Steven Daniel Douglas
Childrens Hospital Of Philadelphia
Project start date: 1995-07-01
Project end date: 2013-01-31
Sponsored Links Excellgen http://Excellgen.com
TACHYKININS MONONUCLEAR PHAGOCYTES AND HIV-1 INFECTION
Steven Daniel Douglas, Professor And Medical Director
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 5R01MH049981-16 from National Institute Of Mental Health
Abstract: The overarching goal of this investigation is to understand the mechanism(s) whereby the tachykinin neuropeptide, substance P (SP), and its preferred receptor, Neurokinin-lR (NK1R) modulate the immunopathogenesis of HIV as central mediators in the interaction between the immune and nervous systems. Our major hypothesis is that altered SP and NK1R, are mechanistically important in HIV pathogenesis and that this receptor and its ligand are altered in association with neurocognitive changes and life stress and depression in HIV-infected individuals. We showed that the non-peptide SP antagonist (CP-96,345) inhibits HIV replication in human mononuclear phagocytes through down-regulation of CCR5, the chemokine receptor, the principal co-receptor for HIV entry into macrophages and also by NK1R antagonist inhibition of endogenous SP production. The SP autocrine loop has an important role in regulating cytokine and inflammatory responses. HIV reciprocally enhances SP expression in human immune cells, eliciting a "feed-forward cycle". We discovered that cell differentiation in vitro from monocyte to macrophage phenotype (THP cells) results in the expression of both the NK1R-T (truncated) and NK1R-F (full-length), whereas the monocyte cell expresses only NK1R-T. The qualitative and quantitative expression of NK1R and its truncated (NK1R-T) and full length forms (NK1R-F) have functional consequences for calcium flux in macrophages. In the brain cingulate cortex, mRNA expression of both the NK1R-T and NK1R-F are reduced in HIV-infected subjects. We will use cells from both the immune and the CNS systems, including peripheral monocyte-macrophages and cells obtained from select human brain regions to examine these mechanisms. We will examine the cell biology of the interaction between NK1R (NK1R-F and NK1R-T) and HIV and chemokine receptors. Our aims are (1) To investigate expression of NK-1RF in monocyte-derived macrophages and their associations with CCR5, CD4, Fractalkine, and IL-8. (2) We will investigate the physical and functional interactions between NK1R-T, NK1R-F receptors and CCR5. (3) We will explore the role of cytosolic Ca2+ increase in the cross-talk between NK1R-F, NK1R-T, and CCR5. (4) We hypothesize that altered levels of either or both NK1R-T or NK1R-F mRNA and protein, or receptor function, are associated with alterations with cognitive function in HIV-1/AIDS infected individuals, and these effects alter CCR5-NK1R interaction. Relevance to Public Health These studies will further lead to understanding the pathogenesis of neurocognitive changes in HIV disease and lead to unique and novel therapeutic intervention
Keywords: (2R)-(1R)-3, 5-bis(trifluoromethylphenyl)ethoxy)-(3S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1, 2, 4-triazole)methyl-morpholine; 3-10C; AIDS; AIDS Seroconversion; AIDS Seropositivity; AIDS Virus; AIDS Virus Receptors; AMCF-I; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Affect; Agonist; Amino Acid Sequence; Amino Acids, Basic; Anti-HIV Positivity; Arg-Lys; Astrocytes; Astrocytus; Astroglia; Autocrine Systems; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Basic Amino Acids; Blood Coagulation Factor IV; Blood Plasma; Blood monocyte; Body Tissues; Brain; Brain region; C-C CKR-5; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5; C-C Chemokine Receptor Type 5 Gene; CC Chemokine Receptor 5; CC-CKR-5; CC-CKR-5 Gene; CC-CKR5; CCCKR5; CCCKR5 Gene; CCL5; CCR-5; CCR-5 Gene; CCR5; CCR5 Protein; CCR5 gene; CD195 Antigen; CD195 Antigen Gene; CHEMR13; CHEMR13 Gene; CKR-5; CKR-5 Gene; CKR5; CKR5 Gene; CMKBR5; CMKBR5 Gene; CX(3)C protein; CXCL8; Ca++ element; Calcium; Cell Communication and Signaling; Cell Differentiation; Cell Differentiation process; Cell Line; Cell Lines, Strains; Cell Signaling; CellLine; Cells; Cellular biology; Chemokine (C-C Motif) Ligand 5; Chemokine (C-C Motif) Receptor 5; Chemokine (C-C) Receptor 5; Chemokine (C-C) Receptor 5 Gene; Chemokine (C-X3-C Motif) Ligand 1; Coagulation Factor IV; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Coupling; Cytokines and Inflammatory Response; Cytokines, Chemotactic; D17S136E; Defect; Depression; Differentiation Factor, B-Cell; Disease; Disorder; Disturbance in cognition; Down-Regulation; Down-Regulation (Physiology); Downregulation; Encephalon; Encephalons; Endocytosis; Euler-Gaddum Substance P; FKN protein; Factor IV; Fractalkine; GCP-1; GCP1; Gene Expression; Gene Products, RNA; Glycine cleavage system P-protein; Glycine dehydrogenase (decarboxylating); Goals; HIV; HIV Antibody Positivity; HIV Infections; HIV Positive; HIV Positivity; HIV Receptors; HIV Seroconversion; HIV Seropositivity; HIV-1; HIV-1 Fusion Co-Receptor; HIV-1 Fusion Co-Receptor Gene; HIV-I; HIV1; HPGF; HTLV-III; HTLV-III