A systematic literature review of efficacy, effectiveness and safety of biologic therapies for treatment of familial Mediterranean fever.

OBJECTIVES: To identify and summarize the existing evidence on the efficacy, effectiveness and safety of biologic therapies used, either as indicated or off-label, in the treatment of FMF. METHODS: A systematic literature review was conducted using Embase®, MEDLINE®, MEDLINE®-In Process, and Cochrane databases to identify randomized/non-randomized controlled trials (RCTs/non-RCTs) and real-world observational studies of FMF published as full-text articles (2000-September 2017) or conference abstracts (2014-September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded. RESULTS: Of the 3342 retrieved records, 67 publications, yielding 38 unique studies, were included. All studies were published after the year 2010, and the majority (21) were full-text articles. Most studies (33/38) were prospective/retrospective observational; three were double-blind, placebo-controlled RCTs (one each of anakinra, canakinumab and rilonacept); and two were non-RCTs (both canakinumab). Anakinra (26), canakinumab (21) and etanercept (6) were the most frequently used biologics across studies, whereas use of adalimumab, tocilizumab, rilonacept and infliximab was limited (1-2 studies). The available evidence suggested benefits of anakinra and canakinumab in FMF. CONCLUSION: Anti-IL-1 therapies (i.e. anakinra and canakinumab) appear to be effective and safe options in the treatment of overall FMF, including patients with colchicine resistance and FMF-related amyloidosis. There is a need for properly designed prospective or controlled studies to conclude the superiority of one anti-IL-1 therapy over another. Evidence on the use of TNF-α and IL-6 inhibitors is limited, and further research is suggested.

Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects.

BACKGROUND: Methotrexate (MTX) is recognized as an anti-metabolite in cancer chemotherapy and is associated with various toxicities assigned to inflammation and oxidative stress. Rutin has been reported to have significant anti-inflammatory, antioxidant along with antiulcer properties. The present study was undertaken to corroborate the effect of rutin against MTX induced intestinal toxicity in experimental animals. METHOD: Six groups of rats (n = 6) were dosed with normal saline (3 ml/kg,i.p.); MTX (2.5 mg/kg,i.p.); rutin (50 and 100 mg/kg,i.p.); rutin + MTX (50 mg/kg + 2.5 mg/kg,i.p.); rutin + MTX (100 mg/kg + 2.5 mg/kg,i.p.) for seven consecutive days and sacrificed on eighth day. The intestinal contents were scrutinized physiologically (pH, total acidity, free acidity, CMDI), biochemically (TBARS, protein carbonyl, SOD, catalase and GSH) and for immunoregulatory cytokines (IL-2, IL-4 and IL-10). RESULTS AND DISCUSSION: The administration of rutin demonstrated significant protection against intestinal lesions damaged by MTX. The treatment with rutin elicited noticeable inhibition of free acidity (26.20%), total acidity (22.05%) and CMDI (1.16%) in the experimental animals similar to control. In MTX treated toxic group, the levels of oxidative markers and immunoregulatory cytokines significantly increased in comparison to control, which was subsequently restored after rutin treatment. Rutin also demonstrated 75.63, 81.00 and 80.43% inhibition of cyclooxygenase-1 and 2, and 15-lipoxygenase respectively. CONCLUSION: The positive modulation of MTX toxicity could be attributed to the free radical scavenging and anti-inflammatory (dual inhibition of arachidonic acid pathways) potential of rutin.

Correlates of the molecular vaginal microbiota composition of African women.

