Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is hardly any other medical field that has experienced changes and developments as dramatic as in the treatment of HIV infection in the last years. In Germany, 19 antiretroviral substances have been approved. New substances are effective in multidrug resistance viruses. The classes of CCR5 receptor antagonists and integrase inhibitors are new therapeutic options for heavily pretreated patients. In spite of this success many problems remain unsolved, e.g., lipodystrophy, osteoporosis, cardiovascular diseases and an increased number of tumors. Once more, the ideal point of treatment initiation needs to be discussed. Treating early prevents new infections and improves the course of HIV infection.
 ...
PMID:[HIV infection 2007]. 1763 71

Pfizer Inc is developing maraviroc, a CCR5 receptor antagonist for the treatment of HIV-1 infection and rheumatoid arthritis. In April 2007, the FDA advisory committee voted to approve maraviroc for HIV-1 infection. Phase II and III clinical trials, and post-approval studies are ongoing in both treatment-experienced and -naive HIV patients. Phase II trials have also been initiated in patients with rheumatoid arthritis.
 ...
PMID:Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. 1766 69

Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Delta32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
 ...
PMID:CCR5 blockade modulates inflammation and alloimmunity in primates. 1767 90

Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is currently under investigation for the treatment of human immunodeficiency virus infection. The objective of this study was to identify human liver cytochrome P450 enzyme(s) responsible for the metabolism of vicriviroc. Human liver microsomes metabolized vicriviroc via N-oxidation (M2/M3), O-demethylation (M15), N,N-dealkylation (M16), N-dealkylation (M41), and oxidation to a carboxylic acid metabolite (M35b/M37a). Recombinant human CYP3A4 catalyzed the formation of all these metabolites, whereas CYP3A5 catalyzed the formation of M2/M3 and M41. CYP2C9 only catalyzed the formation of M15. There was a high correlation between the rates of formation of M2/M3, M15, and M41, which was determined using 10 human liver microsomal samples and testosterone 6beta-hydroxylation catalyzed by CYP3A4/5 (r > or = 0.91). Ketoconazole and azamulin (inhibitors of CYP3A4) were potent inhibitors of the formation of M2/M3, M15, M41, and M35b/M37a from human liver microsomes. A CYP3A4/5-specific monoclonal antibody (1 microg/microg of protein) inhibited the formation of all metabolites from human liver microsomes by 86 to 100%. The results of this study suggest that formation of the major vicriviroc metabolites in human liver microsomes is primarily mediated via CYP3A4. CYP2C9 and CYP3A5 most likely play a minor role in the biotransformation of this compound. These enzymology data will provide guidance to design clinical studies to address any potential drug-drug interactions.
 ...
PMID:Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. 1782 38

CCR5 receptor inhibitors are currently being introduced into clinical practice. In some instances treatment failure is related to the selection of pre-existing CXCR4-tropic minority virus strains. Up to date it is unclear whether the outgrowth of a CXCR4 using reservoir is associated with accelerated HIV-disease. In any case, treatment with CCR5 inhibitors should only be initiated in the absence of a relevant CXCR4-tropic minority. Otherwise treatment failure and the accumulation of mutations may ensue. Tropism tests, clinical data and other laboratory parameters help to determine the risk for an individual patient to harbour CXCR4 tropic virus strains, although the negative predictive value of each of these parameters and tests is quite low. If treatment fails re-assessment of viral tropism can help to differentiate between failure due to the development of CCR5 inhibitor resistance or the selection of CXCR4-tropic virus strains. This article presents and discusses available data on viral tropism and tropism testing in the context of CCR5 inhibitor treatment.
 ...
PMID:Tropism switch in patients infected with HIV-1 and its clinical implications for the treatment with CCR5-receptor inhibitors. 1793 20

A new class of antiretroviral drugs is now available to the HIV provider: The CCR5 Antagonists belong to a group of entry inhibitors with a novel mechanism of action. While these antagonists do not directly interfere with any of the steps of HIV replication, they block the CCR5 receptor, one of the co-receptors HIV uses to enter its target cell. Thus CCR5 antagonists are able to prevent infection of the cell and represent a new and unique mechanism for the treatment of HIV. There is great interest in utilizing this new drug class in early treatment of HIV to prevent infection of large cell pools; CCR5 antagonists even may be useful tools in the various settings of exposure prophylaxis. Maraviroc is now approved in both the European Union and the United States for the treatment of HIV infection. This is the first medication belonging to the new class of CCR5 antagonists, and the first approval of an orally available drug in a new class since 1996. Aplaviroc, maraviroc, and vicriviroc are small molecule inhibitors of CCR5 that block HIV-1 infection in vitro and reduce plasma HIV-1 RNA in HIV infected subjects by approximately 1.5 log10 copies/mL over 10-14 days when given as single agents. Very limited data is available on the use of CCR5 antagonists in treatment naive patients due to early termination of many trials because of inferior performance or toxicity and at the time of this writing in August 2007 there is only one ongoing non-inferiority trial in the naive patient population. The 48 week interim results of this trial using twice daily maraviroc were reported at the International AIDS Society meeting in July 2007. Maraviroc compared to efavirenz was non-inferior in regards to percentage of subjects reaching viral loads below 400 copies/mL, but not so for the analysis of subjects reaching viral loads below 50 copies/mL. On the other hand maraviroc had a superior side-effect profile, fewer adverse events and a greater increase of CD4 cell count than efavirenz. These data will revitalize the interest in CCR5 antagonists as a treatment option for the treatment-naive patients. In order to be used as first line drugs, CCR5 antagonists face a number of challenges: They will have to be proven to be as potent, durable, safe, and convenient as current available options. Important questions unique to this new class will have to be answered: What are the mechanisms and risks of tropism change? What is the role and needed frequency of tropism testing, and what efficacy is seen in patients with dual-tropic/mixed infection in the long term? Clearly until we have answers to these questions CCR5 antagonists should be reserved for the treatment-experienced patient population with limited treatment options.
 ...
PMID:CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1. 1793 24