Infections; HTLV-III Receptors; HTLV-III Seroconversion; HTLV-III Seropositivity; HTLV-III-LAV Infections; Hepatocyte-Stimulating Factor; Homologous Chemotactic Cytokines; Hortega cell; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL-8; IL6 Protein; IL8; IL8 gene; Immune; Immune system; Immunodeficiency Virus Type 1, Human; Immunologic Deficiency Syndrome, Acquired; Impaired cognition; In Vitro; Individual; Infection; Inflammatory Response Pathway; Intercrines; Interleukin 6 (Interferon, Beta 2); Interleukin-6; Intracellular Communication and Signaling; Investigation; Investigators; K60; LAV-HTLV-III; LECT; LUCT; LYNAP; Lead; Length; Life Stress; Ligands; Lymphadenopathy-Associated Virus; Lymphocyte; Lymphocytic; MDNCF; MGC17164; MGI-2; MONAP; Man (Taxonomy); Man, Modern; Marrow monocyte; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Membrane; Mental Depression; Messenger RNA; Microglia; Mononuclear; Myeloid Differentiation-Inducing Protein; NAF; NK-1 Receptors; NK1R; NKIR; NRVS-SYS; Nervous System; Nervous System, Brain; Nervous system structure; Neurocognitive; Neurologic Body System; Neurologic Organ System; Neuropeptides; P-protein; P-protein, glycine decarboxylase; PBMC; Pathogenesis; Pathway interactions; Pb element; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytic Cell; Phenotype; Plasma; Plasmacytoma Growth Factor; Prevalence; Production; Programs (PT); Programs [Publication Type]; Progress Reports; Protein Structure, Primary; Proteins; Public Health; RANTES; RANTES Protein, T-Cell; RNA; RNA, Messenger; RNA, Non-Polyadenylated; Receptor Protein; Receptors, CCR5; Receptors, CKR5; Receptors, HIV; Receptors, Neurokinin-1; Regulation; Reports, Progress; Research Personnel; Researchers; Reticuloendothelial System, Serum, Plasma; Ribonucleic Acid; Role; SCYA5; SCYB8; SIS cytokines; SIS delta; SIS-delta; SISd; SP(1-11); SP-P Receptors; Sampling; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Small Inducible Cytokine A5; Small Inducible Cytokine D1; Source; Substance P; Substance P Receptor; System; System, LOINC Axis 4; T-Cell Specific Protein p288; T-Lymphotropic Virus Type III Infections, Human; TAC1R; TACR1; TACR1 gene; TCP228; TSG-1; Tachykinin; Tachykinin Receptor 1; Tissues; Up-Regulation; Up-Regulation (Physiology); Upregulation; Viral Burden; Viral Load; Viral Load result; Virus; Virus-HIV; Viruses, General; Woman; amebocyte; antibody positive AIDS test; antigen positive AIDS test; aprepitant; arginine-lysine; arginyllysine; autocrine; b-ENAP; base; biological signal transduction; body system, allergic/immunologic; calcium flux; calcium mobilization; cell biology; chemoattractant cytokine; chemokine; chemokine receptor; cingulate cortex; cognitive dysfunction; cognitive function; cognitive loss; cognitively impaired; cultured cell line; design; designing; disease/disorder; feeding; gene product; gitter cell; glycine decarboxylase; heavy metal Pb; heavy metal lead; human T cell leukemia virus III; human T lymphotropic virus III; in vitro Model; interferon beta 2; lymph cell; mRNA; mRNA Expression; macrophage; membrane structure; men; men`s; mesoglia; microglial cell; microgliocyte; monocyte; neurokinin 1; neuropathology; novel; novel therapeutic intervention; organ system, allergic/immunologic; pathway; peripheral blood; perivascular glial cell; programs; protein expression; protein sequence; public health medicine (field); receptor; receptor function; release of sequestered calcium ion into cytoplasm; response; seropositive (AIDS test); social role
Project start date: 1995-07-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
5R01MH049981-16 (2010): $390688
Grants awarded to Steven Daniel Douglas
Steven Daniel Douglas, Professor And Medical Director
Childrens Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Abstract: The neurokinin-1 antagonists (SP antagonist) CP96,345 and aprepitant inhibit HIV infectivity of monocytederived macrophages, derived from healthy individuals and studied in ex vivo cell cultures. We have extended these findings to a two-week in vivo setting in a Phase IB clinical trial (IND 75558 Clinical Trial NCT00428519) in HIV-infected subjects with detectable viral loads and CCR5 HIV strains, and we are awaiting the results of this ongoing blinded clinical trial. The proposed study of NKIR antagonists will be performed using peripheral blood samples to be obtained through recruitment with another NIMH funded study (R01-MH082670, 2008-2013, "Depression, Antidepressants and HIV infectivity") in ex vivo cells obtained from depressed and non-depressed HlV-negative men and women. The goal is to determine whether depression alters susceptibility of cells to HIV infectivity ex vivo. In our long-standing investigations, we have observed differences in resopnise to NKIR antagonists (CP96,345 and aprepitant) related to susceptibility of monocyte-derived macrophages (MDMs) from healthy donors to viral challenge. In this project, we will further investigate anti-viral activity of selected NKI R antagonists targeted against cells from HIV-infected individuals and cells investigated ex viVo from individuals with different