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Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.
Recombinant adeno associated viruses (rAAV) have become an important tool for the delivery of gene therapeutics due to long-standing safety and success in clinical trials. Since humans often become exposed to AAVs and develop anti-AAV antibodies (Abs), a potential impediment to the success of gene therapeutics is neutralization of the viral particle before it has had a chance to bind and enter target cells to release the transgene. Identification of subjects with preexisting Abs having neutralizing potential, and exclusion of such subjects from clinical studies is expected to enhance drug efficacy. In vitro cell-based reporter assays are most often employed to determine the level of neutralizing antibodies in a given population. Such assays measure the ability of the Abs to prevent viral binding and entry into cells by engaging epitopes on the viral capsid involved in host cell receptor binding. In general, cell-based assays are low throughput and labor intensive and may suffer from high variability and low sensitivity issues. In contrast, enzyme-linked immunosorbent assays (ELISAs) are simpler, less variable, and have higher throughput. Demonstrating a correlation between neutralizing Abs assessed by a cell-based assay and total binding Abs measured in an ELISA will enable the use and substitution of the latter for screening and exclusion of subjects. In this work, we describe the development of a highly sensitive, specific, robust, and reproducible chemiluminescent ELISA method for the detection of total anti-AAV9 Abs. Using this method, we analyzed the prevalence of preexisting anti-AAV9 Abs in 100 serum samples from heart disease patients. Analysis of neutralizing Abs in the same samples using an in vitro cell-based assay showed a strong correlation between total anti-AAV9 Abs and neutralizing Abs, indicating the feasibility of using the total Ab ELISA in the future for patient screening and exclusion.
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
AssuntosArtrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P1 with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.
The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.
AssuntosAntivirais/química , Hepacivirus/enzimologia , Oligopeptídeos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Meia-Vida , Coração/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Técnicas In Vitro , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Prolina/química , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Proteínas não Estruturais Virais/metabolismo
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
AssuntosAntivirais/química , Hepacivirus/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Oligopeptídeos/química , Sulfonamidas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , Cães , Esquema de Medicação , Farmacorresistência Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Coelhos , Ratos Sprague-Dawley , Replicon , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).
AssuntosEtanolamina/química , Etanolamina/farmacologia , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite/tratamento farmacológico , Cães , Encefalomielite Autoimune Experimental/tratamento farmacológico , Etanolamina/farmacocinética , Etanolamina/uso terapêutico , Feminino , Haplorrinos , Humanos , Contagem de Linfócitos , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-Atividade
INTRODUCTION: Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. METHODS: From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. RESULTS: Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. DISCUSSION: Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes.
AssuntosTestes de Função Cardíaca/métodos , Coração/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Antiarrítmicos/farmacologia , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Macaca fascicularis , Masculino , Contração Miocárdica , Piridazinas/farmacologia , Valores de Referência , Telemetria
Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
AssuntosAntivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/sangue , Antivirais/química , Cães , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/sangue , Inibidores de Proteases/química , Coelhos , Ratos , Sulfonamidas/sangue , Sulfonamidas/química
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
AssuntosAntivirais/uso terapêutico , Descoberta de Drogas , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/química , Sulfonamidas/química
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
AssuntosCompostos de Fenilureia/química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazóis/química , Ureia/análogos & derivados , Administração Oral , Animais , Cães , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/farmacologia , Ureia/uso terapêutico
AIMS: Previous studies suggested that T-type Ca(2+)-current (I(CaT))-blockers improve cardiac remodelling, but all available I(CaT)-blockers have non-specific actions on other currents and/or functions. To clarify the role of I(CaT) in cardiac remodelling, we studied mice with either of the principal cardiac I(CaT)-subunits (Cav3.1 or Cav3.2) knocked out. METHODS AND RESULTS: Adult male Cav3.1- or Cav3.2-knockout (Cav3.1(-/-), Cav3.2(-/-)) mice and respective wild-type (WT) littermate controls were subjected to left anterior descending coronary artery ligation to create myocardial infarction (MI). Echocardiography and programmed electrical stimulation were performed at baseline and 4 weeks post-MI. At baseline, Cav3.1(-/-) mice had slowed heart rates and longer PR intervals vs. WT, but no other electrophysiological and no haemodynamic differences. Cav3.2(-/-) showed no differences vs. WT. Contractile indices (left ventricular fractional shortening and ejection fraction) decreased more post-MI in Cav3.1(-/-) mice than in Cav3.1(+/+) (e.g. by 34 and 29% for WT; 50 and 45% for Cav3.1(-/-), respectively; P < 0.05 for each). Cav3.1(-/-) mice had increased ventricular tachycardia (VT) inducibility post-MI (9 of 11, 82%) vs. WT (3 of 10, 30%; P < 0.05). Cav3.2(-/-) mice were not different in cardiac function or VT inducibility vs. WT. Quantitative polymerase chain reaction showed that Cav3.1 is the major I(CaT)-subunit and that no compensatory Cav3.2 up-regulation occurs in Cav3.1(-/-) mice. Cav3.1(-/-) and Cav3.2(-/-) mice had no mRNA expression for the knocked-out gene, at baseline or post-MI. CONCLUSION: Our findings suggest that, contrary to suggestions from previous studies with (imperfectly selective) pharmacological agents having T-type Ca(2+)-channel-blocking actions, elimination of Cav3.1 expression leads to impaired cardiac function and enhanced arrhythmia vulnerability post-MI, whereas Cav3.2 elimination has no effect.
AssuntosCanais de Cálcio Tipo T/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular , Animais , Canais de Cálcio Tipo T/deficiência , Canais de Cálcio Tipo T/genética , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Eletrocardiografia , Frequência Cardíaca , Hemodinâmica , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Miocárdica , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Miocárdio/patologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Volume Sistólico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Fatores de Tempo , Ultrassonografia , Função Ventricular Esquerda
BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.
AssuntosAntagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacocinética , Animais , Cães , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias da Próstata/metabolismo , Ratos , Ratos Sprague-Dawley
T-type calcium channel antagonists were designed using a protocol involving the program SPROUT and constrained by a ComFA-based pharmacophore model. Scaffolds generated by SPROUT were evaluated based on their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists containing a biaryl sulfonamide core were discovered.
AssuntosBloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Drogas , Técnicas In Vitro , Técnicas de Patch-Clamp , Relação Estrutura-Atividade
Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
AssuntosAmino Álcoois/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/fisiologia , Tetra-Hidronaftalenos/farmacologia , Amino Álcoois/química , Animais , Canais de Potássio de Retificação Tardia , Cobaias , Cetonas/química , Cetonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Bloqueadores dos Canais de Potássio/química , Tetra-Hidronaftalenos/química
Transient receptor potential (TRP) cation-selective channels are an emerging class of proteins that are involved in a variety of important biological functions including pain transduction, thermosensation, mechanoregulation, and vasorelaxation. Utilizing a bioinformatics approach, we have identified the full-length human TRPM3 (hTRPM3) as a member of the TRP family. The hTRPM3 gene is comprised of 24 exons and maps to human chromosome 9q-21.12. hTRPM3 is composed of 1555 amino acids and possesses the characteristic six-transmembrane domain of the TRP family. hTRPM3 is expressed primarily in kidney and, at lesser levels, in brain, testis, and spinal cord as demonstrated by quantitative RT-PCR and Northern blotting. In situ hybridization in human kidney demonstrated that hTRPM3 mRNA expression is predominantly found in the collecting tubular epithelium. Heterologous expression of hTRPM3 in human embryonic kidney cells (HEK 293) showed that hTRPM3 is localized to the cell membrane. hTRPM3-expressing cells exhibited Ca2+ concentration-dependent Ca2+ entry. Depletion of intracellular Ca2+ stores by lowering extracellular Ca2+ concentration and treatment with the Ca2+-ATPase inhibitor thapsigargin or the muscarinic receptor agonist carbachol further augmented hTRPM3-mediated Ca2+ entry. The nonselective Ca2+ channel blocker, lanthanide gadolinium (Gd3+), partially inhibited hTRPM3-mediated Ca2+ entry. These results are consistent with the hypothesis that hTRPM3 mediates a Ca2+ entry pathway that apparently is distinct from the endogenous Ca2+ entry pathways present in HEK 293 cells.


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Elastomers Market 2019: Global Analysis, Share, Trends, Application Analysis and Forecast To 2023
Elastomers market Expected to reach 42.3 thousand kilotons by 2023 at a compound annual growth rate (CAGR) of 4.1% for the period of 2018-2023.
PUNE, MAHARASHTRA, INDIA, December 4, 2019 /EINPresswire.com/ -- Elastomers Industry
This report breaks the global elastomers market into two major markets: thermoplastic elastomers (TPE) and thermoset elastomers (TSE).
Thermoset elastomers, also known as rubbers, include natural rubber (NR) and synthetic rubber. Synthetic rubbers include isoprene rubber (IR), butadiene rubber (BR), styrene butadiene rubber (SBR), nitrile rubber (NBR), chloroprene rubber (CR), butyl rubber (IIR), ethylene propylene rubber (EPM and EPDM). NR, IR, BR, SBR, NBR and CR are unsaturated rubbers. IIR, EPM and EPDM are saturated rubbers. Other saturated rubbers with relatively small volumes include epichlorohydrin rubber (ECO), polyacrylic rubber (e.g., ACM, ABR), silicone rubber, fluorosilicone rubber (FVMQ), fluoroelastomers (e.g., FKM, FEPM) and chlorosulfonated polyethylene (CSM).
Thermoplastic elastomers include thermoplastic styrenic elastomer (TPS), thermoplastic polyurethane (TPO), thermoplastic vulcanizate (TPV), thermoplastic copolyester (TPEE) and thermoplastic polyurethane (TPU). Other TPEs with relatively small volumes of consumption include thermoplastic acrylics (TPA), thermoplastic polyvinylchloride (TPVC) and Melt Processible Rubber (MPR). TPS, also known as styrene block copolymer (SBC), is the largest product in terms of volume. SBC includes Styrene-butadiene-styrene (SBS), styrene-isoprene-styrene (SIS), styrene-ethylene/butylene-styrene (SEBS) and styrene-isoprene-styrene (SEPS).
Request for Sample Report @ https://www.wiseguyreports.com/sample-request/3506684-elastomers-applications-and-global-markets
Reasons for Doing This Study
There three primary reasons for doing this study are for:
- Elastomers manufacturers and suppliers to understand market trends and new technologies in the industry to plan their production and research & development (R&D) for the next few years and beyond.
- Resins and raw material suppliers to understand the market trends and technological requirements from elastomers.
- Elastomer users such as tires companies to understand the trends of technologies and markets to make the best raw materials choices and to improve their products in the future.
Report Scope:
The scope of the report covers the overview of the global market for the elastomers and analyzes global market trends, with data from 2016, 2017 (considering as base year), estimates for 2018 and forecast for 2023 with projection of compound annual growth rate (CAGR) in the forecast duration.
The report includes discussion of technological, regulatory, security, and economic trends that are affecting the market. Further, it explains the major drivers and regional dynamics of the global elastomers market and current trends within the industry.
The report includes discussion of product types such as styrene butadiene rubber, butadiene rubber, nitrile rubber, isobutylene isoprene rubber, ethylene propylene rubber, polyisoprene rubber, chloroprene rubber, styrene block copolymers, thermoplastic polyolefins, thermoplastic vulcanizate, thermoplastic polyurethane, thermoplastic polyester elastomer and others. It also includes discussion of application types such as tires and automotive components, sports products, medical products, appliances, industrial and others (architecture, modifiers).
