Pharmacokinetics of salbutamol in the pregnant woman after subcutaneous administration with a portable pump.

OBJECTIVE: We sought to determine whether subcutaneous administration of salbutamol resulted in plasma levels comparable to those achieved after intravenous or oral administration. METHODS: Twenty-nine women with preterm labor received subcutaneous infusion of salbutamol through a portable pump. We used three different rates of continuous infusion: a low rate of 3.33 micrograms/minute (20 subjects), an intermediate rate of 6.66 micrograms/minute (four subjects), and a high rate of 9.99 micrograms/minute (five subjects). Plasma salbutamol concentrations were assayed by high-performance liquid chromatography after 48 hours of continuous infusion in the subcutaneous tissue and after bolus injections (184 micrograms in the low-rate group and 368 micrograms in the intermediate- and high-rate groups). RESULTS: Plasma salbutamol concentrations after 48 hours of subcutaneous infusion increased almost linearly with the rate of infusion: 6.29 +/- 1.58, 15.5 +/- 1.0, and 21.7 +/- 4.26 ng/mL in the low-, intermediate-, and high-rate groups, respectively (P less than .001 between the three groups). After bolus injection, maximum plasma concentrations were significantly different between the three groups (P less than .001) and from their respective baseline values (P less than .001): 8.33 +/- 1.9, 18.85 +/- 2.0, and 25.86 +/- 4.8 ng/mL in the low-, intermediate-, and high-rate groups, respectively. CONCLUSION: Subcutaneous tocolysis can provide plasma salbutamol levels similar to the levels obtained orally or intravenously.

Relationship between dose, blood level and haemodynamic response in patients with cirrhosis receiving propranolol.

Fifty-two patients with cirrhosis receiving continuous administration of propranolol in doses reducing the heart rate by 25% were studied. The doses and plasma levels varied widely - 185 +/- 98 mg/day (mean +/- SD) and 208 +/- 153 ng/ml, respectively. These values were significantly correlated. No significant correlation was found between the dose of the drug or plasma level and the liver function tests. Although propranolol significantly decreased cardiac output and the hepatic venous pressure gradient, no correlation was found between drug dose or plasma level and these haemodynamic effects.

Comparative use of fructose and glucose in human liver and fibroblastic cell cultures.

The effect of fructose as a substitute for glucose in cell culture media was investigated in human skin fibroblast and liver cell cultures. Cells were grown for between 2 and 10 days in identical flasks in four different media, containing 5.5 mmol X 1-1 and 27.5 mmol X 1-1 glucose and fructose, respectively. In the presence of fructose, cell growth was stimulated, but less in liver cells than fibroblasts. At Day 6, increases were observed in [3H]thymidine incorporation, protein levels, and amino acid consumption, and a reduction was noted in ATP levels. In media containing 5.5 mmol X 1-1 glucose or fructose, consumption of fructose was four times lower than that of glucose at Day 3 and did not rise until Day 6. In fructose media, the lactate production was very low (four to five times less than that of glucose) and the pH values were always higher. Some findings were different for the fibroblasts and liver cells, owing to the specific characteristics of these two cell types in culture; this applied especially to the effects of glucose and fructose concentrations of 27.5 mmol X 1-1. Several possible explanations for the stimulation of cell growth in fructose medium were discussed.

Metronidazole kinetics in patients with acute renal failure on dialysis: a cumulative study.

Nine patients with acute renal failure who were undergoing dialysis at intervals depending on clinical state were injected with metronidazole, 7.5 mg . kg-1 iv every 8 hr. Plasma samples were drawn during the 8 hr after the first infusion, during the first dialysis session, and during the course of the fourth infusion after the first three dialysis sessions. Metronidazole and its two main metabolites (alcohol [M1] and acid [M2]) were assayed by HPLC. The plasma t 1/2 of metronidazole (6.8 hr) is of the same order as that in healthy subjects. M1 and M2 plasma levels increased continuously until the next infusion. Dialysis clearances of metronidazole and its metabolites were about 60 ml . min-1; 25% of metronidazole in the body at the beginning of hemodialysis was eliminated. The corresponding apparent t 1/2 s are 3.3 hr (metronidazole), 8.0 hr (M1), and 7.9 hr (M2). In patients with acute renal disease under hemodialysis, there was no cumulation of metronidazole and its metabolites; hence there is no need for change in dosage regimen.

Assessment of beta-adrenergic blockade with propranolol in patients with cirrhosis.

Fourteen patients with cirrhosis and bleeding esophageal varices were treated with propranolol. The dose of propranolol was determined by decreasing the resting heart rate by 25% 12 hr after an oral dose of propranolol which was given twice a day. Significant decreases in the hepatic venous pressure gradient and cardiac output after 1 month of propranolol administration was observed. To assess beta-adrenergic blockade, the isoproterenol test and plasma propranolol levels were evaluated. Increasing doses of isoproterenol were injected to increase the resting heart rate 25 beats per minute (chronotropic dose 25 or CD25 ). Plasma propranolol concentrations were measured in blood samples drawn 4 hr after the last oral dose. The mean CD25 was 5 +/- 2 micrograms before and 146 +/- 84 micrograms after 1 month of propranolol administration. The plasma propranolol level after 1 month of drug administration was 0.69 +/- 0.47 microM per liter i.e. 2.33 +/- 1.59 micrograms per ml. A significant correlation was found between the CD25 measured after continuous propranolol administration and plasma propranolol level. In conclusion, the efficacy of beta-adrenergic blockade was estimated by the isoproterenol test which correlates with the plasma propranolol level in patients with cirrhosis. This study suggests that the isoproterenol test is useful in assessing beta-adrenergic blockade with propranolol in patients with cirrhosis.