levels of depression as determined by Hamilton Depression scales and other standard psychiatric measures. We hypothesize that aprepitant inhibits HIV entry and replication in MDMs. We further hypothesize that this effect is mediated through CCR5 down-regulation. We predict that MDMs from subjects with depression will be infected with an HIV ex vivo model more readily and will demonstrate better responses to NKIR antagonists compared with cells from non-depressed subjects. We further propose that Natural Killer cells from subjects with depression will have impaired Natural Killer cell functions relative to impaired ligation of inhibitory Natural Killer cell receptors and that treatment with NK1R antagonists will restore these functions. The ex vivo efficiacy of NKIR antagonists in cells from depressed subjects will be determined
Keywords: (2R)-(1R)-3, 5-bis(trifluoromethylphenyl)ethoxy)-(3S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1, 2, 4-triazole)methyl-morpholine; AIDS Virus; ARRB2; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Anti-Viral Response; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Antiviral Response; BPTP3; Blinded; Blood Sample; Blood monocyte; Blood specimen; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5 Gene; CC-CKR-5 Gene; CCCKR5 Gene; CCL5; CCR-5 Gene; CCR5; CCR5 gene; CD195 Antigen Gene; CFC; CHEMR13 Gene; CKR-5 Gene; CKR5 Gene; CMKBR5 Gene; Cell Culture Techniques; Cell Function; Cell Process; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Chemokine (C-C Motif) Ligand 5; Chemokine (C-C) Receptor 5 Gene; Clinical Trials; Clinical Trials, Unspecified; Closure by Ligation; Cytotoxic cell; D17S136E; Depressed mood; Depression; Down-Regulation; Down-Regulation (Physiology); Downregulation; Drug Receptors; Drugs; Euler-Gaddum Substance P; Fluorescence Microscopy; Funding; Gagging; Goals; HAM-D; HCP; HCPH; HIV; HIV Infections; HIV-1 Fusion Co-Receptor Gene; HPTP1C; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Hamilton Depression Scale; Hamilton Rating Scale for Depression; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; In Vitro; Individual; Infection; Investigation; K lymphocyte; LAV-HTLV-III; Ligands; Ligation; Lymphadenopathy-Associated Virus; MGC17164; Marrow monocyte; Measures; Mediating; Medication; Mental Depression; Microscopy, Fluorescence; Microscopy, Light, Fluorescence; Modeling; NIMH; NK Cells; NK-1 Receptors; NK1R; NKIR; NS1; National Institute of Mental Health; National Institute of Mental Health (U.S.); Natural Killer Cells; PTP-1C; PTP-1D; PTP2C; PTPN11; PTPN11 gene; PTPN6; PTPN6 gene; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phosphorylation; Predisposition; Protein Phosphorylation; RANTES; RANTES Protein, T-Cell; RTV; Receptor Protein; Receptors, Neurokinin-1; Reflex, Pharyngeal; Relative; Relative (related person); Ritonavir; SCYA5; SH-PTP1; SH-PTP2; SH-PTP3; SHP-1; SHP-1L; SHP-2; SHP2; SIS delta; SIS-delta; SISd; SP(1-11); SP-P Receptors; Small Inducible Cytokine A5; Subcellular Process; Substance P; Substance P Receptor; Susceptibility; T-Cell Specific Protein p288; T-Lymphotropic Virus Type III Infections, Human; TAC1R; TACR1; TACR1 gene; TCP228; Tachykinin Receptor 1; United States National Institute of Mental Health; Viral; Viral Activity; Viral Burden; Viral Function; Viral Load; Viral Load result; Viral Physiology; Virus-HIV; Woman; aprepitant; beta-arrestin 2; clinical investigation; depressed; drug/agent; function improvement; functional improvement; functional restoration; improved; in vivo; macrophage; men; men`s; monocyte; neurokinin 1; norvir; peripheral blood; receptor; response; restore function; restore functionality; restore lost function; sadness
Relevance: The effects of a neurokinin-1 drug receptor antagonist (substance P preferring receptor), aprepitant, an HIVantiviral active and Natural Killer cell function improving drug, will be investigated in cells from depressed and non-depressed subjects. The potential anti-HIV activity and natural killer cell functional improvement in depression will be determined
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
5U01MH090325-02_6604 (2010): $219509
1U01MH090325-01_6604 (2009): $231783
ANTI-HIV NEUROIMMUNOMODULATORY THERAPY WITH NEUROKININ-1 (NK1-R) ANTAGONISTS
Steven Daniel Douglas, Professor And Medical Director
Childrens Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 5U01MH090325-02 from National Institute Of Mental Health