In the elastomers market, products have been segmented into thermoplastic and thermoset segments. The thermoset segment is sub-segmented into natural and synthetic elastomers. The synthetic segment is further sub-segmented into isoprene & polyisoprene rubber (IR), butadiene and polybutadiene rubber (BR), styrene-butadiene rubber (SBR), nitrile, nitrile-butadiene, acrylonitrile rubber (NBR), ethylene-propylene rubber (EPM) and ethylene-propylene-diene rubber (EPDM) and others. The thermoplastics segment has been segmented into styrene-thermoplastic-elastomers (TPE-S), elastomeric alloys, thermoplastic urethane elastomers, thermoplastic polyester elastomers and others.
The report concludes with a special focus on the detailed profiles of the major vendors in the global elastomers market.
Leave a Query @ https://www.wiseguyreports.com/enquiry/3506684-elastomers-applications-and-global-markets
Report Includes:
- 50 tables
- An overview of the global market for the elastomers and their applications in different industry vertical
- Analyses of global market trends with data from 2017, estimates for 2018, and projections of compound annual growth rates (CAGRs) through 2023
- Characterization and quantification of global elastomers market by product type, end user, application industry and geographical region
- Coverage of all major elastomers type such as Isoprene & Polyisoprene Rubber (IR), Butadiene & Polybutadiene Rubber (BR), Styrene-Butadiene Rubber (SBR), Nitrile, Nitrile-Butadiene, Acrylonitrile Rubber (NBR), Styrene-Thermoplastic-Elastomers (TPE-S), Thermoplastic Urethane Elastomers, Thermoplastic Polyester Elastomers and others
- Regional dynamics of atrial fibrillation for level covering North America, Europe, Asia-Pacific and Other emerging markets
- Detailed analysis of major drivers, restraints, opportunities and trends in the global elastomers market
- Discussion of the major players across each regional market, including Basf SE, Celanese Corp., Dow Chemical Co., Dupont and Evonik Industries
Company Profiles (Company Overview, Financials, Products, Recent Developments)
Arkema S.A.
Basf Se
Celanese Corp.
Chase Corp.
China Petroleum & Chemical Corporation
Covestro Ag
Dow Chemical Co.
Evonik Industries
Goodyear Tire & Rubber Co.
Japan Synthetic Rubber Co. Ltd.
Kraton Polymers
Kuraray Co. Ltd.
Lanxess Ag
Lcy Chemical Corp.
Lion Elastomers Llc
Lubrizol Corp.
Lyondellbasell Industries N.V.
Nanjing Jinteng Rubber Co. Ltd.
Nantong Huili Rubber Co. Ltd.
Shandong Dawn Polymer Co. Ltd.
Solvay Corp.
Teknor Apex
Trinseo S.A.
Contact Us: email@example.com Ph: +1-646-845-9349 (Us) Ph: +44 208 133 9349 (Uk)
+1 646-845-9349
email us here
EIN Presswire does not exercise editorial control over third-party content provided, uploaded, published, or distributed by users of EIN Presswire. We are a distributor, not a publisher, of 3rd party content. Such content may contain the views, opinions, statements, offers, and other material of the respective users, suppliers, participants, or authors.


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1. Castor Oil
This oil is high in the amino acid ricinoleic, which enters the skin of the scalp and follicles, and regulates the pH levels, preventing hair loss and dandruff.
2. Egg Yolk
The eggs have lots of beneficial ingredients in its content. The protein, fatty acids, and vitamins are one of them which are responsible for giving strength to your hair. The vitamin that provides moisturizing to your hair is vitamin A, which is present in the content of the yolk which also can promote growth. Lecithin as another beneficial ingredient will protect the hair from breakage.
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Do you really want to wander the jungle fighting monkeys for 3 hours to find "bob the elf. By leveling in a group, you'll probably spend a lot less time being dead and running back to get your corpse. Everyone always wants to know about the fastest way to level their world of warcraft characters, and dungeon leveling offers a unique new way to power level. and bunker fuel was spilled. Blue, items that can be resold. They have established a long history of providing fast updates faster than anyone else. Installation of the these leveling guide:. It is the greatest tool, addon that i have ever used. Retailers will get the chance to create simulations and store layout edits, figuring out optimum display locations and lights to increase sales. Even if your character is already high-level, becoming a member will also grant you access to a secret but legal technique you can use to raise the power levels of up 60 characters in a day.
We have included some fresh and interesting information on dugi guide download. Power leveling with the dungeon finder. You can now continue to explore the areas of the game. for new players having a talent advisor is a perfect feature, as you probably don not really know what talents are good and what talents are not. Hmm, where shall i quest next. Four reasons you should try dungeon leveling. If you want to skip something, just put a checkmark in the box next to it, and the guide will consider that step completed and move you on to something new. Meet sumiki, the orc warlock. Oh, and it also covers all the zones for the loremaster. Therefore on the whole when considering the reliability i really will vouch for dugis ultimate wow guide simply because i have experienced marginal troubles during the months i've been dugis ultimate wow guide and found in general the guide runs smoothly and efficiently 24/7.
Mmorpgs gaming forum is filled with opportunity for members, publishers, or programmers. Download dugi world of warcraft guides to level your world of warcraft character solo from level 1 to 90 in 3 days. I love wow once again and it's all because of dugi. Just walk up to a guard in a city, you can ask them where the leatherworking trainer is located. Instead, your time spent instance leveling in the dungeons gets you more. This means you can jump out of the guide at any time, do your own thing, then continue with the guide without any problems.
Never ever pay for leveling guides. Want/need to learn about and use. Dugi is hosting a contest where you can get. Saharun is one of croatia's loveliest but least known spots (picture: alamy). Open my map to see where the nearest quest takes place and go there, through the questtracking you can quickly see what is to be expected of you or even when you look at your tooltip while hovering over mobs. It sounds unrealistic but the video promotion of the guide clearly shows how you can do it. Unfortunately it is a website and you may have to tab out if you aren't sporting a multi-monitor set up.
Hey! Just came back from the game, looking to play bfa but i had no idea what to do when i logged on. It was all a bit confusing and i know nothing about the current content. So after some frustration i bought zygor again (haven't used it since cata ..) and i do currently feel more comfortable. I'm following the guides from the 'suggested' tab in zygor but i'm just really unsure if what i'm doing is even relevant. I know the end of the expansion is coming so i'd hate to waste my time. OK i will list the things it's been telling me to do.
