Costunolide ameliorates angiotensin II-induced atrial inflammation and fibrosis by regulating mitochondrial function and oxidative stress in mice: A possible therapeutic approach for atrial fibrillation.

Atrial fibrillation (AF) is a cardiac disease characterized by disordered atrial electrical activity. Atrial inflammation and fibrosis are involved in AF progression. Costunolide (COS) is a sesquiterpene lactone containing anti-inflammatory and anti-fibrotic activities. This study aims to explore the underlying mechanisms by which COS protects against AF. Male C57BL/6 mice (8- to 10-week-old) were infused with angiotensin (Ang) II for 3 weeks. Meanwhile, different doses of COS (COS-L: 10 mg/kg, COS-H: 20 mg/kg) were administered to mice by intragastric treatment. The results showed irregular and rapid heart rates in Ang II-treated mice. Moreover, the levels of inflammatory cytokines and fibrotic factors were elevated in mice. COS triggered a reduction of Ang II-induced inflammation and fibrosis, which conferred a protective effect. Mechanistically, mitochondrial dysfunction with mitochondrial respiration inhibition and aberrant ATP levels were observed after Ang II treatment. Moreover, Ang-II-induced excessive reactive oxygen species caused oxidative stress, which was further aggravated by inhibiting Nrf2 nuclear translocation. Importantly, COS diminished these Ang-II-mediated effects in mice. In conclusion, COS attenuated inflammation and fibrosis in Ang-II-treated mice by alleviating mitochondrial dysfunction and oxidative stress. Our findings represent a potential therapeutic option for AF treatment.

Nerolidol attenuates dehydroepiandrosterone-induced polycystic ovary syndrome in rats by regulating oxidative stress and decreasing apoptosis.

AIMS: Although nerolidol (NRL) is a naturally occurring sesquiterpene alcohol with many pharmacological activities, its role in dehydroepiandrosterone DHEA-induced polycystic ovary syndrome PCOS is unknown. This study aims to explore the potential beneficial effects and underlying molecular mechanisms of nerolidol treatment on polycystic ovary syndrome. MAIN METHODS: Pre-pubertal female Sprague-Dawley rats were randomly assigned into four groups (n = 8/group); group I: control; group II: PCOS; group III: P + NRL; group IV: NRL. Biochemical parameters related to oxidative stress, inflammation, apoptosis, and hormones were estimated in the blood and ovarian tissues. Histopathological, ultrastructural, and immunohistochemical analyses were performed. Bax, P53, Cas-3, and Bcl-2 gene expression levels were detected with RT-PCR. The membrane array analysis detected chemokine, cytokine, and growth factor protein profiles. KEY FINDINGS: In light of the available data, it can deduce that nerolidol has a significant ameliorating effect on lipid peroxidation, oxidative stress, inflammation, histopathological damage, and apoptosis accompanying PCOS in female rats. SIGNIFICANCE: PCOS is not only a reproductive pathology but also a systemic condition and its etiopathogenesis is still not fully understood. Since changes in PCOS have important long-term effects on health, this study evaluated the efficacy of nerolidol, a phytotherapeutic for the control of biochemical, apoptotic, histopathological, and metabolic changes.

Allergic contact dermatitis to Compositae: An Australian case series.

BACKGROUND: Allergic contact dermatitis (ACD) to Compositae is caused by sensitisation to sesquiterpene lactones (SQLs) and subsequent exposure can occur from direct handling or from airborne transmission. Plants from the Compositae family are ubiquitous globally and their plant extracts are also used in various products. OBJECTIVES: Investigation of contact allergy (CA) and allergic contact dermatitis (ACD) to Compositae at a single dermatology centre. METHODS: A retrospective case review was performed on patients undergoing patch testing to Compositae between January 2011 and December 2020 in Melbourne, Australia. RESULTS: Of 3679 patients, 44 (1.2%) patch tested positive to Compositae and 19 (43.2%) reactions were deemed relevant. Thirteen cases (68.4%) were from direct contact with Compositae plants, mostly in gardeners. Six cases (31.6%) were from personal products and all these patients were female. Involvement of the face was significant (p = 0.007). Simultaneous allergic reactions included SQL mix in eight (42.1%), fragrance mix in seven (36.8%), potassium dichromate in three (15.8%) and colophonium in two (10.5%) cases. CONCLUSION: Contact with Compositae from gardening contributed most cases of ACD; however, personal products accounted almost one-third of cases. Treatment options remain limited and avoidance is the most important aspect of management.

