Evaluation of fever in the immediate post-operative period following shoulder arthroplasty.

AIMS: To determine the incidence and timing of post-operative fevers following shoulder arthroplasty and the resulting investigations performed. PATIENTS AND METHODS: A retrospective review was conducted of all patients undergoing shoulder arthroplasty over a nine-year period. The charts of all patients with a post-operative fever (≥ 38.6°C) were reviewed and the results of all investigations were analysed. RESULTS: A total of 2167 cases (in 1911 patients) were included of whom 92 (4.2%) had a documented fever. Obese cases had a significantly greater risk for fever (relative risk 1.53; 95% confidence interval 1.02 to 2.32; p = 0.041). Investigations were performed in 43/92 cases (46.7%), with a diagnosis being made in six cases (6.6% of the total, two of whom had their diagnosis made post-discharge). CONCLUSION: Around one in 25 cases develop a fever following shoulder arthroplasty; most have no infective aetiology. These patients may be being over-investigated; investigations should be performed in patients with persistent fever or on those with an identifiable source of infection on clinical examination. Cite this article: Bone Joint J 2017;99-B:1515-19.

The in vivo dermal absorption and metabolism of [4-14C] coumarin by rats and by human volunteers under simulated conditions of use in fragrances.

The disposition and metabolic fate of [4-14C]coumarin in a 70% aqueous ethanol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simulate that which may be encountered when using an alcohol-based perfumed product. In both cases, the 6-h exposure was 0.02 mg/cm(2) (rats 0.023 mg/kg and humans 0.77 mg/kg). In both, coumarin was quickly absorbed, distributed and excreted in urine and feces, although fecal excretion of coumarin in humans was only 1% of the applied dose as opposed to 21% in rats. Total absorption was 72% of the applied dose with rats and 60% with humans. Peak plasma radioactivity in both was at 1 h. The mean plasma half-life of coumarin and metabolites was approximately 1.7 h for humans and 5 h for rats. In humans, coumarin was primarily metabolized to and excreted in urine as 7-hydroxycoumarin glucuronide and 7-hydroxycoumarin sulfate. Small amounts of unconjugated 7-hydroxycoumarin and o-hydroxyphenylacetic acid (o-HPAA) were also excreted. In rats, about twenty metabolites were present, but only o-HPAA was identified. These studies show the rat is a very poor model for humans and toxicity in the rat cannot be extrapolated to humans.

The metabolic fate of 14C-ximoprofen in rats, baboons and humans.

1. The metabolic fate of 14C-ximoprofen was compared in rat (2 mg/kg), baboon (2 mg/kg) and human (approx. 0.4 mg/kg). An oral dose was well absorbed in all three species as indicated by urinary excretion of 80%, 86% and 94% dose respectively in 5 days: excreted in the faeces were 14%, 2% and 2% dose respectively. 2. Total 14C in plasma reached peak concentrations at 1-1.5 h in humans and earlier in animals. In humans, plasma 14C was initially associated mainly with unchanged drug which declined with a half-life of about 2 h (plasma 14C t1/2 about 8 h; cf. about 6 h in animals). 3. Tissue 14C concentrations in rats were generally similar to those in baboons at 1 h after dosing, decreasing substantially at later times. The distribution of 14C was consistent with that of a compound readily eliminated. 4. The major biotransformation products of ximoprofen were formed by hydrolysis to the keto-analogue followed by reduction to the hydroxy-analogue and conjugation of these two compounds. The same major metabolites were detected in urine of rat, baboon and humans but there was (a) complete biotransformation of ximoprofen in the rat, (b) an apparent difference in the nature of the conjugated component(s) in rat urine and those in baboon and human urine, (c) only one hydroxy-analogue detected in human urine but two such compounds in animal urine as indicated by mass spectrometry. 5. In human plasma at peak concentrations, the relative importance of circulating components was ximoprofen greater than keto-analogue greater than hydroxy-analogue, whereas in the plasma of the animal species this order was reversed, consistent with the more extensive biotransformation of ximoprofen observed in rat or baboon.

The metabolic fate of 11-bromo[15-3H]vincamine in man.

During 5 days following a single oral dose of 3H-11-bromovincamine (40 mg) to two human subjects, means of 55% and 27% of the 3H dose were excreted in the urine and faeces respectively, mainly within 24 and 48 h. Mean plasma concentrations of 3H reached a peak (1900 ng equiv./ml) at 1 h after dosing and declined biphasically with half-lives of 5 h and 11 h which were similar to half-lives for urinary excretion of 3H. Parent drug and 11-bromovincaminic acid were the major dose-related components in plasma at 1.5 and 3 h. Mean plasma concentrations of 11-bromovincamine reached a peak (620 ng/ml) at 0.75 h and declined biphasically with half-lives of about 1 h and 5 h. The major urinary metabolite was 11-bromovincaminic acid (31% dose). Also present in urine were 11-bromovincamine (3%), 11-bromoapovincamine (1%) and 2 unknown metabolites (9% and 6%). Similar metabolites were detected in faecal extracts. If inadequately stored in biological samples, 11-bromovincamine could be hydrolysed to 11-bromovincaminic acid and be epimerised to 11-bromo-epivincamine.

The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans.

