Time Course Of Onset Research Articles

Persistence of Contact Lens-Induced Corneal Parainflammation Following Lens Removal.

Contact lens wear induces corneal parainflammation involving increased immune cell numbers after 24hours' (CD11c+, Lyz2+, γδ-T cells) and six days' (Ly6G+ cells) wear. We investigated the time course of onset and resolution of these responses. LysMcre or C57BL/6J mice were fitted with a contact lens (four to 48hours). Contralateral eyes did not wear lenses. After lens removal, Lyz2+, MHC-II+ or Ly6G+ cells were examined by quantitative imaging. RT-qPCR determined cytokine gene expression. Lens wear for 24hours increased corneal Lyz2+ cells versus contralateral eyes approximately two-fold. Corneas remained free of visible pathology. The Lyz2+ response was not observed after four or 12 hours' wear, nor after 12 hours' wear plus 12 hours' no wear. Lens removal after 24hours' wear further increased Lyz2+ cells (∼48% after one day), which persisted for four days, returning to baseline by seven days. Lyz2+ cells in contralateral eyes remained at baseline. MHC-II+ cells showed a similar response but without increasing after lens removal. Lens wear for 48 hours showed reduced Lyz2+ cells versus 24hours' wear with one day discontinuation, correlating with reduced IL-1β and IL-18 gene expression. Lens wear for 24hours did not induce Ly6G+ responses six days after removal. Lens-induced corneal parainflammation involving Lyz2+ cells requires 24hours' wear but persists after lens discontinuation, requiring seven days for reversal. Lens wear for 48 hours may suppress initial Lyz2+ cell and cytokine responses. The significance of parainflammation during and after lens wear remains to be determined.

Incidence and Time Course of Symptomatic Thromboembolic Outcomes After Lower Extremity Arthroscopic Surgery, Ankle Fracture Surgery, and Achilles Tendon Repair.

The incidence and time course of acute venous thromboembolism (VTE) after ambulatory surgery for lower extremity orthopaedic conditions is not well-defined. The purpose of this study was to analyze the incidence, the time course, and risk factors associated with clinically diagnosed acute deep vein thrombosis or pulmonary embolism within 3 months of surgery in patients undergoing specific operations for lower extremity injuries. Patients undergoing arthroscopic procedures of the knee, ankle fracture surgery, Achilles tendon repair, and ankle arthroscopy from January 1, 2005, to December 31, 2010, were identified in the California Ambulatory Surgery database with linkage to hospital discharge data, emergency department data, and a death registry. Outcomes were acute VTE and death within 90 days. Time courses were compared using Kaplan-Meier analysis, and risk factors were analyzed using proportional hazard modeling. Analysis of data from 468,699 surgeries showed that the cumulative incidence of acute VTE was significantly higher after Achilles tendon repair (0.72%, P < 0.001) than ankle fracture surgery (0.33%), knee arthroscopy procedures (range, 0.29% to 0.41%), or ankle arthroscopy (0.24%). The time course of diagnosis of VTE was similar for all arthroscopic procedures (median postoperative day for diagnosis = 9 to 10; 80% by 22 to 36 days), whereas for Achilles tendon surgery, the time course was protracted (median postoperative day for diagnosis = 29 days; 80% by 51 days). Ninety-day mortality was low (<0.06%) after all procedures except ankle fracture (0.12%). Predictors of pulmonary embolism included age older than 60 years (HR, 3.1; 95% CI; 2.0 to 4.8, versus younger than 30 years), Achilles tendon repair (HR, 3.8; 95% CI; 2.8 to 5.3), and ankle fracture surgery (Hazard Ratio [HR], 2.1; 95% Confidence Interval [CI]; 1.5 to 2.8); Asian/Pacific Islander (HR, 0.3; 95% CI; 0.1 to 0.6) and Hispanic patients (HR, 0.5; 95% CI; 0.4 to 0.7) had significantly lower risk. The incidence and time course of onset of acute VTE after lower extremity orthopaedic surgeries varies significantly depending on the surgical procedure. These findings have implications regarding the use and duration of pharmacologic thromboprophylaxis.

