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COVERAGE AS OF
508,187SAFETY ALERTS
14,846TARGETS & GENES
14,928DRUGS & BIOLOGICS
7,489ADVERSE EVENTS
COVERAGE AS OF JANUARY 2020:
TARGETS & GENES
DRUGS & BIOLOGICS
Analysis of the VigiBase database focusing on anti-TNF-alpha-associated autoimmune hepatitis. 389 individual case safety reports were identified. There was a significant association with infliximab, adalimumab and etanercept. 91% cases were serious whilst 2.9% were fatal.
Conclusions from a Periodic Safety Update Report of Tecfidera (dimethyl fumarate; NF-kappaB/kelch-like ECH-associated protein 1 inhibitor). It has been reported in literature that female patients with psoriasis treated with fumaric acid esters are at particular risk of Fanconi syndrome. Although no cases of Fanconi syndrome have been reported with Tecfidera in patients with multiple sclerosis, the CHMP has recommended updating the product information to include Fanconi syndrome in the "special warnings and precautions for use" section. Regulatory Agency Communication
Clinical trial of rimabotulinumtoxinB (RIMA; vesicle-associated membrane protein 2 inhibitor) for sialorrhea. Adverse events (AEs) more common with RIMA than with placebo included dry mouth (8.3% placebo, 38.1% 2500 U RIMA, 45.3% 3500 U), dysphagia (1.7%, 11.1%, 4.7%), dental caries (3.3%, 7.9%, 4.7%) and dizziness (0%, 6.3%, 0%). 2 serious AEs were considered possibly drug-related (aspiration pneumonia and severe pneumonia).
Phase II trial of AKCEA-APO(a)-LRx (antisense oligonucleotide targeting apolipoprotein(a)) in 286 patients with cardiovascular disease. The most common adverse events (AEs) were injection-site reaction (27% patients with AKCEA-APO(a)-LRx [including erythema]; 6% patients with placebo), urinary tract infection (13%; 6%), myalgia (12%; 11%), headache (11% vs 8%) and influenza-like symptoms (7%; 6%). The most common AEs leading to discontinuation were myalgia, arthralgia and malaise. Other AEs are listed.
Results from non-clinical studies in rats and monkeys suggested that oxycodegol has a lower abuse potential than morphine or oxycodone. Withdrawal symptoms were milder in oxycodegol-treated rats than in those on morphine. [Data from the Nektar Briefing Information (oxycodegol) for the January 14, 2020 Joint Meeting of the Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management Advisory Committees] Company Communication
Results from clinical studies evaluating the anticancer potential of MAGE-A4/A10-targeted TCR T-cells (ADP-A2M4 and ADP-A2M10). Cytokine release syndrome, neurotoxicities and cytopenias were reported at similar rates to those seen with other TCR T-cell therapies. 2 fatal cases of aplastic anemia were reported: 1 with ADP-A2M4 and 1 with ADP-A2M10. [Data from an Adaptimmune presentation providing updated results from the SPEAR T-cell platform] Company Communication
Results from phase II/III open-label titration studies of oxycodegol (opioid mu receptor agonist). The most common treatment-emergent adverse events (AEs) were constipation (483/1484 patients [32.5%]), nausea (204 [13.7%]), somnolence (127 [8.6%]), headache (94 [6.3%]), dry mouth (79 [5.2%]) and vomiting (77 [5.2%]). 2 serious AEs were considered treatment-related: angioedema and transient blindness (1 each). Other TEAEs are listed. [Data from the FDA Briefing Information (oxycodegol) for the January 14, 2020 Joint Meeting of the Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management Advisory Committees] Regulatory Agency Communication
Phase III trial of luspatercept (GDF-11/TGFbeta inhibitor; 1-1.75 mg/kg) in 229 patients with myelodysplastic syndromes. The most common adverse events (AEs) were fatigue (27% any grade [5% grade 3] with luspatercept; 13% [3%] with placebo), diarrhea (22%; 9%), asthenia (20% [3%]; 12%), nausea (20% [1%]; 8%), dizziness (20%; 5%), back pain (19% [2%]; 7%), cough (18%; 13%), headache (16% [1%]; 7%), dyspnea (15% [1%]; 7%), constipation (11%; 9%), bronchitis (11% [1%]; 1%) and urinary tract infection (11% [1%]; 5% [4%]). The most common serious treatment-emergent AEs were urinary tract infection (2%; 1.3%), back pain and syncope (2%; 0% each). Other treatment-emergent AEs are listed.
Preclinical studies evaluating the anticancer efficacy of OT-82 (NAmPRTase inhibitor) for hematological malignancies. OT-82 caused hepatotoxicity and damaged bone marrow, spleen and lymph nodes at the highest doses tested (90 mg/kg in mice and 30 mg/kg in monkeys). Retinal toxicity and myofibril degeneration were observed in mice receiving GMX1778, while OT-82 showed no signs of retinal or cardiac toxicities. Monkeys receiving OT-82 at 60 mg/kg/day exhibited transient QT interval prolongations. Other toxicities are listed.
Safety analysis of 2 phase I trials of ubrogepant (CGRP receptor antagonist) in healthy male subjects. Adverse events more common with ubrogepant than with placebo in at least 1 of the trials were nasopharyngitis, contusion, excoriation and dizziness. Ubrogepant did not cause clinically significant elevations in alanine aminotransferase levels.
New Zealand's Medsafe has recommended routine pharmacovigilance for a potential association between Prolia (denosumab; RANKL inhibitor) and risk of infection. Regulatory Agency Communication
The FDA has updated the product information of Ocrevus (ocrelizumab; CD20 inhibitor) to include anaphylaxis in the "warnings and precautions" section for infusion reactions. Regulatory Agency Communication
The FDA has updated the product information of Infugem (gemcitabine hydrochloride; ribonucleoside-diphosphate reductase/DNA polymerase inhibitor) adding thrombotic microangiopathy and pulmonary eosinophilia as adverse reactions identified during postmarketing experience. Serious thrombotic microangiopathy has also been added to the "warnings and precautions" section. Regulatory Agency Communication
The FDA is warning of a possible link between lorcaserin (5-HT2C receptor agonist) and increased cancer risk following the results of a clinical trial. Regulatory Agency Communication
Conclusions from a Safety Update Report of Firmagon (degarelix; GnRH receptor antagonist). 8 cases of rhabdomyolysis have been reported postmarketing. The CHMP has recommended updating the product information to include rhabdomyolysis as an adverse reaction with frequency "rare". Regulatory Agency Communication
Phase I study assessing the safety and pharmacokinetics of IW-6463 (guanylate cyclase soluble activator) in healthy volunteers. The most frequent side effects were headache, nausea, dizziness, somnolence and fatigue. Mild reductions in blood pressure were observed, consistent with the drug's mechanism of action. [Data from a Cyclerion communication announcing positive results from a phase I study of IW-6463] Company Communication
Pooled analysis of 2 phase III clinical trials of Arazlo (tazarotene; retinoic acid receptor agonist) in patients with moderate or severe acne. The most common treatment-related adverse events were application-site pain (5.3% with Arazlo vs 0.3% with placebo), dryness (3.6% vs 0.1%), exfoliation (2.1% vs 0) and erythema (1.8% vs 0). [Data from a Bausch Health and Ortho Dermatologics communication announcing publication of positive results from 2 pivotal phase III studies of Arazlo lotion 0.045% for moderate-to-severe acne] Company Communication
Phase III study comparing Skyrizi (risankizumab; IL-23 inhibitor) and Cosentyx (secukinumab; IL-17A inhibitor) for plaque psoriasis. The rates of adverse events (AEs) were similar between groups, and included nasopharyngitis, upper respiratory tract infection, headache, arthralgia and diarrhea. Serious AEs were observed in 5.5% patients on Skyrizi and 3.7% on Cosentyx. [Data from an AbbVie communication announcing new data from a phase III study of Skyrizi] Company Communication
Phase II clinical trial of LY3023414 (PI3K/mTOR/DNA-PK inhibitor) in 28 patients with endometrial cancer. The most frequent treatment-related adverse events were anemia, hyperglycemia (71% each), hypoalbuminemia (68%) and hypophosphatemia (61%).
Review of fedratinib and other JAK inhibitors for myelofibrosis. The most common adverse events (AEs) of fedratinib included gastrointestinal events, fatigue, peripheral edema, dyspnea and anemia. The drug carries a black box warning on the risk of Wernicke's encephalopathy. Thrombocytopenia and anemia are dose-limiting AEs of ruxolitinib. Other AEs of JAK inhibitors are listed.
Review of clinical and preclinical data on the miridesap prodrug GSK3039294 (serum amyloid P-component inhibitor). A clinical study testing GSK3039294 in healthy subjects was terminated after several cases of arrhythmia were reported, although the association with the drug was unclear. Other adverse events are listed.
Study investigating the diabetogenic risk of atorvastatin via the interaction with farnesoid X receptor (FXR). Atorvastatin decreased glucose-stimulated insulin secretion in cultured islets and mice, and reduced FXR activity in mice. Atorvastatin is thought to inhibit insulin release by preventing the positive effects of bile acids via FXR, which may contribute to the progression of type 2 diabetes mellitus.
