Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation.

Trends Mol Med. 2018 04;24(4):348-363

Authors: Toscano MA, Martínez Allo VC, Cutine AM, Rabinovich GA, Mariño KV

Abstract
Although progress has been made in understanding the mechanisms implicated in the pathogenesis of autoimmune inflammation, studies aimed at identifying the mediators of these pathways will be necessary to develop more selective therapies. Galectins, a family of glycan-binding proteins, play central roles in immune cell homeostasis. Whereas some members of this family trigger regulatory programs that promote resolution of inflammation, others contribute to perpetuate autoimmune processes. We discuss the roles of endogenous galectins and their specific glycosylated ligands in shaping autoimmune responses by fueling, extinguishing, or rewiring immune circuits. Understanding the relevance of galectin-glycan interactions in autoimmune inflammation could help to uncover novel pathways of tolerance breakdown, define molecular signatures for patient stratification and therapy responses, and open new avenues for immune intervention.

PMID: 29555188 [PubMed - indexed for MEDLINE]

Safer Prescribing and Care for the Elderly (SPACE): a pilot study in general practice.

BJGP Open. 2018 Oct;2(3):bjgpopen18X101594

Authors: Wallis KA, Elley CR, Moyes S, Kerse N

Abstract
Background: High-risk prescribing places patients at increased risk of adverse drug events (ADEs). High-risk prescribing and ADE hospitalisations are increasingly common as people are living longer and taking more medicines for multiple chronic conditions. The Safer Prescribing and Care for the Elderly (SPACE) intervention is designed to foster patient engagement in medicines management and prompt medicines review.
Aim: To pilot the SPACE intervention in preparation for a larger cluster randomised controlled trial (RCT).
Design & setting: A pilot study in two general practices. Study participants were all patients at increased risk of an adverse drug reaction (ADE) from non-steroidal anti-inflammatory drugs (NSAIDs) and/or antiplatelet medicines. The primary outcome was the proportion of participants receiving high-risk prescribing at 6 months and 12 months compared with baseline.
Method: The SPACE intervention comprised automated practice audit to identify and generate for each GP a list of patients with high-risk prescribing for these medicines; an outreach visit by clinical advisory pharmacist to deliver education and to go through with each GP their list of at-risk patients and indicate in a tick-box the intended action for each patient; and a mail-out from GPs to selected patients containing a medicines information brochure and a letter encouraging patients to discuss their medicines when they next see their GP.
Results: SPACE can be delivered within existing primary care infrastructure. The rate of high-risk prescribing was reduced at 6 months following the delivery of the intervention, but these improvements were not evident at 12 months.
Conclusion: SPACE prompts medicines review and shows promising signs of supporting safer prescribing in general practice in the short term. A randomised trial of SPACE started in 2018.

PMID: 30564727 [PubMed]

ATP-Binding Cassette Transporters in the Clinical Implementation of Pharmacogenetics.

J Pers Med. 2018 Dec 05;8(4):

Authors: López-Fernández LA

Abstract
ATP-binding cassette (ABC) transporters are involved in a large number of processes and contribute to various human genetic diseases. Among other functions, ABC proteins are involved in the transport of multiple drugs through cells. Most of the genes coding for these transporters are highly polymorphic and DNA variants in these genes can affect the normal functioning of these proteins, affecting the way drugs are transported, increasing or decreasing drug levels. These changes in the intracellular and extracellular drug levels may be associated with altered drug effectiveness or severe drug-induced adverse events. This review presents a state-of-art of the most pharmacogenetics clinically relevant ABC transporters closed to the clinical implementation.

PMID: 30563187 [PubMed]

Variations in drug-related problems detected by multidisciplinary teams in Norwegian nursing homes and home nursing care.

