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Article ; Online: Pharmacokinetics of Tildrakizumab (MK-3222), an Anti-IL-23 Monoclonal Antibody, After Intravenous or Subcutaneous Administration in Healthy Subjects.

Khalilieh, Sauzanne / Hodsman, Peter / Xu, Christine / Tzontcheva, Anjela / Glasgow, Shirley / Montgomery, Diana

Basic & clinical pharmacology & toxicology

2018 Volume 123, Issue 3, Page(s) 294–300

Abstract: Tildrakizumab, a high-affinity humanized IgG1k antibody that selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function, is under investigation for treatment of moderate-to-severe chronic plaque psoriasis. The ... ...

Abstract	Tildrakizumab, a high-affinity humanized IgG1k antibody that selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function, is under investigation for treatment of moderate-to-severe chronic plaque psoriasis. The objective of this analysis was to assess the pharmacokinetics, bioavailability and safety/tolerability of single ascending doses of tildrakizumab after intravenous (IV) and subcutaneous (SC) dosing in healthy subjects. P05661 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab IV doses of 0.1, 0.5, 3 and 10 mg/kg, or placebo. P05776 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab SC doses of 50 or 200 mg, or placebo. After either single IV or SC dosing, tildrakizumab exhibited slow systemic clearance (CL), limited volume of distribution and a long t
MeSH term(s)	Adolescent ; Adult ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Neutralizing/immunology ; Area Under Curve ; Biological Availability ; Dermatologic Agents/administration & dosage ; Dermatologic Agents/adverse effects ; Dermatologic Agents/pharmacokinetics ; Dose-Response Relationship, Drug ; Female ; Half-Life ; Humans ; Injections, Intravenous ; Injections, Subcutaneous ; Interleukin-23/immunology ; Male ; Middle Aged ; Tissue Distribution ; Young Adult
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Dermatologic Agents ; Interleukin-23 ; tildrakizumab (DEW6X41BEK)
Language	English
Publishing date	2018-04-20
Publishing country	England
Document type	Clinical Trial, Phase I ; Comparative Study ; Journal Article ; Randomized Controlled Trial
ZDB-ID	2134679-3
ISSN	1742-7843 ; 1742-7835
ISSN (online)	1742-7843
ISSN	1742-7835
DOI	10.1111/bcpt.13001
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Article ; Online: Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study.

Chris Min, K / Dockendorf, Marissa F / Palcza, John / Tseng, Jack / Ma, Lei / Stone, Julie A / Kleijn, Huub J / Hodsman, Peter / Masuo, Kazuko / Tanen, Michael / Troyer, Matthew D / van Vugt, Marianne / Forman, Mark S

Clinical pharmacology and therapeutics

2019 Volume 105, Issue 5, Page(s) 1234–1243

Abstract: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical ... ...

Abstract	β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated. Verubecestat's PK profile was similar in Japanese and non-Japanese subjects. Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aβ proteins Aβ40, Aβ42, and soluble β fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non-Japanese subjects. These results support the continued global development of verubecestat as a potential disease-modifying agent for Japanese and non-Japanese subjects who are at risk for developing AD.
MeSH term(s)	Adult ; Alzheimer Disease/drug therapy ; Alzheimer Disease/ethnology ; Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid beta-Peptides/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; Amyloid beta-Protein Precursor/blood ; Amyloid beta-Protein Precursor/metabolism ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Cyclic S-Oxides/administration & dosage ; Cyclic S-Oxides/pharmacokinetics ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Monitoring/methods ; Female ; Healthy Volunteers ; Humans ; Japan ; Male ; Thiadiazines/administration & dosage ; Thiadiazines/pharmacokinetics
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Cyclic S-Oxides ; Thiadiazines ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46) ; verubecestat (J1I0P6WT7T)
Language	English
Publishing date	2019-01-18
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1258
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Article: Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant.

Brigandi, Richard A / Russ, Steven F / Petit, Chantal / Johnson, Brendan / Croy, Scott / Hodsman, Peter / Muller, Fran

Clinical pharmacology in drug development

2015 Volume 4, Issue 2, Page(s) 130–136

Abstract: Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic ...