Phase I study of ibrutinib (BTK inhibitor) in 8 Japanese patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. All-grade adverse events (AEs) included decreased platelet count (6 [75%]), upper respiratory tract infection, increased lymphocyte count (4 [50%] each), diarrhea, rash, nasopharyngitis and peripheral edema (3 [37.5%] each). Serious AEs possibly, probably or very likely related to the study drug were lung infection, muscle hemorrhage, decreased neutrophil count and pneumonia. 5 (62.5%) patients had hemorrhagic events. Other AEs are listed.
First case report of hepatic bleed induced by dabigatran (thrombin inhibitor; 75 mg twice daily). Congress Alert
Conclusions from a Periodic Safety Update Report of Xiapex (collagenase clostridium histolyticum; collagen degrader). Based on a review on postmarketing data, the CHMP has recommended adding warnings on finger necrosis (which may lead to finger amputation) and finger fracture to the drug's product information. Digital necrosis and digital fracture will be also included in the "undesirable effects" section with a frequency "not known". Regulatory Agency Communication
The warnings and precautions section of the FDA approved drug report for Ayvakit indicates that it may cause intracranial hemorrhage (subdural hematoma and cerebral hemorrhage); central nervous system effects such as cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders and hallucinations; and fetal harm when administered to pregnant women. [Data from FDA approved drug report for Ayvakit (avapritinib; KIT/PDGFRalpha inhibitor)] Regulatory Agency Communication
Evaluation of clinical, pharmacogenomic and metabolomic parameters as biomarkers for the safety and efficacy of azathioprine (amidophosphoribosyltransferase/protein-arginine deiminase type-4 inhibitor) in an Indian population. Common adverse drug reactions included myelosuppression (13.9%), hepatotoxicity (3.48%) and pancreatic toxicity (1.16%). The TPMT*3B polymorphism was associated with a higher occurrence of myelotoxicity. Congress Alert
Real-world experience of ustekinumab (IL-12/23 inhibitor) in 62 patients with Crohn's disease. Adverse events were rash (2 patients), headache and epididymo-orchitis (1 each). Congress Alert
Phase II study of garetosmab (inhibin beta A chain inhibitor) in 44 patients with fibrodysplasia ossificans progressiva. All patients experienced an adverse event (AE). AEs occurring more frequently with garetosmab than with placebo included epistaxis (50.0% vs 16.7%) and skin events (including madarosis [25.0% vs 0%]; acne [30.0% vs 8.3%] and skin infections including abscess, carbuncle, folliculitis and furuncle). 2 patients had serious abscesses requiring hospitalization. [Data from a Regeneron Pharmaceuticals communication announcing results from a phase II trial of garetosmab] Company Communication
Analysis of the FDA Adverse Event Reporting System database focusing on oral onychomycosis medications. The most common adverse event with terbinafine was taste disturbance. Transaminase elevations were rare in the pediatric population. The most common adverse event with itraconazole and fluconazole is drug interaction.
Case report of a patient who experienced generalized tonic-clonic seizures induced by olanzapine.
Study reporting that ibrutinib, but not zanubrutinib, may cause bleeding complications by reducing platelet adhesion. This reduction is due to shedding of GP1BA and GP9 (in an ADAM17-dependent manner) and integrin alphaIIbbeta3.
The FDA has updated the product information of docetaxel (microtubule stabilizing agent), adding warnings on enterocolitis/neutropenic colitis and second primary malignancies (including myelodysplastic syndrome, non-Hodgkin's lymphoma and renal cancer). New adverse reactions added to the drug's product information are listed. Regulatory Agency Communication
Review on the genetic basis of non-alcoholic fatty liver disease (NAFLD). The main genes associated with NAFLD risk and/or progression are PNPLA3, TM6SF2, GCKR and MBOAT7. Other safety issues are listed.
Phase I/II dose-escalation study of AAV5-hFVIII-SQ (coagulation factor VIII gene therapy) in 15 patients with hemophilia A. The most common adverse events (AEs) were increased ALT (11 patients [73.3%]), arthralgia, nasopharyngitis (10 each [66.7%]), increased AST (8 [53.3%]), headache (7 [46.7%]), back pain, fatigue, upper respiratory tract infection (6 each [40%]), arthropathy, cough, insomnia and oropharyngeal pain (5 each [33.3%]). 1 patient experienced serious AEs considered treatment-related: pyrexia, myalgia and headache. Other AEs are listed.
2-year integrated analysis of benralizumab (interleukin 5 receptor, alpha subunit antagonist) in patients with severe asthma. Adverse events (AEs; ≥5% in any treatment group) were viral upper respiratory tract infection (32.3% patients receiving 30 mg Q4W and 38.7% patients receiving 30 mg Q8W), bronchitis (16.1%; 29%), sinusitis (16.1%; 9.7%), arthralgia (12.9%, 3.2%), bacterial bronchitis (9.7%; 6.5%), upper respiratory tract infection (3.2%; 12.9%) and headache (3.2%; 12.9%). The most common serious infections were lower respiratory tract infection, pneumonia and bacterial urinary tract infection (1.6% each). 1 patient had a mild hypersensitivity reaction followed by allergic dermatitis which led to discontinuation of benralizumab. Other AEs are listed.
Phase III clinical trial comparing the efficacy and safety of pegcetacoplan (APL-2; complement C3 inhibitor) and eculizumab (complement C5 inhibitor) in 80 adult patients with paroxysmal nocturnal hemoglobinuria (PNH). The most common adverse events were injection-site reactions (36.6% with pegcetacoplan vs 2.6% with eculizumab), diarrhea (22% vs 0%), hemolysis (9.8% vs 23.1%), headache (7.3% vs 20.5%) and fatigue (4.9% vs 15.4%). 3 patients in the pegcetacoplan group discontinued treatment due to hemolysis. [Data from an Apellis communication announcing positive top-line results from a phase III study comparing pegcetacoplan and eculizumab in patients with PNH] Company Communication
The PRAC has requested supplementary information on a potential association between idelalisib (PI3Kdelta inhibitor) and drug reaction with eosinophilia and systemic symptoms (DRESS). Regulatory Agency Communication
The FDA is evaluating the need for regulatory action regarding a potential association between Yescarta (axicabtagene ciloleucel; CD19-targeted CAR T-cells) and dysphagia. Regulatory Agency Communication
The FDA is evaluating the need for regulatory action regarding a potential association between vancomycin (lipid II ligand) and serious cutaneous adverse reactions (including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis and linear IgA disease). Regulatory Agency Communication
The FDA is evaluating the need for regulatory action regarding a potential association between bosutinib, imatinib, ponatinib and thyroid dysfunction. Regulatory Agency Communication
Adverse outcomes reported in single-dose toxicity studies of quizartinib included dark feces in rats; weight loss, decreased food consumption, generalized icterus and firm liver lobes in dogs; and decreased appetite, body weight loss, soft/loose/liquid feces, increased liver enzymes, total bilirubin elevation, increased creatinine, increased blood urea, and decreased reticulocytes, monocytes and lymphocytes in monkeys. [Data from EMA refusal public assessment report for Vanflyta (quizartinib; FLT3 inhibitor)] Regulatory Agency Communication
Based on data from a Periodic Safety Update Report of Senshio (ospemifene; estrogen receptor modulator), the CHMP has recommended updating the drug's product information to include vaginal bleeding as an adverse reaction reported postmarketing. Regulatory Agency Communication
Conclusions from a Periodic Safety Update Report of Tasigna (nilotinib; BCR/ABL inhibitor). Data from a phase II trial in pediatric patients with chronic myeloid leukemia pointed to a link between nilotinib and growth retardation. The CHMP has recommended updating the product information to include growth retardation with frequency "very common". Close monitoring of growth in pediatric patients is also recommended. Regulatory Agency Communication
Conclusions from a Periodic Safety Update Report of Kyprolis (carfilzomib; 20-S proteasome inhibitor). The CHMP recommended updating the drug's product information to add novel adverse reactions related to carfilzomib: angioedema (considered a class effect) and hepatitis B reactivation. Warnings on hepatitis B reactivation and progressive multifocal leukoencephalopathy will be also included. Regulatory Agency Communication
Review on preclinical and clinical studies of levonadifloxacin and alalevonadifloxacin (DNA gyrase/DNA topoisomerase 4 inhibitors). Levonadifloxacin was less phototoxic than clinafloxacin or sparfloxacin when administered to mice. Other toxicities of levonadifloxacin included phlebitis (in rats) and chondrotoxicity (in dogs). Phlebitis was not observed in a 28-day repeat-dose toxicity study in beagle dogs. No mutagenic effects were observed in mice receiving levonadifloxacin. 1 patient discontinued a phase I study of alalevonadifloxacin after experiencing QT interval prolongation, which was considered possibly drug-related.
Phase I study of indoximod (indoleamine 2,3-dioxygenase 1 inhibitor) in combination with radiation and chemotherapy in 13 children with newly diagnosed diffuse intrinsic pontine glioma. The most common adverse events due to indoximod were thrombocytopenia, diarrhea, nausea, vomiting and fatigue. Congress Alert