Contribution of spathulenol to the anti-nociceptive effects of Psidium guineense.

Objectives: Araçá-verdadeiro is the popular name of Psidium guineense (Myrtaceae), whose fruits and leaves are used in Brazilian folk medicine for treatment of inflammation and pain. The focus of the present research was an investigation of the anti-nociceptive, and anti-inflammatory effects of the essential oil from P. guineense (EOPG) leaves, and of spathulenol. The anxiolytic and antidepressive effects associated with chronic pain were also investigated in models of acute or persistent nociception or/and inflammatory pain.Methods and Results: Oral treatment with EOPG (10-100 mg/kg) or spathulenol (10 mg/kg) significantly inhibited formalin-induced nociceptive responses, both sensitivity to cold and edema. Oral treatment with EOPG (10 mg/kg) and spathulenol (10 mg/kg) did not reduce locomotor activity (open field test). Local administration of spathulenol (1000 µg/paw) significantly prevented formalin-induced nociceptive sensitivity to cold and paw edema, and carrageenan-induced mechanical hyperalgesia, paw edema and sensitivity to cold. In the Freund's complete adjuvant (CFA) model, oral treatment with EOPG (10 mg/kg) or spathulenol (10 mg/kg) for 21 days significantly inhibited all analyzed parameters. The percentage maximal inhibition by spathulenol was 76.00% (mechanical hyperalgesia), 71.90% (cold response), 85.00% (edema), 77.16% (myeloperoxidase activity), 97.72% (time in the closed arms in the elevated plus maze), and 49.00% (immobility time in the tail suspension test), in the CFA model. Models employed male Swiss mice, except for the CFA test, which employed C57bL6 male mice (n=6 /group).Conclusion: This study demonstrates that EOPG is an anti-nociceptive and anti-hyperalgesic agent, in acute and continuous treatment, and an anxiolytic and antidepressive agent when tested with the chronic pain experimental state.

Expanding Patch Testing Beyond the Baseline Series: Usefulness of Customized Antimicrobials, Vehicles, and Cosmetics Series.

BACKGROUND: Testing cosmetics and their ingredients is essential to avoid missing relevant allergens and to monitor fluctuating incidence of hypersensitivity. OBJECTIVE: The aim of this study was to review the usefulness of patch testing with a customized antimicrobials, vehicles, and cosmetics (AVC) series over 15 years at a single Canadian site. METHODS: Between January 1, 2005, and December 31, 2019, patients suspected of having cosmetics allergy were patch tested with a 40-allergen AVC series in addition to the North American Contact Dermatitis Group standard screening series. We reviewed the patch test results of 2868 patients. RESULTS: We consecutively patch tested with the baseline series 6103 patients, of which 2868 (47%) were also tested with the AVC series. Of 53 different allergens that were tested at some point, 26 remained in the series throughout the 15-year span. The most common positive allergens were thimerosal (4.52%), polyvidone-iodine (2.25%), propolis (2.06%), sodium metabisulfite (1.94%), dodecyl gallate (1.53%), carmine (1.10%), lauryl glucoside (1.01%), sandalwood oil (0.7%), and tert-butylhydroquinone (0.7%). CONCLUSIONS: Although the expansion of the North American Contact Dermatitis Group standard screening series has decreased the yield from the AVC series from 21.1% to 13.9%, it still remains a useful adjunct for patients suspected of having cosmetics or disinfectants allergy.

Sesquiterpenes and their derivatives-natural anticancer compounds: An update.