Abstract	Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic activity in preclinical studies. In an effort to reduce the hemolytic potential and develop an IV formulation of vestipitant that could be administered more rapidly, an IV formulation containing sulfobutylether-7-beta-cyclodextrin (SBE7-β-CD, Captisol™) was developed and tested in a phase 1 clinical study. This was a randomized, single-blind (subjects and investigator-blinded, sponsor-unblinded), placebo controlled, dose escalation study in healthy subjects in which 7 cohorts of 8 subjects per cohort received SBE7-β-CD -based vestipitant (2 mg/mL) or placebo (saline) in a 3:1 ratio (active:placebo) at different doses and infusion rates. The results demonstrated the ability to infuse up to 48 mg vestipitant in a 2 mg/mL formulation over 30 seconds with no evidence of hemolytic effects. Cohorts of subjects at lower doses and longer infusion duration (>1 minute) reported more AEs related to the infusion site than those at the higher doses and faster infusion rates.
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.128
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Article ; Online: Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects.

Martin, Kevin J / Bell, Gregory / Pickthorn, Karen / Huang, Saling / Vick, Andrew / Hodsman, Peter / Peacock, Munro

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

2013 Volume 29, Issue 2, Page(s) 385–392

Abstract: Context: Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with ... ...

Abstract	Context: Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease-mineral and bone disorder. Objective: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. Methods: The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18-45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo. Intervention: Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously. Outcomes: Measurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study. Results: Intravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P<0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h. Conclusion: Single IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients.
MeSH term(s)	Adolescent ; Adult ; Biomarkers/blood ; Chronic Kidney Disease-Mineral and Bone Disorder/blood ; Chronic Kidney Disease-Mineral and Bone Disorder/complications ; Chronic Kidney Disease-Mineral and Bone Disorder/drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Fibroblast Growth Factors/blood ; Fibroblast Growth Factors/drug effects ; Follow-Up Studies ; Humans ; Hyperparathyroidism, Secondary/blood ; Hyperparathyroidism, Secondary/drug therapy ; Hyperparathyroidism, Secondary/etiology ; Injections, Intravenous ; Male ; Middle Aged ; Parathyroid Hormone/blood ; Peptides/pharmacokinetics ; Peptides/pharmacology ; Receptors, Calcium-Sensing/agonists ; Reference Values ; Renal Insufficiency, Chronic/blood ; Renal Insufficiency, Chronic/complications ; Renal Insufficiency, Chronic/drug therapy ; Time Factors ; Treatment Outcome ; Young Adult
Chemical Substances	Biomarkers ; Parathyroid Hormone ; Peptides ; Receptors, Calcium-Sensing ; Fibroblast Growth Factors (62031-54-3) ; etelcalcetide hydrochloride (72PT5993DU) ; fibroblast growth factor 23 (7Q7P4S7RRE)
Language	English
Publishing date	2013-11-13
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	90594-x
ISSN	1460-2385 ; 0931-0509
ISSN (online)	1460-2385
ISSN	0931-0509
DOI	10.1093/ndt/gft417
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Zs.A 2198: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics.

Hodsman, Peter / Ashman, Claire / Cahn, Anthony / De Boever, Erika / Locantore, Nicholas / Serone, Adrian / Pouliquen, Isabelle

British journal of clinical pharmacology

2012 Volume 75, Issue 1, Page(s) 118–128

Abstract: Aims: IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating ... ...

Abstract	Aims: IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586. Methods: In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo. Results: GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs. Conclusions: GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.
MeSH term(s)	Adult ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Asthma/drug therapy ; Breath Tests ; Double-Blind Method ; Humans ; Interleukin-13/antagonists & inhibitors ; Male ; Nitric Oxide/metabolism
Chemical Substances	Antibodies, Monoclonal, Humanized ; GSK679586 ; Interleukin-13 ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2012-05-29
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/j.1365-2125.2012.04334.x
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Article ; Online: Acute hyperkalemia associated with inhalation of a potent ENaC antagonist: Phase 1 trial of GS-9411.

O'Riordan, Thomas G / Donn, Karl H / Hodsman, Peter / Ansede, John H / Newcomb, Terry / Lewis, Sandra A / Flitter, William D / White, Vicki Shigekane / Johnson, M Ross / Montgomery, A Bruce / Warnock, David G / Boucher, Richard C

Journal of aerosol medicine and pulmonary drug delivery

2014 Volume 27, Issue 3, Page(s) 200–208

Abstract: Background: Inhaled epithelial sodium channel (ENaC) blockers are designed to increase airway surface liquid volume, thereby benefiting cystic fibrosis patients. This study evaluated the safety, tolerability, and pharmacokinetics of multiple doses of ... ...