The EMA has updated the product information of Rxulti (brexpiprazole) to include a warning on impulse-control disorders. Gambling disorder, impulsive behavior, binge eating, compulsive shopping and compulsive sexual behavior have been added as adverse reactions with a frequency "unknown". Regulatory Agency Communication
The FDA has updated the product information of Mycamine (micafungin sodium; 1,3-beta-glucan synthase inhibitor) to include safety results from clinical studies in pediatric patients aged <4 months. Adverse events are listed. Regulatory Agency Communication
The FDA has updated the product information of Gilenya (fingolimod; S1P1/5 receptor agonist), adding warnings of human papilloma virus (HPV) infections (including papilloma, dysplasia, warts and HPV-related cancer), tumefactive multiple sclerosis and squamous cell carcinoma. Hemolytic anemia and thrombocytopenia have been included as adverse reactions reported postmarketing. Regulatory Agency Communication
Postmarketing study of dupilumab (interleukin-4 receptor subunit alpha antagonist) in 34 patients with atopic dermatitis. Side effects included allergic conjunctivitis, periocular itchiness and redness (15), eosinophil elevations (13), cough/asthma (6), herpes simplex (4) and Kaposi's varicelliform eruption, psoriasis-like eruption and exfoliation of the skin (1 each).
Phase III study of itacitinib (JAK1 inhibitor) in combination with corticosteroids in patients with treatment-naïve acute graft-versus-host disease. The most common adverse events were thrombocytopenia (34.9% for itacitinib+corticosteroids vs 34.7% for placebo+corticosteroids) and anemia (29.8% vs 25.0%). Company Communication
Phase Ib/IIa study evaluating WVE-120102 (huntingtin expression inhibitor) in patients with Huntington's disease. 72% patients treated with WVE-120102 and 83% patients on placebo experienced an adverse event (AE). The most common AEs (≥10% of patients on WVE-120102) were headache, procedural pain, falls and viral upper respiratory infection. No serious AEs related to WVE-120102 were reported. Company Communication
In vitro study evaluating the toxicity of sitagliptin and vildagliptin (DPP4 inhibitors) in murine 3T3 cells. Sitagliptin increased oxidative stress at 1000 microM, which may be associated with some of the drug's side effects observed in humans (including diabetic nephropathy, diabetic neuropathy and diabetic retinopathy).
Phase I trial of TTC-352 (estrogen receptor-alpha partial agonist) in 15 patients with metastatic breast cancer. Grade 1/2 treatment-related adverse events included diarrhea (9), hot flush (4), headache (3), nausea (3), abdominal pain (3), rash (3), blurred vision, vomiting, dizziness, peripheral neuropathy, breast pain, uterine/vaginal hemorrhage and vaginal discharge (2 each). One treatment-related event of asymptomatic pulmonary embolism (grade 3; 30mg BID) was reported. Congress Alert
Pooled analysis of 2 randomized controlled trials of cannabidiol (CB1 receptor negative allosteric modulator) for Dravet syndrome. The most common adverse events (AEs) were somnolence, decreased appetite and diarrhea; the latter took longer to resolve in the 20 mg group than in the 10 mg and placebo groups. 1% patients on placebo, 5% with on 10 mg and 19% on 20 mg had increases in ALT/AST >3x upper limit of normal. Congress Alert
Case report of a 90-year-old woman treated with pregabalin (voltage-dependent calcium channel subunit alpha-2/delta-1 ligand) who developed myoclonic status epilepticus. Congress Alert
Case report of a patient who developed posterior reversible encephalopathy syndrome with possible syndrome of inappropriate secretion of antidiuretic hormone due to pazopanib (tyrosine kinase inhibitor).
The most common adverse reactions (≥5% and greater than twice placebo) to Caplyta were somnolence, sedation and dry mouth. [Data from FDA approved drug report for Caplyta (lumateperone; 5-HT2A/D2 receptor antagonist/SERT inhibitor)] Regulatory Agency Communication
Characterization of 2 families with variants in RIPK1 (D324V and D324H) causing recurrent fever and lymphadenopathy. The mutations impaired cleavage of RIPK1, promoting activation of RIPK1 and leading to the development of an autoinflammatory disease. In mouse embryonic fibroblasts, the variants increased apoptosis, necroptosis and production of pro-inflammatory cytokines.
Article discussing the results of a randomized controlled trial (RCT) of high-dose allopurinol (xanthine dehydrogenase inhibitor; 600 mg/day) in patients with well-controlled hypertension, which highlighted deleterious cardiovascular effects associated with the drug. Allopurinol significantly increased the levels of oxidative stress markers and impaired the regression of left ventricular hypertrophy. In recent RCTs, endothelial-dependent and -independent vasodilation were numerically worse with allopurinol than with placebo, and 10% patients developed allergic-like skin reactions. Higher concentrations of oxypurinol (>100-150 mcmol/L) may also be associated with higher oxidative stress and immune system activation.
Results from 2 phase I/Ib studies of RC48-ADC (HER2/tubulin polymerization inhibitor) in patients with metastatic breast cancer. The most common treatment-related adverse events (TRAEs) were increased AST (62.9%), increased ALT (61.4%), leukopenia, hypoesthesia and neutropenia (51.4% each). Grade 3-4 TRAEs included neutropenia (21.4%), asthenia (15.7%) and leukopenia (10%). The main serious TRAE was ileus (2.9%). Congress Alert
Real-world study of ribociclib (CDK4/6 inhibitor) in 52 patients with hormone receptor-positive refractory advanced breast cancer. Adverse events included grade 3/4 neutropenia (35.4%), grade 2 emesis (2 subjects), grade 4 thrombocytopenia (1), urosepsis (1) and QTc prolongation (2). No cases of febrile neutropenia were observed. Congress Alert
Phase Ib study of talimogene laherparepvec (T-VEC) in combination with atezolizumab for triple negative breast cancer or colorectal cancer. T-VEC-related adverse events (AEs) included pyrexia (3 patients) and chills (2). Atezolizumab-related AEs included pyrexia (5), chills, rash (3 each), fatigue, arthralgia, pain and pruritus (2 each). 1 patient had grade 3 hypersensitivity to atezolizumab and 1 had grade 3 orthostatic hypotension (attributed to both drugs). Congress Alert
Phase I clinical trial of XEN901 (Nav1.6 blocker) in healthy subjects. Adverse events (AEs) reported in the single-ascending dose study included nausea (2 patients), restlessness and dizziness (1 each). AEs of the multiple-ascending dose study were dizziness, muscle twitching (2 each), fatigue, nausea, headache, nerve compression, eye pain and insomnia (1 each). Congress Alert
Identification of 3 heterozygous missense variants of KISS1R (p.A211T, p.G186E and p.A301D) in 3 patients with non-obstructive azoospermia.
Phase III trial of turoctocog alfa (coagulation factor VIII analog) in previously untreated pediatric patients with severe hemophilia A. The most frequent serious adverse events (occurring in ≥ 5% of patients) were device-related infection (5 [8.3%]), traumatic hemorrhage, pyrexia (both 4 [6.7%]), anemia and head injury (both 3 [5%]).
Systematic-review and meta-analysis assessing the risk of non-melanoma skin cancer (NMSC) in patients with rheumatoid arthritis treated with TNF-alpha inhibitors. Patients taking TNF inhibitors were at a higher risk of NMSC (RR = 1.28; 95% CI 1.19-1.38) than those not on this treatment, especially squamous cell carcinoma (RR = 1.30; 95% CI 1.09-1.54), but not basal cell carcinoma (RR = 1.13; 95% CI 0.97-1.31).
Integrated analysis from 3 trials of entrectinib (pan-TRK/Ros/ALK inhibitor) for locally advanced or metastatic NTRK fusion-positive tumors in 355 adults. The most common treatment-related adverse events were dysgeusia (41.4%), fatigue (27.9%), dizziness (25.4%) and constipation (23.7%). Congress Alert
Interim results from a phase I trial of bintrafusp alfa (M7824; PD-L1/TGFbeta inhibitor; 1200 mg every 2 weeks) in 33 patients with pretreated triple-negative breast cancer. Grade ≥3 treatment-related adverse events (TRAEs) were anemia (n=3), asthenia, decreased appetite, generalized rash, hypophysitis and increased transaminases (1 each). 1 treatment-related death was reported (with dyspnea, hemolysis and thrombocytopenia reported as grade 5 TRAEs). Congress Alert
Phase I trial of proxalutamide (GT0918; androgen receptor antagonist) in 18 patients with metastatic breast cancer. Proxalutamide-related adverse events included fatigue, hypertriglyceridemia, anemia, hypercholesterolemia, increased LDL, nausea, loss of appetite, increased ALT, weight loss, constipation and thrombocytopenia. Congress Alert
Post hoc analysis of perampanel (AMPA receptor antagonist) in patients with epilepsy. Treatment-emergent adverse events were dizziness, aggression, somnolence, fatigue, anger, agitation, depression and insomnia. Congress Alert
Study investigating pathogenic mutations in HCN1 causing epileptic encephalopathy. 3 novel de novo loss-of-function mutations were identified (p.E240G, p.A395G and p.I380F). Patients harboring these mutations presented with different phenotypes, including generalized epilepsy with febrile seizure, infantile epileptic encephalopathy and malignant migrating partial seizure. Congress Alert
