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Journal of Acquired Immune Deficiency... Nov 2015Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery.
METHODS
MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.
RESULTS
There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.
CONCLUSIONS
In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.
Topics: Administration, Intravaginal; Adolescent; Adult; Anti-Infective Agents; Area Under Curve; Cyclohexanes; Double-Blind Method; Drug Combinations; Female; Half-Life; Humans; Maraviroc; Pyrimidines; Triazoles; Young Adult
PubMed: 26034880
DOI: 10.1097/QAI.0000000000000702 -
Molecular Cancer Research : MCR Jul 2023Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of...
UNLABELLED
Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of action remain elusive. Our objective was to identify secreted factor(s) that mediate the communication between CAFs and ESCC tumor cells with the aim of identifying potential druggable targets. Through unbiased cytokine arrays, we have identified CC motif chemokine ligand 5 (CCL5) as a secreted factor that is increased upon co-culture of ESCC cells and CAFs, which we replicated in esophageal adenocarcinoma (EAC) with CAFs. Loss of tumor-cell-derived CCL5 reduces ESCC cell proliferation in vitro and in vivo and we propose this is mediated, in part, by a reduction in ERK1/2 signaling. Loss of tumor-derived CCL5 reduces the percentage of CAFs recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists, namely Maraviroc. Maraviroc treatment reduced tumor volume, CAF recruitment, and ERK1/2 signaling in vivo, thus, mimicking the effects observed with genetic loss of CCL5. High CCL5 or CCR5 expression is associated with worse prognosis in low-grade esophageal carcinomas.
IMPLICATIONS
These data highlight the role of CCL5 in tumorigenesis and the therapeutic potential of targeting the CCL5-CCR5 axis in ESCC.
Topics: Humans; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Proliferation; Chemokine CCL5; Chemokines; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fibroblasts; Ligands; Maraviroc; Animals
PubMed: 37027010
DOI: 10.1158/1541-7786.MCR-22-0872 -
The Journal of Allergy and Clinical... Jan 2022Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1...
BACKGROUND
Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-γ expression and variable type 2 responses.
OBJECTIVE
We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA.
METHODS
Bronchoalveolar lavage microarray data from the Severe Asthma Research Program I/II were analyzed for pathway expression and paired with clinical parameters. Wild-type, Cxcr3, and Ccr5 mice were exposed to a type 1-high SA model with analysis of whole lung gene expression and histology. Wild-type and Cxcr3 mice were treated with a US Food and Drug Administration-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression, and histology.
RESULTS
A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3 and Ccr5 mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into the experimental model blunted airway hyperreactivity despite only mild effects on lung inflammation.
CONCLUSIONS
IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. Although these pathways provide redundancy for establishing type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in individuals with type 1-high asthma.
Topics: Adult; Airway Resistance; Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; CCR5 Receptor Antagonists; Female; Humans; Inflammation; Interferon-gamma; Male; Maraviroc; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Receptors, CCR5; Receptors, CXCR3; Respiratory Mucosa; Severity of Illness Index; Young Adult; Mice
PubMed: 34146578
DOI: 10.1016/j.jaci.2021.05.044 -
Drug Metabolism and Disposition: the... Nov 2014CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention....
CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild-type allele *1 and dysfunctional alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in three groups (n = 8 each): homozygous dysfunctional (two dysfunctional alleles), heterozygous (one *1 allele and one dysfunctional allele), and homozygous wild-type (two *1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. The homozygous wild-type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curves from time 0 to infinity (AUC0-inf) were 2099 (1422-2568) ng⋅h/ml, 1761 (931-2640) ng⋅h/ml, and 1238 (1065-1407) ng⋅h/ml for the homozygous dysfunctional, heterozygous, and homozygous wild-type groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5*1 allele, including almost one-half of African Americans.