Remifentanil pharmacodynamics during conscious sedation using algometry: a more clinically relevant pharmacodynamical model

BackgroundThe Minto remifentanil pharmacokinetic/pharmacodynamic (PK/PD) model is used in target-controlled infusion (TCI) devices. The endpoint used to calculate the PD parameters, including the ke0, was the electroencephalogram (EEG), which only changes at high remifentanil concentrations. As the ke0 should adequately predict the time course of drug effects at clinically relevant concentrations, we evaluated the temporal agreement between effect-site concentrations estimated with the Minto model and pressure pain thresholds during conscious sedation. MethodsWe enrolled 100 patients scheduled for gynaecological surgery. The first group (35 subjects) received an effect site targeted remifentanil infusion (target 1.5 ng ml−1); the second group (35 subjects) received the same infusion and a 1 mg bolus of midazolam to evaluate anxiolytic effects; the control group (30 subjects) received a saline infusion. Algometry and vital signs were measured at different time points. ResultsThe Minto model predicted stable effect-site concentrations within 1.5 min of starting the infusion. Haemodynamic variables stabilised within 5 min, whereas there was a significant increase in pressure pain threshold for up to 15 min in both remifentanil groups. Midazolam had no effect on pressure pain threshold. A PD model based on algometry and Minto PK model was developed. ConclusionsOur results demonstrate the limitation of the Minto PD model at low target remifentanil concentrations, with a discrepancy in the time course between EEG and pressure pain threshold changes. Clinicians should be aware that the time course of onset of analgesic effects is slower than the estimates of the Minto model. Investigators should consider using algometry data in future opioid PD modelling studies.

The Time Course of Onset and Peak Effects of Phenol Neurolysis.

The aim of this study was to explore the time course of onset and peak effects of phenol neurolysis. This is a retrospective chart review. Eleven patients with elbow flexor spasticity after brain injury were enrolled. The resting angle of the elbow joint was measured before and after the injection and up to 6 wks of follow-up. Phenol injection was performed to 13 musculocutaneous nerves under ultrasound and electrical stimulation guidance. The resting elbow angles were 84.4° ± 25.8° (before injection), 116.6° ± 20.9° (immediately after injection), 121.2° ± 21.4° (2 hrs after injection), 127.2° ± 19.7° (24 hrs after injection), 145.4° ± 11.8° (7 days after injection), 145.5° ± 10.4° (14 days after injection), and 150.3° ± 12.2° (6 wks after injection; N = 7). The mean resting angle was statistically different among the time points from preinjection to 14 days after (F2.625, 31.505 = 36.805, P < 0.01). Post hoc tests revealed that significant improvements existed immediately after and 7 days after the injection (P < 0.01 for both). The effects seemed to reach its peak in 7 days. The effect sizes immediately and 7 days after the injection were 1.37 and 3.04, respectively. The immediate effect accounted for approximately 60% of the maximal effect. Phenol neurolysis has an immediate effect on spasticity reduction and reaches its peak effect around 1 wk after injection.

Mapping a Reliable Stroke Onset Time Course Using Signal Intensity on DWI Scans.

Identifying a last known well (LKW) time surrogate for acute stroke is vital to increase stroke treatment. Diffusion-weighted imaging (DWI) signal intensity initially increases from onset of stroke but mapping a reliable time course to the signal intensity has not been demonstrated. We retrospectively reviewed stroke code patients between 1/2016 and 6/2017 from the prospective; Institutional review board (IRB) approved University of California San Diego Stroke Registry. Patients who had magnetic resonance imaging of brain from onset, with or without intervention, are included. All ischemic strokes were confirmed and timing from onset to imaging was calculated. Raw DWI intensity is measured using IMPAX software and compared to contralateral side for control for a relative DWI intensity (rDWI). LKW and magnetic resonance imaging (MRI) time were collected by chart review. Correlation is assessed using Pearson correlation coefficient between DWI intensity, rDWI, and time to MRI imaging. 1.5T, 3T, and combined modalities were examined. Seventy-eight patients were included in this analysis. Overall, there was statistically significant positive correlation (.53, P < .001) between DWI intensity and LKW time irrespective of scanner strength. Using 1.5T analyses, there was good correlation (.46, P < .001). 3T MRI analysis further showed comparatively stronger positive correlation (.66, P < .001). There is good correlation between DWI intensity and minutes from onset to MRI. This suggests a time-dependent DWI intensity response and supports the potential use of DWI intensity measurements to extrapolate an LKW time. Further studies are being pursued to increase both experience and generalizability.