Phase I trial of TAS-115 (Met/VEGFR-2/Fes inhibitor) in 67 patients with advanced solid tumors. 3 dose-limiting toxicities were reported in 3 patients: grade 3 rash (650 mg), thrombocytopenia with bleeding and rash (800 mg). Treatment-related adverse events (TRAEs; ≥20%) included increased ALT/AST, rash, fatigue, increased amylase, neutropenia, thrombocytopenia and leukocytopenia. TRAEs leading to treatment discontinuation were rash, pyrexia, peritonitis and neutropenia. Other TRAEs are listed.
The warnings and precautions section of the FDA approved drug report for Enhertu indicates that it may cause severe or fatal interstitial lung disease including pneumonitis; severe neutropenia including febrile neutropenia; left ventricular dysfunction (decreased left ventricular ejection fraction); and fetal harm (in postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death). [Data from FDA approved drug report for Enhertu (fam-trastuzumab deruxtecan-nxki; DNA topoisomerase 1/HER2 inhibitor)] Regulatory Agency Communication
Conclusions from a Periodic Safety Update Report of Vivanza (vardenafil; PDE5A inhibitor). There have been reports of central nervous system hemorrhages and cerebrovascular accidents with a close temporal association after the intake of vardenafil. In line with other PDE5A inhibitors, the CHMP has recommended updating the product information to include a warning about these events and to reflect that it is not possible to determine whether these events are directly related to vardenafil. Regulatory Agency Communication
Based on data from a Periodic Safety Update Report of Kolbam (cholic acid; farnesoid X receptor/GPBA receptor agonist), the CHMP has decided updating the product information to reflect an increased risk of hepatotoxicity in patients with pre-existing liver disease. Relevant cases of hepatotoxicity reported for the drug include 1 fatal case of acute hepatic failure, 2 cases of hepatic failure (1 fatal) and 3 fatal cases of liver disorders. Regulatory Agency Communication
Conclusions from a Periodic Safety Update Report of Gilenya (fingolimod; S1P1/5 receptor agonist). Based on cases identified postmarketing, there is evidence to support a causal relationship between fingolimod and autoimmune hemolytic anemia. The CHMP has recommended updating the product information accordingly. Regulatory Agency Communication
First-in-human phase I study of CC-115 (mTOR/DNA-PK inhibitor) in patients with advanced malignancies. In part A, the most common drug-related adverse events (DRAEs) were fatigue (22/44 patients [50%]; 7% grade 3), vomiting, nausea (18 [41%] each), decreased appetite (16 [36%]), diarrhea (11 [25%]) and hyperglycemia (10 [23%]). Other DRAEs are listed.
Phase Ib/IIa clinical trial of estetrol (estrogen receptor agonist) in 12 postmenopausal women with breast cancer. Adverse events considered possibly drug-related were spotting, fatigue (2 patients each), increased endometrial thickness, dry skin, pruritus, edema, alopecia, acid regurgitation and serious vaginal bleeding (1). Congress Alert
First-in-human phase I/II study of SAR439859 (estrogen receptor degrader) in 16 postmenopausal patients with metastatic breast cancer. The most common treatment-related adverse events were hot flushes (31.3%), diarrhea, nausea (25% each), decreased appetite, constipation, night sweats, asthenia (18.8% each), arthralgia and fatigue (12.5% each). Congress Alert
Phase I clinical trial of the antibody-drug conjugate BAT8001 (HER2/tubulin polymerization inhibitor) in 29 patients with metastatic breast cancer. 5 patients experienced grade 4 dose-limiting thrombocytopenia. The most common adverse events (AEs) were increased AST/ALT, thrombocytopenia, increased alkaline phosphatase, elevated uric acid, neutropenia, diarrhea, nausea, vomiting, fatigue and anemia. 14 patients had grade ≥3 AEs, including thrombocytopenia (12 patients [41.4%]), increased AST (4 [13.8%]), increased ALT, diarrhea (2 [6.9%] each) and anemia (1 [3.4%]). Congress Alert
Long-term phase III trial ZX008 (fenfluramine hydrochloride; 5-HT2B receptor agonist) in 158 pediatric patients with Dravet syndrome. The most common treatment-emergent adverse events (TEAEs; ≥10%) were diarrhea, vomiting, fatigue, pyrexia, ear infection, gastroenteritis and viral gastroenteritis. Other TEAEs are listed. Congress Alert
Study of SEP-363856 (5-HT1A/TA1 receptor agonist) for the treatment of schizophrenia in 193 patients. Adverse events (≥2%) were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decrease (3.2%) and prolactin increase (2.6%). Extrapyramidal-related symptoms were reported in 5 patients and suicidal intention in 3 (with 1 attempt). Congress Alert
Health Canada has updated the product information of Gilenya (fingolimod; S1P1/5 receptor agonist) to include a warning about congenital malformations. Prenatal exposure to fingolimod has been associated with a high risk of major congenital malformations, including heart diseases such as atrial septal defect, renal abnormalities and musculoskeletal anomalies. Regulatory Agency Communication
The FDA is requiring changes to the prescribing information of gabapentin and pregabalin (voltage-dependent calcium channel subunit alpha-2/delta-1 ligands) following reports of serious breathing difficulties (including respiratory depression) in patients with respiratory risk factors, especially when given concomitantly with central nervous system depressants. Respiratory depression was also reported in non-clinical studies of pregabalin. Regulatory Agency Communication
The warnings and precautions section of the FDA approved drug report for Padcev indicates that it may cause hyperglycemia, including death and diabetic ketoacidosis; peripheral neuropathy, predominantly sensory; ocular disorders such as keratitis, blurred vision, limbal stem cell deficiency and dry eye symptoms; skin reactions such as maculopapular rash, pruritus, symmetrical drug-related intertriginous and flexural exanthema, bullous dermatitis, exfoliative dermatitis and palmar-plantar erythrodysesthesia; infusion site extravasation such as erythema, swelling, increased temperature, pain and secondary cellulitis, bullae or exfoliation; and fetal harm when administered to a pregnant woman. [Data from FDA approved drug reported for Padcev (enfortumab vedotin-ejfv; nectin-4 inhibitor/tubulin polymerization inhibitor)] Regulatory Agency Communication
Very common (≥1/10) adverse reactions reported during clinical trials with Spravato were dizziness, nausea, dissociation, headache, somnolence, vertigo, dysgeusia, hypoesthesia and vomiting. [Data from EMA European public assessment report for Spravato (esketamine; NMDA receptor antagonist)] Regulatory Agency Communication
Based on data from a Periodic Safety Update Report of Rizmoic (naldemedine; opioid mu receptor antagonist), the CHMP has recommended updating the drug's product information to include gastrointestinal perforation as an adverse reaction with a frequency "not known". Regulatory Agency Communication
Preclinical study assessing the safety profile of revusiran (transthyretin expression inhibitor). Monkeys receiving revusiran showed no cardiovascular, respiratory or neurological disorders. Revusiran caused reversible microscopic liver changes in rats. Revusiran was not genotoxic or carcinogenic. Other safety issues are listed.
Results from 2 phase I studies comparing AZD9567 and prednisolone (glucocorticoid receptor modulators) in healthy volunteers. Common adverse events (AEs) considered possibly related to AZD9567 included headache (4/35 subjects [11.4%]) and micturition urgency (2 [5.7%]). Other AEs are listed.
Pooled analysis of 5 clinical trials of talazoparib (PARP-1/PARP-2 inhibitor; 1 mg/d) in 494 patients with advanced tumors. The most common all-grade adverse drug reactions (ADR; ≥20%) were anemia (including decreased hemoglobin, decreased hematocrit; 49.6%), fatigue (47.6%), nausea (44.3%), neutropenia (decreased neutrophil count; 30.2%), thrombocytopenia (decreased platelet count; 29.6%), headache (26.5%), diarrhea (22.7%), alopecia (22.3%), vomiting (22.3%) and decreased appetite (20.2%). Grade 3/4 ADRs (≥10%) were anemia (35.2%), neutropenia (17.4%), and thrombocytopenia (16.8%). Congress Alert
First-in-human phase I clinical trial of GDC-0077 (PI3Kalpha inhibitor; 6, 9 or 12 mg) in 20 patients with PI3Kalpha-mutant solid tumors. The most frequent treatment-related adverse events (TRAEs; ≥15%) included hyperglycemia (14 [70%] patients), diarrhea (8 [40%]), decreased appetite, vomiting (4 [20%] each), alopecia, fatigue, nausea and decreased weight (3 [15%] each). Grade ≥3 TRAEs were hyperglycemia (4 [20%]), lymphopenia, fatigue, nausea, weight loss and asthenia (1 [5%] each). Other TRAEs were stomatitis (4 [20%]) and rash (2 [10%]). Dose-limiting toxicities were grade 4 hyperglycemia and grade 3 fatigue (1 patient each at 12 mg). Congress Alert
Our editorial team covers more than 500 scientific conferences each year. Select a congress to discover safety insights made public for the first time:
Asian Pacific Digestive Week (APDW) 2019, Kolkata
ESMO Immuno-Oncology Congress 2019, Geneva
San Antonio Breast Cancer Symposium (SABCS) 2019, San Antonio
58th Annual Meeting of the American College of Neuropsychopharmacology (ACNP), Orlando
61st American Society of Hematology (ASH) Annual Meeting and Exposition, Orlando
American Epilepsy Society (AES) Annual Meeting 2019, Baltimore
12th Clinical Trials on Alzheimer's Disease (CTAD) Conference, San Diego
Nov 30-Dec 3
