CYP2D6 genotype determination in the Danish population

CYP2D6 genotyping was carried out by XbaI restriction fragment length polymorphism analysis and polymerase chain reaction in 168 healthy Danish volunteers, 77 extensive metabolizers (EM) and 91 poor metabolizers (PM) of sparteine. All EM were genotyped correctly as heterozygous or homozygous for the functional (wild type) gene, D6-wt. However, the D6-wt gene was apparently also present in 11 (12%) of the PM who accordingly were incorrectly genotyped as EM. The specificity of genotyping PM thus was 100% but the sensitivity was only 88%. The most common allele was the D6-wt with an apparent frequency of 0.741 (0.026) in the Danish population and the second most common allele was the D6-B with an apparent frequency of 0.194 (0.024). The median (range) of the sparteine metabolic ratio (MR) in 47 homozygous D6-wt EM was 0.28 (0.11–4.10) and the corresponding value in heterozygous EM was 0.36 (0.11–9.10). The median difference was 0.09 (95% confidence interval: 0.02–0.16). CYP2D6 phenotyping is a promising tool in tailoring the individual dose of tricyclic antidepressants, some neuroleplics and some antiarrhythmics. However if the genotype test could be improved with regard to both sensitivity in PM and the ability to predict CYP2D6 activity in EM then it would be of even greater clinical value in therapeutic drug monitoring.     

Sialic acid concentrations in the urine of men with and without renal stones

Summary It has been suggested that urinary sialidase may play a role in the formation of renal stones. The present study was therefore undertaken to compare spectrophotometrically the different types of sialic acid concentrations and sialidase activities in fresh first morning urine specimens of men (21–65 years) with (13) and without (9) calcium oxalate renal stones. Although the free urinary sialic acid concentrations of the two groups of men were statistically about the same (P=0.0614), the total (P=0.003) and bound (P=0.0012) urinary sialic acid concentrations differed significantly. Both the total and bound sialic acid concentrations were lower in the urine specimens of the stone patients than in their healthy counterparts. This decrease in urinary sialic acid concentrations was firstly thought to be the result of elevated breakdown enzymes of sialic acid, which would favour the production of pyruvate. However, spectrophotometric determinations of the endogenous pyruvate concentrations of the two types of urine specimens did not differ significantly (P=0.0708). Secondly, the decrease in total urinary total sialic acid concentration of stone patients, could be attributed to less sialic acid synthesis or less renal excretion. Therefore, the same experiments were repeated using serum of 13 patients and 9 healthy men. Conversely, the total (P=0.4425) and bound (P=0.2850) serum sialic acid concentrations were found to be similar in the two types of subjects. However, the free serum sialic acid concentration of stone patients was significantly lower than in the healthy subjects (P=0.0062). This phenomenon is also reflected in the average ratio for serum free: bound sialic acid in healthy and stone patients, 1:7.9 and 1:18.7 respectively (P=0.0009). The lower free serum sialic acid concentration may lead to lower renal excretions of sialic acid. This may explain the decrease in total urinary sialic acid concentration in stone patients. The lower bound urinary sialic acid concentrations in patients was also reflected in the urinary free: bound sialic acid ratio for healthy (1:2.3) and stone patients (1:1.3). The difference between these two groups of men was highly significant (P=0.0001). This phenomenon might be explained by the urinary sialidase activities, which was spectrophotometrically determined at 334 nm at 37°C of 11 patients with stones and 17 healthy men. The ages of both groups of men were the same (P=0.326). An increase in urinary sialidase activity was observed with the stone patients (P=0.00001) when compared to specimens of healthy men. This might explain the decrease in urinary bound sialic acid concentration of the stone group. It seems from these results that the urinary concentration of sialic acid and the activity of urinary sialidase, may play a role in the pathogenesis of the multifactorial disease, urolithiasis.     