Abstract	Background: Inhaled epithelial sodium channel (ENaC) blockers are designed to increase airway surface liquid volume, thereby benefiting cystic fibrosis patients. This study evaluated the safety, tolerability, and pharmacokinetics of multiple doses of ENaC blocker GS-9411, in healthy participants. Methods: This randomized, double-blind, placebo-controlled, parallel-group, residential, Phase 1 study evaluated inhaled GS-9411 (2.4, 4.8, and 9.6 mg) or placebo, dosed twice daily for 14 days. Results and conclusions: GS-9411 was well tolerated; 86.1% of treated participants completed dosing (n=31/36). Cough and dizziness (27.8% participants each; most of mild severity) were the most commonly reported adverse events and occurred in both placebo and GS-9411 treatment groups. Arrhythmias were not observed for GS-9411-treated participants, and electrocardiographic changes were not considered clinically significant. Serum potassium levels exceeded the upper limit of normal (>5 mmol/L), 4 hr after the morning dose in GS-9411 (n=16/24) and placebo (n=4/12) treatment groups (38 incidences total). Retesting revealed levels had returned to normal within 2-3 hr. In urine electrolyte analyses, obtained 0-6 hr after the Day 1 morning dose, mean sodium/potassium ratios significantly increased from values 0-6 hr before dosing. Increased urine sodium/potassium ratios corresponded with high urine concentrations of active GS-9411 metabolites, which inhibited sodium reabsorption in the kidney, leading to the observed transient hyperkalemia in these participants. Inhaled GS-9411 was well tolerated except for the emergence of transient clinically significant hyperkalemia; this finding resulted in termination of further clinical development of this drug and will necessitate development of a new generation of ENaC blockers, which provide a sustained improvement in mucociliary clearance, while reducing renal exposure to ENaC blockade. Transient increases in mean urine sodium/potassium ratios appeared to be the first signal of electrolyte imbalances resulting from drug-induced block of ENaC in the kidney. The results of this study strongly suggest that clinical trials of novel ENaC blockers will require intensive measurement of plasma and urine electrolyte levels.
MeSH term(s)	Acute Disease ; Administration, Inhalation ; Adult ; Australia ; Biomarkers/blood ; Biomarkers/urine ; Double-Blind Method ; Drug Administration Schedule ; Epithelial Sodium Channel Blockers/administration & dosage ; Epithelial Sodium Channel Blockers/adverse effects ; Epithelial Sodium Channel Blockers/pharmacokinetics ; Female ; Healthy Volunteers ; Humans ; Hyperkalemia/blood ; Hyperkalemia/chemically induced ; Hyperkalemia/diagnosis ; Hyperkalemia/urine ; Male ; Potassium/blood ; Potassium/urine ; Risk Assessment ; Young Adult
Chemical Substances	Biomarkers ; Epithelial Sodium Channel Blockers ; Potassium (RWP5GA015D)
Language	English
Publishing date	2014-06
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2417924-3
ISSN	1941-2703 ; 1941-2711
ISSN (online)	1941-2703
ISSN	1941-2711
DOI	10.1089/jamp.2013.1037
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Article ; Online: The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo.

Tye-Din, Jason A / Anderson, Robert P / Ffrench, Rosemary A / Brown, Gregor J / Hodsman, Peter / Siegel, Matthew / Botwick, Wendy / Shreeniwas, Revati

Clinical immunology (Orlando, Fla.)

2010 Volume 134, Issue 3, Page(s) 289–295

Abstract: Effective treatment of celiac disease is an unmet medical need. A glutenase that destroys immunogenic gluten peptides may be clinically valuable. Twenty patients with celiac disease were randomly assigned to ingest a large gluten meal (16 g daily for 3 ... ...

Abstract	Effective treatment of celiac disease is an unmet medical need. A glutenase that destroys immunogenic gluten peptides may be clinically valuable. Twenty patients with celiac disease were randomly assigned to ingest a large gluten meal (16 g daily for 3 days) pre-treated with ALV003, a mixture of highly specific glutenases (n=10), or pre-treated with placebo (n=10). Peripheral blood T-cell IFN-gamma ELISpot responses to gliadin and an immunogenic 33mer and symptoms were assessed. While baseline IFN-gamma ELISpot responses to gliadin and the 33mer were negative in all patients, a significant ELISpot response to gliadin or the 33mer was observed in 6 of 10 patients consuming placebo-treated gluten and 0 of 10 consuming ALV003 pre-treated gluten (p=0.011). Symptoms typically associated with gluten ingestion occurred in both groups and were not significantly reduced by ALV003 pre-treatment. ALV003 pre-treatment can abolish immune responses induced by gluten in patients with celiac disease.
MeSH term(s)	Adult ; Aged ; Celiac Disease/immunology ; Celiac Disease/metabolism ; Double-Blind Method ; Endopeptidases/administration & dosage ; Endopeptidases/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Gliadin/immunology ; Glutens/immunology ; Glutens/metabolism ; Humans ; Interferon-gamma/blood ; Male ; Middle Aged ; Young Adult
Chemical Substances	Glutens (8002-80-0) ; Interferon-gamma (82115-62-6) ; Gliadin (9007-90-3) ; Endopeptidases (EC 3.4.-)
Language	English
Publishing date	2010-03
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2009.11.001
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Zs.A 880: Show issues

