Determination of detomidine residues in horse meat by negative-ion chemical ionization mass spectrometry.
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Animals↗
Biomedical subjects
M Anttila
Publications and source records attributed to M Anttila.
Metabolism of toremifene in the rat.
Toremifene was labelled to a specific activity of about 20 microCi/mmol with tritium at positions 3 and 5 in the para-substituted phenyl ring. At these positions tritium is not eliminated within the metabolic pathways. A mixture of unlabelled and labelled toremifene (5 or 10 mg/kg, 5 microCi/mg) was given i.v. or p.o. to Sprague-Dawley rats. The elimination of radioactivity was followed up by collecting urine and feces daily for 13 days. The elimination of toremifene which was similar after p.o. and i.v. administration took place mainly in the feces. About 70% of the total radioactivity was eliminated within 13 days, of this amount more than 90% in the feces. All applied radioactivity could be detected in three separate fractions according to the oxidative state of the side chain when counted by Berthold TLC Linear Analyzer. Each fraction was further separated into single metabolites by TLC or HPLC. Altogether 9 metabolites were identified and almost all methanol-extractable components were identified. The main metabolic pathways in the rat were 4-hydroxylation and N-demethylation. The side chain was further oxidized to alcohols and carboxylic acids. Small amounts of unchanged toremifene were found in the feces both after p.o. and i.v. administration indicating biliary secretion.
Administration, Oral↗
Pharmacokinetics of toremifene.
The pharmacokinetics of toremifene has been investigated in man after single and multiple oral doses. Toremifene was completely absorbed without first-pass metabolism. Peak concentration in serum was achieved in 4 h. Mean half-lives of distribution and elimination were 4 h and 5 days, respectively. Kinetics was linear in the studied dose-range of 10-680 mg. Toremifene was over 99% bound to plasma proteins and extensively metabolized. The main metabolites in serum were demethyl- and deaminohydroxytoremifene. In patients receiving multiple dosing of 60 mg/day serum steady-state level of toremifene was 0.8 microgram/ml on average. The level of demethyl metabolite was twice and that of deaminohydroxy metabolite was one tenth of toremifene.
Biological Availability↗
Determination of erythromycin base and 2'-acetylerythromycin in human plasma using high-performance liquid chromatography with electrochemical detection.
A high-performance liquid chromatographic method for the determination of plasma concentrations of erythromycin base and 2'-acetylerythromycin, an ester prodrug of erythromycin, is described. tert.-Butyl methyl ether extracts of 1-ml plasma samples (pH 10) were chromatographed on a C18 reversed-phase column. A three-electrode coulometric detector (oxidation potentials +0.65 and +0.85 V) was used for quantitation. Oleandomycin was used as an internal standard. The method has good precision and accuracy, is linear in the range 0.25-7.5 mg/l and has proved to be suitable for pharmacokinetic studies in humans. Correlation with a microbiological assay was satisfactory (r greater than or equal to 0.95), but the chromatographic method gave ca. 30% higher values.
Biological Availability↗
Multiple-dose pharmacokinetic study with a slow-release carbamazepine preparation.
The pharmacokinetics, clinical efficacy and side effects of carbamazepine (CBZ) in the steady-state condition were studied using a slow-release preparation (SR), Neurotol Slow, and a conventional preparation (C), Tegretol. Eighteen adult epileptic patients under CBZ therapy were evaluated in this single-blind, randomized cross-over study. The previous daily CBZ dose was kept unchanged and divided into 2 daily doses during two 2 week study periods. At the end of each period blood samples were drawn at frequent intervals for 12 h after the administration of the morning CBZ dose. Serum concentrations of unchanged CBZ and its main metabolite, carbamazepine-10,11-epoxide (CBZE), were determined by HPLC. Peak concentrations of CBZ and CBZE were significantly lower, and the time-lapse before CBZ reached its peak was significantly longer during SR treatment. The fluctuations in serum CBZ and CBZE were significantly lower during SR treatment. There was no significant difference in bioavailability between the 2 preparations. The number of epileptic seizures was 31 during SR and 57 during C treatment. Side effects were more common during C treatment. The occurrence of dizziness was significantly lower with SR treatment than with C treatment. We conclude that greater stability in serum CBZ and CBZE concentrations can be obtained by using an SR of CBZ, without reducing the bioavailability of the drug.