Scand J Prim Health Care. 2018 Sep;36(3):291-299

Authors: Devik SA, Olsen RM, Fiskvik IL, Halbostad T, Lassen T, Kuzina N, Enmarker I

Abstract
OBJECTIVE: Traditionally, nursing homes have been associated with suboptimal drug therapy and drug-related problems (DRPs). In contrast, less is known about drug safety in homecare. The aim of this study was to describe and compare DRPs in older persons across two care settings: nursing homes and home nursing care.
DESIGN: Cross-sectional study using descriptive and inferential statistics.
SETTING: Nursing homes (n = 5) and home nursing care units (n = 8) across nine municipalities in the middle of Norway.
PARTICIPANTS: Multidisciplinary medication reviews for 61 nursing home residents and 93 patients receiving home nursing care performed over the 2013-2014 period, were mapped and examined (N = 154).
MAIN OUTCOME MEASURES: DRPs classified by a Norwegian Classification Tool.
RESULTS: In all, 740 DRPs were detected in the total sample, 227 in nursing homes and 513 in home nursing care. DRPs were significantly higher among patients receiving home-based care (Mean =5.5) compared to patients in nursing homes (Mean =3.7, p = 0.002). Among the problem categories, the need for additional drug was most frequent in nursing homes (p = 0.001), while documentation discrepancies reached the highest numbers in patients receiving home nursing care (p = 0.000). Additionally, patients in home nursing care had more problems concerning adverse reactions (p = 0.060); however, this was not statistically significant. Differences in DRP categories leading to changes in the patients' medication lists were also discovered.
CONCLUSIONS: The frequency of unclear documentation and adverse reactions found in the homecare setting is alarming. This is an important issue given the trend in aged care towards caring people in their own homes. Further research is warranted to explore how different care settings may influence the safety of pharmacotherapy for older persons. Key Points Drug related problems are a significant cause of concern among patients receiving home nursing care as well as for patients living in nursing homes. The findings of this study showed that: •Significantly more DRPs were detected among patients receiving home nursing care than patients living in nursing homes. •While patients living in nursing homes were often undermedicated, documentation discrepancies were more frequent in home nursing care. •DRP categories leading to changes on the medication lists differed between the settings.

PMID: 30139278 [PubMed - indexed for MEDLINE]

Anticoagulant-associated adverse drug reactions in 2013-15.

Tidsskr Nor Laegeforen. 2018 08 21;138(12):

Authors: Eek AK, Strøm BO, Bakkehøi G, Stenberg-Nilsen H

Abstract
BACKGROUND: The aim of this study was to obtain a better insight into the adverse effects profiles of the new direct-acting oral anticoagulants (DOACs).
MATERIAL AND METHOD: A review was undertaken of all reports of adverse effects for warfarin, dabigatran, rivaroxaban and apixaban reported to the regional medicines information and pharmacovigilance centres (RELIS) in the period June 2013-May 2015.
RESULTS: Approximately 65 000 persons used direct-acting oral anticoagulants and 80 000 used warfarin in the period of the study. A total of 409 reports of adverse effects were included. Altogether 55 % of the reports applied to men. In 76 % of the reports for direct-acting oral anticoagulants and 85 % for warfarin, the patients were more than 70 years of age. The most common adverse effects were haemorrhages (48 % for direct-acting oral anticoagulants and 75 % for warfarin), most of which were cerebral haemorrhages (91 for direct-acting oral anticoagulants and 92 for warfarin). Blood clots (therapeutic failure), cognitive effects, headache and hair loss were some of the other adverse effects. The highest comorbidity was among the patients who died. The number of reported deaths was highest for rivaroxaban (1.1 deaths/1000 users) with a declining incidence for apixaban (0.9 ‰), dabigatran (0.7 ‰) and warfarin (0.6 ‰). There were different degrees of reporting for these medications, and the spontaneous reporting system cannot therefore be used to compare the incidence of adverse effects for the drugs.
INTERPRETATION: Adverse effects, including serious effects, may occur when using all anticoagulants. Factors that may increase the risk of adverse effects are advanced age, high comorbidity, reduced renal function, and polypharmacy.

PMID: 30132616 [PubMed - indexed for MEDLINE]

Clinically relevant drug-drug interactions among elderly people with dementia.

