Antinociceptive and anti-inflammatory activity of extracts and α-pyrones isolated from Cantinoa stricta.

This study evaluated the composition and the antinociceptive and anti-inflammatory activity of the crude extracts and two isolated compounds, anamarine (ANA) and 10-epi-olguine (eOL), obtained from the leaves of Cantinoa stricta (Lamiaceae). Crude ethanolic extract (EEt) and dichloromethane extract (DCM), selected based on NMR data, were submitted to pharmacological tests in male Swiss mice. The oral administration of EEt and DCM significantly reduced the second phase of formalin-induced nociception (60%), lipopolysaccharide (LPS)-induced mechanical hyperalgesia (90%), and carrageenan (Cg)-induced edema (25%). ANA and eOL, the major compounds in EEt and DCM extracts, administered orally or locally (in the paw), also reduced the LPS-induced mechanical hyperalgesia (Oral ID50 1.9 and 3.9 mg/kg; Local ID50 93.4 and 677.3 ng, respectively) without changing the thermal acute nociception or the motor performance of the animals. Local administration of ANA and eOL also reduced Cg-induced edema (40 and 23%, respectively). These isolated compounds did not change the mechanical hyperalgesia induced by tumor necrosis factor-α, interleukin-1ß, prostaglandin E2, dibutyryl cyclic AMP, or forskolin but reversed the hyperalgesia induced by dopamine, epinephrine, and phorbol 12-myristate 13-acetate. The hyperalgesia induced by epinephrine was reversed in male but not in female mice, in which this response is not dependent on protein kinase C (PKC). These results suggest that C. stricta extracts possess antinociceptive and anti-inflammatory activity which is related to the presence of ANA and eOL. Differently from the known analgesics, these substances seem to exert their action mainly interfering with the sympathetic component of pain, possibly with PKC.

Ferric Maltol: A New Oral Iron Formulation for the Treatment of Iron Deficiency in Adults.

OBJECTIVE: To review the pharmacology, efficacy, and safety of ferric maltol (FM), an oral iron formulation, for iron deficiency anemia (IDA). DATA SOURCES: A MEDLINE/PubMed and EMBASE (January 1, 1985, to June 19, 2020) literature search was performed using the terms ferric maltol, accrufer, feraccru, iron maltol, ferric trimaltol, iron deficiency, iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease. Additional data sources included prescribing information, abstracts, and the National Institutes of Health Clinical Trials Registry. STUDY SELECTION/DATA EXTRACTION: English language literature evaluating FM pharmacology, pharmacokinetics, efficacy, or safety in the treatment of IDA were reviewed. DATA SYNTHESIS: FM is a ferric, non-salt-based oral iron formulation demonstrating improved tolerance in patients with previous intolerance to other iron formulations. Phase 3 trials demonstrated significant improvements in anemia and serum iron parameters in patients with inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Common adverse effects were gastrointestinal intolerance. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: FM is an effective and well-tolerated alternative to oral iron salts for patients with IBD or CKD and IDA. Emerging data suggest that FM is noninferior to intravenous (IV) ferric carboxymaltose in patients with IBD and IDA. Prior to selecting FM over IV iron products, consideration should be given to time to normalization of Hb, ease of administration, cost, and tolerability. CONCLUSION: FM is a relatively safe, effective oral iron therapy that may be better tolerated than other oral iron formulations. FM may be an effective alternative to IV iron in patients with IBD.

Developmental toxicity, antioxidant, and marker enzyme assessment of swertiamarin in zebrafish (Danio rerio).

A secoiridoid glycoside called swertiamarin has been widely used as a herbal medicine for many decades. In particular, swertiamarin from the Enicostema axillare herb has been used as a multipurpose drug to treat innumerable health problems. As this medicine is consumed orally, its toxicity level should be determined. To examine the safety of this compound, toxicology work was done in zebrafish, and this is the first report to describe swertiamarin toxicity in zebrafish. Zebrafish embryos were used in this swertiamarin toxicity study, and morphological changes were observed. Further, the compound was also studied in adult zebrafish to determine the impact of the compound on the fish liver. Enzyme profiling with superoxide dismutase, glutathione peroxidase, catalase, reduced glutathione levels, glutathione S-transferase, lactate dehydrogenase, glutamic oxaloacetic transaminases, lipid peroxidation, Na+ /K+ -ATPase, and glutamic pyruvic transaminases) was evaluated (p ≤ 0.05). Results suggest that swertiamarin is a safe drug only at a low concentration (40 µM). This study also shows that even herbal medicinal compounds may be toxic to humans at higher dosages. Hence, irrespective of whether a drug is synthetic or natural, it needs to be tested for its toxicity before use in humans.

