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Biomedical subjects

F W Merkus

Publications and source records attributed to F W Merkus.

At least 55 records · Page 3Linked to original sources
PubMed1986

Influence of food on the bioavailability of spironolactone.

Nine healthy volunteers received a single oral dose of 200 mg spironolactone, once during fasting conditions and once immediately after a standardized breakfast. Serum concentrations of spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and canrenone were determined by HPLC for 24 hours after dosing. By taking spironolactone with food, the mean (+/- SD) AUC (0 to 24 hours) of the parent drug increased from 288 +/- 138 (empty stomach) to 493 +/- 105 ng X ml-1 X hr (P less than 0.001). The AUC (0 to 24 hours) of the three metabolites together also increased significantly from 8511 +/- 2062 (empty stomach) to 11219 +/- 2471 ng X ml-1 X hr (P less than 0.01). The mean (+/- SD) percent increase in AUC (0 to 24 hours) of spironolactone when it was given with food, compared with the ingestion on an empty stomach (95.4% +/- 66.9%), was much more pronounced than the corresponding increase of 7 alpha-thiomethylspirolactone (45.4% +/- 33.7%), 6 beta-hydroxy-7 alpha-thiomethylspiro-lactone (21.8% +/- 21.5%), and canrenone (40.7% +/- 26.3%). These observations indicate that food promotes the absorption of spironolactone and possibly decreases its first-pass metabolism.

Adolescent↗
PubMed1986

The in vitro and in vivo effect of a new non-halogenated corticosteroid - budesonide - aerosol on human ciliary epithelial function.

The in vitro and in vivo effect on the ciliary epithelial function of a new corticosteroid (budesonide), with a high topical and negligible systemic activity, was investigated. Ciliary function is an important factor in the nasal clearance mechanism. It must not be hampered by drugs or additives. Ciliary beat frequency (CBF) was measured in vitro with a photo-electric method. CBF appeared to be only slightly decreased by the budesonide and placebo aerosols. As there is no significant difference in ciliotoxicity between the aerosols, the small decrease may be caused by the solubilizing excipient. The influence of the aerosols in vivo was measured in human volunteers as changes in mucus transport time (MTT) with the indigocarmine/saccharine sodium method. Ciliotoxicity in vivo could not be found.

Adult↗
PubMed1986

Sustained release properties of an intra-adiposely administered dapsone depot injection.

A dapsone depot injection, consisting of dapsone crystals of bipyramidal shape with a particle size of 38 micron-63 micron suspended in an aqueous vehicle, appeared to result in different concentration/time profiles in men and women when delivered "intramuscularly." This phenomenon can be explained by the larger skin-to-muscle distance in women than in men. Injections intended to be delivered intramuscularly are, in fact, administered into subcutaneous fatty tissue in most of the women. Because sustained release properties were more satisfactory in women than in men, in this study the absorption of dapsone was investigated after administration of the same injection into gluteal fatty tissue. Via this route of administration, for which the term intra-adipose is used, 12 female and 15 male healthy volunteers received 1000 mg dapsone, after which blood samples were taken at regular intervals for 35 days to determine dapsone and monoacetyldapsone concentrations in serum using high-pressure liquid chromatography with fluorometric detection. No important differences between men and women appeared to exist at any time point after injection. The peak concentrations were 0.69 +/- 0.40 mg/l in men and 0.84 +/- 0.31 mg/l in women. No important side effects were observed, either locally or systemically. Volunteers who previously received an intramuscular injection preferred the intra-adipose administration. The good depot properties and better acceptance of intra-adipose dapsone administration are reasons to prefer this route of administration.

Adipose Tissue↗
PubMed1985

Determination of the serum concentration of spironolactone and its metabolites by high-performance liquid chromatography.

A simple and rapid high-performance liquid chromatographic assay is described for the simultaneous determination in serum of the aldosterone antagonist spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone and canrenone. Ultraviolet absorption at 240 nm was used to detect the different compounds after elution on a normal-phase column. Endogenous serum substances did not interfere with the assay. This method provides a convenient tool in pharmacokinetic studies of spironolactone, in contrast to previously reported aspecific fluorimetric assays or time-consuming thin-layer chromatographic analyses of radioactive biological material.

Canrenone↗
PubMed1985

Effect of heparin on digitoxin protein binding.