Abstract: The neurokinin receptor (NK1R), the substance P-preferring receptor, is a novel therapeutic target for neuroAIDS. Neurokinin-1 receptor antagonists (NK1RA) have antiviral activity, positive immunomodulatory effects and neurobehavioral effects. We have demonstrated significant ex vivo anti-HIV activity in monocyte- derived macrophages of NK1RA, which include the FDA licensed drug, aprepitant. The antiviral effect is mediated, in part, through CCR5 down-regulation. Aprepitant crosses the blood-brain barrier. Aprepitant is safe in rhesus macaques, and we have an ongoing two-week blinded Phase IB clinical safety trial of aprepitant in HIV-infected humans (NCT00428519). In this new program-project application, we propose a novel series of studies which will determine the mechanism of action of NK1R. There are three interactive preclinical and clinical projects, which target the development of NK1RA therapy for neuroAIDS 1) Cellular Mechanisms-Neurokinin-1 R Antagonists in the Brain and Immune System; 2) Immune Mechanisms-Anti- HIV Actions of Neurokinin-1 R Antagonists in Depression; and 5) Phase IB Clinical Trial of Neurokinin-1 R Antagonist-Aprepitant with ritonavir boost and direct proof of NK1R antagonism efficacy, and two Cores A) Administration; and C) Quantitative Pharmacology and Biostatistics. The optimization of the use of NKI RA in neuroAIDS therapy is proposed and the program-project encompasses basic, translational, and clinical HIV studies of tachykinin (substance P) and NK1RA. The investigators from the Joseph Stokes, Jr. Rl, CHOP, the UPenn Schools of Medicine (Depts. of Pediatrics, Psychiatry, & Medicine) and Westat. The Philadelphia ACTU and IMPAACT CTU´s, Penn-CHOP CFAR, and Penn CTSU foster the proposed interactions. These molecular, immunologic, pharmacologic, and bench-to-bedside projects address this novel therapeutic target for neuroAIDS treatment. RELEVANCE (See Instructions) An integrated pre-clinical/clinical program (IPCP) is proposed to use NK1RA as anti-HIV agents in neuroAIDS. This class of receptor antagonists crosses the blood brain barrier. This NK1RA has activity as an antiviral HIV agent that improves innate immunity (Natural Killer cells) and has positive neurobehavioral effects. NK1RA are a potential novel therapy for neuroAIDS
Project start date: 2009-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: RFA-MH-09-040
5U01MH090325-02 (2010): $1138312
Steven Daniel Douglas, Professor And Medical Director
Childrens Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Abstract: The long-range goal of this proposal is to continue to evaluate the potential role of neurokinin-1 receptor (NK1R) antagonists as anti HIV-1 agents in vivo. Aprepitant is the only FDA approved substance P antagonist. We have demonstrated in our previous work that NKIR antagonists, in general and aprepitant, in particular, have significant anti HIV-1 activity in vitro possibly mediated through CCR5 down-regulation, although some of our in vitro data suggests that these compounds have some antiviral activity in CXCR4 viruses. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYPIA2 and CYP2C19. This metabolic pathway suggests that aprepitant will interact favorably with the protease inhibitor ritonavir (a potent inhibitor of CYP3A4), as do many ofthe current available antlretrovirals. We will examine the safety and the PK characteristics of the NKI R antagonist, aprepitant, in HIV-infected subjects with well controlled viral replication receiving ritonavir containing antiretroviral therapy. Our hypothesis is that aprepitant will be safe, tolerable and that with the concomitant administration of the protease inhibitor ritonavir, we will be able to attain the therapeutic levels necessary to achieve antiviral activity predicted by both by our in vitro studies and our pharmacokinetic and pharmacodynamic (PK/PD) modeling. We will also examine the antiviral activity of an optimized dose of aprepitant administered for two weeks as an "add on" drug in patients with evidence of virologic failure on a protease inhibitor containing regimen. Further, we hypothesize that aprepitant will improve depressive symptoms, decrease anxiety and improve sleep quality in patients with HIV infection
Keywords: (2R)-(1R)-3, 5-bis(trifluoromethylphenyl)ethoxy)-(3S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1, 2, 4-triazole)methyl-morpholine; 3, 12-bis(1, 1-dimethylethyl)-8-hydroxy-4, 11-dioxo-9-(phenylmethyl)-6-((4-(2-pyridinyl)phenyl)methyl)-2, 5, 6, 10, 13-pentaazatetradecanedioic acid dimethyl ester; AIDS Virus; AIDS neuropathy; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Adjuvant Therapy; Anti-Retroviral Agents; Antiproteases; Antiretroviral Agents; Antiviral Agents; Antiviral Drugs; Antivirals; Anxiety; Arm; Atazanavir; Blood Plasma; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5 Gene; CC-CKR-5 Gene; CCCKR5 Gene; CCR-5 Gene; CCR5; CCR5 gene; CD195 Antigen Gene; CD4 Lymphocyte Count; CD4+ Cell Counts; CD4+ Counts; CHEMR13 Gene; CKR-5 Gene; CKR5 Gene; CMKBR5 Gene; CP33; CP34; CPCJ; CXC-R4; CXCR-4; CXCR4; CXCR4 gene; CYP2C; CYP2C19; CYP2C19 gene; CYP3; CYP3A; CYP3A13; CYP3A3; CYP3A4; CYP3A4 gene; CYPIIIA4; Cell Function; Cell Process; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Characteristics; Chemokine (C-C) Receptor 5 Gene; Clinical Trials; Clinical Trials, Unspecified; Cytotoxic cell; D2S201E; Data; Depression; Dose; Down-Regulation; Down-Regulation (Physiology); Downregulation; Drug Kinetics; Drugs; Emend; Emotional Depression; Endopeptidase Inhibitors; Enrollment; Euler-Gaddum Substance P; FB22; FDA approved; FLR; Failure (biologic function); Gene Products, RNA; Goals; Guidelines; HIV; HIV Infections; HIV-1; HIV-1 Fusion Co-Receptor Gene; HIV-I; HIV1; HLP; HM89; HSY3RR; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Immune; Immunodeficiency