Topics: Adolescent; Adult; Aged; Area Under Curve; Base Sequence; Cyclohexanes; Cytochrome P-450 CYP3A; DNA Primers; HIV Fusion Inhibitors; Healthy Volunteers; Heterozygote; Homozygote; Humans; Maraviroc; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Triazoles; Young Adult
PubMed: 25117426
DOI: 10.1124/dmd.114.060194 -
Neurology(R) Neuroimmunology &... Mar 2017
PubMed: 28210663
DOI: 10.1212/NXI.0000000000000331 -
Journal of Psychiatry & Neuroscience :... Sep 2021Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/μ-opioid...
BACKGROUND
Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/μ-opioid receptor heterodimerization suggests that maraviroc could be a treatment for oxycodone abuse. We treated rats with maraviroc to explore its effect on oxycodone-seeking and its interference with the analgesic effects of oxycodone. We used resting-state blood-oxygen-level-dependent functional connectivity to assess the effect of maraviroc on oxycodone-enhanced coupling in the reward circuitry and performed behavioural tests to evaluate the effect of maraviroc on oxycodone rewarding properties and on oxycodone-seeking after prolonged abstinence.
METHODS
Two groups of rats were exposed to 8 consecutive days of oxycodone-conditioned place preference training and treatment with maraviroc or vehicle. Two additional groups were trained to self-administer oxycodone for 10 days and then tested for drug seeking after 14 days of abstinence with or without daily maraviroc treatment. We tested the effects of maraviroc on oxycodone analgesia using a tail-flick assay. We analyzed resting-state functional connectivity data using a rat 3-dimensional MRI atlas of 171 brain areas.
RESULTS
Maraviroc significantly decreased conditioned place preference and attenuated oxycodone-seeking behaviour after prolonged abstinence. The analgesic effect of oxycodone was maintained after maraviroc treatment. Oxycodone increased functional coupling with the accumbens, ventral pallidum and olfactory tubercles, but this was reduced with maraviroc treatment.
LIMITATIONS
All experiments were performed in male rats only.
CONCLUSION
Maraviroc treatment attenuated oxycodone-seeking in abstinent rats and reduced functional coupling in the reward circuitry. The analgesic effects of oxycodone were not affected by maraviroc.
Topics: Analgesics, Opioid; Animals; Anti-HIV Agents; Behavior, Animal; Magnetic Resonance Imaging; Male; Maraviroc; Opioid-Related Disorders; Oxycodone; Rats
PubMed: 34625487
DOI: 10.1503/jpn.200191 -
Scientific Reports Feb 2018Genotypic tropism testing (GTT) for co-receptor usage is a recommended tool for clinical practice before administration of the CCR5-antagonist maraviroc. For some... (Comparative Study)
Comparative Study
Genotypic tropism testing (GTT) for co-receptor usage is a recommended tool for clinical practice before administration of the CCR5-antagonist maraviroc. For some isolates, phenotypic tropism testing (PTT) revealed discordant results with GTT. In this study, we performed a comparative study between GTT and PTT in HIV-1C from East Africa (HIV-1C) and compared the data with HIV-1B and 01_AE and described the maraviroc susceptibility in the CCR5-tropic strains. Patient-derived HIV-1 envgp120 region was cloned into a modified pNL4-3 plasmid expressing the luciferase gene. rPhenotyping dissected single clones from 31 HIV-1C infected patients and four strains with known phenotype. Additionally, 68 clones from 18 patients (HIV-1B: 5, 01_AE: 7, HIV-1C: 6) were used to determine the PTT in GHOST cell line. The respective V3-sequences were used for GTT. R5-tropic strains from HIV-1C (n = 20) and non-C (n = 12) were tested for maraviroc sensitivity in TZMbl cell line. The GTT falsely called a higher proportion of X4-tropic strains in HIV-1C compared to PTT by both rPhenotyping and the GHOST-cell assay. When multiple clones were tested in a subset of patients' samples, both dual-tropic and R5-tropic strains were identified for HIV-1C. Relatively higher EC values were observed in HIV-1C strains than the non-C strains (p = 0.002).