Author response: Rare side effects of alemtuzumab remind us of the need for postmarketing surveillance.

We thank Drs. Whiteside and Trip for their comment on our editorial.1 The authors highlight noninfectious pneumonitis as a rare potential complication of alemtuzumab.2,3 The time course of onset in the 2 reported cases was different, with symptoms developing a few days or 1 month after infusion. Although not proven, this suggestion of immune-mediated mechanisms seem reasonable.2 This reaction may arise from antibody-dependent cell-mediated or complement-mediated cytolysis, which leads to cytokine release and then type III/IV hypersensitivity reaction and lung-resident T-cell activation. As for the side effects highlighted in our editorial,1 clinicians should recognize noninfectious pneumonitis as a potential rare complication of alemtuzumab, as it can respond well to corticosteroids.

Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial

BackgroundFluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action.MethodsA single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation.ResultsIn the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42–212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61–0.86) with the maximum reduction occurring at day 14, 0.32 (0.27–0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59–1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment.ConclusionsThe anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma.Funding GlaxoSmithKline (201499).Trial registrationProspectively registered on ClinicalTrials.gov registry number NCT02712047.

Complications of Radiotherapy and Radiosurgery in the Brain and Spine.

To recognize the main complications of radiation therapy and stereotactic radiosurgery in the brain and spine, and to highlight the imaging findings to improve the diagnostic process and treatment planning.

Time Course of Onset of Phantom Pain in Male and Female Amputees (P5.334)

Time Course of Onset of Phantom Pain in Male and Female Amputees (P5.334)

Mood, Personality, and Behavior Changes During Treatment with Statins: A Case Series.

Psychiatric adverse drug reactions (ADRs) have been reported with statin use, but the literature regarding statin-associated mood/behavioral changes remains limited. We sought to elicit information germane to natural history and characteristics of central nervous system/behavioral changes in apparent connection with statin and/or cholesterol-lowering drug use, and delineate mechanisms that may bear on an association. Participants (and/or proxies) self-referred with behavioral and/or mood changes in apparent association with statins completed a survey eliciting cholesterol-lowering drug history, character and impact of behavioral/mood effect, time-course of onset and recovery in relation to drug use/modification, co-occurrence of recognized statin-associated ADRs, and factors relevant to ADR causality determination. Naranjo presumptive ADR causality criteria were assessed. Participants (n = 12) reported mood/behavior change that commenced following statin initiation and persisted or progressed with continued use. Reported problems included violent ideation, irritability, depression, and suicide. Problems resolved with drug discontinuation and recurred with rechallenge where attempted. Eight met presumptive criteria for “probable” or “definite” causality; others had additional factors not considered in Naranjo criteria that bear on casual likelihood. (1) Simvastatin 80 mg was followed in 5 days by irritability/depression culminating in suicide in a man in his 40s (Naranjo criteria: possible causality). (2) Simvastatin 10 mg was followed within 2 weeks by depression in a woman in her 50s (probable causality). (3) Atorvastatin 20 mg was followed in ~1 month by depression and irritability/aggression in a male in his 50s (probable causality). (4) Atorvastatin 10 mg was followed in several months by aggression/irritability and depression culminating in suicide in a man in his 40s (possible causality). (5) Fenofibrate + rosuvastatin (unknown dose), later combined with atorvastatin were followed in 1 month by aggression/irritability in a male in his 30s (probable causality). (6) Lovastatin (unknown dose and time-course to reaction) was followed by depression, dyscontrol of bipolar disorder, and suicide attempts in a male in his 40s (possible causality). (7) Atorvastatin 20 mg was followed within 2 weeks by cognitive compromise, and nightmares, depression, and anxiety culminating in suicide in a man in his teens (definite causality). (8) Simvastatin 10 mg was followed (time-course not recalled) by depression, aggression/irritability culminating in suicide in a man in his 60s (possible causality). (9) Simvastatin 20 mg then atorvastatin 10 mg were followed (time-course not provided) by irritability/aggression in a man in his 60s (definite causality). (10) Atorvastatin 10 then 20 then 40 mg were followed shortly after the dose increase by violent ideation and anxiety in a man in his 30s (probable causality). (11) Atorvastatin 20 mg and then simvastatin 20 mg were followed in 2 weeks by aggression/irritability in a man in his 50s (definite causality). (12) Lovastatin, rosuvastatin, atorvastatin, and simvastatin at varying doses were followed as quickly as 1 day by aggression, irritability, and violent ideation in a man in his 40s (definite causality). Most had risk factors for statin ADRs, and co-occurrence of other, recognized statin ADRs. ADRs had implications for marriages, careers, and safety of self and others. These observations support the potential for adverse mood and behavioral change in some individuals with statin use, extend the limited literature on such effects, and provide impetus for further investigation into these presumptive ADRs. Potential mechanisms are reviewed, including hypothesized mechanisms related to oxidative stress and bioenergetics.