Adult↗
Pharmacological effects and pharmacokinetics of atipamezole, a novel alpha 2-adrenoceptor antagonist--a randomized, double-blind cross-over study in healthy male volunteers.
1. Single doses (10, 30 and 100 mg) of atipamezole (MPV-1248), a new potent and selective imidazole-type alpha 2-adrenoceptor antagonist, and saline placebo were administered as 20 min intravenous infusions to six healthy male volunteers in a randomized double-blind, cross-over phase I study. Later, 100 mg atipamezole was given orally to the same subjects in an open fashion. 2. The i.v. doses resulted in linearly dose-related concentrations of atipamezole in plasma. Pharmacokinetic calculations revealed an elimination half-life of 1.7-2.0 h, an apparent volume of distribution of 3.0-3.5 l kg-1 and a total plasma clearance of 1.1-1.5 l h-1 kg-1. No atipamezole could be detected in plasma after oral dosing. 3. Subjective drug effects were seen mainly after the largest i.v. dose and included increased alertness and nervousness, coldness and sweating of hands and feet, tremor and shivering, motor restlessness, and increased salivation. Salivation was also quantitated using dental cotton rolls, with dose-related increases produced by the i.v. doses. 4. The 100 mg i.v. dose increased plasma noradrenaline concentrations on average by 484 +/- 269 (s.d.)%, and also elevated both systolic and diastolic blood pressure (mean increases 17 +/- 7/14 +/- 2 mm Hg). The 30 mg dose had minor and the 10 mg dose no effects on these variables. Adrenaline and cyclic AMP levels in plasma were increased only after the largest dose. No drug effects were observed after oral dosing. 4. Plasma C-peptide and blood glucose levels were not markedly influenced by the drug, and cortisol secretion was not stimulated. 5. The observed effects are compatible with the presumed alpha 2-adrenoceptor antagonistic action of atipamezole and are in general concordance with the reported results of other alpha 2-adrenoceptor antagonists (yohimbine and idazoxan). 6. Although not orally active, atipamezole may prove to be a useful agent in studies of alpha 2-adrenoceptor function in man.
Adrenergic alpha-Antagonists↗
Picogram level determination of medetomidine in dog serum by capillary gas chromatography with negative ion chemical ionization mass spectrometry.
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Animals↗
Randomised comparison of chloramphenicol, ampicillin, cefotaxime, and ceftriaxone for childhood bacterial meningitis. Finnish Study Group.
In a multicentre study, 220 consecutive cases of bacterial meningitis in children older than 3 months were randomised to treatment with chloramphenicol, ampicillin (initially with chloramphenicol), cefotaxime, or ceftriaxone. The drugs were given in four equal daily doses for 7 days, except ceftriaxone which was given only once daily. 200 cases could be assessed; the causative organisms were Haemophilus influenzae type b (Hib) in 146; meningococci (Mnc) in 32; pneumococci (Pnc) in 13; and other or unknown in 9. In patients with Hib meningitis, sterilisation of the cerebrospinal fluid occurred most rapidly with ceftriaxone. Otherwise, in terms of overall clinical recovery, normalisation of laboratory indices, clinically significant adverse reactions, toxic effects, sequelae, and mortality rate, the treatment groups were very similar. However, there were 4 bacteriological failures, all in the chloramphenicol group. Also, the treatment was extended or changed in more cases in the chloramphenicol group than in the other groups. Chloramphenicol was thus inferior to the other three antimicrobials. Ampicillin is a good and cheap alternative, but there are difficulties with resistance. Easy administration tempts the use of ceftriaxone rather than cefotaxime but it causes diarrhoea. A 7-day course of ampicillin, cefotaxime, or ceftriaxone is sufficient in Hib, Mnc, or Pnc meningitis.
