Flemming Elmelund Nielsen

Toxic metals and selenium in blood from pilot whales (Globicephala melas) and sperm whales (Physeter catodon)

Abstract Mercury, lead, cadmium and selenium were measured in blood from pilot whales ( Globicephala melas ) caught at the Faroe Islands and in blood from four sperm whales ( Physeter catodon ) stranded in Denmark. The median whole-blood concentration of mercury in pilot whales was 229 μg/l with a positive correlation to the corresponding selenium concentrations. Blood concentrations of mercury and cadmium up to 2421 and 31xa0100 μg/l, respectively, were found in the sperm whales. Cadmium concentration averaged 500–1000 times higher in stranded sperm whales than in the pilot whales. The mercury and cadmium concentrations dramatically exceed levels which are associated with severe toxicity in several other mammal species.

Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake

AbstractObjective: The analgesic effect of codeine depends on its O-demethylation to morphine via sparteine oxygenase (CYP2D6) in the liver and presumably also via this enzyme in the CNS. We studied the ability of quinidine, which is a potent inhibitor of CYP2D6, to penetrate the blood brain barrier and its pssible impact on codeine O-demethylation in CNS.nMethods: The study comprised 16 extensive and one poor metaboliser of sparteine, who underwent spinal anaesthesia for urinary tract surgery or examination. Eight patients were given an oral dose of 125 mg codeine and 9 patients (including the poor metaboliser) were given 200 mg quinidine 2 h before the same dose of codeine. Plasma and spinal fluid samples were collected 2 h after codeine intake.nResults: Free concentrations of quinidine were 11-times lower in cerebrospinal fluid than in plasma, and ranged from 9–15 nmol·l−1. Morphine concentrations were significantly lower in patients pre-treated with quinidine, both in plasma (median 1.45 nmol·l−1, range 0.74–1.95 nmol·l−1 vs 9.86 nmol·l−1, range 4.59–28.4 nmol·l−1) and in cerebrospinal fluid (0.23, 0.16–0.61 nmol·l−1 vs 3.63, 0.6–8.09 nmol·l−1). The morphine/codeine concentration ratio in plasma (3.07×10−3, 1.68–3.68×10−3 vs 19.87×10−3, 9.87–66.22×10−3) and in cerebrospinal fluid (0.83×10−3, 0.58–1.45×10−3 vs 7.19×10−3, 2.03–17.7×10−3) was also lower. The morphine/-codeine concentration ratios were significantly lower in cerebrospinal fluid both without and with quinidine, but the difference between the plasma and spinal fluid ratios was significantly smaller with quinidine than without (p=0.0002).nConclusion: Quinidine penetrates the blood brain barrier poorly, but quinidine pre-treatment leads to pronounced lowering of the cerebrospinal fluid concentration of morphine after codeine intake. However, the O-demethylation of codeine in CNS may not be totally blocked by quinidine.

Determination of quinidine, dihydroquinidine, (3S)-3-hydroxyquinidine and quinidine N-oxide in plasma and urine by high-performance liquid chromatography

A specific and sensitive method for the quantitation of quinidine, (3S)-3-hydroxyquinidine, quinidine N-oxide, and dihydroquinidine in plasma and urine has been developed. The method is based on a single-step, liquid-liquid extraction procedure, followed by isocratic reversed-phase high-performance liquid chromatography, with fluorescence detection. After extraction from 250 microliters plasma and 100 microliters urine, the limit of determination is 10 nM and 25 nM, respectively. For the use as standards, commercially available quinidine was purified from dihydroquinidine; quinidine N-oxide was synthesized.

Cholesterol-lowering potential in human subjects of fat from pigs fed rapeseed oil

The possibility of achieving blood-lipid-lowering characteristics of pig fat by increasing the content of unsaturated fat in pig feed was evaluated. Three pig feeding regimens were applied: basal feed (no added fat or vitamin E), basal feed + rapeseed oil (60 g/kg feed), and basal feed + rapeseed oil (60 g/kg) + vitamin E (200 mg/kg). Meat and meat products from the three pig groups were incorporated into diets providing 86 g pig fat/10 MJ. The diets were served to twelve healthy human male subjects for 3 weeks each in a randomised crossover design. The diets prepared from pigs fed rapeseed oil had a lower content of saturated fatty acids (approximately 9 v. 11% of energy) and a higher content of polyunsaturated fatty acids (approximately 6 v. 4% of energy) than the diet prepared from pigs fed the basal feed. Diets based on fat from pigs fed the rapeseed oil resulted in significantly lower (approximately 4%, P = 0.019) total serum cholesterol concentration compared with the diet from pigs fed the basal feed. No differences were observed in LDL-, HDL- or VLDL-cholesterol, or in triacylglycerol or VLDL-triacylglycerol concentrations. Addition of vitamin E to the pig feed resulted in only a minor increase in vitamin E content in the human subjects diet and the vitamin E content was low in all three pig diets. Plasma vitamin E concentration in the human subjects at the end of the period with diets from pigs fed rapeseed oil without vitamin E was significantly lower (P = 0.04) than in the other two diet periods. In conclusion, an increased content of rapeseed oil in pig feed changes the fatty acid composition of the pig fat in a way that has a potential to reduce blood cholesterol concentrations in human subjects. However, intake of pig fat with a higher content of unsaturated fatty acids needs to be matched by a higher dietary intake of vitamin E.

Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism.

Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l·h−1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l·h−1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.