Efficacy and safety of piclidenoson in plaque psoriasis: Results from a randomized phase 3 clinical trial (COMFORT-1).

OBJECTIVE: A3 adenosine receptor (A3AR) is overexpressed in the skin and peripheral blood mononuclear cells of psoriasis patients. We investigated the efficacy/safety of piclidenoson (CF101), an orally bioavailable A3AR agonist that inhibits IL-17 and IL-23 production in keratinocytes, in moderate-to-severe plaque psoriasis. METHODS: The randomized, placebo- and active-controlled, double-blind phase 3 COMFORT-1 trial randomized patients (3:3:3:2) to piclidenoson 2 mg BID, piclidenoson 3 mg BID, apremilast 30 mg BID or placebo. At Week 16, patients in the placebo arm were re-randomized (1:1:1) to piclidenoson 2 mg BID, piclidenoson 3 mg BID or apremilast 30 mg BID. The primary end point was the proportion of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline (PASI-75) at Week 16 versus placebo. RESULTS: A total of 529 patients were randomized and received ≥1 dose of study medication (safety population). The efficacy analysis population for the primary end point included 426 patients (piclidenoson 2 mg BID, 127; piclidenoson 3 mg BID, 103; apremilast, 118; placebo, 78). Piclidenoson at 2 and 3 mg BID exhibited similar efficacy. The primary end point was met with the 3 mg BID dose: PASI 75 rate of 9.7% versus 2.6% for piclidenoson versus placebo, p = 0.037. The PASI responses with piclidenoson continued to increase throughout the study period in a linear manner. At week 32, analysis in the per-protocol population showed that a greater proportion of patients in the piclidenoson 3 mg BID arm (51/88, 58.0%) achieved improvement from baseline in Psoriasis Disability Index (PDI) compared to apremilast (59/108, 55.1%), and the test for noninferiority trended towards significance (p = 0.072). The safety/tolerability profile of piclidenoson was excellent and superior to apremilast. CONCLUSIONS: Piclidenoson demonstrated efficacy responses that increased over time alongside a favourable safety profile. These findings support its continued clinical development as a psoriasis treatment (ClinicalTrials.gov identifier: NCT03168256).

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial.

OBJECTIVE: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.

Higher Ca and Na content in the hair of obese people in Poland.

The authors of this paper decided to check whether the content of selected minerals in human hair is projected into the nutritional status of the body expressed as the BMI. The study focused on evaluating the content of calcium, sodium, potassium and magnesium in the hair of 7845 individuals in relation to their BMI. 5126 women and 2719 men aged from 18 to 92, domiciled throughout Poland, were involved in the study. Hair samples were taken from several points of the occipital scalp. Ca, Na, K and Mg in the hair were determined using inductively coupled plasma optical emission spectrometry (ICP-OES). The content of Ca and Na in the hair of obese people (>30.0 kg·m2) was higher (323 mg·kg-1 and 180 mg·kg-1) in comparison with the groups of people with normal body weight and those grade 2 underweight (<16.9 kg·m2): 191 mg·kg-1 and 103 mg·kg-1 respectively. The highest level of K (317 mg·kg-1) was found in the hair of people classed as grade 2 underweight. The body mass index caused no differentiation in the content of Mg in hair. Positive correlations were found between Ca-Na, Ca-Mg and Na-Mg and between the BMI of the subjects and the content of Ca in hair (R = 0.163; p < 0.01) and between the BMI and the content of Na (R = 0.191; p < 0.01). On the other hand, a negative relation between K and the BMI was correlated only to an infinitesimal degree (R = -0.030, p < 0.01). The results point to a relationship between the body mass index and the content of Ca, Na and K in the hair of adults.

Effects of maternal treatment with ß-hydroxy-ß-metylbutyrate and 2-oxoglutaric acid on femur development in offspring of minks of the standard dark brown type.

The aim of the study was to evaluate the effect of the diet, mother type and sex of the offspring on the mechanical and geometric parameters of long bones as well as bone tissue density in minks. Primiparous and multiparous dams were supplemented with ß-hydroxy ß-methylbutyrate (a metabolite of leucine, at the daily dosage of 0.02 g/kg of body weight) and/or 2-oxoglutaric acid (a precursor of glutamine, at the daily dosage of 0.4 g/kg of body weight) during gestation. The diet did not influence bone tissue density and the length of the humerus. An increase in the length of the femur was noted in male offspring delivered by multiparous dams. The diet resulted in an increase in the weight of the humerus in males from multiparous dams and a decrease in offspring from primiparous dams. Heavier femora were noted in male offspring delivered by both types of dams. The maximum elastic strength of the humerus was higher in the offspring delivered by multiparous than primiparous dams, irrespective of the offspring sex. The diet resulted in reduction in the ultimate strength of the femur in the male offspring delivered by primiparous dams. Only females born by multiparous dams, irrespective of the diet, showed a significant increase in the cross-sectional area of the humerus, while a significant decline was noted in males delivered by multiparous dams and in all the offspring delivered by primiparous dams. An increase in the cross-sectional area of the femur was noted in the offspring delivered by multiparous dams, while reduction was observed in the offspring delivered by primiparous dams. These results have shown for the first time that the presence of ß-hydroxy-ß-methylbutyrate or 2-oxoglutaric acid in the diet of pregnant primiparous or multiparous dams unambiguously affects the geometry and mechanical properties of offspring's long bones.

