this end, a carbon and energy balance for itaconic acid formation was established, which is 0.83 moles/mole D-xylose. The effect of Mn2+ ions on itaconic acid formation was indeed similar to that on D-glucose and maximal yields were obtained below 3 µg L-1 Mn2+ ions, which were, however, only 0.63 moles of itaconic acid per mole D-xylose. In contrast to the case on D-glucose, increasing D-xylose concentration over 50 g L-1 did not change the above yield. By-products such as xylitol and α-ketoglutarate were found, but in total they remained below 2% of the concentration of D-xylose. Mass balance of the fermentation with 110 g L-1 D-xylose revealed that >95% of the carbon from D-xylose was accounted as biomass, itaconic acid, and the carbon dioxide released in the last step of itaconic acid biosynthesis. Our data show that the efficiency of biomass formation is the critical parameter for itaconic acid yield from D-xylose under otherwise optimal conditions.

High oxygen tension increases itaconic acid accumulation, glucose consumption, and the expression and activity of alternative oxidase in Aspergillus terreus.

Itaconic acid is a five-carbon dicarboxylic acid with an unsaturated alkene bond, frequently used as a building block for the industrial production of a variety of synthetic polymers. It is also one of the major products of fungal "overflow metabolism" which can be produced in submerged fermentations of the filamentous fungus Aspergillus terreus. At the present, molar yields of itaconate are lower than those obtained in citric acid production in Aspergillus niger. Here, we have studied the possibility that the yield may be limited by the oxygen supply during fermentation and hence tested the effect of the dissolved oxygen concentration on the itaconic acid formation rate and yield in lab-scale bioreactors. The data show that a dissolved oxygen concentration of 2% saturation was sufficient for maximal biomass formation. Raising it to 30% saturation had no effect on biomass formation or the growth rate, but the itaconate yield augmented substantially from 0.53 to 0.85 mol itaconate/mol glucose. Furthermore, the volumetric and specific rates of itaconic acid formation ameliorated by as much as 150% concurrent with faster glucose consumption, shortening the fermentation time by 48 h. Further increasing the dissolved oxygen concentration over 30% saturation had no effect. Moreover, we show that this increase in itaconic acid production coincides with an increase in alternative respiration, circumventing the formation of surplus ATP by the cytochrome electron transport chain, as well as with increased levels of alternative oxidase transcript. We conclude that high(er) itaconic acid accumulation requires a dissolved oxygen concentration that is much higher than that needed for maximal biomass formation, and postulate that the induction of alternative respiration allows the necessary NADH reoxidation ratio without surplus ATP production to increase the glucose consumption and the flux through overflow metabolism.

Perpetuation of Retracted Publications Using the Example of the Scott S. Reuben Case: Incidences, Reasons and Possible Improvements.

In 2009, Scott S. Reuben was convicted of fabricating data, which lead to 25 of his publications being retracted. Although it is clear that the perpetuation of retracted articles negatively effects the appraisal of evidence, the extent to which retracted literature is cited had not previously been investigated. In this study, to better understand the perpetuation of discredited research, we examine the number of citations of Reuben's articles within 5 years of their retraction. Citations of Reuben's retracted articles were assessed using the Web of Science Core Collection (Thomson Reuters, NY). All citing articles were screened to discriminate between articles in which Reuben's work was quoted as retracted, and articles in which his data was wrongly cited without any note of the retraction status. Twenty of Reuben's publications had been cited 274 times between 2009 and 1024. In 2014, 45 % of the retracted articles had been cited at least once. In only 25.8 % of citing articles was it clearly stated that Reuben's work had been retracted. Annual citations decreased from 108 in 2009 to 18 in 2014; however, the percentage of publications correctly indicating the retraction status also declined. The percentage of citations in top-25 %-journals, as well as the percentage of citations in journals from Reuben's research area, declined sharply after 2009. Our data show that even 5 years after their retraction, nearly half of Reuben's articles are still being quoted and the retraction status is correctly mentioned in only one quarter of the citations.

Fentanyl for the treatment of tumor-related breakthrough pain.