Dugis Ultimate world of WarCraft Guide installation is not impossible, nor should it deter you from using another guide; remember many are very satisfied with Dugis Guide. However in order to install Dugi's WoW leveling guide you have to download their installer, you have to download each part of their guide individually (about 16 files). Once you have all the installation setup files and the installer in the same folder, you execute the installers. All the installer does is UnZip each file & place it in your Addons folder. The process is very similar for the Macintosh.


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Philip Seymour Hoffman's tragic death is unfortunately an all too common occurrence – 105 people die from overdosing daily. The founder of the Drug Policy Alliance goes over ten important changes that can help reduce the number of drug-related deaths on CNN.
Sacred Economics: Chapter 14, The Social Dividend (Pt. 15)
Sacred Economics
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icare releases psychological claims update | Insurance Business
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What is PHP?
Who uses PHP?
PHP Integrations
Why developers like PHP?
Here are some stack decisions, common use cases and reviews by companies and developers who chose PHP in their tech stack.
When I joined NYT there was already broad dissatisfaction with the LAMP (Linux Apache HTTP Server MySQL PHP) Stack and the front end framework, in particular. So, I wasn't passing judgment on it. I mean, LAMP's fine, you can do good work in LAMP. It's a little dated at this point, but it's not ... I didn't want to rip it out for its own sake, but everyone else was like, "We don't like this, it's really inflexible." And I remember from being outside the company when that was called MIT FIVE when it had launched. And been observing it from the outside, and I was like, you guys took so long to do that and you did it so carefully, and yet you're not happy with your decisions. Why is that? That was more the impetus. If we're going to do this again, how are we going to do it in a way that we're gonna get a better result?
So we're moving quickly away from LAMP, I would say. So, right now, the new front end is React based and using Apollo. And we've been in a long, protracted, gradual rollout of the core experiences.
React is now talking to GraphQL as a primary API. There's a Node.js back end, to the front end, which is mainly for server-side rendering, as well.
Behind there, the main repository for the GraphQL server is a big table repository, that we call Bodega because it's a convenience store. And that reads off of a Kafka pipeline.
We use PHP because of fast development time, compatibility and maturity. Yes - its not the most elegant programming language and if you're not careful, its very easy to end up with spaghetti monolithic code. But with the right structure and discipline, we find PHP to be one of the fastest ways to go from idea to prototype to production.
We use PHP because we started as a startup and this was the fastest way to prototype our ideas back when we started. Today we are migrating away from most of it by re-implementing our frontend in React. We will most likely still keep the PHP core as our API because the database and the ORM we use is implemented very clean.
For markup and style, I used Pug and Sass, since they're the perfect match to me. I love the clean and strict syntax of both of them and even more that their structure is almost similar. Also, both of them come with an expanded functionality such as mixins, loops and so on related to their "siblings" (HTML and CSS). Both of them require nesting and prevent untidy code, which can be a huge advantage when working in teams. I used JSON to store data (since the data quantity on my website is moderate) – JSON works also good in combo with Pug, using for loops, based on the JSON Objects for example.
To send my contact form I used PHP, since sending emails using PHP is still relatively convenient, simple and easy done.
DevOps: Of course, I used Git to do my version management (which I even do in smaller projects like my website just have an additional backup of my code). On top of that I used GitHub since it now supports private repository for free accounts (which I am using for my own). I use Babel to use ES6 functionality such as arrow functions and so on, and still don't losing cross browser compatibility.
Side note: I used npm for package management. 🎉
*Business Tools: * I use Asana to organize my project. This is a big advantage to me, even if I work alone, since "private" projects can get interrupted for some time. By using Asana I still know (even after month of not touching a project) what I've done, on which task I was at last working on and what still is to do. Working in Teams (for enterprise I'd take on Jira instead) of course Asana is a Tool which I really love to use as well. All the graphics on my website are SVG which I have created with Adobe Illustrator and adjusted within the SVG code or by using JavaScript or CSS (SASS).
For the backend of https://www.rsvpkeeper.com I went with Go.
My past few project have been built with Go and I'm really loving it. It was my first statically typed language after many years with PHP and Node.js - and honestly I couldn't be happier to have made the switch.
The biggest thing for me, is that with the forced declaration of types - it's made me feel like I've made a more solid backend. Sometimes with PHP I felt like a stiff breeze could knock the whole thing down. I know that's an exaggeration - but it's kinda how it feels.
Anyways, everyone knows that it almost doesn't even matter what an app is actually made with - what really matters are the design decisions you make a long the way.
At labinator.com, we use HTML5, CSS 3, Sass, Vanilla.JS and PHP when building our premium WordPress themes and plugins. When writing our codes, we use Sublime Text and Visual Studio Code depending on the project. We run Manjaro and Debian operating systems in our office. Manjaro is a great desktop operating system for all range of tasks while Debian is a solid choice for servers.
WordPress became a very popular choice when it comes to content management systems and building websites. It is easy to learn and has a great community behind it. The high number of plugins as well that are available for WordPress allows any user to customize it depending on his/her needs.
For development, HTML5 with Sass is our go-to choice when building our themes.
Main Advantages Of Sass:
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Date: November 23, 2019
Wife Remy Lacroix anally xnxx punished in front of her husband's secretary xvideo
Date: November 23, 2019
A tearing sensation takes root as her sphincter muscles stretch again, nearly three inches. Spreading until her rectal cavity is a gaping tunnel stretched the full four inches and revealing her intestinal tract opening as he shines his small halogen light inside her body to check for unwanted waste. He spoons the thick chili-like mixture into her rectum, pressing it deeply and packing it into every crevice in her canal. Her body shivers from the coldness of the food and the fullness. She struggles to expel the offending substance but is unable to do so with the retractor holding firm. Turning the audio reconditioning tracts off, she is alarmed by the sudden silence in her brain. He leans into her ear to ensure that she has no doubt what is going to happen. "Have you ever had your ass stuffed this full? "You know what comes next, don't you? "Your cunt is sopping wet. "If only you would obey my rules.