Eur J Clin Pharmacol. 2018 Oct;74(10):1351-1360

Authors: Sönnerstam E, Sjölander M, Lövheim H, Gustafsson M

Abstract
PURPOSE: Increased numbers of drugs and changes in pharmacokinetic and pharmacodynamic parameters among elderly people contribute to increased prevalence of adverse drug reactions. Drug-drug interactions (DDIs) are an important reason for admission to hospital and elderly people with dementia are particularly vulnerable. The aims of the present study were to assess the occurrence and characteristics of clinically relevant DDIs and to investigate potential risk factors associated with DDIs among elderly people with dementia.
METHODS: People ≥ 65 years with dementia, admitted to two hospitals in Northern Sweden, were included. The medical records of 458 patients were reviewed. Clinically relevant DDIs were identified using the Janusmed interactions database. Pharmacological classification was conducted using Stockley's classification system.
RESULTS: A total of 401 DDIs were identified among 43.2% of the study population, of which 98.5% had interactions that may require dose adjustment and 7.6% had drug combinations that should be avoided. Pharmacodynamic interactions were most common, of which furosemide-citalopram (n = 35) were most frequently observed. Omeprazol-citalopram (n = 25) was the most common drug combination among pharmacokinetic interactions. Citalopram and warfarin were the most commonly involved drug substances. An association was found between a higher number of medications being prescribed and having at least one DDI.
CONCLUSION: Clinically relevant drug-drug interactions are prevalent among elderly people with dementia living in Northern Sweden. Drug-drug interactions should be identified in order to manage and prevent adverse outcomes. This is particularly important among this group of people especially when multiple medications are being prescribed.

PMID: 29967921 [PubMed - indexed for MEDLINE]

Analysis of the activity and safety of weekly low-dose bevacizumab-based regimens in heavily pretreated patients with metastatic breast cancer.

Thorac Cancer. 2018 05;9(5):613-620

Authors: Zhai X, Hong R, Fan Y, Yuan P, Wang J, Sang D, Chen J, Zhao C, Ou K, Ma F, Xu B

Abstract
BACKGROUND: Currently, there are no standard regimens for metastatic breast cancer patients (MBC) who have failed ≥ 3 chemotherapy treatments. The aim of this study was to assess whether weekly low-dose bevacizumab-based regimens were well tolerated and would improve efficacy in MBC patients who had failed numerous therapies.
METHODS: Seventeen patients with MBC who were heavily pretreated with a median of five regimens of therapy (range 1-10) between 2012 and 2016 were included in the analysis. Bevacizumab was administered at a dose of 100 mg intravenously once a week combined with one or two types of chemotherapeutic drugs until confirmed disease progression or an intolerable adverse event was observed. Patient characteristics, objective response rate, clinical benefit rate, progression-free survival, and toxicity were assessed.
RESULTS: All 17 patients had been pretreated with taxane-based and anthracycline-based chemotherapy. Weekly low-dose bevacizumab combined with one or two types of chemotherapeutic drugs, which had usually not been previously used (e.g. etoposide, irinotecan, pemetrexed, methotrexate, and nab-paclitaxel), was administered. Three patients achieved a partial response, while one had stable disease for > 24 weeks, and the clinical benefit rate was 23.5%. Median progression-free survival was 3.4 months (95% confidence interval 2.0-4.8). The most common hematological adverse events were neutropenia, anemia, and thrombocytopenia. Bevacizumab-related adverse events included grade 1 bleeding (17.6%) and grade 2 hypertension (5.9%).
CONCLUSIONS: Weekly low-dose bevacizumab combined with chemotherapy shows a relatively favorable clinical response and tolerable toxicity, providing a feasible option for heavily pretreated MBC patients.

PMID: 29575760 [PubMed - indexed for MEDLINE]

Endostar (rh-endostatin) versus placebo in combination with vinorelbine plus cisplatin chemotherapy regimen in treatment of advanced non-small cell lung cancer: A meta-analysis.

