Blood Concentrations Of TNF-α Research Articles

Effects of n-3 fatty acid supplementation from flax oil on growth performance, ruminal fermentation, and immune response in Holstein dairy calves fed either coarsely ground or steam-flaked corn grain

The current study evaluated the effect of corn grain processing method (ground corn: GC vs. steam flaked corn: SFC) with or without calcium salt of α-Linolenic acid (ALA) from flax oil on growth performance, ruminal fermentation parameters, and inflammatory markers in Holstein dairy calves. Forty-eight female dairy calves (averaging 3 d old and 40.1 kg body weight) in a completely randomized design as following treatments; 1) GC with no n-3 FA supplementation (GC-NALA), 2) GC with 30 g/kg n-3 FA source (GC-ALA), 3) SFC with no n-3 FA supplementation (SFC-NALA), and 4) SFC with 30 g/kg n-3 FA source (SFC-ALA). The calves were weaned on d 53 but the study finished 20 d after weaning (d 73 of experiment). Results showed that when calves received SFC with n-3 FA supplementation (SFC-ALA), average daily gain (ADG) improved at pre-weaning; (P = 0.04) and entire period (P = 0.05). Furthermore, calves fed SFC-ALA diet had greater (P = 0.05) blood glucose concentration at pre-weaning period and OM digestibility compared to other groups. The greater (P = 0.04) blood concentrations of tumor necrosis factor-alpha (TNF-α) and serum amyloid A (SAA; tendency; P = 0.07) at pre-weaning period were observed in calves received SFC-NALA diet than other experimental groups. Regarding the corn processing method, the ADG (post-weaning; P = 0.04), hip height (post-weaning; P = 0.04), ruminal concentration of total volatile fatty acids, and butyrate proportion (P = 0.04) increased, but ruminal acetate proportion (P = 0.02) reduced when calves received SFC compared to GC diets during pre-weaning period. Blood concentrations of TNF-α (P = 0.01) and SAA (P = 0.04) during pre-weaning period were lower in calves fed diets containing ALA than those fed diets without ALA. According to these results, supplemental n-3 FA improved growth performance when calves received SFC which could be related to reducing inflammatory responses.

Effects of Nigella sativa supplementation on blood concentration and mRNA expression of TNF-α, PPAR-γ and adiponectin, as major adipogenesis-related markers, in obese and overweight women: a crossover, randomised-controlled trial.

Adipocyte expansion through adipogenesis can offset the adverse metabolic effects of obesity. Nigella sativa (NS) (black seed) oil is shown to have therapeutic features in the management of obesity. NS oil might have beneficial changes in obese populations through mediating serum levels of adipogenesis-related parameters and relative transcriptional gene-diet interactions (nutrigenomics), though no previous studies assessed this mechanism in overweight/obese participants. This study assessed the effects of NS oil supplements on blood concentration and mRNA expression levels of TNF-α, PPAR-γ and serum adiponectin and expression of AdipoR1, as major adipogenesis and obesity-related parameters, in overweight/obese women using a cross-over design. Eligible women were randomised to receive either NS oil supplements (2000 mg/d) or placebo. Two periods of interventions (8 weeks in each) were cross-changed by a 4-week washout period. An individualised diet plan without calorie deficits was given to participants to match their energy/macronutrient intakes. The Pkcross procedure and intention-to-treat analysis were performed using Stata. Cohen's d(d) was estimated to measure the magnitude of the effects. Forty-six participants were included. NS oil capsules reduced transcription levels ((d = -2·31), P < 0·001) and blood concentrations of TNF-α ((d = -0·29), P < 0·001). AdipoR1 expression (d = 2·24, P < 0·001) and serum adiponectin (d = 0·88, P < 0·001) showed a significant augmentation with a medium-high effect size, as did gene expression (d = 0·69, P < 0·001) and serum levels of PPAR-γ (d = 0·97, P < 0·001). There was a moderate but significant decrease in body weight (d = 0·6, P < 0·001). The present beneficial findings would provide strong information for future nutrigenomics/clinical trial studies assessing the role of NS in the management of obesity and other comorbidities.