To investigate the immunological and virological factors that may lead to different patterns of disease progression characteristic of HIV-1-infected children, two HIV-1-infected siblings, a slow and a fast progressor, were followed prospectively before the onset of highly active antiretroviral therapy. Viral coreceptor usage, including the use of CCR5/CXCR4 chimeric receptors, macrophage tropism, and sensitivity to the CC-chemokine RANTES, has been studied. An autologous and heterologous neutralizing antibody response has been documented using peripheral blood mononuclear cells- and GHOST(3) cell line-based assays. Viral evolution was investigated by env C2-V3 region sequence analysis. Although both siblings were infected with HIV-1 of the R5 phenotype, their viruses showed important biological differences. In the fast progressor there was a higher RANTES sensitivity of the early virus, an increased trend to change the mode of CCR5 receptor use, and a larger genetic evolution. Both children developed an autologous neutralizing antibody response starting from the second year with evidence of the continuous emergence of resistant variants. A marked viral genetic and phenotypic evolution was documented in the fast progressor sibling, which is accompanied by a high viral RANTES sensitivity and persistent neutralizing antibodies.
 ...
PMID:Biological and genetic evolution of HIV type 1 in two siblings with different patterns of disease progression. 1816 11

Maraviroc (MVC, UK-427,857) is the first member of a new class, the CCR5 antagonists. By an original mechanism of action, maraviroc binds to the CCR5 receptor in order to prevent HIV from binding and entering human cells. Maraviroc (Celsentri) is an orally administered drug available as 150 and 300 mg film-coated tablets. The current approved daily dosage of maraviroc is 300 mg bid in combination with other antiretroviral medications. Maraviroc plasma exposure is not dose proportional. After a rapid (but moderate) intestinal absorption, several inactive oxidized metabolites are produced via cytochrome P450 3A4 pathway. According to this liver metabolism, dosage adjustments are required when maraviroc is administered in combination with cytochrome P450 inhibitors or inducers. The potential for drug-drug interactions and the well-defined relationship between plasma concentrations and virological response suggest the usefulness of Therapeutic Drug Monitoring of maraviroc in HIV-infected patients.
 ...
PMID:[Clinical pharmacokinetic of maraviroc]. 1845 57

Treatment of HIV-1 infection has produced dramatic success for many patients. Nevertheless, viral resistance continues to limit the efficacy of currently available agents in many patients. The CCR5 antagonists are a new class of antiretroviral agents that target a necessary coreceptor for viral entry of many strains of HIV-1. Recently, the first agent within this class, maraviroc, was approved by a number of regulatory agencies, including the Food and Drug Administration. Herein we review the role of the CCR5 receptor in HIV-1 infection and potential methods to target it in anti-HIV-1 therapy. We review the various categories of agents and discuss specific agents that have progressed to clinical study. We discuss in detail the recently approved, first in class CCR5 antagonist, maraviroc, and discuss aspects of resistance to CCR5 antagonism and the potential role of CCR5 antagonism in the management of HIV-1 infection.
 ...
PMID:New approaches in the treatment of HIV/AIDS - focus on maraviroc and other CCR5 antagonists. 1872 30

The chemokine receptor CCR5 is required for cellular entry by many strains of HIV, and provides a potential target for molecules, including antibodies, designed to block HIV transmission. This study investigates a novel approach to stimulate antibodies to CCR5. Rabbits were immunised with chimaeric peptides which encode a short fragment of the N-terminal sequence of CCR5, as well as an unrelated T cell epitope from Tetanus toxoid. Immunisation with these chimaeric peptides generates a strong antibody response which is highly focused on the N-terminal CCR5 sequence. The antibody to the chimaeric peptide containing an N-terminal methionine also recognises the full length CCR5 receptor on the cell surface, albeit at higher concentrations. Further comparison of binding to intact CCR5 with binding to CCR5 peptide suggest that the receptor specific antibody generated represents a very small fragment of the total anti-peptide antibody. These findings are consistent with the hypothesis that the N-terminal peptide in the context of the intact receptor has a different structure to that of the synthetic peptide. Finally, the antibody was able to block HIV infection of macrophages in vitro. Thus results of this study suggest that N-terminal fragments of CCR5 may provide potential immunogens with which to generate blocking antibodies to this receptor, while avoiding the dangers of including T cell auto-epitopes.
 ...
PMID:HIV blocking antibodies following immunisation with chimaeric peptides coding a short N-terminal sequence of the CCR5 receptor. 1876 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>