Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Human-animal relationship influences husbandry practices, animal welfare and productivity in pig farming.

The nature of the relationship between humans and farm animals has multiple repercussions on the animals and the farmers and varies with farmers attitudes towards their animals. In particular, this relationship influences animal welfare and human working conditions. The present study, part of a larger research project investigating human-animal relationship (HAR) in pig farming and ways to improve it, had two objectives: 1) to investigate the HAR in a diversity of pig farming situations and to evaluate the possible correlation between farmer attitudes, pigs' reactions to humans, husbandry practices, animal health, welfare and productivity and 2) to find a way to rapidly assign a farmer to a profile, in order to better adapt course content during training sessions on HAR. The study focused on 52 farrow-to-finish farms and consisted of a semi-structured interview with the farmer, observations of the farmer in contact with his/her livestock, two human approach tests conducted on sows and growers and productivity data. Finally, a questionnaire was left at the farm to be filled out by all stockpersons on the farm. Interviews, analyzed using a thematic analysis followed by multiple correspondence analysis and ascendant hierarchical clustering, showed that some farmers develop husbandry practices to improve their HARs and identified three farmer profiles that have been named in relation to the place of the HAR in their profession: Profile 1 farmers for whom HAR is secondary in their work with their pigs, Profile 2 for whom the HAR is useful in their work with their pigs and Profile 3 for whom HAR is central in their work with their pigs. Logistic regression models of the relationships between behavioral tests and productivity data showed that confident sows produce and wean more piglets than fearful sows and that sows of Profile 3 farmers trust more humans than those of Profile 1 or 2 farmers. Farmers' responses to the questionnaire did not predict their profile assignment. Our results confirm the main role of the farmer's attitude towards animals on their farming practices, animal welfare and productivity. The farmers who have more confident pigs and better productivity are those for whom the farm animal is central to their profession, express the most pleasure in working with them and convey empathy for them.

Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.

BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.

Oral fluid versus blood sampling in group-housed sows and finishing pigs: Feasibility and performance of antibody detection for porcine reproductive and respiratory syndrome virus (PRRSV).

The feasibility of using individual and pen-based oral fluid samples to detect PRRSV antibodies in growing-finishing pigs and group-housed sows was investigated. The diagnostic performances of a commercial oral fluid ELISA (OF-ELISA) and a serum ELISA (SER-ELISA) performed on individual or pooled samples from 5 or 10 pigs and sows was evaluated. The performance of the OF-ELISA was also assessed for pen-based oral fluids. Eight hundred and thirty-four pigs and 1598 sows from 42 PRRSV-infected and 3 PRRSV-negative herds were oral fluid sampled and bled. PRRSV antibodies were detected by an OF-ELISA performed at individual, pool (5 or 10 samples) and pen levels. Serum samples were tested by a SER-ELISA at individual and pool levels. The sensitivity and specificity of ELISAs for individual samples were assessed by Bayesian analysis. The relative diagnostic performance for the pools was calculated by taking individual samples as the gold standard. SER-ELISA and individual OF-ELISA results were used as references for estimating OF-ELISA performance for pen-based samples. Individual oral fluid collection was feasible in all kinds of pigs, whereas pen-based samples were unsuccessful in 40% of the group-housed sow pens. High levels of sensitivity comparable to those of the SER-ELISA were found for the OF-ELISA when performed on individual, 5-sample pool or pen-based samples from pigs or sows. The OF-ELISA lacked specificity for individual samples from sows. Pooling 5 individual oral fluid samples or using pen-based samples increased test specificity.

Risk Evaluation and Mitigation Strategies (REMSs): Are They Improving Drug Safety? A Critical Review of REMSs Requiring Elements to Assure Safe Use (ETASU).

