Jesper Sonne

Antipyrine clearance in pneumonia

Antipyrine clearance was estimated by a one‐sample technique in 14 patients with acute fever and clinical pneumonia. Antipyrine clearance during the acute illness was 31.4 ± 7.6 ml/min (X ± SD). Fourteen and 28 days later during convalescence, clearance values were higher (47.8 ± 18.9 and 49.2 ± 15.0 ml/ min, respectively). We conclude that microsomal hepatic drug metabolism in adults is impaired during pneumonia.

Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery

Background: Our aim was to study the pharmacokinetics and pain scores following administration of single oral doses of either diclofenac or high‐dose acetaminophen (paracetamol).

Influence of dose and route of administration on disposition of metronidazole and its major metabolites

SummaryThe influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p<0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.

Bioavailability and pharmacokinetics of oxazepam.

SummarySix healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t1/2β) 6.7 h, total clearance (CL) 1.07 ml·min−1·kg−1, volume of distribution (Vc) 0.27 l·kg−1 (0.21–0.49) and volume of distribution at steady-state (Vss) 0.59 l·kg−1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min−1·kg−1 and a distribution volume of 12.3 l·kg−1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t1/2β at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CLR) of the glucuronide metabolite was 1.10 ml·min−1·kg−1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.

Acute hypoxia and cytochrome P450–mediated hepatic drug metabolism in humans

Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.

Metronidazole clearance: A one‐sample method and influencing factors

After 96 administrations of metronidazole to 36 subjects, it was found that the clearance could be determined from one plasma sample, the dose, and a volume of distribution estimated from sex, age, body weight, and height, without loss of precision and accuracy compared with conventional clearance determinations (r > 0.97). In 230 sample pairs the plasma and saliva concentrations of metronidazole were identical (r = 0.99). In 119 subjects the one‐sample clearance of metronidazole was unimodally distributed. Body weight (r = 0.28) and the alcohol consumption (r = 0.23) correlated with the metronidazole clearance. In the same subjects the consumption of tobacco (r = 0.28), alcohol (r = −0.19), coffee/tea (r = 0.27), age (r = −0.24), and sex (r = 0.28) correlated with the antipyrine clearance. The clearances of metronidazole and antipyrine were correlated (r = 0.34). The differential influence of the environmental factors on the elimination rates supports differential metabolism of metronidazole and antipyrine.

Pulmonary disease and antipyrine clearance

We investigated hepatic microsomal enzyme activity by the one‐sample saliva test for antipyrine clearance determination in 35 homozygous, α1‐antitrypsin‐deficient outpatients with chronic pulmonary disease. Twenty‐five outpatients with chronic obstructive lung disease and comparable lung function impairment and 31 healthy volunteers served as controls. Antipyrine clearance did not differ significantly between the two groups of patients with pulmonary disease. However, the clearance was 18% lower in these two groups than in the healthy volunteers (P < 0.01). Antipyrine clearance was lowest in patients with severe lung function impairment (P < 0.01).

Postoperative analgesia is not different after local vs systemic administration of meloxicam in patients undergoing inguinal hernia repair.