Sesquiterpenes belong to the largest group of plant secondary metabolites, which consist of three isoprene building units. These compounds are widely distributed in various angiosperms, a few gymnosperms and bryophytes. Sesquiterpenes and their allied derivatives are bio-synthesized in various plant parts including leaves, fruits and roots. These plant-based metabolites are predominantly identified in the Asteraceae family, wherein up to 5000 complexes have been documented to date. Sesquiterpenes and their derivatives are characteristically associated with plant defence mechanisms owing to their antifungal, antibacterial and antiviral activities. Over the last two decades, these compounds have been reportedly demonstrated health promoting perspectives against a wide range of metabolic syndromes i.e. hyperglycemia, hyperlipidemia, cardiovascular complications, neural disorders, diabetes, and cancer. The high potential of sesquiterpenes and their derivatives against various cancers like breast, colon, bladder, pancreatic, prostate, cervical, brain, liver, blood, ovarium, bone, endometrial, oral, lung, eye, stomach and kidney are the object of this review. Predominantly, it recapitulates the literature elucidating sesquiterpenes and their derivatives while highlighting the mechanistic approaches associated with their potent anticancer activities such as modulating nuclear factor kappa (NF-kB) activity, inhibitory action against lipid peroxidation and retarding the production of reactive oxygen & nitrogen species (ROS&RNS).

Compositae sensitization in Danish children and adolescents.

BACKGROUND: Compositae plant sensitization in children is relatively frequent. From 1995-2006, we found a prevalence of 1.8% sesquiterpene lactone (SL) mix/parthenolide patch test positives among consecutive eczema patients <18 years. OBJECTIVES: To report the results of patch test screening for Compositae sensitization in patients <18 years in the last 13 years. METHODS: Children and adolescents <18 years, diagnosed with Compositae sensitization between 2007 and 2019, were included. RESULTS: Among 388 children tested, 12 (3%) were Compositae-sensitized, and 11 (2.8%) had positive reactions to SL mix. Compositae mix 5% pet. elicited positive reactions in six of seven patients tested, and dandelion extract 2.5% pet. in six of 10 patients tested. The mean age of the five girls and seven boys was 9.4 years and 11.7 years, respectively. Eleven children had a personal and one a family history of atopy, and 11 children had hand eczema. Only two were mono-sensitized to Compositae. CONCLUSIONS: SL mix is a suitable screening agent among children and adolescents in our area, well supplemented with Compositae mix 5% and dandelion extract. The study emphasizes the importance of Compositae screening in children with a personal and/or family history of atopy, hand eczema or widespread airborne dermatitis, summer exacerbation, and plant exposure.

Oral provocation of patients allergic to sesquiterpene lactones with German chamomile tea to demonstrate possible systemic allergic dermatitis.

BACKGROUND: Most patients with contact allergy to Asteraceae plants are patch test positive to sesquiterpene lactone mix (SLM). There are several reports among these patients of a flare-up of hand eczema after ingestion of food and beverages originating from Asteraceae plants. AIM: To investigate whether German chamomile tea can elicit systemic allergic dermatitis. PATIENTS AND METHODS: Individuals with or without contact allergy to SLM were patch tested with an extract of German chamomile tea. Six weeks later, they were provoked with capsules containing either freeze-dried German chamomile tea or placebo capsules containing lactose, in a double-blind, randomized study. A numerical rating scale (NRS) was used to ascertain the volunteers' opinion of their hand eczema status. The study individuals were examined to detect a possible flare-up of healed patch test reactions to chamomile. RESULTS: None of the subjects had a flare-up of healed patch test reactions. According to the NRS, SLM-positive individuals experienced a significant worsening of hand eczema, independently of whether they received chamomile or lactose capsules. CONCLUSION: No evidence suggestive of systemic allergic dermatitis was found.