Adolescent↗
Pharmacokinetics and metabolism of selegiline.
Selegiline is readily absorbed from the gastrointestinal tract. It is distributed rapidly into the tissues, including the brain. It is the L-form of selegiline that is an active MAO-B inhibitor, the D-(+)-form being 25 times less active. Selegiline is metabolised into L-(-)-desmethylselegiline (DES), L-(-)-amphetamine (A) and L-(-)-methamphetamine (MA), mainly in the liver. We measured the steady state concentrations of the metabolites in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's or Alzheimer's diseases who were on continuous selegiline therapy. The mean concentrations in serum and CSF were similar, and were not affected by the addition of levodopa. The mean concentrations of patients with Alzheimer's or Parkinson's disease were 6.5 +/- 2.5 ng/ml for A, 14.7 +/- 6.5 ng/ml for MA and 0.9 +/- 0.7 ng/ml for DES. The metabolites of selegiline were excreted in urine, and the recovery as metabolites was 87%. Due to the stereospecificity and the low CSF concentrations of the (-)amphetamine metabolites during the therapy with 10 mg selegiline, these metabolites do not seem to contribute significantly to the clinical efficacy of selegiline.
Aged↗
Binding of toremifene to human serum proteins.
The in vitro protein binding of toremifene in human serum was measured by ultracentrifugation using 3H-toremifene together with unlabeled toremifene, 50, 500, and 5000 ng/ml. Of the total radioactivity 99.7 per cent was bound to the proteins independent of the concentration of the unlabeled drug. Binding of toremifene to different protein fractions was studied by adding 3H-toremifene and 500 ng/ml of cold toremifene to normal serum. The serum samples were exposed to agarose gel electrophoresis to fractionate different proteins. The radioactivity was localized using a position-sensitive proportional counter. After that the proteins were visualized by staining. Of the total protein bound radioactivity 92 per cent was bound to albumin, about 6 per cent to beta 1 globulin fraction and about 2 per cent to a fraction between albumin and alpha 1 globulins, part of this probably to alpha 1 acid glycoprotein.
Blood Proteins↗
The absorption of acetylsalicylic acid from an enteric-coated formulation and the inhibition of thromboxane formation.
To compare conventional (CT) and enteric-coated (ECT) tablets of acetylsalicylic acid (ASA) six healthy adult subjects ingested one 0.5-g tablet of these formulations daily for fifteen days in a cross-over study. Significant amount of ASA was detected in peripheral blood of every subject after the ingestion of CT or ECT. The rate of absorption of ASA was faster and its peak plasma concentration was higher after the ingestion of CT. The formation of thromboxane B2 (TXB2) decreased during blood clotting concomitantly with the absorption of ASA from both formulations. The formation of TXB2 was equally and completely inhibited by CT and ECT as it decreased to 1% of the control value one day after the first dose. During treatment with a single daily dose of 0.5 g of CT or ECT, the serum level of TXB2 remained at this low level and returned to the control level gradually in two weeks after the last dose. The present study indicates that significant amount of unchanged ASA is absorbed also from ECT and that the formation of TXB2 is equally and completely inhibited with a 0.5-g daily dose of both formulations.
Adult↗
Radioimmunoassay of detomidine, a new benzylimidazole drug with analgesic sedation properties.
