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CCR5 Antagonist (ccr5 + antagonist)
Selected AbstractsEfficient Synthesis of CCR5 Antagonist, 2,3-Dihydro-1-benzothiepine Derivatives by Improved Intramolecular Claisen Type Reaction Using Dialkylcarbonate.CHEMINFORM, Issue 15 2005Tomomi Ikemoto Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Development of a New Synthetic Route of a Non-Peptide CCR5 Antagonist, TAK-779, for Large-Scale Preparation.CHEMINFORM, Issue 15 2001Tomomi Ikemoto Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Facile Synthesis of 4-Substituted-4-aminopiperidine Derivatives, the Key Building Block of Piperazine-Based CCR5 Antagonists.CHEMINFORM, Issue 46 2004Xiao-Hua Jiang Abstract For Abstract see ChemInform Abstract in Full Text. [source] Interaction between the CCR5 chemokine receptors and microbial HSP70EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Trevor Whittall Abstract Evidence is presented that the microbial 70-kD heat shock protein (HSP70) binds to CCR5 chemokine receptors in CCR5-transfected cell lines and in primary human cells. Significant CCR5-mediated calcium mobilization was stimulated by HSP70 and inhibited with TAK,779, which is a specific CCR5 antagonist. HSP70-mediated activation of the p38 MAPK phosphorylation signaling pathway was also demonstrated in CCR5-transfected HEK 293 cells. Direct binding of three extracellular peptides of CCR5 to HSP70 was demonstrated by surface plasmon resonance. Functional evidence of an interaction between HSP70, CCR5 and CD40 was shown by enhanced production of CCL5 by HEK 293 cells transfected with both CD40 and CCR5. Primary monocyte-derived immature DC stimulated with HSP70 produced IL-12 p40, which showed dose-dependent inhibition of >90% on treatment with both TAK 779 and anti-CD40 mAb. Stimulation of IL-12 p40 or TNF-, by HSP70 was related to the differential cell surface expression of CCR5 in primary human immature and mature DC, and those with the homozygous ,,32 CCR5 mutation. These findings may be of significance in the interaction between HSP70 and immune responses of CCR5+ T cells in HIV-1 infection, as well as in inflammatory bowel disease. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636551 [source] Latest news and product developmentsPRESCRIBER, Issue 23-24 2007Article first published online: 8 JAN 200 Cervical cancer risk falls after COC use ends Combined oral contraceptives (COCs) are associated with a slight increase in the risk of cervical cancer but this diminishes with time after use ends, an international study has shown (Lancet 2007;370:1609,21). Analysis of data for 16 573 women with and 35 509 women without cervical cancer confirmed that using a COC for 10 years between the ages of 20 and 30 increases the incidence of invasive cervical cancer from 3.8 to 4.5 per 1000 by age 50. However, the excess risk disappears 10 years after cessation of use. , A new analysis of the US Nurses' Health Study suggests that protection against ovarian cancer does not persist beyond 20 years after cessation of COC use. This study also showed that tubal ligation is associated with reduced risk of ovarian cancer (Am J Epidemiol 2007; 166;894,901). Pharmaceutical services fund moves to PCTs The ,global sum' that provides central funding for NHS pharmaceutical services is being shifted to PCTs. The Government has included legislation for the change in the recent Health and Social Care Bill. The fund pays the fees and allowances for pharmacy contractors and appliance contractors. The Government says this is a ,natural progression and in keeping with moves to devolve NHS funds to the frontline' that will enable PCTs to manage pharmacy services better by ,encouraging best prescribing practice'. Fewer fluoroquinolones in the community Restricting prescribing of fluoroquinolone antibacterials does not increase hospital admissions for infection among older people, say Canadian researchers (Am J Med 2007;120:893,900). Their analysis of an Ontario medical database shows that, in a community where fluoroquinolones were the most widely prescribed antibacterials, a one-third reduction in prescribing was not followed by an increase in hospital admissions for infectious episodes in the over,65s. On the contrary, there was a 32 per cent reduction in admissions for gastrointestinal conditions. FDA reports increased TB risk with infliximab The US Food and Drug Administration has published an analysis of cases of TB associated with infliximab (Remicade) detected via its spontaneous adverse event reporting scheme (Ann Intern Med 2007;147: 699,702). In 2001 the FDA placed a warning about the risk of TB on product labelling for infliximab and advised testing for TB before initiating treatment. This analysis of 130 cases of TB since reported in patients treated with infliximab found that 45 per cent had developed extra-pulmonary disease; risk factors included use of immunosuppressants (including methotrexate), a history of TB and time spent in an endemic area. Of 67 cases in which treatment was initiated after the warning was issued, 34 with a negative tuberculin skin test developed TB