BACKGROUND: Sociodemographic, behavioral and clinical correlates of the vaginal microbiome (VMB) as characterized by molecular methods have not been adequately studied. VMB dominated by bacteria other than lactobacilli may cause inflammation, which may facilitate HIV acquisition and other adverse reproductive health outcomes. METHODS: We characterized the VMB of women in Kenya, Rwanda, South Africa and Tanzania (KRST) using a 16S rDNA phylogenetic microarray. Cytokines were quantified in cervicovaginal lavages. Potential sociodemographic, behavioral, and clinical correlates were also evaluated. RESULTS: Three hundred thirteen samples from 230 women were available for analysis. Five VMB clusters were identified: one cluster each dominated by Lactobacillus crispatus (KRST-I) and L. iners (KRST-II), and three clusters not dominated by a single species but containing multiple (facultative) anaerobes (KRST-III/IV/V). Women in clusters KRST-I and II had lower mean concentrations of interleukin (IL)-1α (p < 0.001) and Granulocyte Colony Stimulating Factor (G-CSF) (p = 0.01), but higher concentrations of interferon-γ-induced protein (IP-10) (p < 0.01) than women in clusters KRST-III/IV/V. A lower proportion of women in cluster KRST-I tested positive for bacterial sexually transmitted infections (STIs; ptrend = 0.07) and urinary tract infection (UTI; p = 0.06), and a higher proportion of women in clusters KRST-I and II had vaginal candidiasis (ptrend = 0.09), but these associations did not reach statistical significance. Women who reported unusual vaginal discharge were more likely to belong to clusters KRST-III/IV/V (p = 0.05). CONCLUSION: Vaginal dysbiosis in African women was significantly associated with vaginal inflammation; the associations with increased prevalence of STIs and UTI, and decreased prevalence of vaginal candidiasis, should be confirmed in larger studies.

A stochastic model for transmission, extinction and outbreak of Escherichia coli O157:H7 in cattle as affected by ambient temperature and cleaning practices.

Many infectious agents transmitting through a contaminated environment are able to persist in the environment depending on the temperature and sanitation determined rates of their replication and clearance, respectively. There is a need to elucidate the effect of these factors on the infection transmission dynamics in terms of infection outbreaks and extinction while accounting for the random nature of the process. Also, it is important to distinguish between the true and apparent extinction, where the former means pathogen extinction in both the host and the environment while the latter means extinction only in the host population. This study proposes a stochastic-differential equation model as an approximation to a Markov jump process model, using Escherichia coli O157:H7 in cattle as a model system. In the model, the host population infection dynamics are described using the standard susceptible-infected-susceptible framework, and the E. coli O157:H7 population in the environment is represented by an additional variable. The backward Kolmogorov equations that determine the probability distribution and the expectation of the first passage time are provided in a general setting. The outbreak and apparent extinction of infection are investigated by numerically solving the Kolmogorov equations for the probability density function of the associated process and the expectation of the associated stopping time. The results provide insight into E. coli O157:H7 transmission and apparent extinction, and suggest ways for controlling the spread of infection in a cattle herd. Specifically, this study highlights the importance of ambient temperature and sanitation, especially during summer.

Real-world effectiveness and safety of advanced therapies for the treatment of moderate-to-severe ulcerative colitis: Evidence from a systematic literature review.

BACKGROUND: Effectiveness and safety of advanced therapies for ulcerative colitis (UC) warrant assessment in the real world. OBJECTIVE: To perform a systematic review and summarize real-world evidence of advanced therapies approved for moderate-to-severe UC. METHODS: A systematic literature review was conducted using real-world studies of biologics or small molecules in UC using Embase, MEDLINE, and MEDLINE-In Process databases. Only products approved in any jurisdiction during the search were included. English-language full-papers (January 2005 to February 2022) and congress abstracts (January 2019 to February 2022) were included. Studies with less than 30 patients or only biologic-naive patients were excluded. RESULTS: A total of 139 studies were included out of 3,930 identified articles (75%, published between 2019 and 2022; 64%, retrospective observational; 53%, from 5 countries [Italy, United States, Spain, United Kingdom, and Belgium]). Most studies were single agent (highest: vedolizumab = 50, tofacitinib = 24, and adalimumab = 18), and rates of clinical remission (CR) and adverse events varied widely. From the published comparative effectiveness studies (16), the rates of CR were numerically higher with vedolizumab vs anti-tumor necrosis factor (TNF)-α agents. Compared with vedolizumab, the effectiveness of tofacitinib was numerically greater in CR (occasionally significant). Rates of steroid-free CR were comparable between ustekinumab and tofacitinib. Infliximab was the most effective anti-TNFα agent, as reported by 2 studies. Remarkably, adverse events were similar across therapies in comparative studies. CONCLUSIONS: Vedolizumab and tofacitinib were the most assessed therapies. In comparative studies, remission rates were numerically higher with tofacitinib vs vedolizumab and for vedolizumab vs anti-TNFα. Tofacitinib was comparable with ustekinumab for steroid-free CR. Safety was comparable across therapies. Future studies should explore the literature gaps identified, including limited comparative studies with small sample sizes, variations in study designs and patient characteristics, varied definitions of CR, and limited use of patient-reported outcome measures in real-world settings.

