Animal trypanosomosis: making quality control of trypanocidal drugs possible.

African animal trypanosomosis is arguably the most important animal disease impairing livestock agricultural development in sub-Saharan Africa. In addition to vector control, the use oftrypanocidal drugs is important in controlling the impact of the disease on animal health and production in most sub-Saharan countries. However, there are no internationally agreed standards (pharmacopoeia-type monographs or documented product specifications) for the quality control of these compounds. This means that it is impossible to establish independent quality control and quality assurance standards for these agents. An international alliance between the Food and Agriculture Organization of the United Nations, the International Federation for Animal Health, the Global Alliance for Livestock Veterinary Medicines, the University of Strathclyde and the International Atomic Energy Agency (with critical support from the World Organisation for Animal Health) was established to develop quality control and quality assurance standards for trypanocidal drugs, with the aim of transferring these methodologies to two control laboratories in sub-Saharan Africa that will serve as reference institutions for their respective regions. The work of the international alliance will allow development of control measures against sub-standard or counterfeit trypanocidal drugs for treatment of trypanosome infection. Monographs on diminazene aceturate (synonym: diminazene diaceturate), isometamidium chloride hydrochloride, homidium chloride and bromide salts and their relevant veterinary formulations for these agents are given in the annex to this paper. However, the authors do not recommend use of homidium bromide and chloride, because of their proven mutagenic properties in some animal test models and their suspected carcinogenic properties.

30-day outcomes in 1 000 consecutive laparoscopic cholecystectomies undertaken in four Cape metropole public hospitals.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard of care for symptomatic gallstone disease. The procedure has a steep learning curve and may result in significant postoperative morbidity and mortality. LC carries a morbidity of 1.6-5.3%, a mortality of 0.05-0.14% and readmission rates of 3.3% (0-11.7%). We aimed to evaluate the 30-day outcomes of LC across four metropole hospitals in the Western Cape (WC) including mortality, length of stay, readmissions and complications according to the Clavien-Dindo classification system. METHODS: A retrospective review of a prospective database was performed. Data were collected between September 2019 and July 2022. Relative clinical, operative findings and postoperative outcomes were analysed. RESULTS: There were 1 000 consecutive LCs included in this study. The mean postoperative length of stay was 1.92 days. Forty surgical complications were noted of which the most common were a bile leak (n = 14) and intra-abdominal collections (n = 11). Seven patients with bile leaks required reintervention. Four (0.4%) bile duct injuries (BDI) were reported in our series. Twenty-five percent of postoperative complications were graded as Clavien-Dindo IIIa and 28% were graded as Clavien-Dindo IIIb. The 30-day readmission rate was 3.8% (n = 38). Thirty-five patients were readmitted with surgical complications. There were three reported deaths (0.3%). CONCLUSION: Laparoscopic cholecystectomy is considered the standard of treatment for gallstone disease but a small percentage may have serious complications. The outcomes reported in this series are similar to that of other reported studies.

Outcomes of complex burn injury patients managed at two primary and one tertiary level burns facilities in the Western Cape province of South Africa - a retrospective review.

BACKGROUND: This study aimed to compare factors contributing to a positive outcome of adult burn injury patients managed at two primary and one tertiary level Western Cape hospitals. These patients from the primary hospitals (PLHs) met the referral criteria for specialised care at the Tygerberg Hospital burns unit (TBU) but were not accepted or were accepted late. METHODS: A total of 1034 adult burn injury patients seen at two primary level ("A" and "B") hospitals and the TBU between 2016 and 2019 were retrospectively analysed. One hundred and eleven (111) primary level patients ("A" 71, "B" 40) met the criteria for referral to the TBU. The outcomes and factors contributing to positive outcome of these patients were compared with the 859 patients treated at the TBU during the same period. RESULTS: Patients treated at the TBU showed longer theatre waiting times, more operations, and higher complication and death rates than their primary level counterparts. The PLHs showed no factors significantly contributing to hospital discharge. At TBU, pregnancy status, younger age, hot water burns, lower abbreviated burns severity index (ABSI) score, and longer time to theatre were associated with hospital discharge. A shortage of beds was the main reason for denial of admission to the TBU. CONCLUSION: The PLHs showed good outcomes in managing severe burn injuries, although no significant contributors to a positive outcome were identified. Patient- and facility-related factors contributed to positive outcomes at the TBU. Upgrading both the Western Cape's primary level capabilities and the TBU's accessibility and efficiency are necessary to improve burns services.

Outcomes of complex burn injury patients managed at two primary and one tertiary level burns facilities in the Western Cape province of South Africa - a retrospective review.

