Increase of Adverse Events After Intravenous Injection of Gentamicin in Horses Between 2015 and 2017-From Marketing Authorization Holder's Point of View.

Between 2015 and 2017, a marked increase of anaphylactic-like reactions after intravenous administration of gentamicin was observed first in horses and, later, also in humans. This worldwide issue led to safety measures including product recalls and safety warnings. Here, a German Marketing Authorization Holder (MAH) of an early and intensely affected veterinary product containing gentamicin describes the clinical approach of the company to analyze the root cause and identify the causative agent in the active pharmaceutical ingredient (API). The pharmacovigilance data of the MAH are presented, along with pharmacovigilance phenomena observed during the affected period. An overview is given on further investigations of the API manufacturer and measures taken by all parties involved, including competent authorities to reestablish a safe use of gentamicin products. The histamine contamination of gentamicin was an exceptional incident of global extent, affecting not only veterinary but also human drug safety. The reactions in horses transpired to also be an indicator of a human health threat, which ultimately contributed to an improvement in the safety of human and veterinary medicinal products containing fermentative APIs. The extreme dimensions of this issue emphasise the important role that veterinary clinicians and practitioners play in spontaneous reporting based pharmacovigilance systems and, by this, in drug safety.

Genital blood flow and endometrial gene expression during the preovulatory period after Prostaglandin F(2alpha)-induced luteolysis in different luteal phases in cows.

The aim of this study was to examine the hypothesis that follicular and uterine perfusion as well as endometrial gene expression during the ovulatory period differs after induction of luteolysis during the 1(st) follicular wave compared with the 2(nd) wave or in intact cycle. Nine healthy non-lactating Holstein-Friesian cows were examined during three estrous cycles. A prostaglandin F(2alpha) analogue (PGF) was administered randomly either on Day 7 (1(st) wave cycle) or Day 11 (2(nd) wave cycle) after detection of ovulation (=Day 1). No hormonal treatment was used in the intact cycle with spontaneous ovulation. Transrectal Doppler sonography was conducted daily after PGF injection and in the intact cycle beginning on Day 18 of the estrous cycle until ovulation. Follicular blood flow (FBF) was determined by measuring the maximum area of colour pixels on digitalized images of the follicles. Uterine blood flow was quantified by the time-averaged maximum velocity (UTAMV) and pulsatility index (PI) in both uterine arteries. Blood flow measurements were carried out on Days -1 and 0. Endometrial biopsy specimens were taken on Day 1 and analyzed for the gene expressions of estrogen, progesterone, oxytocin and VEGF receptors and eNOS and iNOS using RT-PCR. The interval from PGF injection to ovulation was shorter (P<0.05) in 1(st) wave cycles than in 2(nd) wave cycles. On Days 0 and -1, FBF was greater (P<0.05) in 1(st) wave cycles than in intact and 2(nd) wave cycles. On Day -1, UTAMV was greater (P<0.05) in 1(st) wave cycles than in intact and 2(nd) wave cycles. There were no differences (P>0.05) in FBF and UTAMV values between 2(nd) wave and intact cycles. No differences (P>0.05) were detected in the gene expressions of endometrial receptors and enzymes between intact, 1(st) and 2(nd) wave cycles. The results show that follicular and uterine perfusion during the ovulatory phase are higher after induction of luteolysis during the 1(st) follicular wave compared with the 2(nd) wave or intact cycle. There were no effects on endometrial gene expression.