Decrease of inorganic blood sulfate following treatment with selected antirheumatic drugs: potential consequence for articular cartilage

The elimination kinetics of inorganic blood sulfate in mice was followed for four hours after a single, oral administration of an antirheumatic drug. Sodium salicylate, aspirin, diflunisal and benorylate, all in a dose of 1.25 mmol/kg, reduced the sulfate level to the less than half that of control. This phenomenon was also demonstrated by phenylbutazone, oxyphenbutazone (both 1 mmol/kg), chloroquine diphosphate (0.6 mmol/kg) and tiaprofenic acid (0.02-0.35 mmol/kg). Niflumic acid (1.08 mmol/kg), piroxicam (0.03 mmol/kg), indomethacin (6.10(-3) mmol/kg), diclofenac (5.10(-3) mmol/kg), ketoprofen (0.2 mmol/kg), naproxen (0.08 mmol/kg) and ibuprofen (0.24 mmol/kg) possessed no sulfate lowering properties. The potential relevance of the use of sulfate lowering drugs for articular cartilage integrity is discussed in the light of what is already known about this subject.     

Effects of dietary aluminum on chicks Gallus gallus domesticus with different dietary intake of calcium and phosphorus

Birds that feed in acidified areas may be exposed to an increased intake of aluminum, while their intake of calcium and phosphorus may simultaneously be low. In particular, juvenile birds foraging in acidified areas may suffer from increased effects of aluminum due to high demands of calcium. Day old chicks were fed six different diets where aluminum was combined with normal and low concentrations of dietary calcium and phosphorus for 14 days. The normal calcium-available phosphorus (Ca-P) level was 1.05%–0.45%, and the low dietary Ca-P level was 0.49%–0.21%. Aluminum was given in dietary levels of 0%, 0.13%, and 0.31%. Aluminum had no effects on growth, mortality, or hematocrit, but induced hypocalcemia.Bones accumulated more aluminum than kidneys. A high dietary concentration of aluminum (0.31%) increased the accumulation of aluminum twofold in bones and threefold in kidneys when the dietary concentration of calcium and phosphorus was halved. Opposed to the predictions, bone mineralisation was stimulated by an intermediate increase in dietary aluminum (0.13%) at both levels of dietary calcium and phosphorus. Bone stiffness was also stimulated at this dietary aluminum concentration, but only at the diet low in calcium and phosphorus. A high dietary aluminum concentration did not have any effect on bone stiffness or calcium concentration. Bone stiffness correlated positively with the calcium concentration in bone, and negatively with the aluminum concentration in bone. The effect of dietary aluminum on bone stiffness is probably caused by an alteration in bone mineralization, rather than by the presence of aluminum in bones.     

Nonsteroidal cardiotonics. 3. New 4,5-dihydro-6-(1H-indol-5-yl)pyridazin-3(2H)-ones and related compounds with positive inotropic activities

A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.     

Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration

The hemodynamic effects of dopamine and dobutamine (at doses of 6 micrograms X kg-1 X min-1) were compared during fluid resuscitation from septic shock induced by endotoxin (3 mg/kg) in the dog. In the first part of the study, when a standard amount of saline solution was infused (in 24 dogs), dopamine infusion resulted in higher cardiac filling pressures than did dobutamine infusion, whereas dobutamine infusion resulted in higher cardiac output. In the second part of the study, when fluid infusion was titrated to maintain pulmonary artery balloon-occluded pressure at constant level (in 24 dogs), the total amount of fluids was significantly greater with dobutamine than when dopamine was used (109 +/- 13 vs 71 +/- 10 ml/kg). The combination of dobutamine with fluids resulted in significantly greater stroke volume (39.6 +/- 3.8 vs 21.0 +/- 4.0 ml, P less than 0.05) and oxygen consumption (194 +/- 18 vs 144 +/- 8 ml/min, P less than 0.05). The different effects of dopamine and dobutamine on cardiac filling pressures can be due to differences in effects on myocardial contractility, ventricular afterload, and cardiac compliance. This experimental study indicates that when fluid therapy is combined with adrenergic agents in resuscitation from septic shock, dobutamine can be associated with higher cardiac output and oxygen transport and can result in higher tissue oxygen consumption than dopamine.