raltegravir-potassium and Disease-Models--Animal

The aim of this study was to compare an in-person, group-based behavioral weight loss intervention to technology-based interventions in adults with obesity.. Adults (. Findings provide initial information on the use of technology-based interventions that include wearable devices combined with brief monthly telephone calls for weight loss in adults with obesity.. A highly stable amino-coordinated metal-organic framework ZJU-198 has been synthesized and structurally characterized, exhibiting high CO. The use of statins in SLE reduced the serum lipid and high-sensitivity C-reactive protein levels, which suggests a role for the primary prevention of cardiovascular disease. Statins did not affect the SLEDAI score, and therefore their use for modifying SLE disease activity levels is not presently supported.

Topics: Absorptiometry, Photon; Adult; Air Pollutants; Alkynes; Alleles; Animals; Anthracenes; Anthraquinones; Anti-HIV Agents; Benzoxazines; Black or African American; Bone Density; Bone Density Conservation Agents; C-Reactive Protein; Calcium, Dietary; Capsid Proteins; Cardiomyopathy, Dilated; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Collagen Type I; Cyclopropanes; Darunavir; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Emtricitabine; Epitopes; Female; Femur Neck; Gene Expression Profiling; Genetic Predisposition to Disease; Hepatitis, Viral, Animal; Hip Joint; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunization; Inflammation Mediators; Lipoproteins, LDL; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred BALB C; Nitrates; Osteocalcin; Oxidation-Reduction; Parathyroid Hormone; Parvovirus B19, Human; Peptides; Phenotype; Pilot Projects; Polymorphism, Single Nucleotide; Raltegravir Potassium; Ritonavir; RNA, Viral; Sodium Chloride; Tenofovir; Transcriptome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaccines; Vascular Endothelial Growth Factor A; Vitamin D; Young Adult

The aim of this study was to compare an in-person, group-based behavioral weight loss intervention to technology-based interventions in adults with obesity.. Adults (. Findings provide initial information on the use of technology-based interventions that include wearable devices combined with brief monthly telephone calls for weight loss in adults with obesity.. A highly stable amino-coordinated metal-organic framework ZJU-198 has been synthesized and structurally characterized, exhibiting high CO. The use of statins in SLE reduced the serum lipid and high-sensitivity C-reactive protein levels, which suggests a role for the primary prevention of cardiovascular disease. Statins did not affect the SLEDAI score, and therefore their use for modifying SLE disease activity levels is not presently supported.

Topics: Absorptiometry, Photon; Adult; Air Pollutants; Alkynes; Alleles; Animals; Anthracenes; Anthraquinones; Anti-HIV Agents; Benzoxazines; Black or African American; Bone Density; Bone Density Conservation Agents; C-Reactive Protein; Calcium, Dietary; Capsid Proteins; Cardiomyopathy, Dilated; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Collagen Type I; Cyclopropanes; Darunavir; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Emtricitabine; Epitopes; Female; Femur Neck; Gene Expression Profiling; Genetic Predisposition to Disease; Hepatitis, Viral, Animal; Hip Joint; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunization; Inflammation Mediators; Lipoproteins, LDL; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred BALB C; Nitrates; Osteocalcin; Oxidation-Reduction; Parathyroid Hormone; Parvovirus B19, Human; Peptides; Phenotype; Pilot Projects; Polymorphism, Single Nucleotide; Raltegravir Potassium; Ritonavir; RNA, Viral; Sodium Chloride; Tenofovir; Transcriptome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaccines; Vascular Endothelial Growth Factor A; Vitamin D; Young Adult

Two SIVmac251-infected rhesus macaques received tenofovir/emtricitabine with raltegravir intensification. Viral rebound occurred during treatment and sequencing of reverse transcriptase and integrase genes identified multiple resistance mutations. Similar to HIV infection, antiretroviral-resistance mutations may occur in SIV-infected nonhuman primates receiving nonsuppressive ART. As ART administration to nonhuman primates is currently dramatically expanding, fueled by both cure research and the study of HIV-related comorbidities, viral resistance should be factored in the study design and data interpretation.

Topics: Animals; Anti-Retroviral Agents; Disease Models, Animal; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Emtricitabine; Genes, Viral; Humans; Integrases; Macaca mulatta; Mutation; Raltegravir Potassium; RNA-Directed DNA Polymerase; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Tenofovir; Viral Load

Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data.

Topics: Animals; Disease Models, Animal; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mice; Mice, Inbred BALB C; Mucous Membrane; Pre-Exposure Prophylaxis; Raltegravir Potassium

Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Cyclohexanes; Disease Models, Animal; Female; Flow Cytometry; HIV Infections; HIV-1; Humans; Maraviroc; Mice; Mice, Transgenic; Post-Exposure Prophylaxis; Pyrrolidinones; Raltegravir Potassium; Triazoles; Vagina