Вплив моно- та комбінованої антигіпертензивної терапії на активність системного запалення у хворих на гіпертонічну хворобу

Метою дослідження є оцінка впливу моно- та комбінованої антигіпертензивної терапії на показники системного запалення (С-реактивний протеїн (СРП), інтерлейкін (ІЛ)-6 і фактор некрозу пухлини (ФНП) α у взаємозв’язку з динамікою характеристик добового профілю артеріального тиску.Обстежено 99 хворих на гіпертонічну хворобу І–ІІ стадії 1–2-го ступеня, які були рандомізовані в 3 групи терапії: 29 пацієнтів отримували монотерапію телмісартаном у дозі 40–80 мг/добу, 27 — S-амлодипіном у дозі 5 мг/добу та 43 — фіксовану комбінацію валсартану з амлодипіном у дозі 160/5 мг/добу). Визначення вмісту СРП, ІЛ-6 і ФНП-α проводили до початку (після 7-денного безмедикаментозного періоду) та після 6 міс. терапії.Було встановлено, що лікування телмісартаном сприяє зниженню сироваткового рівня СРП на 13,9 % та ІЛ-6 — на 36,4 %, проте не впливає на вміст ФНП-α у крові хворих на гіпертонічну хворобу. Монотерапія антагоністом кальцію S-амлодипіном призводить до зменшення вмісту в крові прозапальних цитокінів: ІЛ-6 — на 39 % та ФНП-α — на 11,9 %. Застосування фіксованої комбінації валсартану з амлодипіном чинить більш суттєвий антигіпертензивний ефект, проте це не супроводжувалося більш вираженим, ніж у групах монотерапії, зниженням СРП і ІЛ-6, що становило відповідно 12,5 і 31,5 %.Було виявлено, що зниження АТ прямо пов’язане зі зменшенням активності системного запалення. Так, зменшення сироваткового вмісту ФНП-α корелює зі зниженням систолічного та діастолічного АТ у всі періоди доби під впливом лікування, а зниження рівня СРП асоціюється зі змінами середньодобового та середньоденного систолічного артеріального тиску, його добового індексу та нічної варіабельності.Отримані нами дані засвідчують зменшення активності запалення низької градації під впливом блокаторів рецепторів ангіотензину ІІ (телмісартан) та антагоністів кальцію (S-амлодипін) як при монотерапії, так і при використанні їх комбінації (валсартан із амлодипіном), яке прямо корелює зі зниженням артеріального тиску за даними амбулаторних вимірювань.

Recombinant thrombomodulin attenuates hyper-inflammation and glycocalyx damage in a murine model of Streptococcus pneumoniae-induced sepsis.

The anticoagulant agent recombinant thrombomodulin (rTM) activates protein C to prevent excessive coagulation and also possibly regulates hyper-inflammation via neutralization of high-mobility-group B1 (HMG-B1). The glycocalyx layer in endothelial cells also plays a pivotal role in preventing septic shock-associated hyperpermeability. The present study examined the effect of rTM in a murine model of Streptococcus pneumoniae-induced sepsis. Male C57BL/6N mice were injected intratracheally via midline cervical incision with 2×107 CFU of S. pneumoniae (capsular subtype 19A). Control mice were sham-treated identically but injected with saline. rTM (10mg/kg) was injected intraperitoneally 3h after septic insult. Blood concentrations of soluble inflammatory mediators (interleukin [IL]-1β, IL-6, IL-10, and tumor necrosis factor [TNF]-α) were determined using a microarray immunoassay. Serum concentrations of HMG-B1 and syndecan-1, as a parameter of glycocalyx damage, were determined by enzyme-linked immunosorbent assay. The glycocalyx was also evaluated with electron microscopy. The lungs were removed, and digested to cells, which were then stained with a mixture of fluorophore-conjugated antibodies. Anti-mouse primary antibodies included PE-Cy7-conjugated anti-CD31, AlexaFluor 700-conjugated anti-CD45, PerCP-Cy5.5-conjugated anti-CD326, APC-conjugated anti-TNF-α, PE-conjugated anti-IL-6, and PE-conjugated anti-IL-10. A total of 1×106 cells per sample were analyzed, and 2×105 events were recorded by flow cytometry, and parameters were compared with/without rTM treatment. The blood concentration of TNF-α was significantly reduced 24h after intratracheal injection in S. pneumoniae-challenged mice treated with rTM (P=0.016). Levels of IL-10 in the lung endothelium of rTM-treated S. pneumoniae-challenged mice increased significantly 12h after intratracheal injection (P=0.03). Intriguingly, serum HMGB-1 and syndecan-1 levels decreased significantly (P=0.010 and 0.015, respectively) in rTM-treated mice 24h after intratracheal injection of S. pneumoniae. Electron microscopy indicated that rTM treatment preserved the morphology of the glycocalyx layer in septic mice. These data suggest that rTM modulates local inflammation in the lung endothelium, thus diminishing systemic inflammation, i.e., hypercytokinemia. Furthermore, rTM treatment reduced serum syndecan-1 levels, thus preventing glycocalyx damage. The use of rTM to treat sepsis caused by bacterial pneumonia could therefore help prevent both excessive inflammation and glycocalyx injury in the lung endothelium.