The stack of DVD's were obviously made by them. Another photo was of her with nipple clamps, gagged, blindfolded, and the older lady pulling her hair back displaying the welts across her tits. WOW I thought to myself. This shit is fucking hot. I have always dreamed about this kind of situation, and always watch videos of this when I jacked off at home. Here it was right in front of me. I quickly took my measurements, adjusted my now growing cock, and gathered myself together enough to head back to the living room. When I walked back towards her, she had a slight grin on her face. Here nipples were now sticking out about a half inch, pushing the tank top tightly around them. Her left foot was up on the coffee table and her right leg was up on the couch. She was purposely showing off that naughty little pussy to me. I asked her if I could sit at the dining table to write the estimate, and to hide my growing cock.
She breathed heavily in quick pants in response to the delicious impalement. Her phantom Lover withdrew so the thick head teased the puckering inner lips and then slithered back into the depths of her seething vagina. Lisa moaned and gurgled as her body vaulted up the arousal ladder. Her gasping sounds registered her body's rising levels of ecstasy. Michael had already made her orgasm three times and she was being pushed rapidly toward a forth. She began thrusting and grinding her hips back onto the thick engorged organ that was plunging into the depths of her sexual being. For the first time she was hearing Michael's deep gasping pants as his lunges took on a sense of urgency. She wanted to return the ecstasy that he had and was giving her and began clenching her vaginal muscles with intense squeezing and massaging action. He gasped as the his straining member became encased within a deep sucking and milking sheath. Lisa now wanted, now needed and now craved for her lover's thick gushes of hot semen to flood her enflamed sex. Her own words surprised her as they flew from her mouth. The lunges became more urgent.
He loves it, i can see it in his eyes as they starr at my boobs. I do it gladly for him and the neighbours. All went very normal, like living in a nice neighbourhood (sure is my first but i imagined it this way and happy that it came so) since last Friday. My lightbulb in my living room burned out. So i had no light at evening, luckily Robert was just in stairway so i called him. I could not chang the lightbulb by my self because i could not reach the bulb fitting from the table (notice to me, buy a small ladder or call Robert again, giggle, soon you will know why). It was the first time i let him in my flat and even closed the door, didn´t want to let it open other neighbours don´t have to spy through the door in my flat, it´s my privacy.
I decided to ask. "Joan, I wish I could go to the swingers club with you and dad. Do you think that is possible? She hesitated as if in deep thought, then continued, "Next Saturday we have invited another couple and my very good friend, Joyce, to our house. She and I were best friends in school and now she is divorced. She could be your date. I might add, the couple we are inviting are swingers and Joyce is interested in getting involved in the life style. I think you will like her. Then I started thinking about the swingers club dad and Joan attended. I wondered if I could go. But how would I get invited especially when single guys were not allowed. I decided to ask. "Joan, I wish I could go to the swingers club with you and dad. Do you think that is possible? She hesitated as if in deep thought, then continued, "Next Saturday we have invited another couple and my very good friend, Joyce, to our house.
Finally having had his fill of cunt juices, Rogue raises up and grasps Katie's hips and maneuvers her a half turn. But still not comfortable. He actually maneuvers her another half turn. Katie hissing and gasping out each time. Then Rogue grip tightens around her hips as he visibly draws her back towards him. He then leans down fully onto her back. Susan zoomed in and I see the tip of his clearly dripping cock pressing up against her labia. Katie let out moan as pushed his hips forward. I could clearly see his bulbous balls dangling and hitting against her thighs. But he wasn't yet in position to fuck her. He was shifting his weigh between each of his hind legs. Katie was visibly trying to move her butt around, clearly trying to help him get inside her. Of course he couldn't see her cunt hole on her back as he was.
While washing, I started to think about Rod; fanaticizing about what he would look like naked. I started to stroke my flaccid soap covered cock. As I imagined Rod, I became erect and excited at the same time with my passion for my friend. I stroked my cock to the thought of Rod. I was about to cum when I thought to myself If i might need to for later tonight. But, I was to late, by the time I started to think, my legs started to shake in the intensity of my orgasm. A hot stream of cum came out of my dick and flew across the shower and hit the doors; my cum running down it. I finished the rest of my shower and turned the water off. I opened the door and grabbed the towel and dried off. I walked into my room completely naked, not caring if anyone seen me. No one did; no one was home.


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This house is being updated and so cute. Lots of trees, close to City Market, restaurants and more. End of the cul-de-sac and a huge fully fenced back yard....What a great home to start a family with or use as a second home. Nice size front porch where you have plenty of room for a couple of rockers to enjoy your coffee or end of your evening. New/ fresh paint, a new range has been installed and heater has been updated, new carpet is finally in so just waiting on the new shower. This home is very inviting and has a wood burning fireplace to snuggle up to in the winter or place plants on in the summer...LOL. 2 Bedrooms plus an office and 1.75 bath. The 3/4 bath also doubles as a laundry room. Brand NEW shower stall being installed 11/4. The master and the guest room both have a door that leads to the back deck which is just a nice size, ideal for a table etc. and steps that lead down to the large back yard which is accessible from the garage and fully fenced for your four legged friends. The trees are beautiful and you can hear the breeze through the trees. This is such a cool home and easy to care for. This is being sold in AS IS condition with a right to inspect. Please make sure you add this to your list - i'm sure you'll be happy you did.


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Women's Stand Collar Designer Diamond Quilted Black Leather Biker Jacket
Quilted leather jacket womens is manufactured from a reliable quality of genuine leather material. The material we use in the production of this jacket is good, lasting and of enduring quality. This jacket will shield you against the cold climate and will make you feel warm and cozy. This jacket will give you a very appealing sight. The inner soft viscose lining makes this outfit very comfortable that you can carry it all day long. Biker jacket women have front ykk branded zippers for the closing. It comes with a stand-up style collar. The padded front makes the appearance of this jacket more attractive. It comes with quilted long length style sleeves on zippered cuffs. There are two front waist pockets for keeping stuff.