Time Course for Onset and Recovery from Effects of a Novel Male Reproductive Toxicant: Implications for Apical Preclinical Study Designs.

In the pharmaceutic ICH S5(R2) guidelines for reproductive toxicity testing, a premating dose duration of 14 days is considered sufficient for assessment of male fertility for compounds that are not testicular toxicants. A novel α7 subtype of nicotinic acetylcholine receptor (α7nAChR) agonist, originally intended for treatment of Alzheimer's disease, did not cause changes in sperm counts, motility, or testicular histopathology in rat toxicity studies of up to 6 months duration. However, profound decrements in male fertility (reduced pregnancy rates and litter sizes) occurred after 11 weeks of dosing in male rats. In two time-course investigations, dosed male rats were paired with undosed females after 5, 14, and 28 daily doses and again after 2 and 4 weeks off-dose. Effects on male fertility were undetectable after 5 days. After 14 days, there was no effect on pregnancy rate, but preimplantation losses were increased. Effects on both pregnancy rates and preimplantation losses were clearly detectable after 28 days, but were of lesser magnitude than after 11 weeks of dosing. Fertility recovered rapidly after dose cessation. These studies illustrate the sensitivity of a long premating dose period at revealing hazard and determining the magnitude of effect on male fertility for compounds that are intended for chronic administration and do not affect testicular histopathology.

A technique for characterizing the time course of odor adaptation in mice.

Although numerous studies have analyzed the temporal characteristics underlying olfactory adaptation at the level of the olfactory receptor neuron, to date, there have been no comparable behavioral measures in an animal model. In this study, odor adaptation was estimated in a group of mice employing a psychophysical technique recently developed for use in humans. The premise of this technique is that extended presentation of an odorant will produce odor adaptation, decreasing the sensitivity of the receptors and increasing thresholds for a brief, simultaneous target odorant presented at different time points on the adaptation contour; adaptation is estimated as the increase in threshold for a target odorant presented simultaneously with an adapting odorant, across varying adapting-to-target odorant onset delays. Previous research from our laboratory suggests that this method provides a reliable estimate of the onset time course of rapid adaptation in human subjects. Consistent with physiological and behavioral data from human subjects, the present findings demonstrate that measurable olfactory adaptive effects can be observed for odorant exposures as brief as 50-100ms, with asymptotic levels evident 400-600ms following adapting odorant onset. When compared with the adaptation contour in humans using the same odorant and stimulus paradigm, some differences in the onset characteristics are evident and may be related to sniffing behavior and to relative differences in thresholds. These data show that this psychophysical paradigm can be adapted for use in animal models, where experimental and genetic manipulations can be used to characterize the different mechanisms underlying odor adaptation.