Thorac Cancer. 2018 05;9(5):606-612

Authors: An J, Lv W

Abstract
BACKGROUND: This meta-analysis was conducted to investigate the efficacy and safety of Endostar (rh-endostatin) versus a placebo in combination with a vinorelbine plus cisplatin (NP) chemotherapy regimen for the treatment of advanced non-small cell lung cancer (NSCLC).
METHODS: Two reviewers independently searched Medline, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, ASCO, ESMO, the Web of Science, and CNKI databases to locate relevant controlled clinical trials. The treatment efficacy and drug-related toxicity of NP + Endostar (NPE) and NP groups were pooled through meta-analysis according to random or fixed effect models.
RESULTS: Fifteen prospective clinical studies were included in this meta-analysis. The pooled risk ratio (RR) for objective response rate was 1.74 (95% confidence interval [CI] 1.43-2.11); the objective response rate in the NPE group was significantly higher than in the NP group (P < 0.05). Nine publications evaluated the incidence of leucopenia between Endostar versus a placebo in combination with an NP chemotherapy regimen. The pooled results showed no statistically significant difference between NPE and NP chemotherapy regimens for leucopenia, thrombocytopenia, and nausea/vomiting risk (P > 0.05). The one-year survival rate in the NPE group was higher than in the NP group, with a statistically significant difference (RR = 1.70, 95% CI 1.07-2.89; P < 0.05).
CONCLUSION: Endostar combined with an NP chemotherapy regimen can improve the prognosis of patients with advanced NSCLC without increasing the risk of toxicity.

PMID: 29575575 [PubMed - indexed for MEDLINE]

Adverse reactions of sorafenib, sunitinib, and imatinib in treating digestive system tumors.

Thorac Cancer. 2018 05;9(5):542-547

Authors: Fu Y, Wei X, Lin L, Xu W, Liang J

Abstract
BACKGROUND: This study was conducted to assess the adverse reactions caused by multi-target tyrosine kinase inhibitor treatment of gastrointestinal tumors.
METHODS: We carried out a retrospective study of drug-related adverse reactions in 115 patients who were treated with sorafenib, sunitinib, and imatinib for primary hepatocellular carcinoma or gastrointestinal stromal tumors from October 2003 to March 2012 at the Peking University International Hospital.
RESULTS: The total incidence of adverse reactions of sorafenib, sunitinib, and imatinib in patients with hepatocellular carcinoma and gastrointestinal stromal tumors was > 80%. The main adverse reactions of sorafenib were hypertension in 38 patients (33.3%) and diarrhea in 28 patients (24.4%). Sunitinib was associated with higher incidence and greater grade 3-4 toxicity. The common toxicities were skin color changes in 105 patients (90.9%), hand-foot skin reactions in 65 patients (54.6%), and leukopenia (63.6%), hypertension (22.7%), proteinuria (22.7%), liver function impairment (22.7%), and hypomagnesemia (27.3%). While imatinib was well tolerated, it was associated with the highest number of adverse reactions, including skin color change (55.6%) and edema (38.9%). Hypophosphatemia (4.4%) and hoarseness (2.2%) only occurred in the sorafenib treatment group.
CONCLUSIONS: The adverse reactions of multi-target tyrosine kinase inhibitor treatments are generally mild to moderate, and most patients can tolerate these without the need for further intervention. Some serious adverse reactions may be alleviated by discontinuing the drugs or by administering symptomatic treatment.

PMID: 29575544 [PubMed - indexed for MEDLINE]

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenomics. 2018 02;19(3):243-247

Authors: Hughes DA, Plumpton CO

Abstract
Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

PMID: 29327657 [PubMed - indexed for MEDLINE]

The pharmacogenetics of medications used in general anesthesia.

Pharmacogenomics. 2018 02;19(3):285-298

Authors: Xie S, Ma W, Guo Q, Liu J, Li W, McLeod HL, He Y

Abstract
General anesthesia is a state of unconsciousness, amnesia, analgesia and akinesia induced by drugs including opioids, hypnotic-sedative agents, muscle relaxants and antiemetics. Clinical and genetic factors are reported to influence the efficacy and side effects of these agents. Based on the evidence, clinical action is needed to improve clinical outcomes. This review summarizes the latest knowledge with regards to the pharmacogenetics of anesthetics and general anesthesia related complications.

PMID: 29318929 [PubMed - indexed for MEDLINE]

Epilepsy field workers, a smartphone application and telephone telemedicine: Safe and effective epilepsy care in rural Nepal.