Interventions for treating iron deficiency anaemia in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials. SELECTION CRITERIA: Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision). AUTHORS' CONCLUSIONS: Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.

Interventions for fatigue in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is an umbrella term used to describe a group of chronic, progressive inflammatory disorders of the digestive tract. Crohn's disease and ulcerative colitis are the two main types. Fatigue is a common, debilitating and burdensome symptom experienced by individuals with IBD. The subjective, complex nature of fatigue can often hamper its management. The efficacy and safety of pharmacological or non-pharmacological treatments for fatigue in IBD is not yet established through systematic review of studies. OBJECTIVES: To assess the efficacy and safety of pharmacological and non-pharmacological interventions for managing fatigue in IBD compared to no treatment, placebo or active comparator. SEARCH METHODS: A systematic search of the databases Embase, MEDLINE, Cochrane Library, CINAHL, PsycINFO was undertaken from inception to July 2018. A top-up search was run in October 2019. We also searched the Cochrane IBD Group Specialized Register, the Cochrane Central Register of Controlled Trials, ongoing trials and research registers, conference abstracts and reference lists for potentially eligible studies. SELECTION CRITERIA: Randomised controlled trials of pharmacological and non-pharmacological interventions in children or adults with IBD, where fatigue was assessed as a primary or secondary outcome using a generic or disease-specific fatigue measure, a subscale of a larger quality of life scale or as a single-item measure, were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results and four authors extracted and assessed bias independently using the Cochrane 'Risk of bias' tool. The primary outcome was fatigue and the secondary outcomes included quality of life, adverse events (AEs), serious AEs and withdrawal due to AEs. Standard methodological procedures were used. MAIN RESULTS: We included 14 studies (3741 participants): nine trials of pharmacological interventions and five trials of non-pharmacological interventions. Thirty ongoing studies were identified, and five studies are awaiting classification. Data on fatigue were available from nine trials (1344 participants). In only four trials was managing fatigue the primary intention of the intervention (electroacupuncture, physical activity advice, cognitive behavioural therapy and solution-focused therapy). Electroacupuncture Fatigue was measured with Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) (scores range from 0 to 52). The FACIT-F score at week eight was 8.00 points higher (better) in participants receiving electroacupuncture compared with no treatment (mean difference (MD) 8.00, 95% CI 6.45 to 9.55; 1 RCT; 27 participants; low-certainty evidence). Results at week 16 could not be calculated. FACIT-F scores were also higher with electroacupuncture compared to sham electroacupuncture at week eight (MD 5.10, 95% CI 3.49 to 6.71; 1 RCT; 30 participants; low-certainty evidence) but not at week 16 (MD 2.60, 95% CI 0.74 to 4.46; 1 RCT; 30 participants; low-certainty evidence). No adverse events were reported, except for one adverse event in the sham electroacupuncture group. Cognitive behavioural therapy (CBT) and solution-focused therapy Compared with a fatigue information leaflet, the effects of CBT on fatigue are very uncertain (Inflammatory Bowel Disease-Fatigue (IBD-F) section I: MD -2.16, 95% CI -6.13 to 1.81; IBD-F section II: MD -21.62, 95% CI -45.02 to 1.78; 1 RCT, 18 participants, very low-certainty evidence). The efficacy of solution-focused therapy on fatigue is also very uncertain, because standard summary data were not reported (1 RCT, 98 participants). Physical activity advice One 2 x 2 factorial trial (45 participants) found physical activity advice may reduce fatigue but the evidence is very uncertain. At week 12, compared to a control group receiving no physical activity advice plus omega 3 capsules, FACIT-F scores were higher (better) in the physical activity advice plus omega 3 group (FACIT-F MD 6.40, 95% CI -1.80 to 14.60, very low-certainty evidence) and the physical activity advice plus placebo group (FACIT-F MD 9.00, 95% CI 1.64 to 16.36, very low-certainty evidence). Adverse events were predominantly gastrointestinal and similar across physical activity groups, although more adverse events were reported in the no physical activity advice plus omega 3 group. Pharmacological interventions Compared with placebo, adalimumab 40 mg, administered every other week ('eow') (only for those known to respond to adalimumab induction therapy), may reduce fatigue in patients with moderately-to-severely active Crohn's disease, but the evidence is very uncertain (FACIT-F MD 4.30, 95% CI 1.75 to 6.85; very low-certainty evidence). The adalimumab 40 mg eow group was less likely to experience serious adverse events (OR 0.56, 95% CI 0.33 to 0.96; 521 participants; moderate-certainty evidence) and withdrawal due to adverse events (OR 0.48, 95%CI 0.26 to 0.87; 521 participants; moderate-certainty evidence). Ferric maltol may result in a slight increase in fatigue, with better SF-36 vitality scores reported in the placebo group compared to the treatment group following 12 weeks of treatment (MD -9.31, 95% CI -17.15 to -1.47; 118 participants; low-certainty evidence). There may be little or no difference in adverse events (OR 0.55, 95% CI 0.26 to 1.18; 120 participants; low-certainty evidence) AUTHORS' CONCLUSIONS: The effects of interventions for the management of fatigue in IBD are uncertain. No firm conclusions regarding the efficacy and safety of interventions can be drawn. Further high-quality studies, with a larger number of participants, are required to assess the potential benefits and harms of therapies. Future studies should assess interventions specifically designed for fatigue management, targeted at selected IBD populations, and measure fatigue as the primary outcome.