Association of tumor necrosis factor-alpha and interleukin-10 levels with ultrasound characteristics of atherosclerotic plaques in patients with essential hypertension

Aim. To study the association of ultrasound characteristics of carotid atherosclerotic plaques (ASPs) with the concentration of tumor necrosis factor-alpha (TNFα) and interleukin-10 (IL-10) in patients with essential hypertension.Material and methods. The study included 117 patients (men, 75; women, 42) with essential hypertension aged 40 to 75 years (mean age, 55,8±7,5 years). All patients underwent anthropometric measurements (height, weight, body mass index, waist circumference), assessment of blood pressure and heart rate, blood tests (levels of glucose, creatinine with the calculation of glomerular filtration rate using CKD-EPI equation, lipid profile), duplex ultrasound of the carotid arteries. Also, the blood concentration of TNFα and IL-10 by the enzyme-linked immunosorbent assay using CYTOKIN-STIMUL-BEST (Novosibirsk,Russia) kit was determined.Results. According to the results of carotid duplex ultrasound, 3 groups of patients were identified. Group 1 included 48 patients with homogeneous hyperechoic ASPs; group 2 — 56 patients with dominant hyperechoic ASPs (&gt;50% of areas); group 3 — 13 patients with anechoic, unstable, low-density ASPs. TNFα concentration in group 3 patients, amounting to 10,51±2.23 pg/ml, was significantly higher than in patients of group 1 (7,26±0,64 pg/ml (p&lt;0,001)) and group 2 (8,93±0,98 pg/ml (p&lt;0,001)). Similar results were obtained for IL-10. The logistic regression showed that the TNFα concentration is an independent factor associated with unstable ASsP (relative risk, 2,72; 95% confidence interval 1,44-5,15 (p&lt;0,02)). It was also revealed that TNFα &gt;10 pg/ml increased the risk of ASP instability by ~8 times.Conclusion. An increase in TNFα &gt;10 pg/ml with a high specificity (95%) was associated with vulnerable unstable carotid ASPs.

Establishment of a murine, lipopolysaccharide-induced sepsis model for testing anaerobic exercise thresholds and early mobilization

BackgroundSeveral methods have been proposed to prevent post intensive care syndrome after sepsis, including early mobilization, but controversy remains in mechanisms and outcomes. Therefore, the aim of this study is to establish a septic mouse model and classify exercise intensities during the acute phase of sepsis to generate a murine sepsis rehabilitation model. MethodsAdult, male C57/B6 mice received lipopolysaccharide (LPS) injections (20 mg/kg). We recorded survival rates and metabolic changes, such as resting energy expenditure (REE), compared with controls up to 72 h after LPS administration. We also observed vital signs (rectal temperature and weight change), inflammation (TNF-α and IL-6), and exercise intensity via metabolic monitoring treadmill. We analyzed the anaerobic threshold (AT) by the V-Slope method. ResultAround 30% of the mice survived 72 h after LPS induction with the lowest REE at around 22–24 h later (REE at 22 h: 2.26 ± 0.34 kcal/day p < 0.05 vs. baseline). Blood concentrations of TNF-α were highest at the 12 h timepoint (41.23 ± 24.39 pg/mL, p < 0.05 vs. baseline) and IL-6 was highest at 24 h after LPS induction (1476.5 ± 274.7 pg/mL, p < 0.05 vs. baseline). With V-Slope, we observed the AT at each timepoint (6 h:14 m/min,12 h: 9 m/min, 24 h:4 m/min,36 h:10 m/min, 48 h:16 m/min, 60 h:20 m/min, 72 h:22 m/min) and classified these into very low intensity exercise training, low intensity exercise training, or moderate intensity exercise training at each timepoint. ConclusionWe classified exercise intensities out to 72 h after sepsis recovery using a mouse model. These data may serve as a bridge to clinical studies to fill gaps in best practice for sepsis rehabilitation.

The effects of gut indigenous microbiota on intensity of oxidative stress and the cytokine immunity in women with recurrent pyelonephritis.