Seizure. 2018 Dec 10;64:54-58

Authors: Rajbhandari H, Joshi S, Malakar S, Paudel P, Jain P, Uppadaya K, Singh M, Patterson V

Abstract
PURPOSE: Most people with epilepsy live in low- or middle-income countries (LMICs) where there are relatively few doctors. Over 50% of people with epilepsy in these countries are untreated so other models of care are needed. In this report we evaluate a novel model of care.
METHODS: We trained four residents of Myagdi, a rural district in Nepal as epilepsy field workers (EFWs). They provided epilepsy awareness to their communities. When they identified someone with possible epilepsy they used a smartphone application (app) to determine the probability score for an episode being epileptic and contacted an epilepsy specialist by phone. If the specialist thought treatment was indicated this was arranged by the EFW. We recorded mortality, change of diagnosis at face-to-face consultation and drug-related events as measures of safety. Seizure frequency and general wellbeing were also recorded, and a questionnaire was devised to measure satisfaction.
RESULTS: 112 patients with app scores suggesting epileptic seizures were identified and managed in 18 months, of whom 15 had provoked seizures. Forty-three percent of epilepsy patients were untreated. At follow-up one had died of a cause other than epilepsy. Diagnostic agreement at face-to-face assessment was 93%. Overall 5% had side-effects of medication. Seizures were stopped in 33% and reduced in 57%. Ninety-six percent of patients preferred this service to travelling to other doctors.
CONCLUSION: This novel service met all criteria of safety and was effective in reducing frequency of seizures. Patients preferred it to conventional services. It should be transferable to other LMICs.

PMID: 30562653 [PubMed - as supplied by publisher]

Pharmacovigilance evaluation of the relationship between impaired glucose metabolism and BCR-ABL inhibitor use by using an adverse drug event reporting database.

Cancer Med. 2018 Dec 18;:

Authors: Okada N, Niimura T, Zamami Y, Hamano H, Ishida S, Goda M, Takechi K, Chuma M, Imanishi M, Ishizawa K

Abstract
Breakpoint cluster region-Abelson murine leukemia (BCR-ABL) inhibitors markedly improve the prognosis of chronic myeloid leukemia. However, high treatment adherence is necessary for successful treatment with BCR-ABL inhibitors. Therefore, an adequate understanding of the adverse event profiles of BCR-ABL inhibitors is essential. Although many adverse events are observed in trials, an accurate identification of adverse events based only on clinical trial results is difficult because of strict entry criteria or limited follow-up durations. In particular, BCR-ABL inhibitor-induced impaired glucose metabolism remains controversial. Pharmacovigilance evaluations using spontaneous reporting systems are useful for analyzing drug-related adverse events in clinical settings. Therefore, we conducted signal detection analyses for BCR-ABL inhibitor-induced impaired glucose metabolism by using the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) database. Signals for an increased reporting rate of impaired glucose metabolism were detected only for nilotinib use, whereas these signals were not detected for other BCR-ABL inhibitors. Subgroup analyses showed a clearly increased nilotinib-associated reporting rate of impaired glucose metabolism in male and younger patients. Although FAERS- and JADER-based signal detection analyses cannot determine causality perfectly, our study suggests the effects on glucose metabolism are different between BCR-ABL inhibitors and provides useful information for the selection of appropriate BCR-ABL inhibitors.

PMID: 30561126 [PubMed - as supplied by publisher]

Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial.

Blood. 2018 Dec 17;:

Authors: Jäger U, D'Sa S, Schörgenhofer C, Bartko J, Derhaschnig U, Sillaber C, Jilma-Stohlawetz P, Fillitz M, Schenk T, Patou G, Panicker S, Parry GC, Gilbert JC, Jilma B

Abstract
Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10 mg/kg sutimlimab followed by a full dose of 60 mg/kg 1-4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5; 95% confidence interval, 2.1-4.5) within 6 weeks (P = 0.005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3-4 weeks after the last dose of sutimlimab. Re-exposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. In conclusion, sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at https://clinicaltrials.gov/ as #NCT02502903.

PMID: 30559259 [PubMed - as supplied by publisher]

Long-term safety and efficacy of deferasirox in patients with myelodysplastic syndrome, aplastic anemia and other rare anemia in Taiwan.

