Biomedical subjects
Publications and source records attributed to M Anttila.
Salicylate concentrations in serum, endometrium, myometrium and fetus were determined 3 h after an oral dose of 1 000 mg of acetylsalicylic acid. The material consisted of 19 females (11 for legal abortion and 8 for operative treatment of fibroids). Tissue salicylate concentrations were at a level at which prostaglandin synthetase is inhibited.
The effects of alcohol consumed during an evening party on the metabolism and response of beta-adrenergic blocking drugs were investigated in healthy subjects. The drugs were given 12 hr after the first drink. The plasma clearance rate of propranolol, metabolized in the liver, increased, while that of sotalol, which is eliminated unchanged, was reduced. Plasma propranolol levels, but not those of sotalol, were related to blood alcohol content. The blood pressure-reducing effect of propranolol diminished after alcohol and that of sotalol increased. Both drugs reduced the heart rate after alcohol although they were unable to cancel out entirely the alcohol-induced increase in the heart rate. The results show that drinking may alter the metabolism of beta-blocking drugs. Drinking habits must be considered in therapy with beta-blocking drugs or when seeking reasons for angina pectoris or arterial hypertension that does not respond to therapy.
The effect of concurrent administration of antacids on the relative bioavailability of sotalol has been examined in five healthy volunteers. Each subject received an oral 160 mg dose after an overnight fast in four different experimental schedules. Venous blood samples were drawn 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, and 32 hours after the drug administration, and sotalol concentrations were determined fluorometrically. The results show that concurrent administration of calcium carbonate or aluminum hydroxide with sotalol has negligible pharmacokinetic consequences. The adsorption of sotalol onto magnesium hydroxide leads to somewhat decreased bioavailability but in long term use the phenomenon is not likely to be of clinical importance.
Methenamine (hexamethylenetetramine), a urinary disinfectant, was determined in human plasma and urine by gas-liquid chromatography with a short (10 m) open-bore glass capillary column (split ratio 1:20) and nitrogen-selective detector. An almost quantitative recovery (92.1%) was achieved by simple dilution of water-containing samples (0.5 ml) with acetone (4.5 ml). After centrifugation an aliquot (2 microliter) of the supernatant was injected into the gas chromatograph. Selectivity and sensitivity of the nitrogen detector allowed the quantitation of unchanged methenamine in plasma and urine up to 24 h after a single therapeutic dose of 1 g. Reproducibility of the method was 7.6 and 2.1% (C.V.) in serum and urine, respectively. The time required for the analysis of one sample was approx. 2 min. Due to the simple extraction and short analysis time it was possible to analyze the samples concurrently with sample taking. Absorption of standard tablets and an enterosoluble preparation of methenamine hippurate was compared.
The pharmacokinetics of naproxen after a single oral dose of 250 mg has been studied in 8 subjects with normal renal function and 16 patients with varying degrees of chronic renal insufficiency. Unchanged naproxen and its main unconjugated metabolite, 6-0-desmethylnaproxen, were determined fluorometrically in serum. In healthy subjects the elimination half-life of naproxen was 17.7 +/- 3.0 h (mean +/- SD) and it was not significantly prolonged in patients with renal failure (18.1 +/- 5.3) h. No accumulation of naproxen in serum occurred in uraemic patients. On the contrary, serum drug levels were slightly but significantly lower in patients with severe renal failure. The total body clearance and apparent volume of distribution of naproxen were significantly increased in this group of patients. Decreased binding of naproxen to serum proteins was observed in patients with renal failure. The apparent half-life of desmethylnaproxen was of the same order of magnitude as that of naproxen (18.6 +/- 4.4 h), and was also independent of renal function. A good correlation was found between the area under the curve (AUC), the peak concentration of the metabolite and the serum creatinine concentration. These observations suggest increased metabolism and an increased apparent volume of distribution of naproxen in severe renal failure, probably caused by decreased serum protein binding of the drug. However, it is proposed that in naproxen therapy no adjustment of the dosage regimen is necessary in patients with impaired renal function.