A sensitive and specific radioimmunoassay was developed for detomidine, 4(5)-(2,3-dimethylbenzyl)imidazole. The antibodies were raised in rabbits against a conjugate of detomidine and bovine thyroglobulin prepared by diazo reaction. Detomidine was iodinated with chloramine-T and immunoreactive tracer was purified in cation exchange chromatography. The sensitivity of the RIA was 1.6 fmol/tube allowing direct detomidine measurements from minute serum and urine samples (0.1-0.2 microliter) as well as tissue homogenates (10 microliters). For concentrations below 16 pmol/ml chloroform extraction was used to extend the measurement range to 0.3 pmol/ml. Detomidine (80 micrograms/kg iv and im) was given to one horse and two calves and blood samples were taken and urine collected for 24 h whereafter the horse was slaughtered and tissue samples taken for RIA analyses. Serially diluted serum, urine and tissue samples produced a linear displacement curve parallel to synthetic detomidine in RIA. HPLC studies showed that serum and tissue immunoreactivity was unchanged detomidine whereas most immunoreactivity in the urine was due to an unknown metabolite.
Animals↗
[Homelike environment in long-term institutionalized care for the elderly].
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Adult↗
Secondary prevention of urinary tract infections. The role of trimethoprim alone.
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Adult↗
The use of clofibrate in patients with renal insufficiency.
Serum clofibrinic acid (CPIB) levels after single and multiple oral doses of clofibrate were studied in 28 patients with elevated serum creatinine values. The half-life of CPIB was prolonged in proportion to the serum creatinine level (r = 0.818 p less than 0.001). Peak CPIB concentrations in serum were not affected by azotemia, although CPIB levels 24 h after a single dose and under steady-state conditions correlated well with the serum creatinine level. The proportion of unbound CPIB was higher in patients with renal insufficiency than in controls (13.9% vs 4.3%), although this difference did not correlate with the serum creatinine level. Hypolipidemic medication is indicated in dyslipoproteinemias associated with renal insufficiency. If a reduced dose is given, clofibrate can be used safely in renal patients, although a CPIB concentration of 70 mg/l in serum should not be exceeded unless the unbound fraction has been measured and found not to exceed a safe level (i.e., 6 mg/l CPIB).
Adolescent↗
Pharmacokinetics of propranolol and sotalol in hyperthyroidism.
The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160 mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p less than 0.05) and its clearance was increased (p less than 0.005), whereas there was no difference in its serum t 1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.
Adult↗
Serum levels of free fatty acids in the first trimester of pregnancy: effect of acetylsalicylic acid.
The serum levels of free fatty acids were determined before and after an oral dose of 1000 mg acetylsalicylic acid (ASA) during the 7-11th weeks of pregnancy in 11 women admitted to hospital for legal abortion and in 8 women admitted for operative (hysterectomy) treatment because of fibroids. Thirteen healthy women of reproductive age served as controls. The levels of linoleic, alpha-linolenic, myristic, oleic, palmitic and palmitoleic acids were significantly lower in pregnant women than in the hysterectomy group. The level of arachidonic acid was higher in the pregnant and hysterectomy groups than in controls. Serum free fatty acids had a negative correlation with the duration of pregnancy. ASA treatment tended to increase the levels of many fatty acids in serum. Serum arachidonic acid levels after ASA treatment correlated significantly with the salicylate concentrations in myometrium and the levels of most other fatty acids with the salicylate concentration in endometrium.
Adult↗
Transfer of propranolol and sotalol across the human placenta. Their effect on maternal and fetal plasma renin activity.
Eighty milligrams of propranolol or sotalol was administered orally to two groups of 8 parturients who were to undergo elective cesarean section. This was performed 3 hours after drug administration. The transplacental passage of both drugs was registered in each patient. The maternal concentration of propranolol was approximately four times that in the umbilical circulation, while the sotalol level in maternal circulation was twice that in the umbilical circulation. The administration of beta-adrenoceptor antagonists caused a significant decrease in maternal plasma renin activity. After these doses of beta blockers, no difference in the plasma renin activity was found in the umbilical circulation, when compared with the previous normal values at cesarean section.
Adult↗