Virus Type 1, Human; In Vitro; Individual; Intermediary Metabolism; K lymphocyte; Kaletra; LAP3; LAV-HTLV-III; LCR1; LESTR; Link; Lopinavir/Ritonavir; Lymphadenopathy-Associated Virus; METBL; Mediating; Medication; Mental Depression; Merck brand of aprepitant; Metabolic Pathway; Metabolic Processes; Metabolism; Minor; NF-25; NK Cells; NK-1 Receptors; NK1R; NKIR; NPY3R; NPYR; NPYRL; NPYY3R; Natural Killer Cells; P450-PCN1; P450C2C; P450C3; P450IIC19; P450PCN1; Patients; Peptidase Inhibitors; Peptide Hydrolase Inhibitors; Peptide Peptidohydrolase Inhibitors; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase; Placebo Control; Plasma; Population; Protease Antagonists; Protease Inhibitor; Proteinase Inhibitors; Protocol; Protocols documentation; RNA; RNA, Non-Polyadenylated; RTV; Randomized; Receptors, Neurokinin-1; Regimen; Relative; Relative (related person); Reticuloendothelial System, Serum, Plasma; Reyataz; Ribonucleic Acid; Ritonavir; Role; SP(1-11); SP-P Receptors; Safety; Serum, Plasma; Sleep; Subcellular Process; Substance P; Substance P Receptor; Symptoms of depression; T-Lymphotropic Virus Type III Infections, Human; T4 Lymphocyte Count; TAC1R; TACR1; Tachykinin Receptor 1; Testing; Therapeutic; Upper arm; Viral; Viral Burden; Viral Load; Viral Load result; Virus; Virus-HIV; Viruses, General; Work; anti-retroviral; antiretroviral; antiretroviral therapy; aprepitant; clinical investigation; depressive; depressive symptoms; drug/agent; enroll; failure; human T cell leukemia virus III; human T lymphotropic virus III; improved; in vitro activity; in vivo; indexing; inhibitor; inhibitor/antagonist; interest; neuroAIDS; neurokinin 1; norvir; open label; pharmacodynamic model; population based; psychologic; psychological; randomisation; randomization; randomly assigned; social role
Relevance: We will examine the safety and PK characteristics of aprepitant in HIV-infected subjects with well controlled viral replication, receiving ritonavir containing antiretroviral therapy. We hypothesize that aprepitant will be safe, tolerable, and will demonstrate antiviral activity. We will also examine the antiviral activity of aprepitant, optimized as an "add-on" drug in patients with evidence of virologic failure on a protease inhibitor containing regimen. This study is a proof-of-principal of NKI R antagonists for adjuvant therapy for neuroAIDS
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
5U01MH090325-02_6608 (2010): $332911
1U01MH090325-01_6608 (2009): $353983
PHILADELPHIA IMPAACT CLINICAL TRIALS UNIT
Steven Daniel Douglas, Professor And Medical Director
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 5U01AI069467-04 from National Institute Of Allergy And Infectious Diseases
Abstract: The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network is a new research collaboration representing a merger of investigators from the Pediatric AIDS Clinical Trials Group (PACTG) and the Perinatal Scientific Working Group of the HIV Prevention Trials Network (HPTN). The mission of the IMPAACT Network will be to significantly decrease the mortality and morbidity associated with HIV disease in pregnant women, children, and adolescents. We propose to establish a Philadelphia IMPAACT Clinical Trials Unit (PICTU) that will affiliate, by prior leadership agreement, as a priority site within the IMPAACT Network. This CTU will be comprised of an Administrative Component, two pediatric clinical research sites at the Children´s Hospital of Philadelphia and St. Christopher´s Hospital for Children, and a maternal/perinatal site at the Drexel University College of Medicine/Hahnemann University Hospital. The PICTU will respond to all four priority research areas identified by the IMPAACT leadership including 1) Vaccine Research and Development, 2) Translational Research and Drug Development, 3) Optimization of Clinical Management including Co-Morbidity, and, 4) Prevention of Mother-to-Child Transmission of HIV. The PICTU will serve as a domestic unit within the Network. The PICTU is positioned to meet the enrollment requirements for the IMPAACT network. In 2004, there were 453 HIV-infected children and youth between 0 and 24 years of age, nearly all of whom are served by our pediatric sites. The Philadelphia HIV community is well-organized and highly-motivated to support the transition to new HIV/AIDS trial networks in the region and PICTU investigators have established ties with local community organizations and action groups. The PI, participating investigators, and senior professional staff have broad experience and success in the enrollment and retention of pregnant women, infants, children, and adolescents in HIV clinical trials, as well as a strong past record of leadership and scientific contributions in NIH-sponsored HIWAIDS research and within the PACTG and other HIV/AIDS research networks (REACH, ATN, HPTN). The proposed clinical research sites and their personnel have collaborated successfully as a PACTG unit in the past and have demonstrated a consistently excellent record of regulatory compliance, timely data submission, data management, and enrollment. The participating clinical research sites have demonstrated expertise in design of randomized controlled clinical treatment trials, pharmacokinetic, immunologic, virologic, and pharmacologic studies and are well-qualified to conduct IMPAACT protocols and contribute to the Network´s scientific agenda. ADMINISTRATIVE COMPONENT