A new methodology to extrapolate disease freedom to an area using surveillance results from selected aquatic populations.

According to Chapter 1.4 of the World Organisation for Animal Health (WOAH) Aquatic Animal Health Code, an entire country or zone can be classified as free of a disease only if there is compelling evidence that all susceptible populations within the country or zone are free. However, the methods for achieving freedom are not prescribed in the WOAH standards and guidelines. Within this context, this paper describes a novel methodology to determine if surveillance results can be extrapolated from a study population to a target population. A framework of six criteria was developed to standardize a method for extrapolating surveillance results to other susceptible populations that have not been sampled. Criteria 1 assesses the internal validity for the freedom claim on the source population. Criteria 2 assesses which other susceptible populations have a non-negligible probability of exposure. Criteria 3 assesses whether the risk of infection upon exposure of the source population is the same or greater than each of the other susceptible populations. Finally, Criteria 4, 5 and 6 assess if the other susceptible populations would transmit the infection to the source population or if they have the same exposure pathways as the source population. We illustrate the use of this novel methodology using two hypothetical case scenarios. The presented methodology has the advantage of being applicable either retrospectively or prospectively. When applied retrospectively, it can be used to assess if the surveillance results of the source population can be extrapolated to the target population. When applied prospectively it can be used to design a more efficient surveillance system by selecting source populations from which it is easier to extrapolate surveillance results to the rest of the target population. Conclusions drawn using this methodology depend on the validity of the assumptions made when working through the methodology. We therefore recommend cautious application of the criteria and thorough review of all assumptions.

Model parameters influencing the cost-effectiveness of sacubitril/valsartan in heart failure: evidence from a systematic literature review.

OBJECTIVES: To summarize cost-effectiveness (CE) evidence of sacubitril/valsartan for the treatment of heart failure (HF) patients with reduced ejection fraction (HFrEF). The impact of different modeling approaches and parameters on the CE results is also described. METHODS: We conducted a systematic literature review using multiple databases: Embase®; MEDLINE®; MEDLINE®-In Process; NIHR CRD database including DARE, NHS EED, and HTA databases; and the Cost Effectiveness Analysis registry. We also reviewed HTA countries' websites to identify CE reports of sacubitril/valsartan, published up to 25-July-2021. Articles published in English as full-texts, conference-abstracts, or HTA reports were included. RESULTS: We included 44 CE models [39 from 37 publications (22 full-texts; 15 conference-abstracts) and 5 HTAs; Europe, n = 20; North and South Americas, n = 14; Asia and Australia, n = 10]. Most models adopted a Markov structure with constant transition probabilities of events (n = 27) or a mix of Markov and regression-based models (n = 16), with variations in structural assumptions and chosen parameters. Study authors concluded sacubitril/valsartan to be a cost-effective therapy in 37/41 models in chronic HFrEF patients and 2/3 models in hospitalized patients stabilized after an acute decompensation for HF. CE models showing sacubitril/valsartan not to be a cost-effective treatment generally modeled a shorter time horizon. Effect of sacubitril/valsartan on cardiovascular and all-cause mortality, cost, duration of effect and time horizon was the main model drivers. CONCLUSIONS: Most evidence indicated sacubitril/valsartan is cost-effective in HFrEF. The use of a lifetime horizon is recommended in future models as HF is a chronic disease. Data on the CE of sacubitril/valsartan in the inpatient setting were limited and further research is warranted.