Topics: Africa, Eastern; Genotype; Genotyping Techniques; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Microbial Sensitivity Tests; Viral Tropism
PubMed: 29403064
DOI: 10.1038/s41598-018-20814-2 -
ACS Medicinal Chemistry Letters Feb 2014CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and infection. To expand the...
CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.
PubMed: 24563723
DOI: 10.1021/ml400370w -
Frontiers in Molecular Neuroscience 2022Vascular dementia (VaD) is considered to be the second most common form of dementia after Alzheimer's disease, and no specific drugs have been approved for VaD...
Vascular dementia (VaD) is considered to be the second most common form of dementia after Alzheimer's disease, and no specific drugs have been approved for VaD treatment. We aimed to identify shared transcriptomic signatures between the frontal cortex and temporal cortex in VaD by bioinformatics analyses. Gene ontology and pathway enrichment analyses, protein-protein interaction (PPI) and hub gene identification, hub gene-transcription factor interaction, hub gene-microRNA interaction, and hub gene-drug interaction analyses were performed. We identified 159 overlapping differentially expressed genes (DEGs) between the frontal cortex and temporal cortex that were enriched mainly in inflammation and innate immunity, synapse pruning, regeneration, positive regulation of angiogenesis, response to nutrient levels, and positive regulation of the digestive system process. We identified 10 hub genes in the PPI network (, , , , , , , , , and ), four central regulatory transcription factors (FOXC1, CREB1, GATA2, and HINFP), and four microRNAs (miR-27a-3p, miR-146a-5p, miR-335-5p, and miR-129-2-3p). Hub gene-drug interaction analysis found four drugs (maraviroc, cenicriviroc, PF-04634817, and efalizumab) that could be potential drugs for VaD treatment. Together, our results may contribute to understanding the underlying mechanisms in VaD and provide potential targets and drugs for therapeutic intervention.
PubMed: 35221911
DOI: 10.3389/fnmol.2022.751044 -
AIDS (London, England) Apr 2016Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a program to develop an...
OBJECTIVE
Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a program to develop an effective prevention strategy, we performed an ex-vivo preclinical evaluation to determine the efficacy of multiple double combinations of maraviroc (MVC) and reverse transcriptase inhibitors (RTIs).
DESIGN
The entry inhibitor, MVC, a nucleotide RTI, tenofovir and two non-nucleoside RTIs, UC781 and TMC120 (dapivirine, DPV), were used in double, combinations against a panel of CCR5-using clade B and clade C HIV-1 isolates and against MVC-escape variants. A gel-formulated version of MVC-DPV combination was also tested.
METHODS
Indicator cells, cocultures of immature dendritic cells with CD4T cells, and colorectal tissue explants were used to assess antiviral activity of drug combinations.
RESULTS
All dual MVC-RTI combinations tested inhibited MVC-sensitive and resistant isolates in cellular and colorectal explants models. All the combinations were positive with no reduction in the activity of MVC. In tissue explants, the combinations against all viral isolates tested produced an increase in the activity of MVC. An initial gel-formulation of MVC-DPV combination showed greater and prolonged antiviral activity of MVC in mucosal tissue explants.
CONCLUSION
This study demonstrates that combinations based on antiretroviral drugs inhibiting HIV transmission at viral entry and reverse transcription have potential as prevention strategies against colorectal transmission of HIV-1 including MVC-resistant isolates. Preclinical evaluation with colorectal tissue explants indicates that a gel-formulation of MVC-DPV is an effective candidate colorectal microbicide.
Topics: Anti-HIV Agents; Cells, Cultured; Chemoprevention; Cyclohexanes; Disease Transmission, Infectious; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Maraviroc; Models, Biological; Organ Culture Techniques; Pre-Exposure Prophylaxis; Reverse Transcriptase Inhibitors; Triazoles
PubMed: 26854808
DOI: 10.1097/QAD.0000000000001043