The aim of our study was to investigate the oxidative stress (OS) intensity and concentration of tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) depending on the content of Lactobacillus spp. in the colon of patients with recurrent pyelonephritis. Materials and methods. The observational study involved 64 women with recurrent pyelonephritis, aged 39.5±3.2 years. According to the quantitative content of Lactobacillus spp. in the patients’ intestine, the women were divided into two groups: the first group of the patients (n=38) had a deficit of Lactobacillus spp. in the intestine, and the second one (n=26) didn’t have any disorders. The intensity of OS was estimated by determining the OS index (OSI) as the ratio of total changes in the activity of oxidative processes to the total antioxidant capacity of blood. The blood concentration of TNF-α and interleukin 10 was determined. The local inflammation was characterized by the determination of the content of C-reactive protein (CRP), malondialdehyde (MDA) and the activity of N-acetyl-β-D-hexosaminidase (HEX) and β-galactosidase (β-gal) in urine. Results. The blood levels of OSI, MDA and TNF-α in the women with the deficit of Lactobacillus spp. in the gut were significantly higher compared with the deficit-free patients (р=0.03, р=0.01and р=0.007, respectively). Moreover, in the patients with the deficit of intestine lactobacillus spp., we observed high levels of CRP (р=0.045), HEX and β-gal (р=0.045) in the urine. In addition, a significant regression was found between IL-10 inthe blood and HEX in the urine (p=0.003), as well as MDA and TNF-α in the blood (p=0.02). Conclusions. Thus, the results of our work confirm the experimental studies data which demonstrate the leading role of gut indigenous microbiota in the development of the OS and inflammatory process.

Effect of Sevoflurane Preconditioning on Inflammatory Cytokines and Oxygen Radicals During Single Lung Ventilation in Patients with Lung Cancer

Objective: To observe the effect of sevoflurane preconditioning on inflammatory cytokines and oxygen radicals during single lung ventilation (SLV) in patients with lung cancer and to discuss the mechanism of sevoflurane induced lung protection. Methods: Thirty patients, ASA I or II, with non-small-cell lung cancer underwent pulmonary surgeries were randomized into two groups: sevoflurane preconditioning group (group S, n=15) and control group (group C, n=15). After general anaesthesia induction. A double-lumen tube was placed and the position was checked by a fibre optic bronchoscope. During the mechanical ventilation, patients in group S, received sevoflurane at 1.0 minimum alveolar concentration (MAC) for 30 min as a preconditioning and then replaced by oxygen for a complete rapid gas exchange to reduce the sevoflurane inhalation concentration to 0 before SLV. While in group C, only intravenous anaesthetic agents, fentanyl and propofol, were administrated before SLV. Blood concentrations of TNF-α, IL-6, IL-8, SOD and MDA were measured at Post-induction of anaesthesia (T1), 30 min after SLV in the lateral position (T2), 60 min after SLV in the lateral position (T3), and at the end of the operation (T4). Results: When compared with Tl, the concentrations of TNF-α, IL-6 and MDA in both groups and the IL-8 in group S were significantly increased at T2-T4 (P<0.05), while the expression of SOD in two groups were decreased significantly(P<0.05). The concentrations of TNF-α, IL-6, IL-8 and MDA in group S were decreased significantly at T2-T4 (P<0.05 or P<0.01) when compared with those in group C. The activity of SOD in group S was significantly increased at T3 and T4 (P<0.05). Conclusion: Sevoflurane preconditioning may moderate the release of inflammatory cytokines to inhibit the inflammatory reaction and may reduce the lipid peroxidation by inhibiting the generation of oxygen free radical. It may protect the lung from the injury during SLV.