Elemene injection combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND: To evaluate the short-term efficacy, long-term efficacy, and adverse events (AEs) of elemene plus transcatheter arterial chemoembolization (TACE) in comparison with TACE alone for the treatment of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, the Cochrane Library, the Chinese Scientific Journal Full-text Database, Wanfang Data, CBM, and VIP were searched by 2 reviewers using the same search strategy for clinical studies on elemene plus TACE in the treatment of HCC. These articles were screened according to pre-established inclusion and exclusion criteria, and the qualities of the included studies were assessed using the Newcastle-Ottawa scale. The primary outcomes were the objective response rate (ORR), the 1-year survival rate and AEs. Review Manager 5.3 and Stata 15.0 were used for the meta-analysis. RESULTS: A total of 10 studies involving 543 patients (TACE + elemene = 277, TACE alone = 266) were included. The results showed that the ORR was significantly improved in the combined treatment group compared to the TACE alone group (odds ratio [OR] = 2.72, 95% confidence interval [CI]: 1.84-4.00, P < .05). TACE + elemene significantly increased the 1-year survival rate (OR = 2.79, 95% CI: 1.58-4.95, P < .05). We also found no significant difference in gastrointestinal reactions (OR = 0.97, 95% CI: 0.57-1.64, P = .90), fever (OR = 0.80, 95% CI: 0.37-1.71, P = .56), or bone marrow suppression (OR = 0.73, 95% CI: 0.44-1.22, P = .23) between the 2 groups. CONCLUSION: Based on current findings, TACE + elemene injection may improve the ORR and the 1-year survival rate for HCC patients compared to TACE alone. Arterial perfusion may be superior to intravenous guttae.

Screening for Compositae contact sensitization with sesquiterpene lactones and Compositae mix 2.5% pet.

BACKGROUND: Compositae contact sensitization may be difficult to diagnose, because of a lack of reliable screening allergens. OBJECTIVES: To assess the suitability of Compositae mix II 2.5% pet. (CM2.5) as a screening mix in the baseline series combined with sesquiterpene lactone (SL) mix and parthenolide (PTH). METHODS: CM2.5 was added to the baseline series, which included SL mix and PTH 0.1% pet., in January 2015, and PTH was included in TRUE Test Panel 3 in October 2015. All Compositae-sensitive patients diagnosed or tested in the next 4 years were assessed. RESULTS: Altogether, 57 patients (2.7%) presented with Compositae allergy. On primary testing in 53 newly diagnosed patients, SL mix elicited positive reactions most frequently (53% positive), followed by CM2.5 (47% positive), and PTH (45% positive). CM2.5 and PTH pet. elicited a few irritant reactions. Three patients had late reactions. Altogether, 16 patients (28%) were not detected by any of the three screening agents. CONCLUSIONS: SL mix is an indispensable, although insufficient, screening mixture in Denmark. It may be relatively safely supplemented with CM2.5 and PTH in the TRUE Test system for screening, but, when Compositae sensitization is suspected, further extracts should be tested on the basis of the history.

Contact sensitization to plants of the Compositae family: Data of the Information Network of Departments of Dermatology (IVDK) from 2007 to 2016.

BACKGROUND: The Compositae plant family includes many thousands of species, making it one of the most widespread group of plants worldwide. Sensitization to Compositae allergens may occur in private or in occupational settings. OBJECTIVES: To monitor the current spectrum of sensitization to Compositae allergens, especially in cooks and florists. METHODS: We retrospectively analysed patch test results obtained with two Compositae mixes (CMs) (CM I and CM II; switch in October 2011), their individual components, and sesquiterpene lactone (SL) mix in 1492 cooks, 851 florists, and a control group (118 358 other patients) registered in the IVDK, 2007 to 2016. RESULTS: Florists reacted significantly more frequently to CM I and II (CM I, 8.7%; CM II, 10.6%) than did cooks (CM I, 2.1%; CM II, 0.8%) and controls (CM I, 1.3%; CM II, 1.2%). Additional testing with SL mix detected 14.3% more sensitizations than CM I or CM II alone. CONCLUSIONS: Florists are at considerable risk of sensitization to Compositae allergens. Patch testing with both CM and SL mix is recommended.

Evaluation of the anti-inflammatory and urotoxicity ameliorative effects of γ-humulene containing active fraction of Emilia sonchifolia (L.) DC.