Hematology. 2019 Dec;24(1):247-254

Authors: Ko BS, Chang MC, Chiou TJ, Chang TK, Chen YC, Lin SF, Chang CS, Lu YC, Yeh SP, Chen TY, Hwang WS

Abstract
OBJECTIVE: Patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemia require chronic blood transfusions which can lead to iron overload and subsequent excess iron-mediated complications. Intensive iron chelation with deferasirox could remove excess iron and can alleviate these events; however, the long-term safety and efficacy in Chinese population are not clearly characterized. This study examined the long-term efficacy and safety of deferasirox in a real-world setting in Taiwan.
METHODS: This observational, non-interventional, single-arm, multi-center, phase IV study was designed to collect the safety and clinical information about patients who were treated with deferasirox according to investigator's judgment and in accordance with the general clinical practice.
RESULTS: From 2009 to 2011, patients with MDS (N = 38), AA (N = 23), and other rare anemias (N = 18) were enrolled. The mean deferasirox exposure was 17.7 ± 4.02 mg/kg/day. The most common drug-related AEs were skin disorders (32.9%) and gastrointestinal disorders (30.4%), while grade 3-4 AEs were rare (5.1%). In the overall patient population, deferasirox effectively decreased serum ferritin levels at 1 year (P = 0.0154) and 3 years (P = 0.0424) from the baseline. Upon the use of deferasirox, 32.9% patients showed erythroid response and 16.7% patients had platelet response.
CONCLUSIONS: For patients with MDS, AA, and other rare anemias, the AEs observed in this 3-year surveillance study with deferasirox were mostly mild or moderate. In addition, the hematological response rate was higher than that in the EPIC study, which primarily enrolled Caucasian patients.

PMID: 30558522 [PubMed - in process]

Emerging technologies for food and drug safety.

Regul Toxicol Pharmacol. 2018 Oct;98:115-128

Authors: Slikker W, de Souza Lima TA, Archella D, de Silva JB, Barton-Maclaren T, Bo L, Buvinich D, Chaudhry Q, Chuan P, Deluyker H, Domselaar G, Freitas M, Hardy B, Eichler HG, Hugas M, Lee K, Liao CD, Loo LH, Okuda H, Orisakwe OE, Patri A, Sactitono C, Shi L, Silva P, Sistare F, Thakkar S, Tong W, Valdez ML, Whelan M, Zhao-Wong A

Abstract
Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18-20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science.

PMID: 30048704 [PubMed - indexed for MEDLINE]

Non-toxic and non teratogenic extract of Thuja orientalis L. inhibited angiogenesis in zebra fish and suppressed the growth of human lung cancer cell line.

Biomed Pharmacother. 2018 Oct;106:699-706

Authors: R EB, Jesubatham PD, V M BG, S V, S S

Abstract
Lung cancer is a malignant tumour with minimal survival rate and the current treatments are not showing complete remission of tumour and have many side effects. Thus a natural herbal medicine with good anti-cancer properties is highly demanded. Thuja orientalis L. is a traditionally used medicine to cure cough, bronchitis, excessive menstruation, asthma, skin infection and premature baldness. In addition, recent studies have revealed that it has anti-proliferative and anti-cancer activity. Angiogenesis is the main reason for the propagation and metastasis of cancers. We therefore intended to study the effects of the leaf extract of Thuja orientalis L. on angiogenesis as well as lung cancer cell growth. We have tested the anti-angiogenesis efficiency by alkaline phosphatase assay and also analysed the in vivo toxicity and teratogenic effects of various concentration of Thuja orientalis L. extract by establishing an in vivo zebra fish (Danio rerio), a promising model for cancer research which share genetic structure similarity to that of human beings. Also we demonstrated an anti-cancer effect of leaf extract from Thuja orientalis L. on human lung cancer cell line (A549) by MTT and trypan blue assay. The results revealed that the Thuja orientalis L. extract is efficient in repressing lung tumour cell growth significantly (p ≤ 0.01) in all treatments (2.4 mg/ml to 0.3 mg/ml) except 0.15 mg/ml compared to the control. The in vivo toxicity assay has proven that it is non-toxic at concentrations 0.6 mg/ml, 0.3 mg/ml and 0.15 mg/ml in zebrafish. The teratogenic assays revealed the therapeutic index (TI) as 0.808 with 0.7029 mg/ml as LC50 concentration at 24 h which is within the desirable value (below 1) for drug administration. Noticeable inhibition of angiogenesis also was observed in treatment with 2.4 mg/ml to 0.3 mg/ml. Overall we found that Thuja orientalis L. plant leaf extract exhibits better anti-cancer properties as we have validated by in vitro and in vivo analysis.