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Hi, the companion app (both new v2.0 and previously) displays the HA frontpage in a very narrow single column. See the attached pic.
Any reason why? It has done this over a few Hassio version updates and for both the old and new 2.0 versions of the app.
Config at https://pastebin.com/xSYJm6w6
On iPhone 8, Hassio 0.102.3


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About Jeff HigginsI have had a passion for weather since I was 8 years old. In 2011 I created Higgins Storm Chasing on Facebook which has now grown into a successful meteorology business.
NSW rain, snow & storms early this weekJeff Higgins2019-09-15T10:35:55+10:00
Issued 15th Sept 2019. New South Wales is in for a mixed weather bag early this week with rain, snow, storms and strong winds on the forecast! A cold front will move North across Southern districts on Monday before developing into a Low across Central East districts on Tuesday. The low is expected to briefly intensify just off the NSW coast on Tuesday night. Above image: rainfall via Windy.com
The heaviest falls of 50-100mm are forecast along the coast from Newcastle, Gosford, Sydney, Wollongong, to Ulladulla between Monday afternoon and Wednesday afternoon. 10-25mm is forecast through Central inland parts of NSW with lighter falls of 5-10mm across Southern inland areas.
Scattered showers and thunderstorms are expected across the North East quarter of the state on Tuesday afternoon and evening. Some of these storms could be severe with damaging winds due to strong in the mid levels of the atmosphere. Those areas directly under storm activity could receive up to 20mm of rain.
5-10cms of snow is likely across the Alps on Monday night and Tuesday morning. Model data is continually suggesting possible heavier snow falls of 7-15cms across higher elevations on the Southern and Central Tablelands of NSW during Monday night and Tuesday morning. This snow is highly subject to low level temperatures remaining cold enough… given the current data it could easily fall as rain and sleet instead of snow but it will be interesting to see what happens!
Maximum temperatures will be well above average across the Northern 2/3rds of NSW on Monday before the arrival of the cold front. Northern districts will see maximum temperatures of 30-34C. On Tuesday an 8-12C temperature drop will push across all districts accept the far North East. The Central Tablelands will see max temps of just 6-10C on Tuesday with most of the state struggling to reach 20C.
On Monday winds will be very warm from the North West across the Northern half of the state while the Southern half will have much cooler Southerlies developing. During Tuesday coastal districts South from Newcastle will see South East winds become very gusty as the low develops. Central inland will experience strong South East winds as well while Northern inland areas are expected to see strong South West winds. These strong South West winds may kick up areas of dust on Tuesday afternoon.
Detailed Higgins in-house rain, storm and snow maps are available to premium members. Find out more or subscribe HERE or by clicking on the image below!
3 days of shower & storm potential for SEQLD & NENSWJeff Higgins2019-08-26T12:43:19+10:00
Issued 26th August 2019. Some locations across SEQLD and NENSW could see 3 days of repeat showers and storms between Tuesday and Thursday this week. A number of locations could see totals of 10-25mm during this time. Above image: next 5 day rainfall totals via ECMWF at Windy.com
There still remains some uncertainty between various forecast models for rainfall totals and the Thursday / Friday daily forecast however most locations in the circled area are likely to see some rain this week.
An upper trough with cold pool of air is expected to enter South East QLD and North East NSW on Tuesday afternoon causing instability. The cold pool will then be located right over both areas on Wednesday and Thursday with increased instability. Thats great upper support but the focus needs to be placed on the surface and mid level trough which delivers moist conditions to its east needed for rainfall.
Tuesday Forecast: The surface trough is expected to be located along the ranges in SEQLD & NENSW with moist unstable conditions in its vicinity. Isolated afternoon showers and storms are forecast to develop along the ranges from about Kingaroy through Toowoomba and Warwick down to Dorrigo in NENSW (Burnett, Eastern Downs, Granite Belt & Northern Tablelands). They are forecast to travel slowly East and could reach the coast South of Brisbane to Coffs Harbour late in the afternoon.
Wednesday Forecast: The surface trough is expected to be located through Southern inland QLD down into North East NSW from Tambo through St George, Goondiwindi, to Coffs Harbour with moist unstable conditions to its east. There is also a mid level trough which is forecast to add additional moisture across SEQLD and NENSW. Morning showers and light rain areas are possible across the Maranoa, Darling Downs & Granite Belt, northern parts of the Northern Tablelands into the Northern Rivers districts. This activity is forecast to slide East South East with additional showers and storms developing further East during the afternoon. This activity should reach the coast from the Sunshine Coast south to Coffs Harbour. There is some potential for overnight showers and rain areas. Any decent showers and storms are likely to contain amounts of small hail due to very cold air aloft.
Thursday Forecast: It remains a little uncertain between data models but the best case for rain will be as follows… The surface trough could be located along the ranges from Gayndah, Kingaroy, Toowoomba, Warwick to Grafton with moist unstable conditions to its East. (some models suggest it will be offshore). Scattered afternoon showers and storms may develop East of the ranges across the Wide Bay, Burnett, South East Coast and Northern Rivers districts. This activity would push East and reach the coast from Bundaberg south to Grafton.
Friday is also a wild card with yet another possible upper cold pool of air over NENSW and SEQLD triggering some showers and storms but we will have to wait and see if that holds or not…
Some will get more than others and a few may miss out but every drop is welcome and we need to be grateful!
SEQLD detailed HSC in-house storm and rainfall maps are available through our membership service. With storm season fast approaching we suggest you see what we have to offer while supporting our work. Click on the image below to find out more information or to subscribe!
Showers & storms on the cards for SEQLD & NSWJeff Higgins2019-08-26T12:44:35+10:00
Updated 26th August 2019 please see here for latest details…
Issued 24th August 2019. Look what we have on the forecast… Showers & storms are on the cards across parts SEQLD & parts of NSW! Above image via BSCH showing the % of models forecasting precipitation on Wednesday.