Risk Evaluation and Mitigation Strategies (REMSs) with Elements to Assure Safe Use (ETASU) are requested for drugs with significant safety risks. We reviewed REMS programs issued since 2011 to evaluate their rationales, characteristics, and consistencies, and evaluated their impact on improving drug safety. We conducted a literature search and a survey of relevant websites (FDA, manufacturers, and REMSs). ETASU characteristics were summarized. REMS risks were compared with labeled risks, including black box warnings. Forty-two programs were analyzed. Seven incorporated drugs of the same class. Most drugs (57%) were indicated for an orphan disease. A single risk was mentioned in 24 REMSs, and multiple risks in 18. Embryo-fetal toxicity and abuse or misuse were the most frequent risks. All risks were identified during clinical development but some were hypothetical. Thirty-six drugs had a black box warning. REMS risks and black box risks differed for 11 drugs. A drug with multiple indications could have a REMS for one of them but not for another. Most REMSs required prescriber training and certification, half required dispenser certification and patient enrolment. REMSs were revised multiple times and only three (7%) were discontinued. No data were available to establish whether REMSs were effective in improving drug safety. Some REMSs were deemed inefficient. REMSs with ETASU continue to be implemented but their impact on improving drug safety is still not documented. Hence, one of the main requirements of the FDA Amendments Act of 2007 is not being addressed. In addition, REMSs are complex and their logic is inconsistent; we recommend a thorough re-evaluation of the REMS program.

The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with Febuxostat When Treating Hyperuricemia Associated with Gout.

OBJECTIVE: Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. METHODS: Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. RESULTS: Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC)(0-t) of ARH acid + FBX/ARH acid was 108%. The AUC(0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. CONCLUSION: ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. TRIAL REGISTRATION: NCT02252835.

Review: Drinking water for liquid-fed pigs.

Liquid feeding has the potential to provide pigs with sufficient water to remain hydrated and prevent prolonged thirst. However, lack of permanent access to fresh water prevents animals from drinking when they are thirsty. Moreover, individual differences between pigs in a pen may result in uneven distribution of the water provided by the liquid feed, leading to some pigs being unable to meet their water requirements. In this review, we look at the need for and provision of water for liquid-fed pigs in terms of their production performance, behaviour, health and welfare. We highlight factors which may lead to water ingestion above or below requirements. Increases in the need for water may be caused by numerous factors such as morbidity, ambient temperature or competition within the social group, emphasising the necessity of permanent access to water as also prescribed in EU legislation. The drinkers can be the target of redirected behaviour in response to feed restriction or in the absence of rooting materials, thereby generating water losses. The method of water provision and drinker design is critical to ensure easy access to water regardless of the pig's physiological state, and to limit the amount of water used, which does not benefit the pig.

A Randomized, Double-Blind, Active- and Placebo-Controlled Efficacy and Safety Study of Arhalofenate for Reducing Flare in Patients With Gout.

OBJECTIVE: Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout. METHODS: This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure. RESULTS: A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups. CONCLUSION: Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy.

Risk factors associated with leg disorders of gestating sows in different group-housing systems: a cross-sectional study in 108 farrow-to-finish farms in France.

Group-housing, rather than individual-housing systems, is mandatory for gestating sows in the European Union (2008/120/EEC). However, leg problems occur more frequently in group-housing than in individual-housing systems and are a welfare and health concern. A cross-sectional study involving 108 farms in western France was carried out to see whether the type of the 4 main group-housing systems (i.e. large groups with electronic feeder station in stable or in dynamic groups, small groups in walk-in lock-in stalls or partial feeding stalls), and other husbandry practices, were associated with leg disorders. In each farm, the sows were examined visually for claw lesions, scored for lameness and their breeding characteristics were recorded. Lameness was positively correlated with heel lesions and dewclaw lesions. A concrete slatted floor, as compared to straw, was a major risk factor (unadjusted relative risk (RR)=9.9; 95% confidence interval (95% CI): 4.4-34.5). Walk-in lock-in stalls were found to be the most protective system. A logistic regression model was used to identify those factors which significantly increased the risk of leg problems. These factors were: housing in large groups (RR=1.5; 95% CI: 1.1-2.4), dirty floors (RR=1.6; 95% CI: 1.0-2.9), high level of ammonia (RR=1.5; 95% CI: 1.1-2.1), severely restricted feeding particularly during the last stage of pregnancy (RR=1.5; 95% CI: 1.0-2.1) and a high number of sows per stockman (RR=1.5; 95% CI: 1.0-2.4).

Resveratrol attenuates NF-κB-binding activity but not cytokine production in mechanically ventilated mice.