19th FIGIJ World Congress of Paediatric and Adolescent Gynaecology (WCPAG19), Melbourne
ESMO Asia 2019 Congress, Singapore
27th Annual Meeting of the European Charcot Foundation, Baveno
24th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO), Phoenix
American Heart Association's (AHA) 2019 Scientific Sessions, Philadelphia
11th European Multidisciplinary Congress on Urological Cancers (EMUC19), Vienna
Connective Tissue Oncology Society (CTOS) Annual Meeting 2019, Tokyo
Society for Endocrinology BES 2019, Brighton
AASLD, The Liver Meeting 2019, Boston
American College of Rheumatology ACR/ARP Annual Meeting 2019, Atlanta
American College of Allergy, Asthma, and Immunology (ACAAI) Annual Scientific Meeting 2019, Houston
17th European AIDS Conference (EACS) 2019, Basel
34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019), Maryland
American Society of Nephrology (ASN) Kidney Week 2019, Washington
European Congress of Oncological Gynecology (ESGO) Annual Meeting, Athens
International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Europe 2019, Copenhagen
Oct 31-Nov 2
The 33rd Annual North American Cystic Fibrosis Conference, Nashville
50th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), Hyderabad
89th Annual Meeting of the American Thyroid Association, Chicago
XXIV World Congress of Neurology, Dubai
31st EORTC-NCI-AACR symposium (ENA 2019), Boston
American College of Gastroenterology (ACG) 2019, San Antonio
20th Annual Fall Scientific Meeting of SMSNA, Nashville
48th Annual Meeting of the Child Neurology Society, Charlotte
51st Congress of the International Society of Paediatric Oncology (SIOP), Lyon
The 13th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD), Madrid
49th Critical Care Congress, Orlando
ASCO Genitourinary Cancers Symposium 2020, San Francisco
ASCO Gastrointestinal Cancers Symposium 2020, San Francisco
THE NEW OFF-X ANALYTICS
DATA IN ACTION TO DE-RISK YOUR R&D PROGRAMS
OFF-X is built from the most comprehensive translational safety dataset (508,187 curated alerts as of January 2020). We are providing access to a series of analytics and visualization extensions to fully exploit the value of the OFF-X dataset and derive new knowledge. Select your option below and start exploring
MOUNTING EVIDENCE CHART
DISCOVER CRITICAL SAFETY TRENDS & SPOT AREAS OF EMERGING CONCERN
The Mounting Evidence Charts illustrate the evolution of the OFF-X Drug Score over a compound's life cycle. Trends can be identified using the estimated strength of evidence supporting a given Drug-Adverse Event association for the 508,187 alerts available in OFF-X.
COMPARATIVE TABLE BUILDER
ASSESS SAFETY FINDINGS FOR MOLECULES
The Comparative Table Builder allows quick comparison of safety findings for molecules under development or that have been launched.
OFF-X SAFETY MAPS
PRIORITIZE AND ASSESS THE SAFETY OF YOUR INVESTIGATIONAL TARGETS
OFF-X Safety Maps allows target safety to be assessed in order to uncover potential liabilities associated to new targets by analyzing the neighborhood targets and proteins. Now available for more than 12,000 targets and proteins of potential therapeutic interest.
MECHANISTIC SAFETY DASHBOARD
ASSESS THE MECHANISMS BEHIND UNEXPECTED ADVERSE EVENTS
The Mechanistic Safety Dashboard allows users to discover potential mechanisms behind unexpected safety issues observed in preclinical and clinical trials. Now available for 7,489 adverse events and toxicological endpoints of interest.
OFF-X CHEMISTRY DASHBOARD
CORRELATE CHEMICAL STRUCTURES WITH SAFETY LIABILITIES
This module facilitates the lead optimization process by identifying toxicophores and the understanding if a liability is compound- or target-related. The sub-structure search is the first in a series of extensions aimed at providing advanced safety assessment capabilities to medicinal chemists and computational toxicologists.
OFF-X
ENABLING TRANSLATIONAL SAFETY
By enabling translational research, OFF-X allows safety liabilities to be monitored and anticipated across all phases of drug R&D and post marketing. From target safety assessment to post-marketing signal evaluation, discover the breadth and depth of OFF-X use cases:
Translational Research Teams & Information Professionals
Biologists & Bioinformaticians
Medicinal Chemists
Toxicologists & Safety Pharmacologists
Pharmacovigilance Professionals
Business Development Executives
Anticipate safety liabilities of targets entering the pipeline: Target Safety Assessment (TSA)
Benchmark target safety profiles across a given indication
Build adverse event-based systems toxicology models
Analyze structures to select candidates and optimize lead compounds by identifying toxicophores
Compare chemical and pharmacological insights associated to toxicological and safety endpoints
Build computational models to predict adverse effects from chemical structures
Anticipate and translate to the clinic toxicity and safety events derived from experimental assays and animal models
Develop hypotheses for off-target effects (secondary pharmacology profiling) and guide experimental assay planning
Determine if an adverse event is compound-related or target-related
Stay up-to-date on liabilities associated with a therapeutic target of interest
Clinical Researchers
Obtain actionable insights to design first-in-human trials and anticipate safety signals
Benchmark the safety profile of compounds as they advance in development
Discover mechanisms behind unexpected adverse events observed in a clinical trial
Pharmacovigilance & Patient Safety Professionals
Evaluate safety signals that do not appear on a drug's label
Compare findings from international regulatory agencies
Track & benchmark the evolution of safety evidence over a compound's or target's life cycle and compare it with that of others drugs
Monitor emerging class liabilities
Assess and compare the safety evidence available for a set of targets in a given indication
Perform safety evidence benchmarking
Provide an independent safety risk assessment of licensing opportunities
Expand and integrate expertly curated information with your in-house data
Enhance artificial intelligence applications with high quality curated data
Improve the performance of predictive analytics
Build chemoinformatic models to predict adverse effects from chemical structures
Extend the value of your visualization capabilities to better support internal projects
OFF-X API
EMPOWER YOUR INTERNAL SAFETY INTELLIGENCE
Connect to the most comprehensive translational safety data ecosystem through our APIs or data feed licenses. As of January 2020, OFF-X covers More than 14,846 targets, 14,928 drugs and biologics, 7,489 toxicity endpoints and adverse events. Updated daily, the portal is populated with a unique pool of more than 508,187 expertly curated safety alerts.
By integrating the OFF-X data with in-house information sources and modeling applications our customers are able to:
Enrich and expand the breadth & depth of internal resources coverage
Build Artificial Intelligence models with high quality curated data
Enhance the performance of predictive analytics
Click here to request more information on the OFF-X APIs
BIOINFOGATE'S OFF-X REACHES HALF MILLION SAFETY ALERTS
OFF-X has become the largest translational safety and toxicity intelligence portal for drugs and targets of pharmacological interest.
BIOINFOGATE TO PRESENT AT THE CHEM-BIO INFORMATICS SOCIETY (CBI) ANNUAL MEETING (TOKYO, JAPAN, OCTOBER 22-24, 2019)
Bioinfogate has been invited to a speak at the Chem-Bio Informatics Society (CBI) Annual Meeting ""Towards Seamless Integration of Structural Biology and Information Science"~Dawn of the AI era in drug discovery~" which takes place in Tokyo, Oct. 22-24, 2019.
VHIO AND BIOINFOGATE PARTNER TO ENHANCE SAFETY ASSESSMENT
Announced today, the Vall d'Hebron Institute of Oncology - Bioinfogate collaboration will validate the utility of the OFF-X translational safety intelligence portal in the design of novel clinical trials, including first-in-human studies.
FDA AND BIOINFOGATE AGREE TO EXTEND THE MATERIAL TRANSFER AGREEMENT (MTA) TO ACCESS THE OFF-X TRANSLATIONAL SAFETY INTELLIGENCE PORTAL
The agreement aims to evaluate new approaches to enhance safety assessments of human pharmaceuticals and their associated molecular targets, supporting the FDA's mission of protecting public health.
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Any reproduction, retransmission or other use is strictly prohibited. Request for permission to reproduce any information contained on this Website should be addressed to Bioinfogate, S.L. at info@bioinfogate.com
Copyright and Legal Notice
About Bioinfogate
BIOINFOGATE is a forward thinking, private company working to solve unmet medical needs. Our innovative data science products support the discovery and development of better and safer drugs. We are committed to building industry leading solutions and also identifying and investing in emerging projects that align with our core business in the life sciences and data analytics.
Our passion and capabilities stem from more than 60 years of experience creating and managing biomedical knowledge, first at Prous Science (1958-2007), acquired by Thomson Reuters in 2007 (now Clarivate Analytics), and then at Prous Institute for Biomedical Research. Bioinfogate is the latest initiative within the Prous family group of companies embracing a long tradition and expertise in scientific knowledge management.