Reduction of digitoxin binding to plasma proteins after heparin has been reported. Our aim was to determine whether this reduction is an in vivo effect or occurs only after blood collection as a result of heparin-induced lipolysis that increases levels of nonesterified fatty acids in vitro. The effect of heparin on digitoxin protein binding was studied in 10 patients undergoing hemodialysis receiving digitoxin maintenance therapy. Digitoxin free fraction increased after heparin, from 2.5% +/- 0.7% to 4.4% +/- 1.1%, but after inhibition of in vitro lipolysis with diethyl p-nitrophenyl phosphate (2mM), a potent lipase inhibitor, there was no increase in the free fraction (2.3% +/- 0.4% before heparin and 2.4% +/- 0.5% after heparin). Digitoxin salivary levels were also unchanged (0.41 +/- 0.08 ng/ml before heparin and 0.41 +/- 0.08 ng/ml after heparin [n = 8]). These data indicate that the binding of digitoxin to plasma proteins in vivo is not altered by heparin. The reduced binding reported elsewhere was a result of heparin-induced in vitro lipolysis.

Aged↗
PubMed1985

New insights into the pharmacokinetics of spironolactone.

Four healthy men took a single oral dose of 200 mg spironolactone after a standardized breakfast. Blood samples were drawn until 24 hours after dosing. A specific HPLC method was used to determine the serum concentrations of spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and canrenone. Pharmacokinetic parameters were derived from the serum concentration-time course of each compound. Spironolactone, 7 alpha-thiomethylspirolactone, and canrenone are known to have antimineralocorticoid activity in man. Our study demonstrated that: (1) 7 alpha-Thiomethylspirolactone is the main metabolite of spironolactone after a single oral dose as judged by the AUC(0-24) and the maximum concentration; and (2) unchanged spironolactone was detected in serum, with a maximum concentration at 1 hour and detectable levels up to 8 hours after dosing. Our findings are contrary to the widely accepted belief that spironolactone is metabolized too rapidly to be detected in serum after oral dosing and that canrenone is the principal metabolite of spironolactone.

Absorption↗
PubMed1985

Correlation between nasal ciliary beat frequency and mucus transport rate in volunteers.

The correlation between mucus transport time (MTT) and nasal ciliary beat frequency (CBF) in human volunteers was investigated. Mucus transport was measured with the indigo carmine/saccharin sodium test. The test can be performed easily, with no need for sophisticated equipment. CBF was measured photometrically in biopsies from the ciliated epithelium of the nose. After statistical analysis with the Shapiro-Wilk test, it appeared that the logarithms of the MTTs were distributed normally. The correlation between the CBF and the log-MTT was tested with the least-square method. Correlation coefficients are r = -0.55 and r = -0.51 (n = 31) for the log-MTTs as measured with saccharin sodium and indigo carmine respectively. The results are significant at a level alpha = 0.005. The highly significant correlation between CBF and log-MTT suggests that CBF is the main factor in the nasal mucociliary clearance in healthy volunteers. The indigo carmine/saccharin sodium test appears to be useful in testing the in vivo effects of nasal drugs on mucociliary clearance.

Adult↗
PubMed1984

Pitfalls in the determination of unbound carbamazepine concentrations in plasma.

The usefulness of three simple, commercially available ultrafiltration systems [ Centriflo CF25 (A), Centriflo CF50A (B) and Ultrafree (C)] in determining concentrations of unbound carbamazepine in plasma was tested. The concentrations of carbamazepine measured in the first fractions of the ultrafiltrate were low, probably as a result of binding of the drug to the ultrafiltration system. The amount of this binding decreased in the order A greater than B greater than C. When using A and B, the first portion of ultrafiltrate obtained after centrifuging for 15 minutes must therefore be discarded. Using the Ultrafree filters this was not necessary. Plasma proteins were found to pass through the Ultrafree filter membrane when more than 0.7 ml ultrafiltrate was collected. Comparison of the ultrafiltration methods with equilibrium dialysis showed a good correlation: r = 0.96 (A), r = 0.97 (B) and r = 0.98 (C). However, in the carbamazepine plasma concentration range 2.5-10.0 micrograms/ml, significantly lower free fractions were measured with the Centriflo cones. The free fractions measured were: 0.28-0.30 (equilibrium dialysis), 0.17-0.18 (A), 0.22-0.24 (B) and 0.29-0.30 (C). The time required to collect the ultrafiltrate was 30 minutes (A and B) and 2 hours (C).

Carbamazepine↗
PubMed1983

Do evacuated blood collection tubes interfere with therapeutic drug monitoring?