PMID: 29990861 [PubMed - indexed for MEDLINE]

Management of Common Side Effects of Apremilast.

J Cutan Med Surg. 2018 Jul/Aug;22(4):415-421

Authors: Langley A, Beecker J

Abstract
Apremilast is a relatively new therapy for the treatment of moderate to severe plaque psoriasis in adults. While this medication is considered safe with a very low risk of serious side effects, a few common (≥5% of patients) mild to moderate side effects have been reported, including diarrhea, nausea, headache, and nasopharyngitis. Not addressing these symptoms may lead to medication nonadherence and unnecessary discontinuation of therapy. These side effects are often easily managed with interventions available to the practicing dermatologist, and in only rare instances will these side effects require dose adjustment or discontinuation of therapy. The purpose of this article is to review common side effects of apremilast at its approved dose of 30 mg orally twice daily (BID) and to provide clear, simple recommendations for their management in dermatological practice.

PMID: 29290125 [PubMed - indexed for MEDLINE]

Fentanyl buccal tablet for breakthrough cancer pain in clinical practice: results of the non-interventional prospective study ErkentNIS.

Support Care Cancer. 2018 02;26(2):491-497

Authors: Masel EK, Landthaler R, Gneist M, Watzke HH

Abstract
PURPOSE: Several patients with advanced cancer suffer from breakthrough cancer pain (BTcP). BTcP is pain exacerbation despite opioid baseline therapy. Fentanyl buccal tablet (FBT) is a rapid-onset opioid for the treatment of BTcP. The aim of this study is to document the feasibility of FBT in patients with BTcP.
METHODS: The study was performed in 64 centers. Basic pain score was rated on a numeric rating scale (NRS) before and after treatment. BTcP episodes, baseline opioid therapy, and FBT dose were rated as well as individual dose titration, findings on tolerability, patient satisfaction, and safety of the drug.
RESULTS: Two hundred sixty-three patients were available for analysis. Patients rated a basic pain score of 6 (range 2-10) points on an NRS and described an average of 2 to 5 BTcP episodes per day. After titration of FBT, BTcP control was achieved within 5 min in 36%, within 10 min in 68%, and within 15 min in 95%. Basic pain score decreased to a mean NRS of 4 and BTcP episodes decreased to < 1 to 3 episodes per day. BTcP control, onset of action of FBT, potency of FBT, tolerability of FBT, and safety of FBT were rated as excellent or good by 89 to 99% of the patients. Adverse drug reactions were registered in 3%.
CONCLUSIONS: Treatment with FBT led to rapid pain relief and reductions in the number of BTcP episodes and patient satisfaction was rated as excellent or good.

PMID: 28849261 [PubMed - indexed for MEDLINE]

Tolerability of Opioid Analgesia for Chronic Pain: A Network Meta-Analysis.

Sci Rep. 2017 05 17;7(1):1995

Authors: Meng Z, Yu J, Acuff M, Luo C, Wang S, Yu L, Huang R

Abstract
Aim of this study was to study the tolerability of opioid analgesia by performing a network meta-analysis (NMA) of randomized-controlled trials (RCTs) which investigated effectiveness of opioids for the management of chronic pain. Research articles reporting outcomes of RCT/s comparing 2 or more opioid analgesics for the management of chronic pain were obtained by database search. Bayesian NMAs were performed to combine direct comparisons between treatments with that of indirect simulated evidence. Study endpoints were: incidence of adverse events, incidence of constipation, trial withdrawal rate, and patient satisfaction with treatment. Outcomes were also compared with conventional meta-analyses. Thirty-two studies investigating 10 opioid drugs fulfilled the eligibility criteria. Tapentadol treatment was top-ranking owing to lower incidence of overall adverse events, constipation, and least trial withdrawal rate. Tapentadol was followed by oxycodone-naloxone combination in providing better tolerability and less trial withdrawal rate. Patient satisfaction was found to be higher with oxycodone-naloxone followed by fentanyl and tapentadol. These results were in agreement with those achieved with conventional meta-analyses. Tapentadol and oxycodone-naloxone are found to exhibit better tolerability characteristics in comparison with other opioid drugs for the management of chronic pain and are associated with low trial withdrawal rate and better patient satisfaction.

PMID: 28515426 [PubMed - indexed for MEDLINE]