after receiving infliximab. MHRA announces anticounterfeit strategy The UK is a transit point, distribution hub and end-user of counterfeit medicines, says the MHRA in its first anti-counterfeiting strategy (www.mhra.gov.uk). Counterfeits have been detected in the legitimate supply chain with increasing frequency since 2004, resulting in nine batch recalls and a further five incidents detected at wholesale level. The MHRA's proposed approach includes: communication to raise awareness of the risk and facilitate reporting, collaboration with the WHO, the industry and law enforcement agencies, and targeted surveillance, prosecution and regulation. Evidence lacking for choosing DMARD There is insufficient evidence to choose one DMARD or biological agent over another in patients with RA, US investigators say (www.annals.org/cgi/content/abstract/0000605,20080115000192v1). Their systematic review of meta-analyses and intervention and observational trials found no evidence of differences among DMARDs or anti-TNF agents. Mono-therapy with an anti-TNF agent was associated with superior radiographic but not clinical outcomes; methotrexate plus an anti-TNF agent was superior in clinical and functional terms to either drug given alone. Be alert to psychiatric ADRs with rimonabant Clinicians should remain alert for the development of anxiety, depression and an increased risk of suicide with rimonabant (Acomplia), say Danish investigators (Lancet 2007;370:1706,13). Their meta-analysis of four randomised trials involving a total of 4105 patients showed that rimonabant was associated with an increased risk of serious adverse events (odds ratio 1.4; number needed to harm, NNH, 59), including a 2.5,fold increased risk of depression (NNH 49) and a threefold increased risk of anxiety (NNH 166). Following a warning from the FDA of an increased risk of suicide with rimonabant, the authors say their findings indicate a need for ,increased alertness by physicians to these potentially severe psychiatric adverse reactions'. New strategy for NHS medicines information The UK Medicines Information Service (www.ukmi.nhs.uk) has published its new management strategy setting out how it will respond to recent developments in the NHS. Developments include greater access to information for patients, support for nontraditional prescribers and new commissioning arrangements. New antiretroviral Maraviroc (Celsentri) is the first CCR5 antagonist to be introduced for the treatment of HIV infection. CCR5 is one of two co-receptors to which the HIV virus must attach to achieve cell entry. Maraviroc is licensed for use by treatment-experienced patients in whom only CCR5-tropic HIV-1 is detectable. The recommended dose ranges from 150 to 600mg twice daily depending on interactions with concurrent medication. Dimeticone superior Dimeticone 4 per cent lotion (Hedrin) is superior to malathion 0.5 per cent in the eradication of head lice, a UK study in 58 children and 15 adults has shown (PLoS ONE 2007;2: e1127. doi:10.1371/journal.pone. 0001127). Two applications of dimeticone lotion one week apart cleared active infestation in 70 per cent of participants compared with 33 per cent in those who used a single application of malathion. Copyright © 2007 Wiley Interface Ltd. [source] Expression of CCL5 (RANTES) and CCR5 in prostate cancer,THE PROSTATE, Issue 2 2006Gayle G. Vaday Abstract Background Expression of the inflammatory chemokine CCL5 (RANTES) by tumor cells is thought to correlate with the progression of several cancers. CCL5 was shown to induce breast cancer cell migration, mediated by the receptor CCR5. A CCR5 antagonist was demonstrated to inhibit experimental breast tumor growth. Recently, CCL5 and CCR5 mRNA expression was reported in prostate cancer (PCa) tissues. Herein, we characterized CCL5 and CCR5 expression in cultures of PCa cells and explored possible functions of CCL5 in PCa progression. Methods Quantitative RT-PCR, ELISA, and immunohistochemical staining were performed to examine CCL5 expression in prostate cell lines. CCR5 expression was measured by flow cytometry. Proliferation and invasion assays were performed to determine potential functions of CCL5 and CCR5 in PCa. Results Expression of CCL5 mRNA and protein was found in human PCa cell lines (PC-3; DU-145; LNCaP) and primary prostate adenocarcinoma cells. CCL5 and CCR5 were also detected in human PCa tissues. CCR5 expression was demonstrated on the cell surface of PCa cells, as well as in intracellular pools. Incubation with CCL5 (10,100 ng/ml) induced PCa cell proliferation, and the CCR5 antagonist TAK-779 inhibited CCL5-induced proliferation. CCL5 was found to stimulate PCa cell invasion, and TAK-779 blocked the effects of CCL5. Conclusions In light of evidence that inflammation influences the pathogenesis of PCa, these results suggest that inflammatory chemokines, such as CCL5, expressed by prostate cells may act directly on the growth and survival of PCa cells. Chemokine receptor antagonists may thus block autocrine mechanisms of PCa progression. Published 2005 Wiley-Liss, Inc. [source] A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2008Phylinda