In folklore medicine, the plant Emilia sonchifolia, belonging to the family Asteraceae, is used for treating tumour and inflammation. In our previous studies, we have done a thorough phytochemical investigation of E. sonchifolia with a report on its potent antimetastatic activity. Further, we isolated and characterised its active fraction (AFES) containing the major compound γ-humulene with an evaluation of the antiangiogenic effect of AFES (5 mg/kg b.wt.). In the first part of the present study, AFES in different concentrations was used for the assessment of its possible anti-inflammatory effect employing three in vivo inflammatory models. Further using the most effective concentration of AFES 5 mg/kg b.wt, its effect on proinflammatory cytokine levels was recorded along with a confirmatory gene expression analysis. The results manifested with a reduction in the paw oedema significantly decreased levels of proinflammatory cytokines, C-reactive protein, nitric oxide and also there was an efficient downregulation of cyclooxygenase-2 and inducible nitric oxide. Urotoxicity is one of the major side effects of conventional chemotherapy. So in the second part of the study, we used AFES in combination with the conventional therapeutic agent cyclophosphamide in vivo in mice. The effect of AFES on urotoxicity was assessed from various biochemical parameters, cytokine markers and finally with a histopathology of the bladder. The current study revealed the protective effects of AFES, implicating reduced levels of urea nitrogen, by revamping of glutathione and marker cytokine levels towards positive amelioration. The results obtained altogether proved the safeguarding effect of AFES in murine experimental models.

Evaluation of the efficacy and safety of elemene in treating malignant pleural effusion caused by tumors: A PRISMA guided meta-analysis.

OBJECTIVE: Elemene is widely used to treat malignant pleural effusion in China. This meta-analysis aimed to evaluate the efficacy and safety of elemene in treating malignant pleural effusion. METHODS: Electronic databases including Pubmed, the Cochrane Library, Embase and Chinese biomedical literature database were searched until March 2017. Clinical controlled trials (CCTs) assessing the efficacy and safety of elemene in the treatment of malignant pleural effusion were included. The quality of the included studies was evaluated using the quality evaluation criteria of the Cochrane Handbook version 5.1.0. RESULTS: A total of 46 CCTs were included, with 2992 patients. Results of meta-analysis showed that elemene significantly improved the overall response rate (ORR) in controlling malignant pleural effusion (risk ratio [RR] = 1.16; 95% CI: 1.08-1.23; P < .05). Subgroup results showed that the ORR of elemene in the treatment of lung cancer patients with malignant pleural effusion (RR = 1.20, 95% CI: 1.07-1.34; P < .05) was higher than that of other cancers (RR = 1.14, 95% CI: 1.05-1.23; P < .05). Meanwhile, elemene did not significantly increase the incidences of chest pain and fever (P > .05). CONCLUSION: Elemene is suggested to have the ability of improving the treatment outcome of malignant pleural effusion with acceptable safety.

Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity.

Cancer is one of the most dangerous diseases that are rapidly increasing globally. After heart disease, it is the second leading cause of death, accounting for seven million deaths each year. Chemotherapy is the use of cytotoxic drugs on cancer cells. But the use of common chemotherapy drugs poses a problem due their high side effects and low efficacy. As a result, efforts are on to find new potent compounds with low side effects. The compounds extracted from plants have been studied in this regard due to their prevalence. Sesquiterpene lactones are a group of natural compounds that were first detected in Asteraceae dark plants. These compounds exercise their effects by reacting with functional groups available on proteins and enzymes, especially the thiol group. Owing to the high side effects as an antitumor synthetic drugs, efforts are being made to find drugs with high efficiency and low side effects. Their high structural ranges have attracted the attention of many researchers as a potential source of new anticancer drugs.

Non-clinical toxicity of ß-caryophyllene, a dietary cannabinoid: Absence of adverse effects in female Swiss mice.