Time Course of Perceptual Adaptation Differs among Odorants

AbstractPerceptual adaptation, a fundamental property of all sensory systems, functions to attenuate neural and perceptual responses to sustained or redundant stimulation as a means of limiting neural saturation and of enhancing the detection of new transient stimuli. While our understanding of the complex physiological mechanisms underlying adaptation has grown in recent years, how these processes are affected by individual odorant properties remains unclear. Recent data from our laboratory demonstrate that the onset time course of perceptual odor adaptation can be estimated by use of a simultaneous‐odorant‐stimulus paradigm, where the delay from the onset of a relatively long‐duration adapting odorant to the onset of a brief target odorant is varied. Adaptation was observed as an increase in threshold with increasing adapting‐to‐target‐odorant onset delay. Using this technique, we compared the estimated onset time course for four common odorants (vanilla extract, coconut extract, vinegar and propanol). Thresholds were estimated for a brief target odorant presented during a simultaneous adapting odorant in a group of college‐aged student volunteers (n = 124; 88 females). Onset of adaptation for the vanilla and coconut mixtures was more rapid than for vinegar and propanol, though the asymptotic levels (approximately 400 ms) of adaptation were similar for coconut extract, vanilla extract and vinegar. In contrast, propanol did not reach asymptotic levels within the 1,000‐ms timeframe. Considering propanol is a pure alcohol, relative differences in trigeminal reactivity may partially explain this variance in adaptation contours.Practical ApplicationsA method for capturing rapid changes in response to odor adaptation is described. The automated method can be reliably used to compare both the magnitude and time course for a wide range of stimuli. The technique may be reproduced to evaluate how individual olfactory sensitivity changes in response to prolonged stimulation. Importantly, this procedure can be used to assess shifts in odor perception on rapid timescales – in the 50–100‐ms range, rather than seconds or minutes.

A Study on the Timeline of Onset of Opportunistic Cytomegalovirus: Infection in Renal Transplant Recipients and Comparison of Various Methods of Its Detection

Infectious complications are still a significant cause of morbidity and death in recipients of organ transplant. Among them Cytomegalovirus is the single most important agent affecting these patients, with at least two-thirds of these patients developing CMV infection 1~4 months after transplantation. This study was aimed to bring out the best and effective methodology or combination to detect CMV disease in post renal transplant Indian patients. We compared Quantitative CMV–DNA Real time PCR with pp65 Antigenemia, serology (anti-CMV IgM/IgG antibody assay) and Anti-CMV IgG avidity. We tried to evaluate the time line of onset of Cytomegalovirus disease post renal transplant. Fifty consecutive renal transplant recipients with clinical suspicion of CMV disease were studied prospectively. CMV Disease was defined clinically based on some criteria. These patients were subjected to a detailed viral diagnostic workup. The clinical response to treatment was considered as a strong clinical evidence of CMV disease in retrospect. The time course of onset of CMV disease post-transplant in majority of patients was found to be between 8 to 14 weeks. Five tests were done in all 50 patients and 20 healthy subjects (control group).Out of the 50 patients who formed our study population, 32 (64%) were found to have CMV disease. All the diseased cases were picked by the Real-Time PCR giving a sensitivity of 100% and specificity of 88.8%. The sensitivity and specificity of pp-65 antigenemia was found out to be 53% and 100%. 32% of patients were found positive for CMV IgM antibody showing a sensitivity 47.05%. Out of the 32 positive patients, 9 had low avidity showing recent infection, 11 patients had high avidity showing long term infection and 12 patients had avidity in the indeterminate range. The Quantitative Real Time PCR stood out as a sensitive test and detected all CMV infections which were considered to be clinically significant and went on to receive treatment whereas pp-65 antigenemia was found to be a more specific and confirmatory test. CMV DNA copy numbers of >500 detected by the Real-time PCR correlate 100% with the presence of CMV disease. We found CMV-IgM antibody assay was not sensitive enough for diagnosis and monitoring of active CMV disease since there is a prolonged presence of IgM antibodies after recent CMV infection. Anti-CMV IgG antibody avidity was found to have a marginal role in diagnosis of this disease.