BACKGROUND: Breakthrough cancer pain (BTCP) is common among cancer patients and markedly lowers their quality of life. The treatment for BTCP episodes that is recommended in current guidelines involves extended-release formulations in combination with rapid-onset and short-acting opioids. In the past few years, several new preparations of fentanyl, an opioid with a very rapid onset, have been approved for this indication. Treating physicians need to be aware of the clinical differences between the newer fentanyl preparations and immediate-release opioids. METHODS: We searched the PubMed and Embase databases for randomized controlled trials (RCTs) of fentanyl for buccal, sublingual or intranasal administration in comparison with other opioids or a different fentanyl preparation for the treatment of BTCP. RESULTS: In 6 trials of buccal, sublingual or intranasal fentanyl versus oral immediate-release opioids for the treatment of BTCP episodes, the use of fentanyl was associated with significantly less intense pain. In particular, fentanyl more often lowered the intensity of pain by at least 33% (range between studies: 13% to 57%) or by at least 50% (range between studies: 9% to 38%) within 15 minutes. Please change to "versus" if you agree.] Dose titration should begin at the lowest dose. When one fentanyl preparation is exchanged for another, the effective dose will probably differ. CONCLUSION: The newer fentanyl preparations extend the treatment options for BTCP. They relieve pain within a short time better than conventional, immediate-release oral opioids do and may therefore be very helpful for patients with suddenly arising, intense, and short-lasting BTCP episodes. Further comparative trials are urgently needed.

Ferritin and transferrin are associated with metabolic syndrome abnormalities and their change over time in a general population: Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR).

OBJECTIVE: The aim of this work was to study cross-sectional and longitudinal relations between iron stocks (ferritin) and the iron transport protein (transferrin) with the metabolic syndrome and its abnormalities. RESEARCH DESIGN AND METHODS: A total of 469 men and 278 premenopausal and 197 postmenopausal women from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, aged 30-65 years, were followed over 6 years. RESULTS: Higher concentrations of both ferritin and transferrin were associated with the International Diabetes Federation (IDF) and the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III original and revised definitions of the metabolic syndrome at baseline: for the IDF definition of the metabolic syndrome, the standardized, age-adjusted odds ratios (95% CI) for log(ferritin) were 1.49 (1.14-1.94) for men, 2.10 (1.27-3.48) for premenopausal women, and 1.80 (1.21-2.68) for postmenopausal women; for transferrin they were, respectively, 1.94 (1.53-2.47), 2.22 (1.32-3.75), and 2.14 (1.47-3.10). After 6 years of follow-up, the change in the presence of the metabolic syndrome was associated with higher baseline values in all three groups: log(ferritin), 1.46 (1.13-1.89), 1.28 (0.85-1.94), and 1.62 (1.10-2.38); and transferrin, 1.41 (1.10-1.81), 1.63 (1.05-2.52), and 1.51 (1.02-2.22). Among syndrome components, hypertriglyceridemia at 6 years was the component most strongly associated with baseline ferritin and transferrin. The odds of an incident IDF-defined metabolic syndrome after 6 years was more than fourfold higher when ferritin and transferrin values were both above the group-specific top tertile, in comparison with participants with both parameters below these thresholds. CONCLUSIONS: This is the first prospective study associating ferritin and transferrin with the metabolic syndrome and its components. When both markers of the iron metabolism are elevated, the incidence of the metabolic syndrome is increased in men and both pre- and postmenopausal women.

[Metabolism of ipriflavone]. / Az ipriflavon metabolizmusa.

Ipriflavone is intensively metabolized by the organism, due to strong first-pass metabolism only a small fraction of the dose absorbed is unchanged Ipriflavone. Seven metabolites were identified in animal as well as in human studies. Ipriflavone is metabolized exclusively in the liver by elimination, or oxidation of the isopropyl group and hydroxylation of the beta-ring followed by conjugation with glucuronic and/or sulphuric acid. In animals 7-hydroxy-isoflavone (M1) was the main metabolite of Ipriflavone, while in man 7-(1-carboxy-ethoxy)-isofla-vone (M5). There was no sex-difference in the metabolism of Ipriflavone either in animal, or in human studies.

[Pharmacokinetics of ipriflavone]. / Az ipriflavon farmakokinetikája.

Ipriflavone administered to rats orally is well absorbed from small intestine via the portal route, distributed widely in tissues, metabolized extensively by oxidation, and eliminated from the body preferentially in urine. The absorption of ipriflavone is less effective in dogs, than in rats. In dogs, the compound absorbed is metabolized in the same way as in rats and the metabolites formed are eliminated largely in faeces, together with unabsorbed ipriflavone. In human, ipriflavone administered orally is rapidly absorbed, and quickly metabolized. The dose is eliminated mainly via the urinary route as metabolites (57% of the dose), and the smaller fraction with the faeces, mostly as ipriflavone (40% of the dose). There is no significant change in the pharmacokinetics of ipriflavone even after multiple dose. In the serum, ipriflavone and its metabolites are primarily bound to albumin, the binding is 94-99% and totally reversible.