Tuesday: Isolated showers and storms will be possible through inland areas of SEQLD (along the ranges from Yarraman to Warwick and across the Scenic Rim). Moisture and instability are pretty weak but there is still a 50% chance of these developing. Showers and some storms will be more likely along the Central and Northern NSW coast (Sydney to Newcastle showers, Taree to Byron Bay showers and storms).
Wednesday: Scattered showers and storms are likely across SEQLD in the yellow circled area. Some of these storms will also contain small hail due to very cold air above. They are expected to develop through inland areas during the early afternoon and slowly move East into the South East coast. Shower and storm activity in NSW will contract into the far North East (yellow circled area).
Given the current severe drought conditions we are pleased to see any activity forecast especially in August & September. Our new public "severe thunderstorm watch maps" are ready for public release on thunderstorm days in NENSW and SEQLD. Find out more about what a "severe thunderstorm watch" is HERE!
We predict that October will be a very active storm month across NENSW and SEQLD!
HSC premium members please keep an eye on our website forecasts from tomorrow morning as the detailed rain and storm maps will be issued for this system.
If you would like to subscribe to our premium weather service and gain access to detailed thunderstorm and rainfall forecast maps find out more about our premium weather service by clicking here > https://higginsstormchasing.com/higgins-storm-chasing-membership/ or on the image below.
Another snow producing Polar airmass for SE AustJeff Higgins2019-08-14T10:44:05+10:00
Issued 14th August 2019. After a huge polar low delivered massive amounts of snow over the weekend, negative SAM (Southern Annular Mode) is going to hang in there for another round later this week into next week. A low pressure system south of Tasmania will push a polar airmass northwards over Victoria, the ACT Southern and Central NSW this Sunday & Monday. Above image via Pivotal Weather showing the very cold air.
VICTORIA: A cold front will sweep East across Victoria with a band of showers on Sunday. Northerly winds could reach 90km hr across Alpine areas and some data suggests Thunder snow is possible on Sunday night with blizzards conditions. 20-30cms of fresh snow is forecast in the 24hrs from Sunday to Monday across the Alps. Snow levels are also forecast to drop to 700 meters across the state so some snow flurries will be possible at Ballarat and Trentham.
ACT: Showers are forecast to develop on Sunday afternoon and continue overnight possibly into Monday. Showers will falls as snow on the ranges with 10-20cms expected on the peaks. Some brief snow flurries will be possible in Canberra early Monday morning.
NSW: The cold front moves East across the interior on Sunday with strong cold Westerly winds developing through the Western half of the state. A band of showers and isolated storms are forecast across Southern areas which will eventually reach the Central Tablelands Sunday night. The coldest airmass arrives late Sunday night and hangs around until Midday Monday so snow will be possible on the CTs during this time. AT this stage the snow producing cold air and precipitation does NOT reach the Northern Tablelands.
For SA the front moves through on Sunday with showers and isolated storms across the South East. In Tasmania the front moves through on Sunday and Monday with showers across the state and snow to low levels on Monday. Below image snow accumulation forecast totals via Windy.com
We produce accurate daily snow forecasts and maps across Victoria, the ACT and NSW with amounts, times and locations listed. Click here to subscribe to our membership or on the image below for more information!
Snow possible in Canberra – likely on the hillsJeff Higgins2019-08-08T09:58:31+10:00
Issued 8th August 2019. Snow often falls on the ACT ranges during strong cold fronts but it always struggles to reach Canberra city due to the lower elevation. The polar airmass coming this weekend is a ripper and computer models are suggesting anywhere from 2 to 7cms of snow to fall in Canberra and the surrounding suburbs. Above image GFS snow accumulation forecast via Windy.com
On Saturday a -40C cold pool of air at 20,000ft moves over the ACT which also hangs around into Sunday. This significantly lowers the freezing levels down to 800 meters ASL. This snow level height brings most of the Canberra Hills into likely contention. The key for Canberra to get snow is the surface temperature minimums… On Friday night into Saturday morning and Saturday night into Sunday morning its expected to drop to -2C. Then all you need is precipitation during these times to produce snow to lower levels of say 500 meters. The ranges do act as a rain / snow shadow so it will be very interesting to see if and how much snow makes it into the city and the surrounding suburbs. The potential is very high and models suggest it will happen. Below image showing the very cold polar airmass on Saturday via GFS/BSCH
We provide detailed rain, snow and storm forecasts and maps to the ACT on our members website. Subscribe HERE or click on the image below for more information.
SNOW for Northern NSW and a good chance in QLD this weekend!Jeff Higgins2019-08-16T13:39:05+10:00
Issued 7th August 2019. A perfect forecast opportunity exists to experience SNOW on the Northern Tablelands of NSW this weekend with snow also possible in QLD on the Granite Belt! Above image: Torah Higgins enjoying the snow at Ben Lomond Northern NSW in early June this year. HSC Thomas will be chasing and reporting this snow event in Northern NSW.
Forecast data is confidently predicting snow falls to occur on the Northern Tablelands of NSW late this Saturday into Sunday night. The places most likely to receive the best settled snow is at Guyra and Ben Lomond with between 5 and 10cms expected. Further South at Walcha and Hanging Rock near Tamworth they are forecast to get 10-15cms. Snow is also likely at Nundle, Uralla, Armidale, Glen Innes and Deepwater in NSW. Snow is also a good chance but may not settle on the ground at Tenterfield (Mt Mackenzie), Wallangarra, Ballendean, Stanthorpe, Applethorpe and Eukey in QLD. Below image snow forecast via Windy.com
With all these regions suffering from extreme drought and hardship the tourism is most welcome! Its not very far to drive to experience a white wonderland with the family from anywhere in South East Queensland. Accommodation will be in high demand at Guyra but places like Glen Innes and Tenterfield offer many options which are just a short drive away from the best snow. You can also try Dunmore Trout Waters not far from Ben Lomond. Please PRESERVE ALL WATER USAGE take bottled water or buy it locally. Below image is the best travel option to Ben Lomond NSW for the best snow opportunity.