Know the difference between a fire tube boiler and water tube boiler ? We can help take the guesswork out of selecting a commercial boilers .
When it's time to select a new boiler , there are typically two options: water tube boilers and fire tube boilers . Read more about these today.
12 Feb 2018 In the UK there are two primary types of boiler which are used for steam generation in industrial installations – water tube and fire tube .
This Article Discusses What is a Fire Tube Boiler ?, Working Principle, Types, Differences Between Fire Tube and Water Tube , Advantages and Disadvantages .


El Cariso Campground is a 24-site campground in the Santa Ana Mountains near the intersection of Ortega Highway (Route 74) and Main Divide Road on the border between Orange County and Riverside County. At 2,600 feet above sea level, the campground straddles a scenic mountain pass and can be reached easily from Lake Elsinore to the east or San Juan Capistrano to the west. Adding even more convenience, the campground sits across from the El Cariso Visitor Center, the start of the short but scenic El Cariso Nature Trail.
El Cariso Campground is open year round but may close during fall and months (or any time) when fire danger is not too high. El Cariso Campground is suitable for tents but not RVs (the max vehicle length is 22 feet). Each site is first-come first-serve for $15 per night for up to 8 people. There is a $5 fee for to park a second vehicle at the campsite (prices as of 2018). Fire rings, charcoal grills, and picnic tables are provided at each campsite. Drinking water is available at the campground, and there are vault toilets. Dogs are allowed on leashes in the campground.
The campsites are clustered around one loop that lies parallel to Ortega Highway, so you will hear vehicle noise in the campground, especially during the daytime. Some sites are closer together than others, so on busy weekend you may not get as much privacy here as you might prefer, although that could be an asset if you are camping with a large (multi-site) group. Quality stonework has ensure that every campsite has a good level spot for a tent. El Cariso Campground was constructed during the 1930s by the Civilian Conservation Corps and the sturdy stonework exemplifies their hard work and American determination.
To get to the campground: From Orange County, take the 405 Freeway to San Juan Capistrano and take exit 82 for Ortega Highway (Route 74). Take Ortega Highway up into the mountains for 23 miles and turn left into El Cariso Campground, across from El Cariso Visitor Center (the trailhead for El Cariso Nature Trail). If you reach Main Divide Road, you drove a quarter mile to far.
From Riverside County, take the 15 Freeway to Lake Elsinore and take exit 77 for Ortega Highway (Route 74). At the end of the ramp, head south on Central Avenue, make a right on Collier Avenue and left on Riverside Drive (which are all also Route 74) to take Ortega Highway through town and up into the mountains. It is 10 miles from the freeway to El Cariso Campground, which will be on the right just past the intersection with Main Divide Road.
This 1.5-mile round trip hike ventures up a wilderness canyon to a tall, five-tier waterfall along San Mateo Creek in the Santa Ana Mountains.
This 42-site campground in Cleveland National Forest offers camping near the world-renowned Palomar Observatory for $15 per night.
What months are the campgrounds open?
El Cariso Campground is currently open and can stay open year round as long as fire danger is not too high.
How do I reserve a site?
When we were 15 years old we went to El Cariso to plant pine trees. Now we are 67 years old and have put the Mariner Senior Girl Scout troop back together. Can we see the forest we planted? Are there records of scout work like this? No reservations? How can we count on getting a spot.
Is this campground open now? Any idea if it will be open in January?
The national forest webpage for this campground now says that this campground is open year round.