First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors.

Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.

Cytotoxic Compounds from the Saudi Red Sea Sponge Xestospongia testudinaria.

Bioassay-guided fractionation of the organic extract of the Red Sea sponge Xestospongia testudinaria led to the isolation of 13 compounds including two new sterol esters, xestosterol palmitate (2) and xestosterol ester of l6'-bromo-(7'E,11'E,l5'E)-hexadeca-7',11',l5'-triene-5',13'-diynoic acid (4), together with eleven known compounds: xestosterol (1), xestosterol ester of 18'-bromooctadeca-7'E,9'E-diene-7',15'-diynoic acid (3), and the brominated acetylenic fatty acid derivatives, (5E,11E,15E,19E)-20-bromoeicosa-5,11,15,19-tetraene-9,17-diynoic acid (5), 18,18-dibromo-(9E)-octadeca-9,17-diene-5,7-diynoic acid (6), 18-bromooctadeca-(9E,17E)-diene-7,15-diynoic acid (7), 18-bromooctadeca-(9E,13E,17E)-triene-7,15-diynoic acid (8), l6-bromo (7E,11E,l5E)hexadeca-7,11,l5-triene-5,13-diynoic acid (9), 2-methylmaleimide-5-oxime (10), maleimide-5-oxime (11), tetillapyrone (12), and nortetillapyrone (13). The chemical structures of the isolated compounds were accomplished using one- and two-dimensional NMR, infrared and high-resolution electron impact mass spectroscopy (1D, 2D NMR, IR and HREIMS), and by comparison with the data of the known compounds. The total alcoholic and n-hexane extracts showed remarkable cytotoxic activity against human cervical cancer (HeLa), human hepatocellular carcinoma (HepG-2), and human medulloblastoma (Daoy) cancer cell lines. Interestingly, the dibrominated C18-acetylenic fatty acid (6) exhibited the most potent growth inhibitory activity against these cancer cell lines followed by Compounds 7 and 9. Apparently, the dibromination of the terminal olefinic moiety has an enhanced effect on the cytotoxic activity.

Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities.

This open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n = 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiologically evaluable (ME) population. Within the ME population, 82.9% of patients had a ≥ 20% decrease in the area of erythema, and 77.9% of patients had a ≥ 20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n = 37 patients with methicillin-resistant S. aureus [MRSA], and n = 39 with methicillin-sensitive S. aureus [MSSA]). No isolates had increased AFN-1252 MICs posttreatment. Microbiologic eradication rates for S. aureus were 93.2% at short-term follow-up (STFU) and 91.9% at long-term follow-up (LTFU) in the ME population. Eradication rates for MRSA and MSSA were 91.9% and 92.3%, respectively, at STFU and 91.9% and 89.7%, respectively, at LTFU. The most frequently reported drug-related adverse events, which were mostly mild or moderate, were headache (26.2%) and nausea (21.4%). These studies demonstrate that AFN-1252 is generally well tolerated and effective in the treatment of ABSSSI due to S. aureus, including MRSA. (This study has been registered at ClinicalTrials.gov under registration no. NCT01519492.).

Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir.

PURPOSE: Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. METHODS: The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated. RESULTS: The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively. CONCLUSIONS: Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.

Combined use of monopolar radiofrequency and transdermal drug delivery in the treatment of melasma.