Burden of elevated lipoprotein(a) among patients with atherosclerotic cardiovascular disease: Evidence from a systematic literature review and feasibility assessment of meta-analysis.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] level is an independent genetic risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD) by 2-4 fold. We aimed to report the burden of clinically relevant elevated Lp(a) in secondary prevention ASCVD population as the evaluation of such evidence is lacking. METHODS: A systematic literature review (SLR) was conducted using Embase®, MEDLINE®, and MEDLINE® In-Process databases to identify studies reporting burden of elevated Lp(a) levels from January 1, 2010, to March 28, 2022. Full-text, English-language studies including ≥500 participants with ≥1 Lp(a) assessment were included. RESULTS: Sixty-one studies reported clinical burden of elevated Lp(a). Of these, 25 observational studies and one clinical trial reported clinical burden of clinically relevant elevated Lp(a) levels. Major clinical outcomes included major adverse cardiovascular event (MACE; n = 20), myocardial infarction (MI; n = 11), revascularization (n = 10), stroke (n = 10), cardiovascular (CV) mortality (n = 9), and all-cause mortality (n = 10). Elevated Lp(a) levels significantly increased the risk of MACE (n = 15) and revascularization (n = 8), while they demonstrated a trend for positive association with remaining CV outcomes. Meta-analysis was not feasible for included studies due to heterogeneity in Lp(a) thresholds, outcome definitions, and patient characteristics. Three studies reported humanistic burden. Patients with elevated Lp(a) levels had higher odds of manifesting cognitive impairment (odds ratio [OR] [95% confidence interval; CI]: 1.62 [1.11-2.37]) and disability related to stroke (OR [95% CI]:1.46 [1.23-1.72)]) (n = 2). Elevated Lp(a) levels negatively correlated with health-related quality of life (R = -0.166, p = 0.014) (n = 1). A single study reported no association between elevated Lp(a) levels and economic burden. CONCLUSIONS: This SLR demonstrated a significant association of elevated Lp(a) levels with major CV outcomes and increased humanistic burden in secondary prevention ASCVD population. These results reinforce the need to quantify and manage Lp(a) for CV risk reduction and to perform further studies to characterize the economic burden.

Characteristics and lipid lowering treatment patterns in patients tested for lipoprotein(a): A real-world US study.

Objective: Elevated lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic cardiovascular disease (ASCVD) and has no approved pharmacotherapies. Limited real-world data exists on the proportion of patients with available Lp(a) test results, characteristics of these patients, and their use of lipid lowering therapies (LLTs) for secondary prevention (SP) and primary prevention (PP) of ASCVD. Methods: Patients with measured Lp(a) receiving LLTs for SP or PP of ASCVD were identified in the Optum Clinformatics® Data Mart database. Lp(a) distribution and LLT utilization including persistence and adherence were assessed. Logistic regression was used to assess the association between Lp(a) levels and low-density lipoprotein cholesterol (LDL-C) levels after index LLT, adjusting for baseline characteristics. Results: Overall, 2154 SP and 7179 PP patients met eligibility criteria. Of patients with available laboratory data, only 0.7% (SP) and 0.6% (PP) had Lp(a) test results. In the SP cohort, Lp(a) levels ≥125 nmol/L and ≥175 nmol/L were 26.4% and 17.6%, respectively, and the mean (SD) Lp(a) levels (overall SP cohort 90.4 [97.9] nmol/L) were highest in Black patients (123.4 [117.4]; p<0.001). Statin monotherapy was the most frequently prescribed LLT in SP patients overall (89.4%). Median (interquartile range [IQR]) persistence of LLTs was 227 (91, 649) days and 33.6% achieved ≥80% proportion of days covered (PDC). Patients with Lp(a) ≥175 nmol/L had 2.1 times greater odds of having elevated LDL-C (≥70 mg/dL) post-LLT than those with Lp(a) <175 nmol/L (p = 0.031). Similar findings were observed in the PP population. Conclusions: Lp(a) screening was rare. Elevated Lp(a) was observed in more than one-quarter of patients receiving LLTs, with the highest mean Lp(a) levels observed in Black patients. Low adherence to LLTs was prevalent and at least half of patients failed to achieve their respective LDL-C target thresholds despite treatment. Finally, high Lp(a) levels were associated with worse LDL-C control.