Keywords: 0-11 years old; AIDS Virus; AIDS clinical trial group; AIDS in Pediatric Population; AIDS/HIV; AIDS/HIV problem; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Adolescent; Adolescent Youth; Age-Years; Agreement; Area; Child; Child Youth; Childhood; Children (0-21); Clinical Management; Clinical Treatment; Clinical Trial Protocol; Clinical Trials; Clinical Trials Network; Clinical Trials Unit; Clinical Trials, Unspecified; Clinical trial protocol document; Collaborations; Communities; Data; Development and Research; Disease; Disorder; Drug Kinetics; Enrollment; HIV; HIV prevention trials network; HIV/AIDS; HIV/AIDS problem; HTLV-III; Hospitals, Pediatric; Hospitals, University; Human Immunodeficiency Viruses; Human Resources; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human, Child; IMPAACT; Immunologic, Immunochemical; Immunologics; Infant; International Maternal Pediatric Adolescent AIDS Clinical Trials; Investigators; LAV-HTLV-III; Leadership; Lymphadenopathy-Associated Virus; Manpower; Medicine; Mission; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Pediatric Hospitals; Perinatal; Pharmacokinetics; Philadelphia; Position; Positioning Attribute; Pregnant Women; Prevention; Qualifying; R & D; R&D; Randomized; Research; Research Personnel; Research Priority; Researchers; Science of Medicine; Site; Translational Research; Translational Research Enterprise; Translational Science; Universities; University Hospitals; Vaccine Research; Vertical Disease Transmission; Vertical Transmission; Virus-HIV; children; clinical investigation; clinical research site; clinical site; college; community organizations; data management; design; designing; disease/disorder; drug development; enroll; experience; juvenile; juvenile human; meetings; mother to child transmission; pediatric; pediatric AIDS; personnel; randomisation; randomization; randomly assigned; research and development; success; translation research enterprise; treatment trial; trial regimen; trial treatment; working group; youngster
Project start date: 2007-02-01
Project end date: 2013-11-30
Budget start date: 1-DEC-2009
Budget end date: 30-NOV-2010
PFA/PA: RFA-AI-05-002
5U01AI069467-04 (2010): $2087680
ADOLESCENT MEDICINE TRIALS NETWORK FOR HIV/AIDS INTERVE*
Steven Daniel Douglas, Professor And Medical Director
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 5U01HD040481-10 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Project Summary and Relevance The Adolescent Trials Unit at The Children´s Hospital of Philadelphia seeks to continue their work with the Adolescent Trials Network for HIV/AIDS Interventions. The site will conduct clinical studies developed or co-endorsed by the ATM that will focus on the following 1) primary prevention through the Connect to Protect project. 2) secondary prevention through ATM clinical studies including both behavioral and biomedical interventions. 3) tertiary prevention through ATN clinical studies including therapeutic and behavioral trials targeting infected, ill youth. The site will accomplish these goals as follows. The Connect to Protect Project will continue to build community mobilization and partnerships through participation in ATN 016B, ATN 040,and other C2P specific studies. To address the second and third aims, the site will recruit and retain HIV-infected and at-risk youth into clinical trials. To accomplish this goal successfully, the site will continue with their targeted outreach and linkage program to identifyHIV- infected youth and link them to care. The site will provide a broad array of targeted, multidisciplinary services to support youth once engaged in research. The site PI will continue to work with the TLG to develop and implement the therapeutic agenda of the Network. Other staff will support the research agenda through participation on protocol teams. Finally, the site will contribute to the Network management through active participation in conference calls and meetings. This project addresses the epidemic of HIV infection in adolescents and young adults to provide the much needed scientific data to prevent new infections and maintain the health of those infected. The data from the clinical trials developed and implemented by the ATN will contribute significantly to understanding better ways to treat HIV infection in adolescents and prevent new infections from occurring. Relevance This project will have major public health implications. Through well designed targeted clinical trials, the much needed data will be collected to learn better how to prevent the spread of new HIV infections in adolescents and young adults. The trials with HIV-infected adolescents and young adults will provide data required to prevent the spread of HIV from infected persons through better management strategies for infected individuals.