BACKGROUND: Melasma is a common acquired pigmentary disorder that has a considerable psychological impact on the patient. The recurrent and refractory nature of this condition makes it difficult for treatment. OBJECTIVE: We aim to evaluate the efficacy and safety of a combined system that simultaneously uses monopolar radiofrequency (RF) and transdermal drug delivery of phytocomplex containing 1% kojic acid in the treatment of melasma. MATERIALS AND METHODS: Fifty patients affected by melasma underwent 6 sessions of treatment at 1-week intervals. The outcome was evaluated before treatment (T0) and 1 month (T1) and 6 months (T2) after treatment using the Melasma Area and Severity Index score, a Mexameter, and Visioface devices for digital and ultraviolet computerized image analysis of skin color. RESULTS: The image analysis showed that hyperpigmentation was significantly reduced at T1 and T2 compared with baseline. Melasma Area and Severity Index score, the average melanin score, and the average erythema values showed a significant reduction. No side effects were observed or reported. CONCLUSION: This study describes the first report of improvement in melasma through the combined use of monopolar RF with transdermal delivery of depigmenting agents. This could be a safe, tolerable, and effective alternative tool for the treatment of melasma.

Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients.

UNLABELLED: More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from -0.97 log(10) IU/mL with filibuvir given at 100 mg twice daily to -2.30 log(10) IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log(10) IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing. CONCLUSION: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients.

Long-Term Effectiveness of Oral Ferric Maltol vs Intravenous Ferric Carboxymaltose for the Treatment of Iron-Deficiency Anemia in Patients With Inflammatory Bowel Disease: A Randomized Controlled Noninferiority Trial.

BACKGROUND: Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. METHODS: In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center's standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. RESULTS: For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. CONCLUSIONS: Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated.

Asperlin from the marine-derived fungus Aspergillus sp. SF-5044 exerts anti-inflammatory effects through heme oxygenase-1 expression in murine macrophages.

Asperlin is a fungal metabolite isolated from Aspergillus sp. SF-5044. In the present study, we isolated asperlin from the marine-derived fungus Aspergillus sp. SF-5044 and demonstrated that it inhibited inducible nitric oxide synthase (iNOS) expression, reduced iNOS-derived NO, suppressed cyclooxygenase (COX)-2 expression, and reduced COX-derived prostaglandin (PG) E2 production in lipopolysaccharide (LPS)-stimulated RAW264.7 and murine peritoneal macrophages. Similarly, asperlin reduced the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. In addition, asperlin inhibited the phosphorylation and degradation of IκB-α, as well as the nuclear translocation of p65 caused by the stimulation of LPS in RAW264.7 macrophages. Furthermore, asperlin induced heme oxygenase (HO)-1 expression through nuclear translocation of nuclear factor E2-related factor 2 and increased HO activity in RAW264.7 macrophages. The effects of asperlin on the LPS-induced expression of iNOS and COX-2 and production of NO, PGE2, TNF-α, and IL-1ß were partially reversed by a HO-1 inhibitor, tin protoporphyrin. These findings suggest that asperlin-induced HO-1 expression plays a role in the anti-inflammatory effects of asperlin in macrophages.

Lack of a pharmacokinetic interaction between steady-state tipranavir/ritonavir and single-dose valacyclovir in healthy volunteers.

OBJECTIVE: This study assessed the single-dose pharmacokinetics of the herpes antiviral acyclovir (administered as the pro-drug valacyclovir) alone and in combination with twice-daily 200 mg ritonavir-boosted tipranavir (500 mg) at steady state. METHODS: The study was an open label, one-sequence cross-over pharmacokinetic study in HIV-negative adults. Plasma drug concentrations were measured by validated LC/MS/MS assays; pharmacokinetics (AUC, C(max)) were determined using noncompartmental methods. The geometric mean ratio and 90% confidence interval [GMR, 90% CI] were used to evaluate the drug interaction. RESULTS: Twenty-six of 29 subjects completed the trial. With steady-state tipranavir/ritonavir, acyclovir C(max) decreased 4.9% [0.95, 0.88-1.02] and AUC increased 6.6% [1.07, 1.04-1.09]. The majority of subjects experienced at least one adverse event, most of which were mild gastrointestinal disorders. Three subjects discontinued tipranavir/ritonavir treatment as a result of drug-related increases in ALT/AST, including one subject who experienced mild upper abdominal pain. All subjects recovered without sequelae. CONCLUSIONS: When administered as a single dose of valacyclovir with steady-state tipranavir/ritonavir, there were no clinically important changes in acyclovir pharmacokinetics. This result indicates that valacyclovir can be co-administered safely with no dose adjustments.

