Reduced antibody response to tetanus toxoid (TT) was previously demonstrated during vitamin A deficiency but the response to bacterial lipopolysaccharide (LPS) was normal. We addressed whether anti-TT IgG responses are enhanced in vitamin A-sufficient and deficient rats by immunization with LPS plus TT. Antibody responses in vitamin A-sufficient and deficient rats increased significantly after coimmunization (LPS + TT) compared with the response of rats immunized with TT alone. In additional studies, recombinant tumor necrosis factor-alpha (TNF-alpha) also significantly increased the anti-TT IgG concentrations. Because pretreatment with anti-TNF before coimmunization or immunization with TT alone markedly reduced the anti-TT IgG responses, we infer TNF to be a mediator of both the adjuvanticity of LPS and the unstimulated response to TT. In conclusion, vitamin A-deficient rats can be stimulated to respond to TT by coimmunization with LPS or by treatment with TNF.

Purpose: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. Methods: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries.Results: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris.Conclusions: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Two experiments using 42 crossbred neonatal pigs to compare the effects of caprine and bovine milk on growth, apparent nutrient digestibility and body composition were conducted. At age 72 h, pigs were removed from their dams and randomly divided into two groups, housed separately in stainless steel metabolism cages and were fed a predetermined amount (300 mL/kg body weight) of pasteurized, nonfortified whole, caprine or bovine milk. Body composition was determined using dual energy X-ray absorptiometry (DXA). In Experiment 1, 22 intact male pigs were used for a 31-d experimental period. There was no significant (P > 0.05) dietary effect on growth, apparent nutrient digestibility or body composition. Significant differences (P < 0.05), however, were observed in plasma of C 8:0, C 10:0 and C 12:0 concentrations. In Experiment 2, 20 pigs (10 intact males and 10 females) were used in a 2 x 2 factorial experiment for 52 d. Pigs fed caprine milk had higher (P < 0.05) plasma concentrations of C10:0 and C12:0 as well as Na, Mg and Zn than those fed bovine milk. At Day 52, pigs fed caprine milk had less body fat (P < 0.001) and higher (P < 0.06) bone mineral density than those fed bovine milk. Drymatter, N and total mineral intake of male pigs was higher (P< 0.05) than female pigs. Also, male pigs had higher (P < 0.05) plasma concentrations of C12:0 than females. This study demonstrates that the type of milk consumed can influence plasma concentrations of fatty acids, minerals and body composition in pigs.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open‐label, multi‐dose study, 73 subjects were divided into six treatment groups: (1) 55–65 years; (2) 66–75 years; (3) >75 years (dosing for groups 1–3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired‐no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0−τ)ss was 112.2 (90% CI; 92.0–136.8) and Cmax,ss was 109.9 (89.6–134.8), Group 3 and 1 of AUC(0−τ),ss was 140.5 (115.9–170.3) and Cmax,ss was 137.8 (112.9–168.2), Group 4 and 1 of AUC(0−τ),ss was 114.2 (90.3–144.4) and Cmax,ss was 120.8 (92.5–157.8), Group 5 and 1 of; AUC(0−τ),ss was 213.0 (153.1–296.3) and Cmax,ss was 123.3 (92.2–164.7) and Group 6 and 1 of AUC(0−τ),ss was 247.4 (197.8–309.6) and Cmax,ss was 95.6 (73.0–125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well‐tolerated.

Aim This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. Methods This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. Results Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h−1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h−1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. Conclusion Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.