BACKGROUND: Mechanical ventilation (MV) can result in inflammation and subsequent lung injury. Toll-like receptor (TLR)4 and NF-κB are proposed to play a crucial role in the MV-induced inflammatory response. Resveratrol (RVT) exhibits anti-inflammatory effects in vitro and in vivo supposedly by interfering with TLR4 signaling and NF-κB. In the present study, we investigated the role of RVT in MV-induced inflammation in mice. METHODS: RVT (10 mg/kg, 20 mg/kg and 40 mg/kg) or vehicle was intraperitoneally administered 1 h before start of MV (4 h, tidal volume 8 ml/kg, positive end-expiratory pressure 1,5 cmH2 O and FiO2 0.4). Blood and lungs were harvested for cytokine analysis. DNA binding activity of transcription factor NF-κB was measured in lung homogenates. RESULTS: MV resulted in elevated pulmonary concentrations of IL-1ß, IL-6, keratinocyte-derived chemokine (KC) and NF-κB DNA-binding activity. RVT at 10, 20 and 40 mg/kg reduced NF-κB's DNA-binding activity following MV compared with ventilated controls. However, no differences in cytokine release were found between RVT-treated and control ventilated mice. Similarly, in plasma, MV resulted in elevated concentrations of TNF-α, KC and IL-6, but RVT did not affect cytokine levels. CONCLUSIONS: RVT abrogates the MV-induced increase in pulmonary NF-κB activity but does not attenuate cytokine levels. This implies a less prominent role for NF-κB in MV-induced inflammation than previously assumed.

Gene therapy as a new treatment option for inherited monogenic diseases.

BACKGROUND: Gene therapy, replacing a defective gene by a functional copy, has been in development for more than 40years. Initial efforts involved engineering viral vectors to deliver genes to the appropriate cells. Early successes in severe combined immunodeficiency (SCID) were later derailed by safety issues including host reaction to the vector and gene insertion near promoters that favored secondary leukemia. METHODS: Systematic review of the literature using PubMed.gov with key word gene therapy from 1972 to March 2013. Google search with key word gene therapy. RESULTS: Despite early setbacks, progresses for monogenic diseases continued unabated. Patients with SCIDs have been cured and the first gene therapy has been approved for lipoprotein lipase deficiency. Many clinical research studies are ongoing as part of systematic clinical development program with a view to have more gene therapies approved. CONCLUSION: Our review highlights progresses and questions that remain to be answered to make gene therapy an integral part of our therapeutic arsenal.

Clinical studies in lysosomal storage diseases: past, present and future.

Lysosomal storage disorders (LSDs) are made of over 40 diseases. Costly treatments have been developed. In this review, we consider the regulatory context in which LSDs studies are performed, and highlight design specificities and operational aspects. Orphan drug legislations in Europe and US were effective to stimulate LSDs drug development. However the flexibility of regulators to facilitate approval is inconsistent leading to worldwide differences in access to LSD treatments. Study designs are impacted because only few patients can be studied. This implies LSDs treatments need to demonstrate a large efficacy effect. Otherwise the level of evidence is difficult to demonstrate. While biomarkers could accelerate approvals, in LSDs none have been accepted as primary outcome of efficacy. Enrichment of study population can increase the chance of success, especially with clinical outcome. Adaptive designs are challenging. Innovative methods of analysis can be used, notably using a patient as his/her own control and responder analysis. Other characteristics include extension phases and patient registries to further data collection. Few patients are available per centers and more centers need to be initiated in multiple countries. This impacts time-lines and budget. For LSDs, development program should be individualized. Regulators flexibility will be essential to provide patients access to innovative treatments.

Clinical studies in lysosomal storage diseases: Past, present, and future.

Lysosomal storage disorders (LSDs) consist of over 40 diseases, some of which are amenable to treatment. In this review, we consider the regulatory context in which LSDs studies are performed, highlight design specificities and explore operational challenges. Orphan drug legislations, both in Europe and US, were effective to stimulate LSDs drug development. However, regulators flexibilities toward approval vary leading to global discrepancies in access to treatments. Study designs are constrained because few patients can be studied. This implies LSDs treatments need to demonstrate large levels of clinical efficacy. If not, an appropriate level of evidence is difficult to achieve. While biomarkers could address this issue, none have been truly accepted as primary outcome. Enrichment of study population can increase the chance of success, especially with clinical outcomes. Adaptive designs are operationally challenging. Innovative methods of analysis can be used, notably using a patient as his/her own control and responder analysis. The use of extension phases and patient registries as a source of historical comparison can facilitate data interpretation. Operationally, few patients are available per centers and multiple centers need to be initiated in multiple countries. This impacts time-lines and budget. In the future, regulators flexibility will be essential to provide patients access to innovative treatments.