The influence of various brands of evacuated blood collection systems (the old type, red stoppered Vacutainer; the new type, blue stoppered Vacutainer; Monoject and Venoject) on therapeutic drug monitoring was investigated. No interferences were found in the assay of ethosuximide, phenobarbital, phenytoin, valproic acid, digitoxin, digoxin, procainamide, gentamicin and theophylline. Using Monoject and old type Vacutainer tubes, lower levels were found in the disopyramide assay: 91.3 +/- 4.6% (p less than 0.05) and 91.7 +/- 7.0% (not significant) respectively, and in the quinidine assay: 82.8 +/- 6.7% (p less than 0.02) and 83.9 +/- 4.4% (p less than 0.001) respectively as compared with glass tubes. In the carbamazepine assay a decrease was found in the Monoject tubes only: 93.7 +/- 1.7% (p less than 0.01). The stoppers of Monoject tubes and the old type Vacutainer tubes contained the plasticizer tris-(2-butoxyethyl)phosphate (TBEP), which has been shown to be a potent inhibitor of the binding of several drugs to alpha 1-acid glycoprotein. Using the new type Vacutainer and the Venoject, no interferences were found.

Blood Specimen Collection↗
PubMed1983

Sex differences in the absorption of dapsone after intramuscular injection.

A trial was performed with a long-acting dapsone (DDS) injection, consisting of an aqueous suspension of dapsone crystals, in doses of 900 mg and 1200 mg. Forty-one Ethiopian leprosy patients, 13 women and 28 men, participated in the study. There appeared to be a large discrepancy in the serum concentration curves of dapsone between men and women. Following injection of 900 mg dapsone in men, a peak of 2.28 +/- 1.06 micrograms/ml (mean +/- S.D.) was observed in the first week. After two weeks the serum concentrations had fallen to 0.42 +/- 0.29 micrograms/ml, and after four weeks they fell to 0.11 +/- 0.09 micrograms/ml. Following injection in women, the curves were smooth with a peak in the first week of only 1.04 +/- 0.40 micrograms/ml, while the serum concentrations after four weeks were still 0.42 +/- 0.23 micrograms/ml. The differences between the mean curves of men and women were statistically significant (p less than 0.001). The 1200 mg dapsone injections were only given to men. The explanation of the sex difference in intramuscular absorption can probably be found in the differences in the thickness of gluteal fat in men and women. In these Ethiopian leprosy patients, the non-protein-bound fraction of dapsone comprised 17 +/- 4%. In saliva, 19.5 +/- 7.0% of the dapsone level in serum was found. Methemoglobin levels were raised but did not reach levels of clinical importance. No other significant side effects were observed.

Absorption↗
PubMed1982

Decreases in ciliary beat frequency due to intranasal administration of propranolol.

Recently the intranasal application of 5% propranolol was proposed in order to prevent the extensive first-pass metabolism of this drug. The ciliary epithelium in the nose affects the removal of dust, allergens, and microorganisms. The decreasing effect of propranolol on the ciliary beat frequency of human adenoid tissue and chicken embryo tracheas was measured with a photoelectric registration device. After nasal application of 5% propranolol, the drop is diluted by the nasal mucus. It was found that even 0.1% propranolol had a deleterious effect on the cilia of chicken and human tissue. Ciliary movement was arrested irreversibly within 20 min.

Adenoids↗
PubMed1982

Correlation between the sensitivity of the ciliary beat frequency of human adenoid tissue and chicken embryo tracheas for some drugs.

The effects of benzalkonium chloride, chlorbutol,xylometazoline and naphazoline on the ciliary beat frequency of human adenoids and chicken embryo tracheas have been determined and compared. Chlorbutol 0.5% appeared to arrest ciliary motion in both tissues within 5 minutes. Rinsing with Locke Ringer solution (LR) restored the ciliary motion almost completely in both cases. Benzalkonium chloride 0.006% +EDTA 0.1% decreased the ciliary beat frequency 35% for the human tissues and 50% for the chicken tissues after a contact of 20 minutes. In both cases the frequency hardly changed after rinsing with LR. Naphazoline nitrate 0.1% and xylometazoline HCl 0.05% have reversible effects on the ciliary beat frequency of both human adenoids and chicken embryo tracheas. Cilia of human adenoids appeared to be more sensitive for xylometazoline than for naphazoline; whereas cilia of chicken embryo tracheas were more affected by naphazoline than by xylometazoline. The results with human adenoids and chicken embryo tracheas show a correlation (correlation coeff. = 0.82, p less than 0.005). In the initial response the differences in sensitivity to preservatives and drugs were in many cases statistically significant, but the final effects were similar.

Adenoids↗