Keywords: 12 year old; AIDS; AIDS Virus; AIDS in Pediatric Population; AIDS/HIV; AIDS/HIV problem; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Address; Adolescent; Adolescent Medicine; Adolescent Medicine Trials Network; Adolescent Trials Network; Adolescent Youth; Analysis, Data; Behavioral; Behavioral Research; Caring; Clinical; Clinical Research; Clinical Services; Clinical Study; Clinical Trials; Clinical Trials Unit; Clinical Trials, Unspecified; Collaborations; Communities; Complex; Comprehensive Health Care; Comprehensive Healthcare; Data; Data Analyses; Development; Disease; Disorder; Drugs; Dysfunction; Environment; Epidemic; Functional disorder; Goals; HIV; HIV Infections; HIV/AIDS; HIV/AIDS problem; HRSA; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Health; Health Resources and Services Administration; Health Resources and Services Administration (U.S.); Hospitals, Pediatric; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Immunologic Deficiency Syndrome, Acquired; Individual; Infection; Intervention; Intervention Strategies; LAV-HTLV-III; Learning; Life; Link; Lymphadenopathy-Associated Virus; Manuscripts; Medical Research; Medication; Methods; Modeling; Pediatric Hospitals; Pennsylvania; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Philadelphia; Physiopathology; Population; Preparation; Primary Prevention; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; Public Health; Qualifying; Recruitment Activity; Research; Research Activity; Research Support; Research, Medical; Risk; Safety; Schools, Medical; Secondary Prevention; Services; Site; T-Lymphotropic Virus Type III Infections, Human; Testing; Therapeutic; United States Health Resources and Services Administration; Universities; Virus-HIV; Work; Youth; Youth 10-21; adult youth; clinical investigation; comprehensive care; conference; design; designing; disease/disorder; drug/agent; improved; innovate; innovation; innovative; interventional strategy; juvenile; juvenile human; medical schools; meetings; multidisciplinary; outreach; pathophysiology; pediatric AIDS; performance site; prevent; preventing; programs; protocol development; public health medicine (field); recruit; research facility; social; symposium; tertiary prevention; twelve year old; young adult
Project start date: 2001-04-16
Project end date: 2011-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: RFA-HD-04-025
5U01HD040481-10 (2010): $739565
NEUROKININ-1R (SP RECEPTOR) ANTAGONISTS FOR HIV THERAPY
Steven Daniel Douglas, Professor And Medical Director
Childrens Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Abstract: New HIV-1 therapies that utilize novel antiviral mechanisms and exert a positive immunomodulatory effect are needed. Neurokinin-1 receptor (NK-1R) antagonists target the substance P (SP) receptor and have demonstrated antiviral and immunomodulatory effects. The NK-1R antagonists are a new therapeutic target with the potential to interrupt a pathway critical to HIV replication. The goal of this Integrated Preclinical/Clinical Program (IPCP) is to identify an NK-1R antagonist that is (a) active as an anti-HIV agent through interaction with chemokine/cytokine receptors (Project 1); (b) specific for NK-1R interaction with CCR-5 (Project 2); (c) safe for use in SIV-infected non-human primates and provides proof of concept related to antiviral, immunomodulatory, and neurobehavioral effects (Project 3); and (d) safe in humans and has positive immunomodulatory effects (Project 4). We will demonstrate the safety, pharmacokinetics and therapeutic potential of an NK-1R antagonist (aprepitant or alternative) in SIV infection in the Rhesus macaque (Project 3). We will determine safety of an NK-1R antagonist (aprepitant or alternative) in relation to toxicity and effects on HIV viral load in a Phase I study of adults with HIV infection (Project 4). All projects contribute to understanding the basic virologic, molecular and cellular immunologic mechanisms of SP, NK-1R antagonists, and HIV/SIV infection. In a private sector partnership, with BBI Biotech Research Labs, Inc. (BBI) (Core B), synergy of candidate NK-1R antagonists with current antiretroviral drugs and in vitro antiviral activity against non-laboratory and resistant strains of HIV will be evaluated. An Administrative Core (Core A) and a Biostatistics and Pharmacology Core (Core C) will support the organizational study design, data management, and analysis needs of the program. Building on 10 years of HIV and SP collaborative research at The Children´s Hospital of Philadelphia, this AIDS program project (investigators at the University of Pennsylvania Dept. of Pediatrics, Medicine and Psychiatry, PENN CFAR, PACTU, GCRC,Tulane National Primate Research Center, and BBI Biotech), will foster interactions across molecular, cellular, biopharmaceutical, and translational research, leading to novel HIV drug development
Project start date: 2005-08-18
