Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

The aim of this study was to assess the biochemical profile of tench blood plasma during preand postspawning period under the conditions of hormonally-induced artificial reproduction. A total of 59 females and 27 males were examined during the postspawning period of 1999 and 52 females and 25 males were examined during the prespawning period of 2000, as well as 48 females after reproduction. Biochemical indices determined in blood plasma were as follows: cortisol, glucose, total protein (TP), triacylglycerols (Tcg), cholesterol (Chol), transaminases (ALT and AST), creatine kinase (CK), alkaline phosphatase (ALP) and electrolytes (Na). In females in the pre-spawning period, higher values of TP (P < 0.05) and Tcg (P < 0.01) were found compared to males. Immediately after reproduction, males had higher TP (P < 0.01) and Chol (P < 0.01) than females. No significant sex-related differences were found in other indices under study. Higher values of glucose (P < 0.01), Tcg (P < 0.01), Chol (P < 0.05), AST (P < 0.01) and ALP (P < 0.01) were found for females after reproduction in June compared to values found in April, i.e. two months prior to reproduction. Differing water temperature (10.3 °C in April; 22 °C in June) associated with metabolic rate also played an important role. Induction of ovulation by GnRH synthetic analogue and carp pituitary was not successful in all females. However, between the spawned and unspawned female fish, differences were found in glucose concentration (P < 0.01) but non-significant differences were recorded for other biochemical indices. The blood plasma biochemical profile enabled to assess the state of internal milieu of broodstock during the reproduction period.

ABSTRACT:The aim of the study was to compare physiological statuses of stripped and not stripped tench females with ovulation induced by GnRHa or carp pituitary extract (CPE). The comparison was based on selected biochemical stress indices (cortisol, glucose), condition (TP, TGA), and cell membrane characteristics (ALT, AST, CK). In the first and in the second year, 37 and 29 tench females were monitored, respectively. No differences in the values of biochemical parameters in either period were found between the two groups of stripped female tench whose ovulation was induced by GnRHa and CPE, respectively. No significant differences in TP, TGA, ALT, AST and CK values were found between the groups of stripped and not stripped females with ovulation induced by GnRHa or CPE. Different values were found in stress indices, specifically in glucose concentrations. A significant increase (P < 0.01) in glucose concentrations was found in tench females immediately after stripping and, in not stripped females, about 48 hrs after ovulation induction. Both artificial stripping and the inability to release eggs are important stress factors for female tench.

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