The current snow window of opportunity is very specific… Saturday late afternoon until Sunday night in NSW and Saturday night or Sunday early morning on the Granite Belt. Below image the chances of precipitation from Saturday 9am to Sunday 9am via OCF/BSCH
We have detailed HSC snow forecast maps and times for QLD and NSW available on our website. Subscribe for the latest up to date information here or click on the image below for more information!
3 days of wild weather for SA with snow possible!Jeff Higgins2019-08-07T10:43:23+10:00
Issued 7th August 2019. The weather is about to turn pretty wild and nasty across large parts of South Australia including Adelaide. A weak low is bringing some rain today but tomorrow a powerful cold front will open the proceedings for 3 days worth of severe weather. An incredibly cold polar airmass will arrive on Friday with snow being possible across the ranges in the South East. Above image showing the mid level polar airmass via GFS/BSCH
Rain, Storms, Hail & possible Snow: The best falls are expected across the Mt Lofty ranges due to orographic lifting with locally moderate to heavy falls possible and totals near 50mm likely. The Southern agricultural areas, Lower west coast, Central coast and South east coasts are forecast to receive 15-30mm from the system. Lighter falls of 5-15mm are forecast through the Northern agricultural areas. Showers with hail are likely across the South East of the state. Storms with hail are possible across the South East of the state.
The snow level is currently forecast at 900 meters which is just above most ranges in the South East… however when showers with hail occur they drag down the much colder air from aloft effectively lowering the snow level. Given this scenario the coldest airmass is forecast to arrive late Friday and last into Saturday. The highest chances for snow will be during this time along the highest ranges in the South East (Mt lofty). Showers will start off producing small hail at first then snow is possible for brief periods as the cold air comes down. Its definitely something worth keeping an eye on that the kids would love to experience. Below image rainfall forecast totals via windy.com
Wind: Damaging Westerly winds up to 110kmhr are forecast across the South East quarter of the state with the arrival of the cold front on Thursday afternoon. The initial front could produce raised dust across the state and a dust storm through the Murraylands, Riverland and North East districts. Winds will ease slightly on Friday but remain very strong and gusty during Friday and Saturday.
Temperatures: COLD with a bitter wind chill of up to 10C so most places will have feels like temps in the single digits. Below image damaging winds on Thursday via Windy.com
4 lows to merge into 1 big one this week!Jeff Higgins2019-08-06T12:40:36+10:00
Issued 6th August 2019. Four multiple complex low pressure systems are forecast to form into a very large polar low that will impact South East Australia from Tuesday through until Sunday this week.
The first low (10S) with a pressure of 985hpa will move East across the Southern Ocean to the South of Tasmania on Tuesday and Wednesday bringing strong winds and showers to South East SA, Tasmania and Victoria. Bloew image via Weatherzone.
A second low (10B) 1005hpa develops over South East SA near Adelaide on Wednesday and slides South East across Victoria and into Bass Straight then across Tasmania on Thursday deepening to a pressure of 985hpa. The system will produce rain and storms with hail across South East SA, rain and possible storms with hail across Victoria with moderate snow on the Alps. Rain and snow also across Tasmania. Below image via Windy.com
A third stronger low (11B) 979hpa approaches South East SA on Thursday then moves East into Bass Straight on Friday. This low will produce damaging winds to 110km hr across South East SA, Victoria and parts of NSW. Rain areas, scattered showers and storm with hail is also expected. Heavy snow and blizzards are forecast across the Alps with snow in the ACT and Central Tablelands of NSW. below image via Windy.com
This is where things get serious…
The second low 10B is forecast to be located just East of Tasmania and merges with the third low 11B on Friday to produce a very large dominant low pressure system (10T) 970hpa. The new low remains slow moving East of Tasmania during Friday, Saturday and Sunday and eventually drifts East towards New Zealand as a new high 1030hpa builds in the Bight.
The very strong pressure gradient between the large polar low near Tasmania and the large high in the Bight will project a 100km hr polar airmass Northwards across the Southern Ocean impacting South East Australia during the 3 days. This weather system will then produce another round of strong to damaging winds, showers with hail, rain areas, storms with hail and low level snow across South East SA, Tasmania, Victoria, the ACT and NSW. Below image via Windy.com
Our Higgins premium weather service offers detailed forecasts and maps across NSW, the ACT and Victoria. These include daily rainfall and snow forecasts. Become a subscriber here to gain access and support our business. Or click on the image below to find out more details!
Big Polar Low To Hit South East Aust – damaging winds, heavy snow & rain!Jeff Higgins2019-08-05T11:38:01+10:00
Issued 5th August 2019. Here comes the biggest Winter storm for 2019 as a Polar Low lines up South East Australia! This system will impact well over half of the population for 4 days so its worth taking note of. Above image the big polar low forecast position on Thursday via Pivotal.
South Australia, Tasmania, Victoria, the ACT and NSW will all be directly impacted while Queensland will feel the affects.


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Re: google has acquired soft card
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03-06-2015 04:23 a.m.
Keep in mind, you may have to check your NFC settings. NFC must be turned activated and Google Wallet must be the touchless payment system associated with it. The phone will not allow you to have both Google Wallet and Softcard available to use NFC at the same time. You have to choose one or the other.


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Threesome with a snake
Tentacle BJ action
Tentacles are horny
Tentacle violation
Weird tentacle sex
Weird fucking in HQ
Aliens inspect human ass
Tentacles rape a girl
Easter bunny fucks a girl
Blonde and a monster
Mouth rape with tentacles
Fish blows a guy
Tentacle monster and girl
Cow in a threesome
Blonde blows a monster
Sexy snail brunette
Hardcore sex in the dark
Tentacles ravage her
Anal with a monster
Tentacle throat-fucking
Asian chick eaten alive
Snake creature captures
Plants capture a slut
Asian porn at its best
Asian almost eaten alive
Toys spit-roasting a girl
Tentacle monster
Superhero captured
Asian captured slut
Sexy-ass pig gets a BJ
BJ for a mosnter
Asian brunette suffering
Forced tentacle BJ
Whorish brunette and pig
Brunette blows a pig