PurposeTo distinguish between local and systemic drug effects, we compared pain scores, analgesic consumption and plasma concentrations after local vsiv administration of meloxicam 7.5 mg in patients with inguinal hernia repair.MethodsIn a double-blind, randomized study 56 patients received either local oriv meloxicam 7.5 mg. Postoperative pain was assessed with a visual analogue scale (VAS) at rest, on mobilization, and on coughing, the need for supplementary analgesics (fentanyliv and/or acetaminophen-codeine tablets) was recorded, and blood samples were drawn during 24 hr after meloxicam administration.ResultsNo significant differences were found between groups with respect to pain scores, or in the consumption of supplementary analgesics. Following local application of meloxicam, the peak plasma concentration (Cmax) of 0.5 ± 0.2 mg·L−1 achieved after 1.8 ± 0.5 hr was much lower than the Cmax of 2.5 ± 0.9 mg·L−1 achieved immediately afteriv administration (P < 0.05). Mean meloxicam plasma concentration after infiltration was significantly lower than afteriv doses for the first three hours after administration (P < 0.05).ConclusionWe showed no differences in pain scores and analgesic consumption between local andiv administration of meloxicam 7.5 mg during the first 24 hr after herniorrhaphy, while plasma concentration of meloxicam was lower after local administration. These results indicate a lack of difference in pain relief after concentrating meloxicam at the hernia wound or after achieving high blood levels rapidly (iv). Local administration of meloxicam may confer an advantage over systemic administration by eliciting lower incidences of systemic adverse effects.RésuméObjectifDistinguer les effets médicamenteux locaux et systémiques en comparant les scores de douleur, la consommation analgésique et les concentrations plasmatiques après l’administration locale ou iv de 7,5 mg de méloxicam chez des patients qui subissent une herniorraphie inguinale.MéthodeII s’agit d’une étude randomisée et à double insu auprès de 56 patients qui ont reçu 7,5 mg de méloxicam local ou intraveineux. La douleur postopératoire a été évaluée avec une échelle visuelle analogique (EVA) au repos, pendant le mouvement et la toux. Le besoin d’analgésie complémentaire (fentanyl iv et/ou comprimés d’acétaminophène-codéine) a été enregistré et les échantillons sanguins prélevés pendant 24 h après l’administration de méloxicam.RésultatsAucune différence intergroupe significative n’a été trouvée quant aux scores de douleur ou à la consommation d’analgésique complémentaire. Après l’infiltration de méloxicam, la concentration plasmatique maximale (Cmax) de 0,5 ± 0,2 mg·L−1 atteinte après 1,8 ± 0,5 h a été plus faible que la Cmax de 2,5 ± 0,9 mg·L−1 atteinte immédiatement après l’administration iv (P < 0,05). Pendant les trois premières heures après l’administration de méloxicam, la concentration plasmatique moyenne était plus basse après l’infiltration qu’après les doses iv (P < 0,05).ConclusionPendant les 24 premières heures suivant une herniorraphie, les douleurs et la consommation d’analgésique n’ont présenté aucune différence après l’administration locale ou iv de 7,5 mg de méloxicam. Mais, la concentration plasmatique de méloxicam a été plus faible après l’administration locale. La douleur nést pas mieux soulagée avec le méloxicam concentré au site de la plaie herniaire ou administré par voie iv permettant d’atteindre rapidement des concentrations plasmatiques élevées. Par ailleurs, l’infiltration pourrait réduire davantage l’incidence déffets secondaires généralisés.

Opposed latitudinal patterns of network‐derived and dietary specialization in avian plant‐frugivore interaction systems

Latitudinal patterns of biodiversity have been studied for centuries, but it is only during the last decades that species interaction networks have been used to examine the proposed latitudinal gradient of biotic specialization. These studies have given idiosyncratic results, which may either be because of genuine biological differences between systems, different concepts and scales used to quantify biotic specialization or because the methodological approaches used to compare interaction networks were inappropriate. Here we carefully examine the latitudinal specialization gradient using a global dataset of avian plant-frugivore assemblages and interaction networks. In particular, we test whether network-derived specialization patterns differ from patterns based on assemblage-level information on avian dietary preferences on specific food types. We found that network-derived measures of specialization (complementary specialization H2’ and , modularity Q) increased with latitude, i.e. frugivorous birds divide the niche of fruiting plants most finely at high latitudes where they also formed more modular interaction networks than at tropical latitudes. However, the strength and significance of the relationship between specialization metrics and latitude was influenced by the methodological approach. On the other hand, assemblage-level information on avian specialization on fruit diet (i.e. the proportion of obligate frugivorous bird species feeding exclusively on fruit diet) revealed an opposed latitudinal pattern as more bird species were specialized on fruit diet in tropical than in temperate assemblages. This difference in the latitudinal specialization gradient reflects that obligate frugivores require a high diversity of fruit plants, as observed in tropical systems, and fulfil more generalized roles in plant-frugivore networks than bird species feeding on different food types. Future research should focus on revealing the underlying ecological, historical and evolutionary mechanisms shaping these patterns. Our results highlight the necessity of comparing different scales of biotic specialization for a better understanding of geographical patterns of specialization in resource-consumer interactions. . This article is protected by copyright. All rights reserved.

The effect of dietary energy and protein deficiency on drug metabolism

SummaryThe influence of a diet deficient in energy or protein on hepatic oxidation (Phase I reactions) and glucuronidation (Phase II reactions) in man has been examined. Nine healthy volunteers were fed an energy deficient diet (daily energy intake 4.3 MJ; daily protein intake 0.94 g/kg) and a protein deficient diet (daily energy intake 11.4 MJ; daily protein intake 0.31 g/kg) in random order. The control energy and protein intakes were 12.0 MJ and 1.52 g/kg, respectively. Each test diet period lasted 12 days. On Day 10, antipyrine 1000 mg and metronidazole 500 mg were given and elimination in saliva was determined.The metabolism of neither drugs was changed during the two dietary interventions, nor was their clearance to metabolites. On Day 12, the metabolism of oxazepam 15 mg was studied. The energy deficient and the protein deficient diet reduced the clearance rate of oxazepam by 20.3%, and 14.1% respectively. The elimination half-life was prolonged by 17.4% after the former and by 11.4% after the latter diet.Thus, both a low energy and a low protein intake decreased the glucuronidation of oxazepam, whereas no effect was observed on the rate of oxidation, expressed as the metabolism of antipyrine and metronidazole.