MARKERS OF INFLAMMATION IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME AND CARDIOVASCULAR PATHOLOGY

Objective: to estimate the levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), and soluble TNF-α receptor type 1 (sTNF-R1) in patients with antiphospholipid syndrome (APS) and their association with cardiovascular pathology. Subjects and methods. Ninety-six patients, including 52 with primary APS and 44 with systemic lupus erythematosus and APS, were examined. A control group comprised 29 individuals without the signs of autoimmune disease. The levels of hsCRP, IL-6, TNF-α, sTNF-R1, antiphospholipid antibodies, and plasma lipids were studied; ultrasonography measuring the carotid intima-media complex (IMC), electrocardiography (ECG), echocardiography, and Holter ECG monitoring were made. Results. The concentrations of hsCRP, IL-6, TNF-α, and sTNF-R1 were significantly higher in the patient groups than in the controls (p < 0.05). Elevated sTNF-R1 concentrations were more common in angina pectoris than in its absence (OR = 2.13; 95% CI [1.51; 2.99]; p < 0.001). In patients with damage to the valvular apparatus, IL-6, TNF-α, and sTNF-R1 concentrations were significantly higher than those in patients without the defects (p = 0.02, 0.02, and 0.01, respectively). The levels of TNF-α and sTNF-R1 were significantly higher in hypertensive patients than those in non-hypertensives (p = 0.002 and p < 0.001; respectively). The blood concentration of TNF-α was significantly higher in patients having the risk factors and subclinical signs of atherosclerosis that that in those without the signs and risk factors of atherosclerosis (p < 0.05). Analysis showed a direct correlation between the levels of TNF-α, hsCRP, IL-6, and sTNF-R1 and an inverse correlation of those of IL-6 and TNF-α with the duration of posttrombosis (p < 0.05). A correlation was found between the concentrations of TNF-α and sTNF-R1, and IMC of the great arteries, as well as the cumulative coronary risk (p < 0.05). Conclusion. In patients with APS, the levels of all the test markers were significantly higher than those in the controls. An association was revealed between the values of TNF-α and sTNF-R1 and the risk factors and subclinical signs of atherosclerosis.

Classic and Alternative Complement Cascades in Post-Traumatic Stress Disorder

Hemolytic activity of classic and alternative complement cascades and blood concentrations of TNF-α, IL-1β, and IL-6 were measured in patients with post-traumatic stress disorder. The results attest to hyperactivity of the classic complement cascade associated with elevated content of proinflammatory cytokines and hypoactivation of the alternative complement cascade in patients with post-traumatic stress disorder in comparison with healthy individuals.

Inducible Nitric Oxide Synthase Expressions in Different Lung Injury Models and the Protective Effect of Aminoguanidine

Objective Our aim was to study the expression of inducible nitric oxide synthase (iNOS) in 2 experimental models: (1) ischemia/reperfusion (I/R) of the lung tissues and (2) oleic acid infusion. The protective effect of an iNOS inhibitor, aminoguanidine, was evaluated in these 2 injury models. Materials and Methods Real-time polymerase chain reactions and Western blots were used to assess the mRNA and protein expressions of iNOS in lung tissues after applying 2 injury models. In the I/R model, ischemia was induced by clamping one branch of the pulmonary artery for 60 minutes and then reperfusing for 120 minutes. In the bone fracture model, lung injury was induced by intravenous (IV) infusion of oleic acid (0.1 mL/kg); analysis was performed 6 hours after injury. Blood samples were collected for the assay of 3 inflammatory parameters: tumor necrosis factor α, hydroxyl radicals, and nitric oxide (NO). The wet/dry lung weight ratio was used as a parameter reflecting the lung injury level. Results mRNA and protein expressions of iNOS were significantly increased in these 2 lung injury models compared with the controls. Blood concentrations of TNFα, hydroxyl radicals, NO, and wet/dry lung weight ratio were also significantly higher in the 2 experimental groups than in the sham-treated group. The iNOS inhibitor aminoguanidine (20 mg/kg) significantly attenuated the lung injury induced by these challenges. Conclusions Reperfusion of the ischemic lung tissues or IV infusion of oleic acid can both induce lung injury by activating systemic inflammatory responses and inducing iNOS expression. Administration of aminoguanidine can significantly attenuate the injury, suggesting that iNOS expression may play a critical role in the lung injury induced in these 2 models.

Endothelial cell activation by tumour necrosis factor-alpha (TNF-alpha) and the development of pre-eclampsia.