Differences in colonization and shedding patterns after oral challenge of cattle with three Escherichia coli O157:H7 strains.

Experimental oral challenge studies with three different genotypes of Escherichia coli O157:H7 were conducted in cattle to determine the genotype-specific variability in shedding frequencies and concentrations and the frequency and extent of contamination of the environment. The results indicated that the E. coli O157:H7 genotype and ecological origin maybe important factors for the occurrence and concentration in the cattle host. Four groups of six young Holstein steers each were orally challenged with 10(6) CFU of one of three E. coli O157:H7 strains: FRIK 47 (groups 1 and 2), FRIK 1641 (group 3), and FRIK 2533 (group 4). Recto-anal mucosal swabs (RAMS) and environmental samples were taken on alternate days over 30 days. The numbers of E. coli O157:H7 cells and generic E. coli cells per sample were determined. Also, the presence and absence of 28 gene targets were determined for 2,411 isolates using high-throughput real-time PCR. Over the study period, strains FRIK 47, FRIK 1641, and FRIK 2533 were detected in 52%, 42%, and 2% of RAMS, respectively. Environmental detection of the challenge strains was found mainly in samples of the hides and pen floors, with strains FRIK 47, FRIK 1641, and FRIK 2533 detected in 22%, 27%, and 0% of environmental samples, respectively. Based on the panel of 28 gene targets, genotypes of enterohemorrhagic E. coli (EHEC) and generic E. coli from the experimental samples were clustered into three subgroups. In conclusion, the results suggested that the type and intensity of measures to control this pathogen at the preharvest level may need to be strain specific.

Reasons for Initiating Canakinumab among Patients with Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease in the U.S. Real-World Settings.

INTRODUCTION: The aim of this study was to understand the reasons for canakinumab initiation among patients with Still's disease, including systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still's disease (AOSD), in US clinical practice. METHODS: Physicians retrospectively reviewed the medical charts of patients with Still's disease (regardless of age at symptom onset) who were prescribed canakinumab from 2016 to 2018. Patients aged < 16 years at symptom onset were classified as having SJIA and those aged ≥ 16 years at symptom onset (calculated from case-record forms) were classified as having AOSD. Patient treatment history and physician reasons for canakinumab initiation were analyzed. Overall results were presented as SJIA/AOSD. Sensitivity analyses were performed for the robustness of the results. RESULTS: Forty-three physicians in the USA (rheumatologists/dermatologists/immunologists/allergists: 51.2/27.9/11.6/9.3%; subspecialty in adults/pediatrics: 67.4/32.6%) abstracted information for 72 patients with SJIA/AOSD (SJIA/AOSD/age unknown at symptom onset: 75.0/18.1/6.9%; mean age 19.4 years; children 61.1%; females 56.9%). Most patients (90.3%) received treatment directly preceding canakinumab initiation (etanercept 27.7%; anakinra 18.5%; adalimumab 16.9%); the respective treatment was discontinued due to lack of efficacy/effectiveness (43.1%) and availability of a new treatment (27.8%). Most common reasons for canakinumab initiation were physician perceived/experienced efficacy/effectiveness of canakinumab (77.8%; children/adults: 81.8/71.4%), lack-of-response to previous treatment (45.8%; children/adults: 36.4/60.7%), convenient administration/dosing (26.4%; children/adults: 29.5/21.4%) and ability to discontinue/spare steroids (25.0%; children/adults: 20.5/32.1%). The sensitivity analysis provided similar results. CONCLUSIONS: In US clinical practice, physician perceived/experienced efficacy/effectiveness of canakinumab and lack-of-response to previous treatment were the primary reasons for canakinumab initiation among patients with SJIA/AOSD. Physician perceived/experienced efficacy/effectiveness and convenient administration/dosing of canakinumab were the most common reasons for canakinumab initiation among children, whereas lack-of-response to previous treatment and ability to discontinue/spare steroids being the most frequent reasons among adults.

Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents.

Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stellatin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were more than that of stellatin and indomethacin at 0.5mg/ear. The derivatives were further evaluated for antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its derivatives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors.

Simultaneous determination of naphthalene and anthraquinone derivatives in Rumex nepalensis Spreng. roots by HPLC: comparison of different extraction methods and validation.

INTRODUCTION: Rumex nepalensis contains mainly anthraquinone and naphthalene derivatives. Although HPLC methods have been reported for the analysis of anthraquinones, neither a phytochemical analysis of Rumex species nor the simultaneous determination of anthraquinone and naphthalene derivatives in other samples has been reported so far. OBJECTIVE: To develop and validate a HPLC method for the simultaneous determination of anthraquinone and naphthalene derivatives in R. nepalensis roots. METHODOLOGY: Anthraquinones and naphthalenes were extracted from R. nepalensis roots by three methods (reflux, ultrasonication and pressurized liquid extraction) using methanol. Separation was achieved on an RP C18 column with a gradient mobile phase consisting of 0.05% orthophosphoric acid in water (solvent A) and methanol (solvent B) using a UV detector (254 nm). RESULTS: Small differences were observed in the contents of anthraquinone and naphthalene derivatives extracted by the three methods. Chrysophanol-8-O-ß-D-glucopyranoside and nepodin were detected as major constituents. The method showed a good linearity (r² > 0.9992), high precision (RSD < 5%) and a good recovery (97-105%) of the compounds. The lowest detection limit was found to be 0.97 ng and the method was found to be robust. CONCLUSION: Reflux and ultrasonication were found to be the best suited methods for the extraction of glycosides and aglycones, respectively. The developed and validated HPLC method is simple, precise and accurate; and can hence be recommended as the method of choice for the analysis of anthraquinones and naphthalenes in R. nepalensis and other Rumex species for both quality control as well as routine analytical purposes.

Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States.

BACKGROUND: Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). METHODS: Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. RESULTS: Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). CONCLUSIONS: This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.

Synthesis and biological evaluation of arylidene analogues of Meldrum's acid as a new class of antimalarial and antioxidant agents.

A series of arylidene analogues of Meldrum's acid were synthesized and evaluated for in vitro antimalarial and antioxidant activities for the first time. The influence of various physico-chemical parameters such as dielectric constant (epsilon), donor number (DN), acceptor number (AN), hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), and solubilizing power of the solvents on Meldrum's acid anion generation and thus on promoting the Knoevenagel condensation of Meldrum's acid with aryl aldehydes has been discussed. Five compounds 9l, 9m, 9n, 9r, and 9s were found to be most active against Plasmodiumfalciparum with IC(50) values in the range of 9.68-16.11 microM. Compound 9l exhibited the most potent antimalarial activity (IC(50) 9.68 microM). The compounds were also found to possess antioxidant activity when tested against DPPH and ABTS free radicals.

Anti-inflammatory, cyclooxygenase (COX)-2, COX-1 inhibitory, and free radical scavenging effects of Rumex nepalensis.

