Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with ...estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain.
In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18–50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 NCT03204318 and SPIRIT 2 NCT03204331) and EudraCT (SPIRIT 1 2017–001588–19 and SPIRIT 2 2017–001632–19). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION NCT03654274, EudraCT 2017-004066-10). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication.
638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 33%), placebo (213 33%), or relugolix delayed combination therapy (213 33%). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 33%), placebo (208 33%), or relugolix delayed combination therapy (207 33%). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% 95% CI 39·3–56·0; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% 95% CI 36·2–53·5; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% 9·5–28·2; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% 95% CI 13·9–32·8; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was –0·70% versus 0·21% in SPIRIT 1 and –0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was –2·0% in SPIRIT 1 and –1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo.
Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment.
Myovant Sciences.
Excessive nutrient loading is a major threat to aquatic ecosystems worldwide that leads to profound changes in aquatic biodiversity and biogeochemical processes. Systematic quantitative assessment of ...functional ecosystem measures for river networks is, however, lacking, especially at continental scales. Here, we narrow this gap by means of a pan-European field experiment on a fundamental ecosystem process—leaf-litter breakdown—in 100 streams across a greater than 1000-fold nutrient gradient. Dramatically slowed breakdown at both extremes of the gradient indicated strong nutrient limitation in unaffected systems, potential for strong stimulation in moderately altered systems, and inhibition in highly polluted streams. This large-scale response pattern emphasizes the need to complement established structural approaches (such as water chemistry, hydrogeomorphology, and biological diversity metrics) with functional measures (such as litter-breakdown rate, whole-system metabolism, and nutrient spiraling) for assessing ecosystem health.
We tested the hypothesis that cancer cachexia progression would induce oxidative post‐translational modifications (Ox‐PTMs) associated with skeletal muscle wasting, with different responses in ...muscles with the prevalence of glycolytic and oxidative fibers. We used cysteine‐specific isotopic coded affinity tags (OxICAT) and gel‐free mass spectrometry analysis to investigate the cysteine Ox‐PTMs profile in the proteome of both plantaris (glycolytic) and soleus (oxidative) muscles in tumor‐bearing and control rats. Histological analysis revealed muscle atrophy in type II fibers in plantaris muscle, with no changes in plantaris type I fibers and no differences in both soleus type I and II fibers in tumor‐bearing rats when compared to healthy controls. Tumor progression altered the Ox‐PTMs profile in both plantaris and soleus. However, pathway analysis including the differentially oxidized proteins revealed tricarboxylic acid cycle and oxidative phosphorylation as main affected pathways in plantaris muscle from tumor‐bearing rats, while the same analysis did not show main metabolic pathways affected in the soleus muscle. In addition, cancer progression affected several metabolic parameters such as ATP levels and markers of oxidative stress associated with muscle atrophy in plantaris muscle, but not in soleus. However, isolated soleus from tumor‐bearing rats had a reduced force production capacity when compared to controls. These novel findings demonstrate that tumor‐bearing rats have severe muscle atrophy exclusively in glycolytic fibers. Cancer progression is associated with cysteine Ox‐PTMs in the skeletal muscle, but these modifications affect different pathways in a glycolytic muscle compared to an oxidative muscle, indicating that intrinsic muscle oxidative capacity determines the response to cancer cachectic effects.
To date, nutritional epidemiology has relied heavily on relatively weak methods including simple observational designs and substandard measurements. Despite low internal validity and other sources of ...bias, claims of causality are made commonly in this literature. Nutritional epidemiology investigations can be improved through greater scientific rigor and adherence to scientific reporting commensurate with research methods used. Some commentators advocate jettisoning nutritional epidemiology entirely, perhaps believing improvements are impossible. Still others support only normative refinements. But neither abolition nor minor tweaks are appropriate. Nutritional epidemiology, in its present state, offers utility, yet also needs marked, reformational renovation. Changing the status quo will require ongoing, unflinching scrutiny of research questions, practices, and reporting-and a willingness to admit that "good enough" is no longer good enough. As such, a workshop entitled "Toward more rigorous and informative nutritional epidemiology: the rational space between dismissal and defense of the status quo" was held from July 15 to August 14, 2020. This virtual symposium focused on: (1) Stronger Designs, (2) Stronger Measurement, (3) Stronger Analyses, and (4) Stronger Execution and Reporting. Participants from several leading academic institutions explored existing, evolving, and new better practices, tools, and techniques to collaboratively advance specific recommendations for strengthening nutritional epidemiology.
High genetic and phenotypic variability between
species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of ...several diverse
species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species:
,
, and
. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any
species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents.
A palladium-catalyzed aerobic oxidative annulation of indoles is described. We have demonstrated that a variety of factors influence these cyclizations, and in particular the electronic nature of the ...pyridine ligand is crucial. It is also remarkable that these oxidative cyclizations can proceed in good yield despite background oxidative decomposition pathways, testament to the facile nature with which molecular oxygen can serve as the direct oxidant for Pd(0). We have also shown that the mechanism most likely involves initial indole palladation (formal C−H bond activation) followed by migratory insertion and β-hydrogen elimination.
No extra functionalization step is required for palladium(II)‐catalyzed oxidative carbocyclizations like that shown, which provide highly substituted benzofuran and dihydrobenzofuran derivatives by ...net dehydrogenation. The mechanism is similar to that of Heck cyclizations. Products containing quaternary carbon stereocenters can be obtained in diastereomerically pure form.
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•Biodiesel was produced by hydroesterification using WCO and enzymatic catalysis.•A low-cost used crude extract (GCL-I) fully hydrolyzed WCO within a 80-min reaction.•PFL was ...immobilized on SDB which was used in the esterification step.•The prepared biocatalyst retained around 98% of its activity after 6 cycles of 9 h.•Highly quality and purity of biodiesel were assessed by 1H NMR and FTIR analysis.
Biodiesel production was investigated by hydroesterification using enzymatic catalysis in both hydrolysis and esterification reactions. Soybean oil resulting from food frying processes (WCO) was used as feedstock. Lipase from Geotrichum candidum was produced by submerged fermentation and used without prior purification as biocatalyst in WCO hydrolysis, which was optimized using a factorial design. A complete hydrolysis of WCO (44.1% mass fraction) was obtained after 80 min of reaction at 40 °C, performed in an emulsifier-free system with no buffer (40 °C and 900 rpm). In a subsequent step, FFA obtained from the hydrolysis reaction were esterified (40 °C, 200 rpm) using ethanol as acyl-acceptor (1:1.5) and Pseudomonas fluorescens lipase (PFL) immobilized on styrene-divinylbenzene (SDB) as biocatalyst (15% m/v). This biocatalyst was recycled for 6 cycles with no significant activity losses. The biodiesel composition was found by gas chromatography, and proton nuclear magnetic resonance (1H NMR) spectra and Fourier transform infrared spectroscopy (FTIR) were used to verify the quality and purity of biodiesel. Enzymatic biodiesel achieved FAEE content of 94.1 ± 0.5% and no traces of monoacyglycerol (MAG), diacylglycerol (DAG), triacylglycerol (TAG) or free glycerol were observed, indicating that the hydroesterification route produced high-quality biodiesel, despite the fact that WCO was used as feedstock.
Leishmaniasis are diseases caused by parasites belonging to
genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also ...have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from
. Three compounds were tested against
sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of
, without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in
-infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against
.
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