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies.

BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. METHODS: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. RESULTS: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. CONCLUSIONS: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.

Preventive vaccination contributes to control classical swine fever in wild boar (Sus scrofa sp.).

Over the last 20 years, oral vaccination implementing a live attenuated vaccine has been experimented in Europe in order to control classical swine fever (CSF) in Wild Boar (Sus scrofa sp.). This has generally led to an enhanced seroprevalence and a decreased viroprevalence at the scale of the whole vaccinated populations, but no quantitative analysis has demonstrated the protective effect of preventive vaccination or intensive baiting. In the present paper we conducted a retrospective analysis at the scale of the municipality, taking into account the local dynamics and possible covariates of infection to test the effect of preventive vaccination and of the baiting effort. To be efficient, vaccination was expected to increase seroprevalence above the level considered as suitable for preventing disease invasion (40-60%) independently of infection, to protect free areas from disease invasion or contribute to control subsequent disease intensity and duration. We also hypothesized that a better baiting effort would be correlated with an improvement of immunisation and disease control. In uninfected municipalities, seroprevalence increased up to 40% after 1 year, i.e., three vaccination campaigns. We observed a significant protective effect of preventive vaccination, especially within municipalities that had been vaccinated at least 1 year before disease emergence and where virus detection did not last more than one quarter. On the other hand, we did not detect a significant effect of the baiting effort on local seroprevalence or disease dynamics, suggesting that the baiting system could be improved. We discuss these results regarding the improvement of management measures and further research perspective.

Isoflurane attenuates pulmonary interleukin-1beta and systemic tumor necrosis factor-alpha following mechanical ventilation in healthy mice.

BACKGROUND: Mechanical ventilation (MV) induces an inflammatory response in healthy lungs. The resulting pro-inflammatory state is a risk factor for ventilator-induced lung injury and peripheral organ dysfunction. Isoflurane is known to have protective immunological effects on different organ systems. We tested the hypothesis that the MV-induced inflammatory response in healthy lungs is reduced by isoflurane. METHODS: Healthy C57BL6 mice (n=34) were mechanically ventilated (tidal volume, 8 ml/kg; positive end-expiratory pressure, 4 cmH(2)O; and fraction of inspired oxygen, 0.4) for 4 h under general anesthesia using a mix of ketamine, medetomidine and atropine (KMA). Animals were divided into four groups: (1) Unventilated control group; (2) MV group using KMA anesthesia; (3) MV group using KMA with 0.25 MAC isoflurane; (4) MV group using KMA with 0.75 MAC isoflurane. Cytokine levels were measured in lung homogenate and plasma. Leukocytes were counted in lung tissue. RESULTS: Lung homogenates: MV increased pro-inflammatory cytokines. In mice receiving KMA+ isoflurane 0.75 MAC, no significant increase in interleukin (IL)-1beta was found compared with non-ventilated control mice. PLASMA: MV induced a systemic pro-inflammatory response. In mice anesthetized with KMA+ isoflurane (both 0.25 and 0.75 MAC), no significant increase in tumor necrosis factor (TNF)-alpha was found compared with non-ventilated control mice. CONCLUSIONS: The present study is the first to show that isoflurane attenuates the pulmonary IL-1beta and systemic TNF-alpha response following MV in healthy mice.

Two outbreaks of classical swine fever in wild boar in France.

In 2002 and 2003, two successive outbreaks of classical swine fever were declared in wild boar in northern France. The first was in Moselle, near the town of Thionville and the border with Luxembourg, and the second was in the northern Vosges area, near the German border. The outbreaks were investigated by serological and virological diagnosis of dead or shot animals. Hunting restrictions were applied to limit the spread of the outbreaks. The virus was detected eight times between April and July 2002 in the Thionville area, an area well delimited by natural or artificial barriers such as rivers or highways. Cooperation between the authorities concerned was good, and hunting restrictions were applied for one year. No virus was detected after July 2002 and the Thionville outbreak was officially considered over in March 2005. In the northern Vosges the situation was different, with no barriers to animal movements, continuous forest, difficulties in establishing hunting restrictions in this huge area, and the circulation of the virus in Germany close to the frontier. Virus of a different strain from that isolated in the Thionville outbreak was still being isolated in the northern Vosges in 2004, and owing to the failure of the hunting restrictions, the French health authorities decided to vaccinate wild boar.

