The drug titration paradox: more drug does not correlate with more effect in individual clinical data.

BACKGROUND A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip' the observed correlation, such that increasing dose increases drug effect. METHODS We tested whether a mixed-effects analysis could correctly reveal the underlying pharmacology using previously published data obtained during automatic feedback control of mean arterial pressure (MAP) with alfentanil (effect site concentration, CeAlf) during surgery. The relationship between MAP and CeAlf was explored with linear regression and a linear mixed-effects model. RESULTS A linear mixed-effects model did not identify the correct underlying pharmacology because of the presence of the titration paradox in the individual data. CONCLUSIONS The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect

Optimization Methods to Minimize Emergence Time While Maintaining Adequate Post-Operative Analgesia

A rapid emergence from anesthesia combined with an extended duration of adequate analgesia is desired. Difficulties arise when trying to achieve a rapid emergence and provide adequate analgesia for procedures associated with moderate post operative pain. We propose to use pharmacokinetic (PK) and pharmacodynamic (PD) models with optimization techniques to determine anesthetic drugs ratios to improve post-anesthetic outcomes of emergence and analgesia. We hypothesize that optimized propofol, remifentanil, and fentanyl administrations will shorten emergence time and extend the period of adequate analgesia during patient recovery. Anesthesiologists administered a general anesthetic to 21 patients for laparoscopic procedures with propofol, remifentanil, and fentanyl according to their standard practice. The theoretical improvement provided by the optimization was measured by comparing the time differences between the control predictions and the optimized prediction of the TROR time and TRON time. In the control group the TROR was 10.2+-5.8 minutes (mean +- SD) and TRON was 3.5+-5.0 minutes after emergence. In the optimized group the TROR was 7.5+-2.2 minutes or 26% faster (p \u3c .001, paired t-test) and the TRON was 7.4 +-2.4 minutes or 88% longer (p \u3c .00001, t-test). Optimized administrations of propofol, remifentanil, and fentanyl resulted in a theoretically shorter emergence time and a longer period of adequate postoperative analgesia. The optimization algorithm shows potential for real-time clinical guidance in drug management

Boson stars in massive dilatonic gravity

We study equilibrium configurations of boson stars in the framework of a class scalar-tensor theories of gravity with massive gravitational scalar (dilaton). In particular we investigate the influence of the mass of the dilaton on the boson star structure. We find that the masses of the boson stars in presence of dilaton are close to those in general relativity and they are sensitive to the ratio of the boson mass to the dilaton mass within a typical few percent. It turns out also that the boson star structure is mainly sensitive to the mass term of the dilaton potential rather to the exact form of the potential.Comment: 9 pages, latex, 9 figures, one figure dropped, new comments added, new references added, typos correcte

Structural and Functional Analysis of the Human Nuclear Xenobiotic Receptor PXR in Complex with RXRα

The human nuclear xenobiotic receptor PXR recognizes a range of potentially harmful drugs and endobiotic chemicals, but must complex with the nuclear receptor RXRα to control the expression of numerous drug metabolism genes. To date, the structural basis and functional consequences of this interaction have remained unclear. Here we present 2.8 Å resolution crystal structures of the heterodimeric complex formed between the ligand binding domains (LBDs) of human PXR and RXRα. These structures establish that PXR and RXRα form a heterotetramer unprecedented in the nuclear receptor family of ligand-regulated transcription factors. We further show that both PXR and RXRα bind to the transcriptional coregulator SRC-1 with higher affinity when they are part of the PXR-RXRα heterotetramer complex than they do when each LBD is examined alone. Furthermore, we purify the full-length forms of each receptor from recombinant bacterial expression systems, and characterize their interactions with a range of direct and everted repeat DNA elements. Taken together, these data advance our understanding of PXR, the master regulator of drug metabolism gene expression in humans, in its functional partnership with RXRα

Effect of Carbonate Chemistry Alteration on the Early Embryonic Development of the Pacific Oyster (Crassostrea gigas)

Ocean acidification, due to anthropogenic CO2 absorption by the ocean, may have profound impacts on marine biota. Calcareous organisms are expected to be particularly sensitive due to the decreasing availability of carbonate ions driven by decreasing pH levels. Recently, some studies focused on the early life stages of mollusks that are supposedly more sensitive to environmental disturbances than adult stages. Although these studies have shown decreased growth rates and increased proportions of abnormal development under low pH conditions, they did not allow attribution to pH induced changes in physiology or changes due to a decrease in aragonite saturation state. This study aims to assess the impact of several carbonate-system perturbations on the growth of Pacific oyster (Crassostrea gigas) larvae during the first 3 days of development (until shelled D-veliger larvae). Seawater with five different chemistries was obtained by separately manipulating pH, total alkalinity and aragonite saturation state (calcium addition). Results showed that the developmental success and growth rates were not directly affected by changes in pH or aragonite saturation state but were highly correlated with the availability of carbonate ions. In contrast to previous studies, both developmental success into viable D-shaped larvae and growth rates were not significantly altered as long as carbonate ion concentrations were above aragonite saturation levels, but they strongly decreased below saturation levels. These results suggest that the mechanisms used by these organisms to regulate calcification rates are not efficient enough to compensate for the low availability of carbonate ions under corrosive conditions

HLA-A2–Matched Peripheral Blood Mononuclear Cells From Type 1 Diabetic Patients, but Not Nondiabetic Donors, Transfer Insulitis to NOD-scid/γcnull/HLA-A2 Transgenic Mice Concurrent With the Expansion of Islet-Specific CD8+ T cells

OBJECTIVE: Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing beta-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS: We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/gammac(null)/HLA-A*0201 (NOD-scid/gammac(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/gammac(null)/A2 mice after transfer. RESULTS: Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/gammac(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/gammac(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS: We show that insulitis is transferred to NOD-scid/gammac(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-gamma after in vitro peptide stimulation. This indicates that NOD-scid/gammac(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes

Effects of Elevated Temperature and Carbon Dioxide on the Growth and Survival of Larvae and Juveniles of Three Species of Northwest Atlantic Bivalves

Rising CO2 concentrations and water temperatures this century are likely to have transformative effects on many coastal marine organisms. Here, we compared the responses of two life history stages (larval, juvenile) of three species of calcifying bivalves (Mercenaria mercenaria, Crassostrea virginica, and Argopecten irradians) to temperatures (24 and 28°C) and CO2 concentrations (∼250, 390, and 750 ppm) representative of past, present, and future summer conditions in temperate estuaries. Results demonstrated that increases in temperature and CO2 each significantly depressed survival, development, growth, and lipid synthesis of M. mercenaria and A. irradians larvae and that the effects were additive. Juvenile M. mercenaria and A. irradians were negatively impacted by higher temperatures while C. virginica juveniles were not. C. virginica and A. irradians juveniles were negatively affected by higher CO2 concentrations, while M. mercenaria was not. Larvae were substantially more vulnerable to elevated CO2 than juvenile stages. These findings suggest that current and future increases in temperature and CO2 are likely to have negative consequences for coastal bivalve populations