Changes in permeability of the plasma membrane of myoblasts to fluorescent dyes with different molecular masses under sustained uniaxial stretching

Deep tissue injury (DTI) is a serious pressure ulcer which onsets in skeletal muscle tissues adjacent to weight-bearing bony prominences. Recent literature points at sustained large deformations in muscle tissue, which translate to static stretching of the plasma membrane (PM) at the cell-scale, as the primary cause of accumulated cell death in DTI. It has been specifically suggested that prolonged exposure to large tensional PM strains interferes with normal cellular homeostasis, primarily by affecting transport through the PM which could become more permeable when stretched. In this context, using confocal imaging and fluorescence-activated cell sorter (FACS), we visualized and quantified here the uptake of fluorescent Dextran dye by myoblasts that were statically stretched uniaxially, up to physiological strains of 3%, 6% and 9%, using two different molecular masses for the Dextran (4kDa and 20kDa). The confocal and FACS studies provided consistent evidence that the permeability of the PM increased at large static deformations. Furthermore, the FACS data indicated that the kinetics of the PM permeability very likely depends on the size of the biomolecular marker. Both results were consistent with reports published in the neurotrauma literature on the kinetics of uptake of fluorescent biomolecules by dynamically stretched neurons; hence there are some analogues in the biomechanical pathways of cellular-level injury between DTI and impact insults. The present work provides additional empirical support to the theory of cell-scale deformation-diffusion damage in the etiology of DTI, and may lead to better understanding of time courses for onset of cellular damage in DTI, by exploring mass transport processes across the PM of the involved cells.

Basic Pharmacokinetics and Pharmacodynamics, an Integrated Textbook and Computer Simulations

This book covers the basics of pharmacokinetics, pharmacodynamics and linked pharmacokinetic–pharmacodynamic systems. The book is covered in 17 chapters and six appendices. Chapters 3–13 and 15–17 provide problems that the reader can work through. Chapters 2, 7–9 and 11–17 have a companion set of simulation exercises that are available on the Faculty of Pharmacy's website at the University of Rhode Island. Sara Rosenbaum attempts to pull together the individual pieces of a jigsaw puzzle that explains the dosing regimen. Understanding the dosing regimen requires an understanding of the time course of drug effects: How quickly do drugs act? How long do the effects last? What extent of effect might occur? Will the effects be the same on every dose? What dose and dose interval will be optimal to meet therapeutic needs? These topics are covered in 17 chapters. Chapter 1 starts with a simple explanation of pharmacokinetics and pharmacodynamics, which leads onto sections on biopharmaceutics and basic pharmacokinetics, pharmacokinetic models and integrated pharmacokinetic and pharmacodynamic models. Despite increasing complexity as the reader progresses through the book, the author brings the concepts back to their defining routes and no fundamental aspects are glossed over. The writing style is informative while being relaxed in its approach and where possible jargon terms are kept to a minimum. Each chapter starts with a set of learning objectives and follows with exercises that test those learning objectives (note answers are not provided). In many chapters a fully integrated approach is used where the reader is introduced to the topic and models, followed by an online simulation exercise which is then succeeded by an explanation and this cycle is continued often several times during the chapter. Formulae which are used from previous chapters are usually revisited to remind the reader about their structure and use. The book claims to offer a basic overview of pharmacokinetics and pharmacokinetic–pharmacodynamic systems. While in some sense the author has kept to this promise, readers should not be complacent about the content. This book covers topics that provide the underpinnings of much of the advanced research in the area of pharmacokinetics and pharmacodynamics. Graduate students would do well to familiarize themselves with its content. Whether the book achieves its aim of being an introductory textbook suitable for accompanying courses in pharmacy and medicine is unclear. Certainly for many medicine and pharmacy courses the material covered in this book greatly exceeds the general curriculum which often does not move beyond consideration of pharmacokinetics and pharmacodynamics as independent entities. Most introductory books in this area shy away from considering the fully integrated approach required to understand the time course of drug effects. This puts this book a head and shoulders above its companions. Could the book be improved? Like many attempts to link the areas of pharmacokinetics and pharmacodynamics within a confined space it does so partly at the cost of the fully integrated pharmacokinetic and pharmacodynamic models. A little more than one chapter in this book is dedicated to integrated pharmacokinetic and pharmacodynamic models (part of chapter 16 and all of chapter 17). This is also, arguably, the most complex part of the jigsaw puzzle where time delays in drug effects, tolerance and disease progression models are covered. Understandably the topic must be pulled to a close at some stage, and it is noted that there is no coverage of schedule dependence nor is there consideration for non-continuous pharmacodynamic measures. I hope that Sara Rosenbaum is considering a next edition where she might expand chapter 17 into the much needed additional chapters to do greater justice to those areas of pharmacokinetics and pharmacodynamics that have difficulty squeezing into a single chapter. In summary, I believe that this book is successful in what it sets out to do. For those readers who are interested in getting to grips with the basics of the time course of onset, offset and extent of drug effects then this is the book for you. I am certainly recommending this book for my graduate students.