BACKGROUND: This study aimed to compare factors contributing to a positive outcome of adult burn injury patients managed at two primary and one tertiary level Western Cape hospitals. These patients from the primary hospitals (PLHs) met the referral criteria for specialised care at the Tygerberg Hospital burns unit (TBU) but were not accepted or were accepted late. METHODS: A total of 1034 adult burn injury patients seen at two primary level ("A" and "B") hospitals and the TBU between 2016 and 2019 were retrospectively analysed. One hundred and eleven (111) primary level patients ("A" 71, "B" 40) met the criteria for referral to the TBU. The outcomes and factors contributing to positive outcome of these patients were compared with the 859 patients treated at the TBU during the same period. RESULTS: Patients treated at the TBU showed longer theatre waiting times, more operations, and higher complication and death rates than their primary level counterparts. The PLHs showed no factors significantly contributing to hospital discharge. At TBU, pregnancy status, younger age, hot water burns, lower abbreviated burns severity index (ABSI) score, and longer time to theatre were associated with hospital discharge. A shortage of beds was the main reason for denial of admission to the TBU. CONCLUSION: The PLHs showed good outcomes in managing severe burn injuries, although no significant contributors to a positive outcome were identified. Patient- and facility-related factors contributed to positive outcomes at the TBU. Upgrading both the Western Cape's primary level capabilities and the TBU's accessibility and efficiency are necessary to improve burns services.

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner.

Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD(+)) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD(+) promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD(+)-dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD(+) does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors.

[Doxycycline: pharmacokinetics and suggested dosage in dogs and cats]. / Doxycycline: farmacokinetiek en doseringsvoorstellen bij hond en kat.

Data on the pharmacokinetics of doxycycline in dogs and cats are reported. Doxycycline was given orally in the form of palatable tablets of Ronaxan. Tablets of 100 mg of doxycycline (as hyclate) were used in dogs, whereas cats were given tablets of 20 mg. The doses administered were 10 mg/kg in both species. The pharmacokinetics of doxycycline in dogs and cats were compared with those obtained in man (at a dosage of 3 mg/kg/day). It is concluded that a dosage of 10 mg/kg/day of doxycycline is required to obtain effective plasma concentrations in dogs and cats for 24 hours, when this dose is administered once daily.

Use of cymelarsan in goats chronically infected with Trypanosoma evansi.

Toxicity and therapeutic trials using Cymelarsan (an arsenical compound) against Trypanosoma evansi infection were carried out using chronically infected goats. For the toxicity trial, 40 goats were divided into four groups of 10 animals each; the first three groups received s.c. injections of 5, 10, and 15 mg/kg bw of Cymelarsan, respectively, and the last one served as control. No systemic reaction was observed in any goat throughout the experiment. For the therapeutic trial, 15 adult female goats were inoculated intravenously with at least 1 x 10(5)T. evansi isolated in the Canary Islands. Six months after inoculation, the animals were treated with Cymelarsan at single dose of 0.3 mg/kg (5 animals), 0.5 mg/kg (5 animals), and 0.625 mg/kg (5 animals). At 4 and 6 weeks after treatment, two goats belonging to 0.3 mg/kg group showed recurrence of trypanosomes. Parasitemia, however, was negative in all animals belonging to 0.5 and 0.625 mg/kg groups until the end of the experiment (6 months after treatment). Thus, it can be concluded that Cymelarsan is a safe trypanocidal drug for goats and that the curative dose is 0.5 mg/kg or above.

Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity.

A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.

Evaluation of nitroxynil and closantel activity using ELISA and egg counts against Fasciola hepatica in experimentally and naturally infected cattle.

The responses of cattle infected with Fasciola hepatica to treatment with nitroxynil or closantel were monitored by faecal egg counts and by ELISA assay of anti-fluke antibodies. A first trial with experimentally infected heifers showed an increase in anti-fluke antibody titre as early as 2 weeks post-infection. Eggs were first detected in the faeces 10 weeks after infection. Egg output increased steadily over the next 8 weeks and then rapidly decreased. Treatment of a 20-week infection with nitroxynil was followed by a slow decrease in antibody titre 4 weeks later. This decrease continued over the next 40 weeks, but returned to pre-infection levels in only 2 out of 4 animals. The faecal egg count fell to zero 2 weeks after treatment and remained so for the following 30 weeks, although 1 animal produced a few eggs 32 and 34 weeks post-treatment. Within this period, neither diagnostic technique discriminated between this persistently infected animal and the others. In a second trial, 45 cattle from a naturally infected herd were treated with nitroxynil or closantel. The faecal egg counts of the treated cattle were zero within the following 2 months, whereas there were eggs in the faeces of the control (untreated) group. Nevertheless, the treated cattle showed a small, non-significant drop in anti-fluke antibody titre. These results demonstrate the need for new tools to monitor and evaluate accurately the efficacy of anthelmintic treatment.

Pharmacokinetics of ketoprofen in the donkey (Equus asinus).

The pharmacokinetic parameters of ketoprofen were determined in four donkeys after a single intravenous injection of a dose of 2.2 mg/kg body weight. The total body clearance (ClB) was 414.0 +/- 98.70 ml/h/kg (mean +/- SD), the volume of distribution at steady state (Vss) 263.10 +/- 55.43 ml/kg and the elimination half-life 1.30 +/- 0.75 h. These values were compared to those obtained in horses.