Population pharmacokinetics and pharmacodynamics of ponesimod,a selective S1P1 receptor modulator

Ponesimod (ACT-128800), a reversible, orally active, selective S1P₁ receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The availability of a variety of doses, dosing regimens, and treatment durations permitted estimation of the pharmacokinetics characterized by an absorption lag time followed by a sequential zero/first-order absorption and two compartments with first-order elimination. The PD are modeled as an indirect-effect model with rates of appearance and disappearance of lymphocytes in blood with a circadian rhythm and a drug effect on the rate of appearance. The model suggests a circadian variation of 9 % and a maximum inhibition of 86 % of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 0.5 × 10⁹ counts/L.     

Experimentelle Tumortherapie

Strahlentherapie und Onkologie -     

Health, secondary conditions, and life expectancy after spinal cord injury

Krause JS, Saunders LL. Health, secondary conditions, and life expectancy after spinal cord injury.

Objective

To evaluate the association of health status, secondary health conditions, hospitalizations, and risk of mortality and life expectancy (LE) after spinal cord injury (SCI).

Design

Prospective cohort study.

Setting

Preliminary data were collected from a specialty hospital in the Southeastern United States, with mortality follow-up and data analysis conducted at a medical university.

Participants

Adults with traumatic SCI (N=1361), all at least 1-year postinjury at the time of assessment, were enrolled in the study. There were 325 deaths. After elimination of those with missing data on key variables, there were 267 deaths and 12,032 person-years.

Interventions

None.

Main Outcome Measures

The mortality status was determined by routine follow-up using the National Death Index through December 31, 2008. A logistic regression model was developed to estimate the probability of dying in any given year using person-years.

Results

A history of chronic pressure ulcers, amputations, a depressive disorder, symptoms of infections, and being hospitalized within the past year were all predictive of mortality. LE estimates were generated using the example of a man with noncervical, nonambulatory SCI. Using 3 age examples (20, 40, 60y), the greatest estimated lost LE was associated with chronic pressure ulcers (50.3%), followed by amputations (35.4%), 1 or more recent hospitalizations (18.5%), and the diagnosis of probable major depression (18%). Symptoms of infections were associated with a 6.7% reduction in LE for a 1 SD increase in infectious symptoms.

Conclusions

Several secondary health conditions represent risk factors for mortality and diminish LE after SCI. The presence of 1 or more of these factors should be taken as an indicator of the need for intervention.     

Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells

Mitochondrial reactive oxygen species (ROS) and endothelial dysfunction are key contributors to cerebrovascular pathophysiology. We previously found that 17beta-estradiol profoundly affects mitochondrial function in cerebral blood vessels, enhancing efficiency of energy production and suppressing mitochondrial oxidative stress. To determine whether estrogen specifically affects endothelial mitochondria through receptor mechanisms, we used cultured human brain microvascular endothelial cells (HBMECs). 17beta-Estradiol treatment for 24 h increased mitochondrial cytochrome c protein and mRNA; use of silencing RNA for estrogen receptors (ERs) showed that this effect involved ERalpha, but not ERbeta. Mitochondrial ROS were determined by measuring the activity of aconitase, an enzyme with an iron-sulfur center inactivated by mitochondrial superoxide. 17beta-Estradiol increased mitochondrial aconitase activity in HBMECs, indicating a reduction in ROS. Direct measurement of mitochondrial superoxide with MitoSOX Red showed that 17beta-estradiol, but not 17alpha-estradiol, significantly decreased mitochondrial superoxide production, an effect blocked by the ER antagonist, ICI-182,780 (fulvestrant). Selective ER agonists demonstrated that the decrease in mitochondrial superoxide was mediated by ERalpha, not ERbeta. The selective estrogen receptor modulators, raloxifene and 4-hydroxy-tamoxifen, differentially affected mitochondrial superoxide production, with raloxifene acting as an agonist but 4-hydroxy-tamoxifen acting as an estrogen antagonist. Changes in superoxide by 17beta-estradiol could not be explained by changes in manganese superoxide dismutase. Instead, ERalpha-mediated decreases in mitochondrial ROS may depend on the concomitant increase in mitochondrial cytochrome c, previously shown to act as an antioxidant. Mitochondrial protective effects of estrogen in cerebral endothelium may contribute to sex differences in the occurrence of stroke and other age-related neurodegenerative diseases.     

Chronologic age, time since injury, and time of measurement: effect on adjustment after spinal cord injury

People are now living longer after spinal cord injury (SCI), yet only limited research has addressed the issue of aging and adjustment after SCI. The purpose of this study was to use a time-sequential design to identify the relationship between adjustment after SCI and three facets of aging; chronologic age, time since injury, and time of measurement. Life Situation Questionnaires were obtained from one sample of participants with SCI in 1974 (n = 256) and from a second sample in 1985 (n = 193). Participants were grouped into five cohorts based on chronologic age, five cohorts based on time since injury, and two groups based on time of measurement (1974, 1985). Two two-way MANOVA's were performed, one between chronologic age and time of measurement, and the other between time since injury and time of measurement. Results indicated that chronologic age and time since injury often worked in opposing directions; as some aspects of adjustment declined with greater chronologic age, but other aspects improved with increasing time since injury. Activity was strongly related to chronologic age, but medical stability was more strongly related to time since injury. Both chronologic age and time since injury were correlated with some aspects of life satisfaction. Comparisons between the two times of measurement (1974, 1985) indicated some limited positive changes in adjustment with time. The results point to the complexity of the relationship between aging and adjustment and the need for rehabilitation professionals to consider multiple aging factors.     