Evaluation of the topical anti-inflammatory activity of chloroform and ethyl acetate extracts of RUMEX NEPALENSIS roots in a TPA-induced acute inflammation mouse model demonstrated a significant reduction in ear edema. The extracts were further tested on purified enzymes for COX-1 and COX-2 inhibition to elucidate their mechanism of action, and a strong inhibition was observed. Six anthraquinones and two naphthalene derivatives were isolated from the ethyl acetate extract. Among the isolated compounds, emodin was found to be a potent inhibitor with slight selectivity towards COX-2, and nepodin exhibited selectivity towards COX-1. Emodin, endocrocin, and nepodin also exhibited significant topical anti-inflammatory activity in mice. Interestingly, nepodin showed better radical scavenging activity than trolox and ascorbic acid against DPPH and ABTS radicals. The strong radical scavenging activity of chloroform and ethyl acetate extracts could be explained by the presence of nepodin as well as by the high phenolic content of the ethyl acetate extract. Thus, the anti-inflammatory effect of R. NEPALENSIS roots was assumed to be mediated through COX inhibition by anthraquinones and naphthalene derivatives and through the radical scavenging activities of naphthalene derivatives.

Evaluation of the effects of transendoscopic diode laser palatoplasty on clinical, histologic, magnetic resonance imaging, and biomechanical findings in horses.

OBJECTIVE: To determine the effects of diode laser palatoplasty on the soft palate in horses. ANIMALS: 6 clinically normal horses and 6 euthanized horses from another study. PROCEDURES: 6 horses underwent diode laser palatoplasty (treated horses); 3 received low-dose laser treatment (1,209 to 1,224 J), and 3 received high-dose treatment (2,302 to 2,420 J). Six other horses received no treatment (control horses). The upper respiratory tracts of all treated horses were evaluated immediately following surgery (day 0) and on days 2, 7, 14, 21, 30, and 45. Horses were euthanized on day 45, and magnetic resonance imaging (MRI) of the head was performed. The soft palate was removed from treated and control horses, evaluated grossly, and scored for edema, inflammation, and scarring. Soft palates from all horses were sectioned for histologic and biomechanical evaluations. RESULTS: Endoscopic examination revealed a significant increase in soft palate scarring and decrease in edema and inflammation in treated horses by day 7. Gross postmortem findings corresponded with MRI findings. Gross and histologic examination revealed a significant increase in scarring, edema, and inflammation at day 45. Histologic evaluation of palatal tissue from high-dose-treated horses revealed full-thickness injury of skeletal muscle, with atrophy of muscle fibers; findings in low-dose-treated horses indicated superficial injury to skeletal muscle. After surgery, treated horses had a significant decrease in soft palate elastic modulus, compared with control horses. CONCLUSIONS AND CLINICAL RELEVANCE: Laser palatoplasty resulted in soft palate fibrosis and skeletal muscle loss; however, the fibrosis did not result in an increase in soft palate elastic modulus.

Detection of antibodies against Leptospira serovars via microscopic agglutination tests in dogs in the United States, 2000-2007.

