Human urotensin II in the plasma of anephric subjects.
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Humans↗
Biomedical subjects
Theodore M Danoff
Publications and source records attributed to Theodore M Danoff.
Pharmacokinetic properties of a new controlled-release formulation of carvedilol.
This review summarizes the pharmacokinetics (PK) of carvedilol after administration of a new once-daily controlled-release (CR) formulation. The plasma concentration-time profiles for both R(+)- and S(-)-carvedilol indicate that carvedilol CR will provide coverage over a 24-hour period similar to the current immediate-release (IR) twice-daily formulation. Exposures for both enantiomers, based on area under the curve (AUC), maximum plasma concentrations (C(max)), and trough concentrations, are equivalent for carvedilol CR compared with carvedilol IR. C(max) and AUC of the enantiomers of carvedilol increase in an approximate dose-proportional manner after administration of carvedilol CR over the dose range of 10-80 mg, indicating that the formulation provides consistent PK performance across the dose strengths proposed for marketing. The intrasubject and intersubject variability of carvedilol CR was comparable to carvedilol IR. For carvedilol CR, mean AUC and C(max) were increased <20% after a high-fat meal compared with a standard meal. The CR and IR formulations of carvedilol exhibited equivalent steady-state PK characteristics in the target hypertension and heart failure populations. The availability of once-daily dosing is expected to improve treatment adherence and thereby enhance the effectiveness of carvedilol in routine clinical use.
Administration, Oral↗
Pharmacokinetic and pharmacodynamic comparison of controlled-release carvedilol and immediate-release carvedilol at steady state in patients with hypertension.
Carvedilol is indicated for the treatment of essential hypertension and mild-to-severe chronic heart failure, as well as the reduction of cardiovascular mortality in clinically stable post-myocardial infarction patients with left ventricular dysfunction. Carvedilol is a racemic mixture of R(+) and S(-) enantiomers that combines beta(1)-, beta(2)-, and alpha(1)-adrenoceptor blockade. For all indications, the immediate-release (IR) formulation of carvedilol is taken twice daily. A controlled-release (CR) formulation of carvedilol that allows once-daily dosing has recently been developed. In this double-blind, parallel-group, crossover study, 122 patients with essential hypertension were randomly allocated to receive low and high doses of carvedilol or placebo. Patients received either a constant low dose (CR 20 mg once daily or IR 6.25 mg twice daily) or were titrated to a high dose (CR 80 mg once daily or IR 25 mg twice daily) before being crossed over to an equivalent dose of the alternative formulation. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles were compared between patients receiving carvedilol CR and carvedilol IR. The PK profiles for R(+)- and S(-)-carvedilol for the 2 formulations were equivalent (based on area under the curve, maximum plasma concentration [C(max)], and trough drug concentration). Consistent with an extended-release formulation, carvedilol CR delayed C(max) by 3.5 hours compared with carvedilol IR. For both carvedilol CR and IR, the attenuation of exercise-induced heart rate in patients with hypertension was maintained over the entire 24-hour period, and the 2 formulations demonstrated equivalent beta(1)-blocking effects at trough (end of the dosing interval [PD(min)]), suggesting that the rate of absorption does not interfere with the PD effect. In this first direct comparison of carvedilol CR and IR in subjects with hypertension, fewer adverse events were reported while subjects were receiving carvedilol CR (59.1% overall) compared with carvedilol IR (77.5% overall). This was true regardless of dose received. Headache was the most commonly reported adverse event for subjects receiving either formulation of carvedilol and placebo. Importantly, dizziness and headache were reported less often when subjects received carvedilol CR. This is the first study to show that both formulations had comparable beta(1)-adrenergic blockade in patients with essential hypertension under steady-state conditions. Notably, carvedilol CR provides consistent beta(1)-adrenergic blockade over 24 hours with a once-daily dose.
Administration, Oral↗
Multiple dose pharmacokinetics of paroxetine in children and adolescents with major depressive disorder or obsessive-compulsive disorder.
The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive-compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for C(max) and AUC(0-24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (p<0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.
Adolescent↗
CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection.
Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.
Animals↗
Impaired T cell function in RANTES-deficient mice.
The chemokine RANTES is a chemoattractant for monocytes and T cells and is postulated to participate in many aspects of the immune response. To evaluate the biological roles of RANTES in vivo, we generated RANTES-deficient (-/-) mice and characterized their T cell function. In cutaneous delayed-type hypersensitivity assays, a 50% reduction in ear and footpad swelling was seen in -/- mice compared to +/+ mice. In vitro, polyclonal and antigen-specific T cell proliferation was decreased. Quantitative analysis using the fluorescent dye carboxy-fluorescein succinimidyl ester revealed that this proliferative defect was due both to fewer antigen-reactive T cells and to a reduction in the capacity of these cells to proliferate. In addition, IFN-gamma and IL-2 production by the -/- T cells was dramatically decreased. Together, these data suggest that RANTES is required for normal T cell functions as well as for recruiting monocytes and T cells to sites of inflammation.
Animals↗
Role of RANTES in the development of autoimmune tissue injuries in MRL-Fas lpr mice.
MRL-Fas lpr mice spontaneously develop a severe autoimmune disease closely resembling human SLE. To investigate the possible role of RANTES in autoimmune tissue injuries, we have constructed RANTES-deficient MRL-Fas lpr mice by gene targeting. In the RANTES-deficient mice, axillary lymph nodes were significantly reduced in size compared with those of RANTES-intact mice. Flow cytometric analysis revealed that double-negative (DN) T cells were significantly reduced. Image analyzer showed that cell-infiltrated areas in peribronchial lesions were decreased in the lung of RANTES-deficient MRL-Fas lpr mice. Furthermore, we detected continuous expression of RANTES mRNA in the lung of MRL-Fas lpr mice. In contrast, the degree of histological renal injuries and survival rate was similar in both genotypes. We speculate that RANTES is involved in the development of peribronchial pulmonary lesions in MRL-Fas lpr mice. Further studies using RANTES-deficient mice might contribute to the elucidation of the role of RANTES in autoimmune tissue injuries.
Animals↗
Evidence that fibroblasts derive from epithelium during tissue fibrosis.
Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
Animals↗
Pharmacogenetics to predict drug-related adverse events.
Identification of reliable markers to predict drug-related adverse events (DRAEs) is an important goal of the pharmaceutical industry and others within the healthcare community. We have used genetic polymorphisms, including the most frequent source of variation (single nucleotide polymorphisms, SNPs) in the human genome, in pharmacogenetic approaches designed to predict DRAEs. Three studies exemplify the principles of using polymorphisms to identify associations in progressively larger genomic regions: polymorphic repeats within the UDP-glucuronysltransferase I (UGT1A1) gene in patients experiencing hyperbilirubinemia after administration of tranilast, an experimental drug to prevent re-stenosis following coronary revascularization; high linkage disequilibrium within the Apolipoprotein E (ApoE) gene in patients with Alzheimer Disease (AD); and the polymorphic variant HLA-B57 in patients with hypersensitivity reaction after administration of abacavir, a nucleoside reverse transcriptase inhibitor for the treatment of HIV. Together, these studies demonstrate in a stepwise manner the feasibility of using pharmacogenetic approaches to predict DRAEs.
Alzheimer Disease↗