L. S. Chan AIMS To develop a population pharmacokinetic model for maraviroc, a noncompetitive CCR5 antagonist, after oral administration of tablets to healthy volunteers and asymptomatic HIV-infected subjects and to quantify the inherent variability and influence of covariates on the parameters of the model. METHODS Rich pharmacokinetic data available from 15 studies in healthy volunteers (n = 365) and two studies in asymptomatic HIV-infected subjects (n = 48) were analysed using NONMEM. Maraviroc was administered as single or multiple oral tablet doses under fasted and fed conditions. Doses ranged from 100 to 1800 mg day,1. RESULTS A two-compartment model parameterized to separate out absorption and clearance components on bioavailability was used. Absorption was described by a lagged first-order process. A sigmoid Emax model described the effect of dose on absorption. A visual predictive check and nonparametric bootstrap evaluation confirmed that the model was a good description of the data. Typical CL, Vc and Vp values for a 30-year-old non-Asian are 51.5 l h,1, 132 l and 277 l, respectively. CONCLUSIONS For the typical non-Asian subject, fasted bioavailability increased asymptotically with dose from 24% at 100 mg to 33% at 600 mg. A high-fat meal taken with maraviroc reduced exposure by 43% for a 100-mg dose to approximately 25% at doses of 600 mg. The typical Asian subject had a 26.5% higher AUC than the typical non-Asian subject irrespective of dose, a difference not considered to be clinically relevant. None of the other covariates tested had any clinically relevant effects on exposure. [source] The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Kimberly K. Adkison Aims This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. Methods In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg +,LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. Results In Part 1, a single RTV dose increased the APL AUC0,, by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, Cmax, and Cmin, respectively. No change in LPV AUC or Cmax and a small increase in RTV AUC and Cmax (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. Conclusions Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations. [source] The chemokine system and CCR5 antagonists: potential in HIV treatment and other novel therapiesJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2009H. Dhami PharmD (Student) Summary Since the recognition of human acquired immune deficiency syndrome, numerous classes of pharmacologic therapeutics have been developed to manage the disease. Current therapy includes co-administration of combinations of drugs classified by their mechanism of action as ,transcriptase inhibitors', ,protease inhibitors', ,integrase inhibitors' and the more recent ,fusion inhibitors'. This review focuses on the chemokine system and the recognition of chemokine receptors as targets for anti-human immunodeficiency virus (HIV) therapy. The FDA-approved chemokine (C,C motif) receptor 5 (CCR5) antagonist maraviroc (Selzentry®) is discussed in detail, along with another compound vicriviroc, currently in clinical trials. The mechanism of action, pharmacokinetics, toxicity and current status of research on CCR5 antagonists is described. Further, potential therapeutic uses of these agents other than anti-HIV therapy are discussed. [source] Prevalence of X4 tropic HIV-1 variants in patients with differences in disease stage and exposure to antiretroviral therapyJOURNAL OF MEDICAL VIROLOGY, Issue 8 2007Eva Poveda Abstract Viral tropism plays an important role in HIV pathogenesis. However, its correlation with the clinical outcome and following exposure to antiretroviral drugs are still unclear. HIV-1 co-receptor usage was examined in 206 infected individuals: 67 seroconverters, 52 chronically drug-naïve, and 87 antiretroviral-experienced patients. The V3 loop was sequenced from plasma HIV-RNA and co-receptor usage was inferred using a phenotype predictor software (http://genomiac2.ucsd.edu:8080/wetcat/v3.html), which classifies V3 sequences as R5 or X4. The overall prevalence of X4 viruses was 26.2%, with significant differences among groups: 13.4% in seroconverters, 25% in drug-naïve, and 36.8% in antiretroviral- experienced patients (P,=,0.001). The presence of X4 variants in the latter group was associated with higher viral load (P,=,0.002) but not with lower CD4 counts. There was no association between HIV tropism and gender, transmission route or age. Neither with the CCR5 ,32 genotype. Moreover, no association was found between HIV-1 tropism and drug resistance mutations nor with failure to regimens based on either protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Finally, no significant association was found between IL-7 plasma levels with HIV-1 tropism. In summary, X4 viruses are particularly frequent among antiretroviral-experienced patients with high viral loads, irrespective of the CD4 count. Thus, CCR5 antagonists should be used with special caution in this subset of patients. J. Med. Virol. 79: 1040,1046, 2007. © 2007 Wiley-Liss, Inc. [source] | ||||||||||