Time course of action of sugammadex (Org 25969) on rocuronium-induced block in the Rhesus monkey, using a simple model of equilibration of complex formation.

BACKGROUND: Reversal of neuromuscular block can be accomplished by chemical encapsulation of rocuronium by sugammadex (Org 25969), a synthetic gamma-cyclodextrin derivative. The present study determined the time course of the reversal action of sugammadex on rocuronium-induced block in the anaesthetized Rhesus monkey using train-of-four stimulation. METHODS: A bolus injection of rocuronium 100 microg kg(-1) (about 1xED(90)) was given to determine the degree of neuromuscular block reached by this dose. After complete spontaneous recovery, a rapid bolus injection of sugammadex, 1 mg kg(-1), was given and at different time intervals (15, 30 or 60 min, in three different experiments) the effect of another rocuronium bolus injection of 100 microg kg(-1) was determined. RESULTS: Injection of the first dose of rocuronium resulted in a mean neuromuscular block (depression of first twitch) of 93 (SEM=1.6)%. Fifteen minutes after injection of sugammadex the same rocuronium dose resulted in 17% (SEM=5.6) block. After 30 and 60 min these maximum blocks amounted to 49% (SEM=7.6) and 79% (SEM=4.2), respectively. The estimated half-life of sugammadex in Rhesus monkey is 30 (SEM=4.9) min. CONCLUSIONS: The half-life of sugammadex (Org 25969), a new fast and efficient reversal agent for rocuronium-induced block, is relatively short in the Rhesus monkey, implying the possibility to perform neuromuscular block by rocuronium shortly after reversal of a prior block. In translation to the human situation differences in rocuronium sensitivity and kinetics should be taken into account.

The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee.

Ximelagatran is a new oral anticoagulant that acts by direct and reversible inhibition of thrombin and has the potential to replace warfarin. In 2004, the FDA Cardiovascular and Renal drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program. Three indications were proposed: the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR), the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF), and the long-term secondary prevention of VTE after standard treatment of an episode of acute VTE. The database consisted of a total of 30,698 subjects and included five phase III pivotal studies. During the advisory panel debate, widely divergent analyses of the benefits and risks of ximelagatran were presented. Ximelagatran hepatic toxicity was a key feature leading the CRAC to conclude that the benefit risk ratio of ximelagtran was unfavorable for the three proposed indications. Some design issues also undermined the strength of efficacy data. This paper reviews the benefits and risks of ximelagatran and analyzes the reasons leading to conflicting conclusions among various experts. The aim of this review is to facilitate the interpretation of benefits and risks associated with a new drug product and to improve future clinical drug developments.

Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey.

BACKGROUND: Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. The present study evaluated the ability of Sugammadex Org 25969, a synthetic gamma-cyclodextrin derivative, to reverse constant neuromuscular block of about 90% induced by rocuronium or the non-steroidal neuromuscular blocking drugs, mivacurium or atracurium, in the anaesthetized Rhesus monkey. METHODS: After a bolus injection of rocuronium, mivacurium or atracurium, a continuous infusion of these drugs was started to maintain the first twitch contraction of the train-of-four at approximately 10% of its baseline value. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either sugammadex 0.5 or 1.0 mg kg(-1) was given in the rocuronium-induced blockade and sugammadex 1.0 mg kg(-1) was given in the mivacurium- and atracurium-induced blockade. RESULTS: Sugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block. The recovery time to train of four ratio=0.9 after spontaneous recovery was 14.4 min (sd=3.4 min; n=14). This was reduced significantly (P<0.001) to 3.7 min (sd=3.3 min; n=4) with sugammadex 0.5 mg kg(-1) and to 1.9 min (sd=1.0 min; n=4) with sugammadex 1.0 mg kg(-1). Signs of residual blockade or re-curarization were not observed. Reversal of mivacurium- or atracurium-induced neuromuscular block (n=2 in each experiment) by sugammadex (1.0 mg kg(-1)) was not effective. In all experiments, injection of sugammadex had no effects on blood pressure or heart rate. CONCLUSIONS: Sugammadex is effective in reversing rocuronium, but not mivacurium- or atracurium-induced neuromuscular block.