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Article ; Online: SPL7013 Gel (VivaGel®) retains potent HIV-1 and HSV-2 inhibitory activity following vaginal administration in humans.

Price, Clare F / Tyssen, David / Sonza, Secondo / Davie, Ashley / Evans, Sonya / Lewis, Gareth R / Xia, Shirley / Spelman, Tim / Hodsman, Peter / Moench, Thomas R / Humberstone, Andrew / Paull, Jeremy R A / Tachedjian, Gilda

PloS one

2011 Volume 6, Issue 9, Page(s) e24095

Abstract: Unlabelled: SPL7013 Gel (VivaGel(®)) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. ... ...

Abstract	Unlabelled: SPL7013 Gel (VivaGel(®)) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants received 5 single doses of product with ≥5 days between doses. A cervicovaginal fluid (CVF) sample was collected using a SoftCup™ pre-dose, and immediately, or 1, 3, 12 or 24 h post-dose. HIV-1 and HSV-2 antiviral activities of CVF samples were determined in cell culture assays. Antiviral activity in the presence of seminal plasma was also tested. Mass and concentration of SPL7013 in CVF samples was determined. Safety was assessed by reporting of adverse events. Statistical analysis was performed using the Wilcoxon signed-rank test with Bonferroni adjustment; p≤0.003 was significant. Eleven participants completed the study. Inhibition of HIV-1 and HSV-2 by pre-dose CVF samples was negligible. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). At 24 h, >90% of initial HIV-1 and HSV-2 inhibition was maintained in 6/11 women. SPL7013 was recovered in CVF samples obtained at baseline (46% of 105 mg dose). At 3 and 24 h, 22 mg and 4 mg SPL7013, respectively, were recovered. More than 70% inhibition of HIV-1 and HSV-2 was observed if there was >0.5 mg SPL7013 in CVF samples. High levels of antiviral activity were retained in the presence of seminal plasma. VivaGel was well tolerated with no signs or symptoms of vaginal, vulvar or cervical irritation reported. Potent antiviral activity was observed against HIV-1 and HSV-2 immediately following vaginal administration of VivaGel, with activity maintained for at least 3 h post-dose. The data provide evidence of antiviral activity in a clinical setting, and suggest VivaGel could be administered up to 3 h before coitus. Trial registration: The study is registered at ClinicalTrials.gov under identifier: NCT00740584.
MeSH term(s)	Administration, Intravaginal ; Adult ; Anti-Infective Agents/pharmacology ; Antiviral Agents/pharmacology ; Cross-Over Studies ; Dendrimers/chemistry ; Female ; Gels/chemistry ; Herpesvirus 1, Human/metabolism ; Herpesvirus 2, Human/metabolism ; Humans ; Placebos ; Polylysine/chemistry ; Time Factors ; Vagina/pathology
Chemical Substances	Anti-Infective Agents ; Antiviral Agents ; Dendrimers ; Gels ; Placebos ; Polylysine (25104-18-1) ; astodrimer (F8H3J9KSY9)
Language	English
Publishing date	2011-09-15
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0024095
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Article ; Online: SPL7013 Gel (VivaGel®) retains potent HIV-1 and HSV-2 inhibitory activity following vaginal administration in humans.

Clare F Price / David Tyssen / Secondo Sonza / Ashley Davie / Sonya Evans / Gareth R Lewis / Shirley Xia / Tim Spelman / Peter Hodsman / Thomas R Moench / Andrew Humberstone / Jeremy R A Paull / Gilda Tachedjian

PLoS ONE, Vol 6, Iss 9, p e

2011 Volume 24095

Abstract: Unlabelled SPL7013 Gel (VivaGel(®)) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants ...

