Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants.

Background: JNJ-4964 is a TLR7 agonist, which, via a type I interferon (IFN)-dependent mechanism, may enhance host immunity suppressed by persistent exposure to hepatitis B antigens in chronic hepatitis B.

Methods: PK and PD data were pooled from 2 studies involving 90 participants ( = 74 JNJ-4964, dose range 0.2-1.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults.

Background: This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults.

Methods: In the SAD phase, participants received JNJ-4964 0.2 ( = 6), 0.

Electrocardiographic and cardiovascular diagnostic characteristics of patients receiving long-term opioid therapy for pain.

Objective: To examine cardiovascular and electrocardiogram (ECG) abnormalities seen in patients with chronic pain receiving long-term opioid therapy and to compare them with findings in normal subjects.

Setting: Clinical pharmaceutical drug trial in a phase I pharmacology unit (normal subjects) and multiple phase 2b study sites (pain patients).

Patients: Four hundred sixty-one pain patients with constipation due to long-term opioid therapy who were screened for a clinical trial of an investigational treatment for opioid-induced constipation.

Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease.

Background: Interleukin-11 has shown benefit in animal inflammatory bowel disease models. Recently, recombinant human interleukin-11 (rhIL-11) has been observed to induce remission in a subset of patients with mild to moderate Crohn's disease (CD). The present study compared the efficacy of rhIL-11 versus prednisolone in remission induction in CD.

Molecular classification of Crohn's disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells.

Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, approximately 10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases.

A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects.

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects.

Anti-interleukin-12 antibody for active Crohn's disease.

Background: Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses.

Methods: This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn's disease.

A multiple-dose, safety, tolerability, pharmacokinetics and pharmacodynamic study of oral recombinant human interleukin-11 (oprelvekin).

A study in healthy men and women was performed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered recombinant human interleukin-11 (oprelvekin) (OAO). Four cohorts of 10 subjects each received 3, 5, 10 or 30 mg (8:2/OAO:placebo ratio), first as a single dose with a 7-day washout period, then 7 consecutive daily doses. Safety was assessed by ongoing evaluation of adverse events (AEs) and laboratory values.

K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis.

Background: K16, a type I keratin, is upregulated in hyperproliferative states including psoriasis. It has been used as a marker of psoriasis and its expression is upregulated in relapsing psoriasis and downregulating in resolving. We evaluated non-lesional psoriatic skin for K16 expression.

The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

A study in healthy male volunteers was completed to evaluate the safety, tolerability, and pharmacokinetics of a single oral dose of the antiparasitic moxidectin (MOX). This drug is registered worldwide as a veterinary antiparasitic agent for use in companion and farm animals. This is the first study of MOX in humans.

Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling.

Psoriasis is recognized as the most common T cell-mediated inflammatory disease in humans. Genetic linkage to as many as six distinct disease loci has been established but the molecular etiology and genetics remain unknown. To begin to identify psoriasis disease-related genes and construct in vivo pathways of the inflammatory process, a genome-wide expression screen of multiple psoriasis patients was undertaken.

Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease.

Background: Interleukin-11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin-11 (rhIL-11) in patients with Crohn's disease.

Aim: To determine the safety and preliminary estimate of efficacy of rhIL-11 in treating active Crohn's disease.

Multiple-dose, safety, pharmacokinetics, and pharmacodynamics of a new selective estrogen receptor modulator, ERA-923, in healthy postmenopausal women.

ERA-923 is a new selective estrogen receptor modulator under clinical investigation for use in tamoxifen refractory metastatic breast cancer. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of once-daily oral ERA-923 (10-200 mg) for 28 days in healthy postmenopausal females. ERA-923 was well tolerated, and adverse events were mild and reversible.

Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis.

Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed.

Preclinical pharmacologic basis for clinical use of rhIL-11 as an effective platelet-support agent.

Preclinical studies have shown that rhIL-11, also known as oprelvekin (Neumega), stimulates early and later stages of megakaryocytopoiesis (including proliferation and differentiation of megakaryocyte precursors and maturation of megakaryocytes), to produce an increase in peripheral platelet count. Because of these effects, rhIL-11 must be administered to patients with cancer sufficiently in advance of the platelet nadir (within 6 to 24 hours postchemotherapy) to allow adequate time for megakaryocyte maturation and platelet formation. Therefore, the maximum platelet response coincides with the time when the platelet nadir would normally be experienced.

Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthy subjects.

Recombinant human interleukin-11 (rhIL-11), or Neumega rhIL-11 Growth Factor, is a recombinant cytokine that stimulates megakaryocytopoiesis, increases platelet production, and also has shown anti-inflammatory and immune-modulating activity. Mild, reversible anemia was the most common adverse event observed in clinical studies and was demonstrated to be related to hemodilution. The purpose of this study was to examine the renal mechanisms of the rhIL-11-induced volume retention and devise a possible therapeutic intervention to ameliorate this effect.

Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions.

Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia results from skin infiltration by type I T lymphocytes and release of associated cytokines. A multifunctional cytokine, rhIL-11, modulates macrophage and type I T-lymphocyte function in cell culture and shows anti-inflammatory activity in animal models. We are testing subcutaneous delivery of rhIL-11 to patients with psoriasis in a phase 1 open-label dose-escalation clinical trial.

Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants.

Purpose: To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy.

Patients And Methods: Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea.

Hematopoietic, immunomodulatory and epithelial effects of interleukin-11.

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.

Background & Aims: Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity.

Methods: A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed.

Mitigating effects of interleukin 11 on consecutive courses of 5-fluorouracil-induced ulcerative mucositis in hamsters.

Ulcerative mucositis is a painful, debilitating and dose-limiting toxicity of cancer chemotherapy. Current treatment is largely palliative and no adequate preventive treatment exists. Recently, we reported that recombinant human(rh) interleukin 11 (IL-11) favourably modified the course of mucositis following a single stomatotoxic regimen of 5-fluorouracil in hamsters.

The renin angiotensin aldosterone system and frusemide response in congestive heart failure.

1. To test the hypothesis that basal renin angiotensin aldosterone system (RAAS) activity impairs the acute natriuretic response to frusemide in patients with mild or moderate congestive heart failure (CHF), we studied eight adult volunteers with preserved renal function, stable New York Heart Association Class II or III CHF, and echocardiographic evidence of left ventricular dysfunction due to myocardial infarction, hypertension, or both causes. 2.

Effect of tibenelast (a phosphodiesterase inhibitor) and theophylline on isoproterenol-stimulated heart rate, cyclic AMP and norepinephrine levels.

The effect of the phosphodiesterase inhibitors (tibenelast, theophylline) and placebo on isoproterenol-induced changes in heart rate, cAMP and norepinephrine levels in normal male volunteers was studied. Heart rates in response to isoproterenol dosing were fitted by linear regression, and horizontal shifts in the regression lines were examined between the three treatments. The shift of the regression line after placebo compared to the preplacebo line was to the right by 2.

Nonimmunological alterations of glomerular filtration by s-PAF in the rat kidney.

Rat kidneys were isolated and perfused with a cell-free perfusion buffer containing 4% albumin. Infusion of platelet activating factor (s-PAF) into the isolated perfused kidney caused a dose-dependent fall in renal vascular resistance (RVR): 12 +/- 6% at 10 nM s-PAF, 18 +/- 3% at 100 nM s-PAF and 20 +/- 7% at 1 microM s-PAF. Glomerular filtration rate fell by 32 +/- 5% at 10 nM, 38 +/- 6% at 100 nM, and 52 +/- 10% at 1 microM.