Pre-eclampsia may develop as a result of an endothelial activation. Tumour necrosis factor-alpha (TNF-alpha) activates endothelial cells which release soluble E-selectin, a putative circulating marker specific for endothelial damage. A retrospective longitudinal study of maternal blood samples, collected at different gestational ages in pregnancy, was undertaken to determine whether the development of pre-eclampsia is associated with TNF-alpha-mediated endothelial activation. This study included 19 women who developed pre-eclampsia and 22 women whose pregnancy outcome was normal. Ten women had blood samples taken before pre-eclampsia was clinically detected and, in all these, TNF-alpha was below the immunoassay limit of detection (< 80 pg/ml). Five had further samples taken after pre-eclampsia was clinically diagnosed and, initially, TNF-alpha was still below the lower limit of detection in all five pregnancies, but rose later in three (80, 156 and 250 pg/ml). In nine other patients with diagnosed pre-eclampsia, TNF-alpha was detected in only two (80 and 650 pg/ml). TNF-alpha was identified in only one of the 22 normal pregnancies (80 pg/ml), this being at term. There was no statistical difference in soluble E-selectin levels between normal and pre-eclamptic pregnancies, neither before nor after pre-eclampsia was diagnosed. Hence, blood TNF-alpha levels measured by immunoassay can be elevated in approximately 36% of cases of established pre-eclampsia, but this rise occurs only after the syndrome is detected clinically. Blood concentrations of TNF-alpha and soluble E-selectin are not related to severity of the disorder. These findings suggest that circulating TNF-alpha does not contribute to the initiation of endothelial cell activation that may be associated with the development of pre-eclampsia, but may rise as a consequence of the pathological processes of this disorder.

Biocompatibility Parameters of Different Dialysis Membranes Assessed during Systemic Inflammation

Background: We explored whether biocompatible dialyzer membranes modulate the inflammatory response during blood contact in patients with systemic inflammation. Methods: 15 patients with end-stage renal disease and systemic inflammation (mean serum C-reactive protein 86 ± 4 mg/l) were randomly treated with Cuprophan (CU), polyamide (PA) and vitamin-E coated (VEC) membrane-based dialyzers. Results: Changes in blood pressure, capillary blood oxygen saturation and differential blood counts during the hemodialysis session were not significantly different between the three dialyzers. Baseline blood levels of activated circulating complement (C3a) were more than 100 times above normal, and unlike expected they decreased during hemodialysis treatments (CU: from 7,389 ± 783 to 5,423 ± 761 ng/ml; PA: from 7,379 ± 980 to 5,690 ± 714 ng/ml; VEC: from 7.377 ± 714 to 5,360 ± 1,005 ng/ml; all n.s.). No significant differences between treatments were found with respect to changes in blood concentrations of TNF-α, interleukin-6 and interleukin-1 receptor antagonist as well as ICAM-1 (CU: from 451 ± 41 to 477 ± 41 ng/ml; PA: from 437 ± 42 to 449 ± 40 ng/ml; VEC: from 461 ± 43 to 460 ± 47 ng/ml). Furthermore, generation of reactive oxygen species by mononuclear blood cells was comparable during hemodialysis with the CU, PA and VEC dialyzer. Conclusion: The choice of dialyzer membrane material does not affect most aspects of biocompatibility when patients have significant systemic inflammation. This confounding variable should be taken into account in studies exploring the effects of biocompatible dialyzer membranes.

The pharmacokinetics (PK) and pharmacodynamics (PD) of VX-702, a novel, oral P38MAP kinase inhibitor, in healthy volunteers

VX-702, an oral p38MAP kinase inhibitor, is being developed to treat inflammatory diseases. A Phase I study evaluated 1) the PK and PD of single oral doses (SD) of 2.5 to 80 mg, 2) the effect of food on absorption, and 3) the PK and PD of multiple oral doses (MD) of 10 and 20 mg given once daily for 14 days. This double-blind, placebo-controlled, randomized study was conducted in healthy male and postmenopausal female volunteers. Plasma and urine VX-702 concentrations and ex vivo lipopolysaccharide (LPS)-stimulated whole blood concentrations of TNFα, IL-6 and IL-1β were measured pre- and post-dose. PK and PD were evaluated using noncompartmental analyses and nonlinear mixed effects modeling. VX-702 PK were linear, dose proportional, and modestly variable. The population mean apparent clearance and distributive volume were 3.75 L/hr and 72.8 L. The terminal elimination half life was 16 hours. Steady state, achieved within 3 days during MD regimens, had exposures that were 25–45% greater than the first dose. 66% of the dose was excreted unchanged in the urine. Gender or food had no clinically significant effect on exposure. VX-702 was a potent and effective inhibitor of LPS-stimulated TNFα, IL-6 and IL-1β production, with IC50s of 99 ng/mL, 59 ng/mL, and 122 ng/mL, respectively. The maximum inhibition of cytokine production was approximately 80% of baseline. Based on the favorable PK and PD profile, further clinical development of VX-702 is warranted. Clinical Pharmacology & Therapeutics (2004) 75, P52–P52; doi: 10.1016/j.clpt.2003.11.197