Rapid Olfactory Adaptation Induced by Perithreshold Odorant Concentrations in Human Observers

A recent study from our laboratory described the development and use of a novel psychophysical method to characterize the onset time course of rapid olfactory adaptation (Smith et al., Chem Senses 35:717–725 2010). In the present study, we used this same approach to measure adaptation-induced changes in olfactory sensitivity following exposure to different self-adapting perithreshold-level stimuli. We used a custom-built liquid-dilution olfactometer to estimate two-odor discrimination thresholds for 600-ms presentations of a vanilla odorant alone and 500 ms after the onset of a 1,500-ms simultaneous vanilla adapting stimulus. Our previous findings suggest that a 500-ms exposure to a suprathreshold stimulus is sufficient to induce an asymptotic level of rapid olfactory adaptation in most participants. Twenty normosmic college-aged volunteers (ages 18–24; 14 females) served as subjects in this experiment. Thresholds were initially estimated for the 600-ms vanilla target alone, then compared in the presence of a simultaneous adapting stimulus set to 0.25, 0.5, 1.0, or 2.0 times the participant’s initial threshold to assess the effects of adapting odorant level on adaptation magnitude. The results suggest that significant decreases in odorant sensitivity were evident even with subthreshold adapting odorant levels, but that the magnitude of adaptation was unaffected by adapting odorant concentration.

Time course and pattern of COPD exacerbation onset

BackgroundThe natural history and time course of the onset of exacerbation events of chronic obstructive pulmonary disease (COPD) is incompletely understood.MethodsA prospective cohort of 212 patients with COPD was monitored...