In Vitro Evaluation of the Toxicological Profile and Oxidative Stress of Relevant Diet-Related Advanced Glycation End Products and Related 1,2-Dicarbonyls.

During food processing and storage, and in tissues and fluids under physiological conditions, the Maillard reaction occurs. During this reaction, reactive 1,2-dicarbonyl compounds arise as intermediates that undergo further reactions to form advanced glycation end products (AGEs). Diet is the primary source of exogenous AGEs. Endogenously formed AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, or chronic disease. AGEs may differently contribute to the diet-related exacerbation of oxidative stress, inflammation, and protein modifications. Here, to understand the contribution of each compound, we tested individually, for the first time, the effect of five 1,2-dicarbonyl compounds 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), and methylglyoxal (MGO) and four different glycated amino acids N-ε-(carboxyethyl)lysine (CEL), N-ε-(carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pyrraline (Pyrr) in a cell line of human keratinocytes (HaCaT). We found that most of the glycated amino acids, i.e., CEL, CML, and MG-H1, did not show any cytotoxicity. At the same time, 1,2-dicarbonyl compounds 3-DGal, 3,4-DGE, GO, and MGO increased the production of reactive oxygen species and induced cell death. MGO induced cell death by apoptosis, whereas 3-DGal and 3,4-DGE induced nuclear translocation of the proinflammatory NF-κB transcription pathway, and the activation of the pyroptosis-related NLRP3 inflammasome cascade. Overall, these results demonstrate the higher toxic impact of 1,2-dicarbonyl compounds on mucosal epithelial cells when compared to glycated amino acids and the selective activation of intracellular signaling pathways involved in the crosstalk mechanisms linking oxidative stress to excessive inflammation.

Leucoderma after use of a skin-lightening cream containing kojic dipalmitate, liquorice root extract and Mitracarpus scaber extract.

A lighter or whiter complexion is socially desirable in many cultures. This has led to an unregulated and highly profitable market in skin-lightening creams that are readily available over the counter or on the internet. Plant extracts and newer tyrosinase inhibitors such as kojic acid or its derivative kojic dipalmitate are popular ingredients in these creams. We report a patient who developed depigmented patches after using such a cream.

Evaluation of a kojic acid, emblica extract, and glycolic acid formulation compared with hydroquinone 4% for skin lightening.

Hydroquinone has been the standard prescription agent for skin lightening; however, its use recently has become controversial. Hydroquinone is banned in Europe and parts of Asia because of potential long-term consequences, including carcinogenesis when orally consumed. These concerns have stimulated research to develop alternative skin lightening agents with efficacy comparable to hydroquinone but with a better safety profile. This double-blind study examined the skin lightening ability of a topical formulation containing kojic acid, emblica extract, and glycolic acid compared with prescription generic hydroquinone cream 4%. Eighty multiethnic participants with mild to moderate facial dyschromia were randomly assigned to use the study product or hydroquinone 4% twice daily for 12 weeks to evaluate product efficacy, tolerability, and safety using investigator assessment, participant assessment, and dermospectrophotometry. Study results demonstrated efficacy parity between the study product and hydroquinone 4%. Thus this novel skin lightening preparation is an alternative to hydroquinone 4% for participants with mild to moderate facial dyschromia.

Virologic and immunologic effectiveness of tipranavir/ritonavir (TPV/r)- versus darunavir/ritonavir (DRV/r)-based regimens in clinical practice.

BACKGROUND: Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. OBJECTIVE: To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). METHODS: Multicenter, retrospective cohort study. RESULTS: The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm( 3) (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm(3) (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). CONCLUSION: No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression.

[Adverse reactions of atazanavir, fosamprenavir and tipranavir in "real life"]. / Effets indésirables de l'atazanavir, du fosamprénavir et du tipranavir en situation réelle d'emploi.

OBJECTIVE: To precise adverse effects of atazanavir, fosamprenavir and tipranavir "in real life". METHOD: Descriptive study of 3 protease inhibitor adverse effects stored in the French Bank of Pharmacovigilance. RESULTS: Nineteen adverse effects having at least possible links with antiretroviral drugs studied were reported. It was essentially hepatobiliary (atazanavir: 29/59, tipranavir: 4/6) and skin (fosamprenavir: 10/20) adverse reactions. These reactions, relatively "serious" (35.1%) led to the interruption of the person (or persons) medication (s) suspected (s) in 69 folds (82.1%) and evolved to healing without sequelae in 68 folds (81%). CONCLUSION: The drug side effects were for the most expected. However, their frequency and their seriously underline the interest of a post-AMM monitoring to reassess the drugs risk-benefit report.