ß-caryophyllene is a food additive that is found in food plants and has broad pharmacological potential. However, little toxicological information has been reported and its use is based on the fact that this bicyclic sesquiterpene is daily consumed as a plant food in much larger quantities than as a food additive. Thus, this study evaluated acute (14-day) and repeated-dose (28 days) oral ß-caryophyllene toxicity in female Swiss mice analyzing changes in body weight, food intake, water intake, hematological and biochemical parameters, organ weight after necropsy, oxidative stress markers and histopathology of various tissues. Acute (300 and 2000 mg/kg) and repeated-dose (300 and 2000 mg/kg) toxicity studies were performed according to the Organization for Economic Cooperation and Development (OECD) guideline 423 and 407, respectively. There was absence of adverse clinical signs and mortality in any animal subjected to acute and repeated-dose toxicity study. In addition, no significant changes in body weight, food and water intake, oxidative stress biomarkers, hematological and biochemical parameters were observed when compared to control group from single-dose and repeated-dose toxicity study. Therefore, the results of this study provide an understanding of the toxicity profile of ß-caryophyllene which can be considered a compound with toxicity at doses higher than 2000 mg/kg body weight.

Efficacy and Safety of Serotonin Receptor Ligands in the Treatment of Irritable Bowel Syndrome: A Review.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. OBJECTIVE: This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. RESULTS AND CONCLUSION: We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi.

BACKGROUND: Leishmaniasis and Chagas disease are life-threatening illnesses caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. They are known as "neglected diseases" due to the lack of effective drug treatments and the scarcity of research work devoted to them. Therefore, the development of novel and effective drugs is an important and urgent need. Natural products are an important source of bioactive molecules for the development of new drugs. In this study, we evaluated the activity of enhydrin, uvedalin and polymatin B, three sesquiterpene lactones (STLs) isolated from Smallanthus sonchifolius, on Leishmania mexicana (MNYC/BZ/62/M) and Trypanosoma cruzi (Dm28c). In addition, the in vivo trypanocidal activity of enhydrin and uvedalin and the effects of these STLs on parasites' ultrastructure were evaluated. METHODS: The inhibitory effect of the three STLs on the growth of L. mexicana amastigotes and promastigotes as well as T. cruzi epimastigotes was evaluated in vitro. The changes produced by the STLs on the ultrastructure of parasites were examined by transmission electron microscopy (TEM). Enhydrin and uvedalin were also studied in a murine model of acute T. cruzi infection (RA strain). Serum activities of the hepatic enzymes alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase were used as biochemical markers of hepatotoxicity. RESULTS: The three compounds exhibited leishmanicidal activity on both parasite forms with IC50 values of 0.42-0.54 µg/ml for promastigotes and 0.85-1.64 µg/ml for intracellular amastigotes. Similar results were observed on T. cruzi epimastigotes (IC50 0.35-0.60 µg/ml). The TEM evaluation showed marked ultrastructural alterations, such as an intense vacuolization and mitochondrial swelling in both L. mexicana promastigotes and T. cruzi epimastigotes exposed to the STLs. In the in vivo study, enhydrin and uvedalin displayed a significant decrease in circulating parasites (50-71%) and no signs of hepatotoxicity were detected. CONCLUSIONS: Enhydrin, uvedalin and polymatin B possess significant leishmanicidal and trypanocidal activity on different parasite stages. These results show that these compounds may provide valuable leads for the development of new drugs against these neglected parasitic diseases.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

NEOADJUVANT СHEMOTHERAPY FOR LOCALLY ADVANCED BREAST CANCER.

93 patients with LABC (T2N1-2M0, T3N0-2M0) at the age from 35 to 75 years were included in the trial. With 2 stage - 60 patients, with the third stage - 33 patients. All patients were randomized into 3 groups: The I control group (n=36) received 4 courses of neoadjuvant chemotherapy according to AC-protocol (doxorubicin 50 mg/m2, cyclophosphan-500 mg/m2 on day 1, repeated every three weeks) followed by radical mastectomy, 4 courses of adjuvant chemotherapy (АС), radiotherapy and hormone therapy if indicated. II investigative group (n=30) received the same CTX but in combination with Arglabin at a dose of 370 mg/m2 for 7 days. III investigative group (n=27) received Arglabin as monotherapy. The clinical efficacy of neoadjuvant chemotherapy according to the scheme of AC and AC + arglabin was the same and significantly exceeded Arlabine monotherapy. There was no statistically significant difference in pathological response in patients of all three groups. Arglabin has very low toxicity and eliminates the toxic effects of standard chemotherapy.