Quantitative sensory testing in cluster headache: increased sensory thresholds

To determine if recently reported changes in sensory thresholds during migraine attacks can also be seen in cluster headache (CH), we performed quantitative sensory testing (QST) in 10 healthy subjects and in 16 patients with CH. Eight of the patients had an episodic CH and the other eight a chronic CH. The tests were performed on the right and left cheeks and on the right and left side of the back of the hands to determine the subjects' perception and pain thresholds for thermal (use of a thermode) and mechanical (vibration, pressure pain thresholds, pin prick, von Frey hairs) stimuli. Six patients were examined in the attack-free period. Three were also willing to repeat the tests a second time during an acute headache attack, which was elicited with nitroglycerin. The healthy subjects performed the experiments in the morning and evening of the same day to determine if sensory thresholds are independent of the time of day. If they were, this would allow estimation of the influence of the endogenous cortisone concentration on these thresholds. The control group showed no influence of the time of day on the thresholds. There was a significant difference in pain sensitivity between the back of the hands and the cheeks (P<0.05): higher thresholds were found on the back of the hands. The thresholds generally exhibited little intersubject variability, indicating that QST is a reliable method. There was also a significant difference between the test areas in the patient group (P<0.001): the cheeks were also more sensitive than the back of the hands. In comparison with reference data of healthy volunteers, the detection thresholds were increased in the patients on both test areas. These were statistically significant for warmth, thermal sensory limen (TSL), heat and pressure on the back of the hands (P<0.04) and for the warmth and TSL thresholds on the cheeks (P<0.05). There were no differences in the thresholds regardless of whether the patients were examined in or outside of a cluster bout. Furthermore, we found no cutaneous allodynia in the three patients tested during an attack. The increased sensory thresholds on the cheeks as well as on the back of the hands are in agreement with an increased activation of the patients' antinociceptive system. The seasonal variation and the temporal regularity of single attacks as well as the findings in imaging studies indicate that the hypothalamus is involved in the pathophysiology of CH. In view of the strong connectivity between the hypothalamus and areas involved in the antinociceptive system in the brainstem, we hypothesize that this connection is the reason for the increased sensory thresholds in CH patients found in our study.     

Blood cardioplegia filtration

The introduction of blood cardioplegia has been proven to limit ischaemia and reperfusion injury in cardiac surgery. But the presence of activated neutrophils in the capillary bed may cause further damage. Leukocyte filters have been shown to be very effective in reducing the leukocytes in blood cardioplegia to less than 10%. Leukocyte depletion of blood cardioplegia provides an excellent approach to minimizing myocardial injury, predominantly in high-risk cardiac surgery.     

A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. It presents as a papulovesicular rash and is often associated with enteropathy. The rash resolves when the patient is placed on a gluten-free diet and/or dapsone. DH, as well as celiac disease, is tightly associated with DQ2 and DQ8. A novel mouse model for DH is described that utilizes the NOD background and the HLA-DQ8 transgene. The addition of DQ8 contributes sensitivity to gliadin, and the addition of the NOD background contributes to autoimmunity and pathogenesis. Fifteen NOD DQ8+ mice of 90 that were sensitized to gluten developed blistering pathology similar to that seen in DH. Neutrophil infiltration of the dermis, deposition of IgA at the dermal-epidermal junction, and a complete reversal of the blistering phenomenon with the administration of a gluten-free diet with or without dapsone were observed. None of the 3 blistering mice examined had small-bowel pathology. This animal model of DH will be useful to determine the specificity of the IgA deposits, as well as the pathogenic mechanisms that occur in the skin as a result of gluten ingestion.     

Class II MHC antigen (HLA-DR3) predisposes to sarcoid arthritis

Recent studies indicate that the susceptibility to various inflammatory rheumatic diseases is an inherited trait determined by gene products of the class II histocompatibility complex (HLA-DR determinants). In a study designed to evaluate the concept of inherited susceptibility to sarcoid arthritis (SA), 42 patients with histologically proved acute disease underwent typing of HLA-A, -B, -C and -DR antigens. Using the microdroplet assay of human serum cytotoxins, we employed 156 antiserums to identify 52 antigens on A, B and C loci and 35 to identify 7 DR antigens on the surface of B cells. An ethnically matched control group consisted of 134 healthy volunteers. The frequency of B cell isoantigen DR3 specificity was significantly increased in patients with SA (relative risk, 4.8); HLA-DR3 was found in 25 (60%) of the patients, compared with 31 (23%) of the controls. This study lends further support to the hypothesis that the putative role of an infectious agent triggering SA cannot be judged without considering genetic cofactors.