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Q: jquery.lazyload.js plugin download I am trying to download jquery.lazyload.js plugin, Please guide me from where I can download
 this plugin? I am trying to implement lazyloading, and when I search online, I found that we need this plugin.

A: Copy of comments:

*

*Have you tried its website? appelsiini.net/projects/lazyload

*Have you tried google: google.co.uk/search?q=laxzyload+download See: Download jQuery LazyLoad Ad - Web2ajaX
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*Or this: "Lazy loader is a jQuery plugin written in JavaScript. It delays loading of images ... Download: appelsiini.net/download/jquery.lazyload.pack.js " – Pez Cuckow

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LTD and the Buyer shall be the person, firm or company ordering the goods. These Conditions shall apply to every order accepted by the Company and no variation or obligation shall be effective unless given in writing by the Company and signed by a Director. Orders are accepted on the understanding that if any conflict arises between the Company's Conditions of Sale and any terms or conditions of the Buyer then the Company's shall prevail in all cases. The placing of an order by the Buyer is deemed as acceptance of the Company's Condition of Sale.
addition of Value-Added Tax at the rate ruling on the date of the invoice.
address as notified to the Company. Any apparent discrepancy to delivered quantities or damage to the goods must be notified by the Buyer to the Company within 48 hours of receipt. If the Buyer fails or refuses to take delivery, the Company shall be entitled to immediate payment in full for the goods so tendered, notwithstanding the Company's payment terms stated herein, and shall be entitled to dispose of the goods in such manner as the Company may determine.
plus 8% (per cent) daily to run from the date due for payment to receipt of payment by the Company whether before or after Judgement. The Company reserves the right to charge compensation of £40 per invoice on any invoice that remains unpaid after the due date has past. The Company reserves the right to charge £20 for represented cheques and failed cheques. The Buyer shall also reimburse the Company all expenses incurred in the collection of such overdue sums. If the Buyer is overdue with any payment to the Company, then the Company may suspend the delivery of any other order.
control of the Company, and no liability can be accepted by the Company for any loss or damage resulting from such circumstances.


Everything you need to know about why ISAs are important, and which one is right for you.
Should I get a Help to Buy ISA or a Lifetime ISA?
For first time buyers, having one of these accounts is a great way to boost your deposit savings. Find out which one is right for you.


About three years ago, we visited Annapolis, MD and walked through Old Town. While it was a bit hot during the early afternoon hours, it cooled off nicely toward the evening and we had a wonderful time walking about.
I love it when towns make the effort to preserve their historic sections. Not only is it good for business (because of the tourists) but it helps to ground the townspeople, because they're always reminded of their heritage.


The product works good, it gets the temperature pretty fast and because it is double I can wax in half time. You can even choose whether using only one roll or both, since it has two on/off buttons (one for part). I recommend this product if you are looking for a system to get your own waxing.
This roll on wax heater gives you all the benefits of waxing, but with an easy to roll on applicator. No more spatulas and sticks! Waxing gives your skin that smooth and flawless feel you've always wanted. And this unit comes with 2 heater cartridges for your convenience! Heat up more wax and save time.
1.Before use, make sure the skin is absolutely clean.
3.Place the wax machine into the charging base, plug it in and turn on the power.
5.Roll the product over skin in the direction that the hair grows in small areas that you want depilated.
7.Tear off the hair-removal paper in the reverse direction that the hair grows.
8.After hair removal, use the cleanser to clean off any residues the wax may have left behind.
9.After cleaning, use a moisturizer for the smoothest skin you've ever had!
Just wanted to show you guys how I wax at home!! It's super easy and saves so much money!!
Thanks for watching and for all the amazing support you have all been showing me!!
Hope u all enjoy this video and please comment, rate and subscribe!!!
Hope u all have an amazing day!!!
This entry was posted in Depilatories and tagged Belle®, Brand, Double, Hair, Heater, Removal, Roll.