1. Single oral doses of the anticholinergic drug [14C]Sormodren to rats (1 mg/kg), dogs (0.3 mg/kg) and humans (0.03 mg/kg) were well absorbed. Excreted in urine and faeces were means of 31 and 70%, 53 and 39%, and 78 and 4% in rats, dogs, and humans, respectively, during five days: excretion was prolonged and still incomplete at five days in humans. 2. Peak plasma levels of 14C (scaled for dose) were generally reached within 1-2 h after oral doses in rats, 49 (ng/ml)/(mg/kg), dogs 290 (ng/ml)/(mg/kg) and humans 410 (ng/ml)/(mg/kg), and declined with half-lives of approx. 5, 12 and 30 h, in these species respectively. Repeated oral doses of [14C]Sormodren to dogs resulted in some accumulation of 14C in the plasma. 3. Tissue concn. of 14C in dogs were generally higher than those in rats, particularly in the brain, lungs and eyes. The tissue distribution of 14C in rats and dogs was consistent with that of a compound readily eliminated by both renal and hepatic routes. 4. Basic metabolites in dog and human, urine and plasma were investigated using a combination of h.p.l.c. and g.l.c.-mass spectrometry. Unchanged Sormodren was not detected in the dog samples and was only a minor component in human urine and plasma. Some metabolites were present as conjugates. 5. A basic extract of enzyme-hydrolysed dog urine (5 mg/kg dose) contained 42% of the urine 14C. The major metabolites in this fraction were identified as three isomers of monohydroxy-N-desethyl-Sormodren and three isomers of monohydroxy-Sormodren, resulting from hydroxylation in the bicyclic ring. The positions of oxidation were not determined. A similar extract from dog urine (0.3 mg/kg dose) contained 26% of the urine 14C and the major metabolites were identified as isomers of monohydroxy-N-desethyl-Sormodren. 6. A basic extract of enzyme-hydrolysed human urine (0.03 mg/kg dose) contained 23% of the urine 14C. The unchanged drug was only a minor component and most of the radioactivity was associated with five isomers of monohydroxy-Sormodren, hydroxylation having occurred in the bicyclic ring. 7. Basic extracts of dog and human plasma only contained about 10% of the plasma 14C. Metabolites were chromatographically similar to the hydroxylated metabolites identified in the corresponding urine samples.

Biotransformation of methyl 5-cyclopropylcarbonyl-2-benzimidazolecarbamate (ciclobendazole) in rats and dogs.

A major metabolite of ciclobendazole (methyl 5-cyclopropylcarbonyl-2-benzimidazolecarbamate) excreted in the urine, bile, and feces of rats was methyl 5-cyclopropylcarbonyl-6-hydroxy-benzimidazolecarbamate, established by comparison of the proton magnetic resonance and mass spectra with that of the authentic compound. This compound represented 8.2% and 7.1% of the dose, respectively, in extracts of 24-hr urine and 48-hr feces samples of rats, but was only a minor metabolite in dog urine (1% of the dose). The unchanged drug was only detected in dog feces, the major route of excretion of radioactivity in the dog. 5-Cyclopropylcarbonyl-2-amino-benzimidazole was present in rat urine (2.5% of the dose). A major metabolite in dog bile was probably 5-cyclopropylcarbinol-2-aminobenzimidazole, formed by loss of the methoxycarbonyl group and reduction of the carbonyl function in the 5-position.

The disposition of radioactivity after administration of the anthelminthic methyl-14C-5-cyclopropylcarbonyl-2-benzimidazole carbamate (ciclobendazole) to rats and dogs.

1. The disposition of radioactivity has been studied in rats and dogs after administration of a new anthelminthic agent, 14C-labelled methyl-5-cyclopropylcarbonyl-2-benzimidazole carbamate (14C-ciclobendazole). 2. An oral dose of 14C-ciclobendazole (4 mg/kg) to rats was rapidly absorbed and about 70% and 20% of the dose was excreted in the faeces and urine, respectively, during 2 days. Bile duct cannulated rats excreted about 80% of the dose in 48-h bile, about 2% in the faeces and about 10% in the urine showing that an oral dose was well-absorbed and that some enterohepatic circulation probably occurred. The excretion of radioactivity in the bile was less after i.v. administration. 3. An oral dose of 14C-ciclobendazole (4 mg/kg) to dogs was mainly eliminated during 2 days with about 80% of the dose in the faeces and only about 10% in the urine. Anaesthetised bile duct-cannulated dogs, excreted between 26% and 35% of an oral dose in the bile during 24 h and up to 58% of an oral dose was absorbed at this time. 4. The tissue distribution of radioactivity in rats and dogs after single or multiple oral doses of 14C-ciclobendazole (4 mg/kg) showed that there was no unusual accumulation or localisation of radioactivity in the measured tissues. Highest concentrations were present in the intestinal tract, liver and kidneys, organs associated with biotransformation and excretion and also in the lungs and adrenals. 5. After oral administration of 14C-ciclobendazole to rate at three different dose levels (4, 40 and 400 mg/kg), peak plasma levels occurred at 15-30 min and declined with similar half-lives (about 20 h). A comparison of peak concentrations and areas under the plasma concentration-time relationships showed that the absorption of ciclobendazole was probably dose-dependent, a lower proportion probably being absorbed at higher doses. After repeated daily oral dosing with 14C-ciclobendazole (4 mg/kg), there were no significant changes in either the daily plasma concentrations or the biological half-life measured after the last dose, indicating that ciclobendazole probably did not induce or inhibit its own metabolism when dosed repeatedly at 4 mg/kg. 6. A comparison of the areas under the plasma concentration-time relationships after oral, i.p. and i.v. administration of 14C-ciclobendazole to rates indicated that there was no signigicant uptake by the liver during first pass and that an oral dose was well absorbed by rats. 7. The peak plasma concentration in the dog, after an oral dose of 14C-ciclobendazole (4 mg/kg) was reached at about 30 min and declined with a half-life of about 3 h. 8. Ciclobendazole was probably well-absorbed by rats and dogs and excreted more rapidly by the latter species than by the former Relatively higher plasma concentrations of drug and/or metabolites were thus achieved in rats than in dogs.