Abstract	Unlabelled SPL7013 Gel (VivaGel(®)) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants received 5 single doses of product with ≥5 days between doses. A cervicovaginal fluid (CVF) sample was collected using a SoftCup™ pre-dose, and immediately, or 1, 3, 12 or 24 h post-dose. HIV-1 and HSV-2 antiviral activities of CVF samples were determined in cell culture assays. Antiviral activity in the presence of seminal plasma was also tested. Mass and concentration of SPL7013 in CVF samples was determined. Safety was assessed by reporting of adverse events. Statistical analysis was performed using the Wilcoxon signed-rank test with Bonferroni adjustment; p≤0.003 was significant. Eleven participants completed the study. Inhibition of HIV-1 and HSV-2 by pre-dose CVF samples was negligible. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). At 24 h, >90% of initial HIV-1 and HSV-2 inhibition was maintained in 6/11 women. SPL7013 was recovered in CVF samples obtained at baseline (46% of 105 mg dose). At 3 and 24 h, 22 mg and 4 mg SPL7013, respectively, were recovered. More than 70% inhibition of HIV-1 and HSV-2 was observed if there was >0.5 mg SPL7013 in CVF samples. High levels of antiviral activity were retained in the presence of seminal plasma. VivaGel was well tolerated with no signs or symptoms of vaginal, vulvar or cervical irritation reported. Potent antiviral activity was observed against HIV-1 and HSV-2 immediately following vaginal administration of VivaGel, with activity maintained for at least 3 h post-dose. The data provide evidence of antiviral activity in a clinical setting, and suggest VivaGel could be administered up to 3 h before ...
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: Re-exposure to mismatched HLA class I is a significant risk factor for graft loss: multivariable analysis of 259 kidney retransplants.

House, Andrew A / Chang, Peter C W / Luke, Patrick P / Leckie, Stephen H / Howson, William T / Ball, Edward J / Tan, Ann K L / Rehman, Faisal / Muirhead, Norman / Hollomby, David J / McAlister, Vivian C / Hodsman, Anthony B / Jevnikar, Anthony M

Transplantation

2007 Volume 84, Issue 6, Page(s) 722–728

Abstract: Background: Kidney retransplants carry increased immunologic risk. One possible contributor to this risk may be re-exposure to human leukocyte antigens (HLA) common to a previous donor but foreign to the recipient. Conflicting publications have assessed ...

Abstract	Background: Kidney retransplants carry increased immunologic risk. One possible contributor to this risk may be re-exposure to human leukocyte antigens (HLA) common to a previous donor but foreign to the recipient. Conflicting publications have assessed this risk, so to examine our experience 259 kidney retransplants were analyzed. Methods: A retrospective cohort of retransplant patients from 1973 to 2005 with minimum 12 months follow up was examined. Using multivariable modeling, important confounders were controlled for identifying factors significantly affecting graft survival. Results: Re-exposure to HLA class I (HLA-A or B) antigens, peak panel reactive antibodies and donor source were the most important determinants of allograft survival, despite a negative conventional or anti-human globulin-augmented T cell crossmatch. We failed to demonstrate that recipient re-exposure to HLA class II (HLA-DR) or positive B cell crossmatch were associated with adverse outcomes. Sample size and molecular versus serologic methods may have influenced the former, while inability to determine antibody specificities may have influenced the latter. Controlling for other variables, the adjusted risk of graft loss associated with re-exposure to HLA class I increased by 71% (P=0.006) and occurred early, consistent with recall of memory cytotoxic T lymphocyte or antibody responses. Conclusions: Kidney recipients re-exposed to mismatched HLA class I antigens appear to be at heightened risk of early graft loss. Such patients may benefit from pretransplant identification of donor specific antibodies using solid phase methods and heightened vigilance for acute rejection. Future studies may indicate whether more intensive immunosuppression for these patients is warranted.
MeSH term(s)	Female ; Graft Rejection/epidemiology ; Graft Survival/immunology ; HLA-A Antigens/immunology ; HLA-B Antigens/immunology ; Histocompatibility ; Histocompatibility Antigens Class I/immunology ; Humans ; Kidney Transplantation/immunology ; Male ; Reoperation ; Risk
Chemical Substances	HLA-A Antigens ; HLA-B Antigens ; Histocompatibility Antigens Class I
Language	English
Publishing date	2007-09-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/01.tp.0000281398.41670.1f
Database	MEDical Literature Analysis and Retrieval System OnLINE

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