1 The roles of the hepatic blood flow and the drug oxidizing enzyme system in eliminating oral propranolol and sotalol were studied in twelve subjects with biopsy proven liver parenchymal disease. 2 The apparent plasma clearance of propranolol was closely related both to the in vivo (antipyrine test) and in vitro (cytochrome P-450) indices of the activity of the hepatic mixed function oxidase system. 3 Propranolol clearance had also a clear relationship to the estimated liver blood flow. Altered flow was, however, suggested to be a minor factor when compared with changes in the enzyme system. 4 The elimination rate of sotalol had no correlation to the indices of hepatic drug metabolism or to the estimated liver blood flow. 5 It is concluded that both the deteriorated sinusoidal perfusion and the decreased mass of drug metabolizing enzymes may be responsible for the impaired elimination of oral propranolol in subjects with parenchymal liver disease.
Plasma renin activity (PRA), antidiuretic hormone (ADH), urinary aldosterone excretion (U-Aldo) and electrolyte excretions were studied in a randomized study after furosemide (80 mg) (F), furosemide + triamterence (80 + 100 mg) (F + T), and after placebo were administered to seven healthy volunteers. F + T preparation showed a slower absorption of furosemide, a slower natriuresis and a slower excretion of potassium as compared to F-präparation. After application of the diuretics, PRA reached the maximal level in four hours, three times higher than the control level after F and four times higher after F + T. At 24 hrs after drug intake PRA did not differe from the control level. No significant difference could be found between F and F + T. U-Aldo of 24 hrs increased 1.9-fold after F and 2.2-fold after F + T, as compared with placebo. Between the individual natriuretic and hormonal responses no correlation could be found. After F + T, U-Aldo and U-K showed a positive correlation (P < 0.05). ADH did not change after diuretics from the pretreatment fasting level. The results show a fast but transient response of the renin-aldosterone system after furosemide and the furosemide-triamterene combination which could not be correlated with the natriuretic effects. The result differs from that found earlier with hydrochlorothiazide.
The role of hepatic drug-metabolizing enzyme activity for plasma propranolol and sotalol levels was investigated in 68 patients with hypertension or angina pectoris by comparing elimination rate with antipyrine kinetics and cytochrome P-450 content in the liver. All subjects were resistant to or had hepatotoxic reaction to previous treatment. Plasma antipyrine clearance and cytochrome P-450 content in biopsies were related to propranolol elimination from plasma, the best fit being obtained with the clearance values. Sotalol plasma clearance was not related to any indirect or direct reflector of the hepatic drug-metabolizing enzyme system. The results demonstrate that plasma clearance of the short-acting beta blocker, propranolol, depends on the activity of hepatic drug-metabolizing enzyme system and indicates a trial with a drug such as sotalol which is not dependent on liver metabolizing capacity.
A comparative bioavailability study was performed using two commercially available types of carbamazepine tablets, by statistical analysis of serum levels and other bioavailability parameters. After single oral dose the extent of absorption from the two preparations was similar, although a statistically significant difference in absorption rates was observed. In a multiple-dose study no significant difference in serum carbamazepine levels was found, so the tablets could be considered as bioequivalent drug products.
The effect of food, some food constituents, and large volumes of fluid taken with the drug on the relative bioavailability of sotalol has been examined in five healthy volunteers. Each subject received an oral 160 mg dose in six different experimental schedules. Venous blood samples were drawn 1, 2, 3, 4, 6 and 8 hrs after the dosing, and sotalol concentrations in serum were determined fluorometrically. The results indicate that large volumes of fluid delay but do not affect the extent of sotalol absorption. Food, especially milk, decreases the bioavailability of the drug and an interaction with calcium seems to be the major reason for the reduced absorption.
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Free and total concentrations of amikacin, tobramycin and gentamycin were measured separately in the rat kidney after equal weight by weight doses. The accumulation of aminoglycosides followed the order amikacin less than tobramycin less than gentamycin. The ratio between free and total aminoglycosides was similar (about 0.6) in all 3 aminoglycosides and independent on the length of administration.
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