This is a placeholder page for Karl Lutzi, which means this person is not currently on this site. We do suggest using the tools below to find Karl Lutzi.
You are visiting the placeholder page for Karl Lutzi. This page is here because someone used our placeholder utility to look for Karl Lutzi. We created this page automatically in hopes Karl Lutzi would find it. If you are not Karl Lutzi, but are an alumni of Lomira High School, register on this site for free now.


What are enduring powers of attorney (EPAs)?
An enduring power of attorney (EPA or EPoA) is a legal document that allows you to appoint someone you trust to make decisions about your life, if you can't. This person is then said to have power of attorney and can be a trusted relative, friend or an independent organisation like Public Trust.
Personal care and welfare EPA – in which you appoint someone to make decisions about personal matters, like where you live, and your healthcare treatment.
Property EPA – in which you appoint a person, or an organisation like Public Trust, to manage financial and property decisions. Their responsibilities can include paying bills, managing bank accounts, and buying or selling assets.
What are the benefits of having enduring powers of attorney?
An enduring power of attorney (EPA) gives you control over what happens later on, in the event that you lose the capacity to take care of your personal or financial matters due to accident or illness.
It can also save time and money, and unnecessary stress on your family, who may struggle to complete simple tasks such as paying bills on your behalf without it. Without an EPA the Family Court may be left to decide about your property and personal matters.
The Protection of Personal and Property Rights Act 1988 (PPPR) is designed to assist and protect adults who, because of incapacity, are no longer able to make or communicate decisions or manage their own affairs and don't have an EPA in place.
Completing these EPA documents is just as important as writing a will. You could think of it like an insurance policy - because it protects you and your loved ones if the worst should happen, but you need to prepare now, to gain that protection.
It's horrible to think about. But now imagine how stressed and frustrated you'd feel, if you couldn't even complete simple tasks on their behalf - like paying the bills, or cancelling the Sky subscription.
Unfortunately, this is a reality for many people. Because unless you have powers of attorney, organisations won't give you information or let you change any existing arrangements for someone else, due to the Privacy Act.
How do enduring powers of attorney work?
You choose when your EPA comes into effect, any special terms and conditions, and who your attorney must report to and consult with when making decisions on your behalf.
Find out more about the role and responsibilities of an attorney.
How much do enduring powers of attorney cost?
We do everything we can to keep our prices reasonable. Our charges vary depending on the services you need. For details please see our fees and charges.
Whenever you're ready to take the next steps we're here to help. To find out more or to make an appointment, please get in touch online, or call us on 0800 371 471.
It's a good idea to update your will whenever your circumstances change.


text:
TheGrio's 100
theGrio's 100: David Johns, closing the achievement gap for black students
David J. Johns (courtesy of the U.S. Department of Education)
Who is David Johns?
David J. Johns, 31, lives, breathes and sleeps education. A former NYC elementary school teacher, Johns has risen through the ranks to achieve prominent roles in politics and federal government.
He was a senior education policy adviser in the Senate for five years and a policy adviser to the Obama campaign in Nevada.
Throughout his career, Johns has worked on issues affecting HBCUs, minority and low-income students, under-served youth and early childhood education. His research as an Andrew W. Mellon Fellow served as a catalyst for a better understanding of negative perceptions of black males within academia and society.
His career success is backed by impeccable academic qualifications. Johns graduated with honors from the ivy league school Columbia University in 2004 with a triple major in English, creative writing, and African-American studies. He earned his master's degree in sociology and education policy at Teachers College of Columbia University, where he graduated summa cum laude.
Why is he on theGrio's 100?
Johns has recently been appointed executive director of the White House Initiative on Educational Excellence for African-Americans. As executive director, Johns has been asked to identify evidence-based best practices to improve African-American student achievement.
The goal of the initiative is to work with federal, state, and local agencies as well as community groups to produce a more effective continuum of education programs for African-American students.
What's next for David Johns?
He told theGrio that he aims to work towards President Obama's goal for America to have the highest proportion of college graduates in the world by 2020.
"I want to continue to strive to meet the president's ambitious goal of leading the world by college graduates by 2020," he said. "I recognize that the work of the initiative can help go a long way towards fulfilling this goal."
"It's important that we are supporting our African-American students, schools and communities throughout their educational journey from cradle to career. Expanding access to high-quality early childhood programs, raising standards for our elementary and high school students and making sure that college is affordable are among the key factors I look forward to continuing to work on in the years ahead."

redpajama_set_name: RedPajamaCommonCrawl


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Voters can get to know candidates for Ketchum City Council seats this week, as the city gears up for a special election May 15.
Voters will decide which of five candidates will fill two open seats, serving four-year terms. In the running are Michael David, Charles Friedman, Mickey Garcia, Julie Lynn and Jim Slanetz.
The Idaho Mountain Express will host a Pizza and Politics forum tomorrow, April 26, at 6:30 p.m. in Ketchum City Hall. All candidates vying for a seat on the council have stated they will attend. Candidates will present their ideas and then take questions from the public and the press.
The Ketchum Committee for Better Government—founded last year by Ketchum residents Anne Corrock and Ed Simon—is hosting a candidates' forum tonight, April 25. One or two questions from the committee will be asked to candidates, then the public can ask questions. The forum will take place at 5:30 p.m. at Ketchum City Hall.
Occupation: Owner/operator Sawtooth Produce Co.
Government experience: 10 years as board member and executive director of housing authorities in Blaine and Valley counties.
Education: Bachelor of Arts degree from UCLA and Juris Doctor from Loyola Law School.
Why are you running for office? "I care deeply about our community, the community where I am raising my family. I want Ketchum to be economically and socially vibrant. My goal is to give a voice to the citizens and stakeholders on all the issues we face."
Government experience: Currently serving on the Ketchum City Council, Ketchum URA and Ketchum CDC.
Education: Bachelor of Arts in English literature, Colgate University; completed Level I of charted financial analyst program.
Why are you running for office? "I'm running for City Council because this is my home and I've chosen to pursue my career here. I want to encourage smart growth for Ketchum, transparency from the government and involvement from all segments of the community."
Occupations: Retired forester, wildland firefighter, electrical contractor, work camp director, correctional officer.
Government experience: U.S. Air Force, Vietnam veteran, U.S. Forest Service, BLM, California Division of Forestry, Governor's Office, state of California.
Education: Bachelor of Science in forest resource management, University of Montana. Various technical schools in electronic and electrical control technology.
Why are you running for office? "I run because it is my duty and my right to run as a U.S. citizen and a veteran."
Occupation: Homemaker, Girl Scout leader, and freelance writer/photographer.
Government experience: Active duty in the Army and work as a journalist and media representative at the Infantry Training Center at Fort Benning, Ga., and at the 7th Army Headquarters in Heidelberg, Germany. While in college, also served in public affairs for the Oregon National Guard.
Education: Bachelor of Arts in journalism from the University of Oregon; Department of Defense School of Journalism.
Why are you running for office? "I'm excited about helping the city become more a friendly place, fine tuning the new comprehensive plan and implementing the downtown master plan. With my media experience, I can help keep voters in the loop, something the city needs."
Occupation: Owner/operator of The Board Bin.
Government experience: "Basically, I'm an outsider."
Education: Bachelor of Arts in political science, University of New Hampshire.
Why are you running for office? "As the father of two boys, I want to make our community as vibrant and sustainable as possible. I believe that by bringing people and community-minded organizations together we can make Ketchum a unique and special place."