OBJECTIVE: To use results of microscopic agglutination tests (MATs) conducted at a commercial veterinary diagnostic laboratory to determine temporal and demographic distributions of positive serologic test results for leptospirosis in dogs and identify correlations among results for various Leptospira serovars. DESIGN: Serosurvey. STUDY POPULATION: MAT results for 33,119 canine serum samples submitted to a commercial veterinary diagnostic laboratory from 2000 through 2007. PROCEDURES: Electronic records of MAT results for dogs were obtained from a veterinary diagnostic laboratory. Seropositivity for antibodies against Leptospira serovars was determined by use of a cutoff titer of >or=1:1,600 to reduce the possible impact of postvaccinal antibodies on results. Correlations between results for all possible pairs of serovars were calculated by ordinal ranking of positive (>or=1:100) antibody titer results. RESULTS: 2,680 samples (8.1%; 95% confidence interval [CI], 7.8% to 8.4%) were seropositive for antibodies against Leptospira serovars. The highest percentage of positive MAT results was for the year 2007 (10.2%; 95% CI, 9.5% to 10.9%) and for the months of November and December during the study period. Antibodies were most common against serovars Autumnalis, Grippotyphosa, Pomona, and Bratislava. Seroprevalence of leptospirosis was lowest for dogs>10 years of age but was similar across other age strata. CONCLUSIONS AND CLINICAL RELEVANCE: Leptospirosis can affect dogs of small and large breeds and various ages. Although an increase in proportions of positive MAT results was evident in the fall, monthly and annual variations suggested potential exposure in all months. Because of the limitations of MAT results and the limited number of serovars used in the test, bacterial culture should be used to identify infective Leptospira serovars.

Systematic literature review of efficacy/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome.

OBJECTIVES: Several therapies are used for the treatment of rareautoinflammatory conditions like cryopyrin-associated periodic fever syndromes (CAPS), hyperimmunoglobulin Dsyndrome (HIDS)/mevalonate kinase deficiency (MKD) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS). However, reviews reporting on treatment outcomes of these therapies are lacking. METHODS: A systematic literature review was conducted using Embase, MEDLINE, MEDLINE-In Process and Cochrane databases to identify the randomised/non-randomised controlled trials (RCTs/non-RCTs) and real-world observational studies of CAPS, HIDS/MKD and TRAPS published as full-texts (January 2000-September 2017) or conference abstracts (January 2014-September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded. RESULTS: Of the 3 342 retrieved publications, 72 studies were included (CAPS, n=43; HIDS/MKD, n=9; TRAPS, n=7; studies with ≥2 cohorts, n=13). Most studies were full-text (n=56), published after 2010 (n=56) and real-world observational studies (n=58). Among included studies, four were RCTs (canakinumab, n=2 (CAPS, n=1; HIDS/MKD and TRAPS, n=1); rilonacept, n=1 (in CAPS); simvastatin, n=1 (in HIDS/MKD)). Canakinumab and anakinra were the most commonly used therapies for CAPS and HIDS/MKD, whereas etanercept, canakinumab and anakinra were the most common for TRAPS. The available evidence suggested the efficacy or effectiveness of canakinumab and anakinra in CAPS, HIDS/MKD and TRAPS, and of etanercept in TRAPS; asingle RCT demonstrated the efficacy of rilonacept in CAPS. CONCLUSIONS: Canakinumab, anakinra, etanercept and rilonacept were reported to be well tolerated; however, injection-site reactions were observed frequently with anakinra, rilonacept and etanercept. Data on the use of tocilizumab, infliximab and adalimumab in these conditions were limited; thus, further research is warranted.

Recent developments in anti-inflammatory natural products.

Many of the inflammatory diseases are becoming common in aging society throughout the world. The clinically used anti-inflammatory drugs suffer from the disadvantage of side effects and high cost of treatment (in case of biologics). Alternative to these drugs are traditional medicines and natural products, which offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Since ancient times traditional medicines and phytopharmaceuticals are being used for the treatment of inflammatory and other disorders. The present review article describes anti-inflammatory natural products derived from plants and marine sources reported during last decade. The compounds described belong to different chemical classes such as alkaloids, steroids, terpenoids, polyphenolics, phenylpropanoids, fatty acids and lipids, and various miscellaneous compounds. The attempt is also being made to enumerate the possible leads, e.g. curcumin, resveratrol, baicalein, boswellic acid, betulinic acid, ursolic acid, and oleanolic acid, for further development with the help of structure-activity relationship (SAR) studies and their current status. In addition SAR studies carried out on the anti-inflammatory activity of flavonoid compounds and clinical studies performed on anti-inflammatory natural products are also discussed.