Comparative effects of glucose and fructose on growth and morphological aspects of cultured skin fibroblasts.

The growth rate of human skin fibroblasts was evaluated when glucose was replaced by fructose in the culture medium. Four mediums containing respectively 5.5 mmol/l glucose (G1), 27.5 mmol/l glucose (G5), 5.5 mmol/l fructose (F1), and 27.5 mmol/fructose (F5) were used. Skin fibroblasts from fourteen subjects were continuously cultured for 20 days and the number of cells was counted at days 1, 3, 7, 10, 15 and 20 after plating. The morphological patterns were observed and compared, the pH values of the medium were calculated, as were hexose consumption and lactate production. The results established clear differences in cell growth, pH and morphology: up to day 7, the growth rate was lower in fructose than in glucose medium, and the pH values were higher. In addition, marked steatosis appeared, with increased pyruvate dehydrogenase (PDH) activity. After day 10, the mean values gave a significant increase in the number of cells grown in fructose mediums, even if variations occurred between different cell strains. This increase was accompanied by loss of density-dependent growth inhibition and a reduction in the quantity and size of the vacuoles caused by steatosis. These findings were also established for other cell types, like aponeurosis fibroblasts. In addition, the longevity of the strains increased. These observations indicate that intermediary metabolism is considerably influenced by the carbohydrate present in the cell culture medium and that there are also repercussions on the growth rate. Under our experimental conditions, metabolism pathways seemed to differ on day 7 and on day 20. The various metabolic events suggested by the differences in the pH values are now being studied in our laboratory.

Pharmacokinetics of tinoridine after oral administration to healthy subjects and patients with renal failure.

The pharmacokinetics of tinoridine was studied after oral administration (200, 400, and 800 mg in random order) to six healthy subjects and (200 mg) to patients with renal disease. Plasma concentrations of tinoridine were determined by GLC with electron-capture detection and urine concentrations by HPLC. The plasma half-life of tinoridine was about 8.2 h in healthy subjects and was not affected by renal failure. Total body clearance (Clc/F) was very high, but renal clearance was small, about 0.30 1.h-1. There was no correlation between dose (200 mg vs 400 or 800 mg) and Cmax or AUC, suggesting a first-pass effect. Renal failure did not affect pharmacokinetic parameters. However, there was a strong linear correlation between Cmax and age (r = 0.919) and AUC and age (r = 0.838). These results suggest an increase of bioavailability in the elderly.

Influence of two cell harvesting methods on intracellular ATP and amino acid concentrations in human fibroblast cultures.

The intracellular ATP and amino acid concentrations were determined in human fibroblast cultures reaching confluence. The values obtained were very different, depending on the cell harvesting method: trypsinization or scraping. Trypsinization appeared to be the better method for measuring the ATP concentrations (21.25 +/- 0.96 nmol per mg cell protein), this level being much lower with scraping. On the contrary, scraping was the most appropriate method for amino acid measurement. This work underlines the importance of harvesting methods for metabolic studies in human cell cultures.

Pharmacokinetics in man of acebutolol and hydrochlorothiazide as single agents and in combination.

The pharmacokinetics of acebutolol and hydrochlorothiazide (HCT) alone or in combination were studied in 12 healthy subjects in a cross over study. Acebutolol and diacetolol (the main metabolite) in plasma and urine were determined by HPLC and hydrochlorothiazide by GLC. The main pharmacokinetic parameters of acebutolol did not differ significantly: AUC 4492 +/- 272 micrograms l-1h given alone versus 4118 +/- 354 micrograms l-1h with HCT, half-life (7,69 +/- 0,32 h vs 8,10 +/- 0,72 h) and renal clearance (13,1 +/- 0,5 lh-1 vs 13,8 +/- 0,9 lh-1), respectively. There was no difference in diacetolol pharmacokinetics. HCT values were not significantly different: AUC 784 +/- 48 micrograms l-1h given alone and 720 +/- 42 micrograms l-1h with acebutolol, t 1/2 (4,79 +/- 0,37 h vs 4,73 +/- 0,43 h). The renal clearance was slightly higher when HCT was given with acebutolol (26,2 +/- 2,6 vs 20,3 +/- 2,1 lh-1, p less than 0,05). This increase, observed during the first four hours, was probably due to competition between the drugs for binding to red blood cells.

The beta-blocking effect of diacetolol in humans and its relationship to plasma levels.

The beta-blocking action of diacetolol was studied in six healthy subjects after oral administration of placebo, 200, 400, and 600 mg diacetol in random order by means of exercise tests. Diacetolol plasma levels were determined by the HPLC method. Drug administration had No significant influence on resting heart rate and resting systolic or diastolic blood pressure. The beta-adrenoreceptor blockade was expressed as percentage reduction of exercise heart rate (delta FC%). This value increased with the size of the dose. There was a linear relationship between delta FC% and log plasma levels of diacetolol for each subject, except one. Analysis of variance did not provide a common regression line for all subjects.

[Total acid phosphatase. Trials of commercial kits and control sera (author's transl)]. / Phosphatases acides totales. Essais de trousses commerciales et de sérums de contrôle.

The authors estimated the total serum acid phosphatase activity of human serum and that of ten commercial sera using seven commercial kits. The reproducibility and the average of the results, the value of the control sera are given for these seven commercial kits.