Long-bone properties and development are affected by caponisation and breed in Polish fowls.

1. The aim of the study was to investigate the effects of caponisation on bone development of males of two native breeds in Poland. 2. The weight, length and cross-sectional area of tibiae and femora were measured, densitometric measurements and tests of strength were determined and dimensions were calculated. 3. Breed and caponisation did not influence bone weight and length. Higher mechanical strength of the femur was found in entire males, mainly in the Polbar breed. Tibial strength was reduced in capons of the Green Partridge breed. Maximum elastic strength was greater in the Polbar, irrespective of caponisation. Bone cross-sectional area was influenced by breed, while caponisation reduced femoral bone mineral density in both breeds. 4. Caponisation thus increased growth rate but had adverse effects on bone development. 5. Caponisation had fewer negative effects in the Polbar than in the Greenleg Partridge.

Phenotypic and genetic variation in longevity of Polish Landrace sows.

The influence of some production traits on the longevity of Polish Landrace sows was evaluated using survival analysis. Estimates of genetic parameters were obtained from the sire and animal components in linear and survival methodologies. Comparison between survival and linear models was based on heritabilities and ranking of estimated breeding values of sires. The same data set, 13,031 sows, was used for both methodologies, even in the presence of censored observations. The effects of herd*year and year*season of the first farrowing had the largest influence on the risk of culling of sows. Sows born in spring season (March-May) had a 24% (p < 0.001) lower hazard for removal than those born in winter (December-February). The age at first farrowing had a small but significant effect on culling: the hazard regression coefficient for this trait was 0.002 per day. Sows that had more piglets born alive and fewer stillborn in the first litter had a decreased risk of being culled. Within a contemporary group, slower growing gilts had decreased removal risk. The relative risk ratios show a marginal decreased rate of culling for sows with backfat thickness between 9.5 and 11 mm compared to the leaner sows. Loin depth had no effect on sow longevity. Heritability estimates ranged from 0.09 to 0.38 depending on the model and type of analysis. In survival analysis, all heritabilities for longevity were higher when analysed with sire models (0.21 and 0.38) compared to animal models (0.09 and 0.16). The use of animal or sire models in the linear analysis gave similar heritability estimates (0.12 and 0.10). Correlations between breeding values for sires were moderate and high, with absolute values from 0.51 to 0.99, depending on the model fitted and methodology. A stronger correlations within methodologies (0.83-0.99) than within models with different methodologies (0.51-0.63) were obtained.

Relationships between longevity, lifetime productivity, carcass traits and conformation in Polish maternal pig breeds.

The objective of this study was to obtain heritability estimates for longevity (length of life, length of productive life, number of litters) and lifetime productivity traits (lifetime pig production, lifetime pig efficiency, lifetime litter efficiency) and genetic correlation between them and litter size at first farrowing, growth (ADG), backfat thickness (BF), loin depth, lean meat percentage (LMP), phenotypic selection index (PSI), and exterior in 19423 Polish Landrace (L) and 16049 Polish Large White (LW) sows. Heritabilities for longevity and lifetime productivity traits were 0.10-0.13 for L sows and 0.09-0.11 for LW sows depending on the trait definition. The genetic correlations among these traits were all high and positive, ranging from 0.76 to 0.99. Antagonistic genetic correlations (-0.21 to -0.26) were found between longevity traits and PSI and LMP in LW sows, while in L sows the respective parameters were lower and not significant for length of productive life. The number of live-born piglets in the first litter was positively correlated with lifetime pig production and lifetime pig efficiency in both breeds. The genetic correlations of longevity and lifetime pig production with ADG, BF, loin depth and exterior were small, and in most cases, not significant.

Embryofetotoxicity of acetaminophen (paracetamol) in experimental in vivo model.

The aim of the study was to evaluate the toxic effect of acetaminophen on rat fetuses. Acetaminophen, suspended in Tween 80 solution, was administered once a day, orally by a stomach tube to pregnant Wistar rats from day 8th to 14th of pregnancy at the dose: 3.5 (P1), 35.0 (P2), 350.0 mg/kg (P3). The pregnant females were terminated on day 21st of pregnancy and the number of corpora lutea, implants, resorptions, and fetuses was counted. The fetuses and the placentas were weighed and the length of the fetuses and their tails were checked. The slides of the fetal liver were examined via light microscopy in four stains: hematoxylin and eosin, silver Gomorii, van Giesson, and periodic acid-Schiff. There was a statistical (p < 0.05) difference in fetal body length in group P3 without any macroscopic malformation, except for the non-statistical number of subcutaneous ecchymoses. Histological adaptive changes of the fetal liver were observed occasionally in all the studied groups. In conclusion, the oral administration of acetaminophen caused an embryotoxic effect in the highest doses without any macroscopic malformation, and only slightly impaired morphology of the rat fetal liver.