Project end date: 2010-07-31
Budget start date: 1-AUG-2008
Budget end date: 31-JUL-2010
PFA/PA: PAR-03-138
5P01MH076388-04 (2008): $0
Sponsored Links Excellgen http://Excellgen.com
Steven Daniel Douglas, Professor And Medical Director
Childrens Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Abstract: Core A will serve all projects and cores in the Novel neuroAIDS Therapies Integrated Preclinical/Clinical IPCP and will be responsible for oversight ofthe scientific, administrative, regulatory and operational aspects of the program´s activities. The overall goal of the Administrative Core is to enable the IPCP to fulfill its scientific mission, as defined in the introduction and overview at the beginning of this proposal, as a specified in the Specific Aims of the three projects. The Principal Investigator, Dr. Steven D. Douglas, will direct this core and will provide leadership, direction, and organization to the overall program project effort and assist each of the Project Leaders and Core Leaders in the successful execution of their planned experiments or support services. The objectives ofthe Administrative Core are to (1) Coordinate and supervise this IPCP; (2) Oversee the development plan ofthe IPCP by coordinating regular review of study results and integration of this information into the decision-making process that is integral to the drug development mission of the research program; (3) Promote a high degree of collaboration and synergistic interaction among the investigators and core leaders; (4) Facilitate participation of this IPCP within NIH IPCP Program activities; (5) Insure efficient and appropriate use of core services by the individual projects; (6) Provide investigators and core directors with timely and accurate information regarding core and project expenditures and resources; (7) Insure that the program´s development plan is conducted in compliance with all applicable regulatory guidelines and NIH policies and procedures; (8) Organize and implement regular internal and external oversight of the IPCP´s activities; and, (9) Support the program in fulfilling its obligations related to information dissemination, scientific publication and data sharing. This will include management of intellectual property issues in collaboration with the CHOP Department of Technology Transfer. The Administrative Core will be utilized equally by all participating projects and scientific cores
Keywords: AIDS neuropathy; Clinical; Collaborations; Communication; Cooperative Agreements; Cooperative Agreements, U-Series; Decision Making; Development Plans; Expenditure; Fostering; Goals; Guidelines; Individual; Information Dissemination; Institution; Intellectual Property; Investigators; Leadership; Mission; NIH; NIMH; National Institute of Mental Health; National Institute of Mental Health (U.S.); National Institutes of Health; National Institutes of Health (U.S.); Operation; Operative Procedures; Operative Surgical Procedures; Participant; Policies; Principal Investigator; Procedures; Process; Program Development; Programs (PT); Programs [Publication Type]; Publications; Research; Research Activity; Research Personnel; Research Priority; Research Resources; Researchers; Resource Allocation; Resources; Role; Scientific Publication; Scientist; Services; Specific qualifier value; Specified; Supervision; Surgical; Surgical Interventions; Surgical Procedure; Technology Transfer; Therapeutic; TimeLine; U-Series Cooperative Agreements; United States National Institute of Mental Health; United States National Institutes of Health; design; designing; drug development; experiment; experimental research; experimental study; innovate; innovation; innovative; meetings; neuroAIDS; novel; pre-clinical; preclinical; programs; research study; response; sharing data; social role; surgery
Relevance: An Administrative Core is essential to the functioning of the IPCP. Its role is to foster excellence in communication, decision-making and resource allocation and to assure that the program achieves its scientific mission. Innovation and synergy in a collaborative research effort depend on regular information sharing, review of progress, and the ability to assimilate and re-direct research as necessary to meet milestones and timelines. The Administrative Core provides the engine that drives these functions
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
5U01MH090325-02_6609 (2010): $175114
1U01MH090325-01_6609 (2009): $172664
Steven Daniel Douglas
Childrens Hospital Of Philadelphia
Project start date: 2007-02-01
Project end date: 2013-11-30
ANTI-HIV NEUROIMMUNOMODULATORY THERAPY WITH NEUROKININ-1 (NK1-R) ANTAGONISTS
Steven Daniel Douglas, Professor And Medical Director
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 1U01MH090325-01 from National Institute Of Mental Health
Project start date: 2009-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
PFA/PA: RFA-MH-09-040
1U01MH090325-01 (2009): $1166337