Rhadbomyolysis associated with co‐administration of danazol and lovastatin

We report a probable, drug–drug interaction between danazol and lovastatin that led to an episode of severe rhabdomyolysis. A 91-year-old White male (weight 73 kg, height 172 cm) with a past medical history of coronary artery disease, hypertension, hyperlipidaemia, diabetes mellitus, hypothyroidism and idiopathic thrombocytopenic purpura (ITP) presented with a 2-week history of progressively increasing bilateral leg weakness involving both the distal and proximal muscle groups. He denied fever, skin rashes, back or joint pain. There was no bladder or bowel incontinence or other neurological symptoms. Active medications included aspirin (81 mg day−1), clopidogrel (75 mg day−1), metoprolol (200 mg day−1), lisinopril (10 mg day−1), isosorbide dinitrate (10 mg day−1), lovastatin (40 mg day−1), levothyroxine (50 µg day−1), glipizide (5 mg day−1) and danazol (400 mg day−1). About 2 months previously, he was changed from atorvastatin (10 mg day−1) to lovastatin, because his insurance declined to provide payment coverage for atorvastatin. Physical examination was notable for diffuse lower extremity weakness and skin ecchymosis but no rash, and no other significant cardiovascular, respiratory, abdominal or neurological findings or signs suggestive of dermatomyositis. Laboratory investigations were notable for an elevated white blood cell count of 14 200 (normal 3500–10 500 U l−1), elevated creatine kinase of 22 504 (normal 52–336 U l−1), aspartate aminotransferase of 368 (normal 15–46 U l−1), alanine aminotransferase of 415 (normal 12–63 U l−1) and a serum creatinine of 2.5 (normal <1.2 mg dl−1). He was managed with intravenous hydration, discontinuation of lovastatin and danazol and physical therapy. His symptoms improved, his creatine kinase and liver enzymes trended back to normal and renal function normalized within 4 days. Danazol, 17-alpha-ethinyl testosterone, is used clinically to treat of endometriosis, fibrocystic breast disease, hereditary angioedema and ITP. This patient had been on a stable dose of danazol for ITP (400 mg once daily) for over 25 years and concomitantly receiving several statins in the last 10 years including fluvastatin (dose range 20–40 mg daily), simvastatin (dose range 10–40 mg daily) and, most recently, atorvastatin 10 mg daily. He had never previously developed symptoms consistent with statin-induced myopathy. HMG-CoA reductase inhibitors are metabolized in the liver by the CYP450 enzymes [1] (see Table 1). Both atorvastatin and lovastatin are metabolized by CYP3A4 and danazol is reported to be a CYP3A4 inhibitor [2]. The combination of high-dose lovastatin and danazol was the likely offender in this patient. The inhibition of CYP3A4 likely led to increased accumulation of the high-dose of lovastatin. In this case, the adverse drug reaction Naranjo probability score was 8, suggestive of a probable causal relationship [3]. This putative danazol precipitated drug–drug interaction causing rhabdomyolysis with statins has been reported previously with lovastatin [4, 5] and simvastatin [6, 7]. In these reports, the adverse event was dose-related and the time course of onset of rhabdomyolysis was about 8–10 weeks. Table 1 Cytochrome metabolism of statins [1] Statin-related myopathy is an important side effect that can be precipitated by a number of drug–drug interactions. Physicians should be cautious of these drug interactions particularly when switching statin drugs, especially in the elderly who are on multiple concomitant medications.

A Novel Psychophysical Method for Estimating the Time Course of Olfactory Rapid Adaptation in Humans

In this presentation, we describe a novel method for estimating the onset time course of psychophysical odor adaptation in human observers. The method employs stimulus conditions derived from an analogous stimulus paradigm in audition. To test this procedure, we used liquid-dilution olfactometry to estimate 2-bottle discrimination thresholds for brief (600 ms) presentations of vanilla odor; 17 volunteers (14 females; ages 18-24) served as participants. The adapting odorant concentration for each participant was set relative to baseline threshold for the 600-ms target alone (i.e., the same level relative to each participant's threshold). To characterize the adaptation-onset time course, we compared thresholds for targets presented simultaneously with the adapting stimulus as a function of the relative delay between the onset of the adapting stimulus and onset of the target. As predicted from the analogous auditory studies, thresholds for the target stimulus increased in an orderly manner with increases in adaptation-to-target onset delay (i.e., as the adaptation process progressively decreased sensitivity). Initial increases in threshold were consistently observed for the briefest onset delays of 50-100 ms. An onset time constant was estimated at 319 ms by fitting a 2-component exponential to the mean group function. Adaptation magnitude was dependent on the level of adapting odorant, relative to threshold. When thresholds were measured in one participant with a different, unrelated target odorant, cineole, there was no effect of the vanilla-adapting stimulus on threshold. The results suggest that olfactory rapid adaptation is measurable psychophysically within 50-200 ms after odor onset, values consistent with physiological measures of adaptation in olfactory receptor neurons. This novel stimulus paradigm offers a powerful psychophysical tool to study both odor adaptation and stimulus interactions at the olfactory periphery.