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F W Merkus

Publications and source records attributed to F W Merkus.

At least 37 records · Page 2Linked to original sources
PubMed1993

Nasal administration of an ACTH(4-9) peptide analogue with dimethyl-beta-cyclodextrin as an absorption enhancer: pharmacokinetics and dynamics.

1. The systemic absorption and the neurotrophic effect of the metabolically stabilized ACTH (4-9) analogue, Org2766, were investigated following intranasal (i.n.) administration. 2. Without additives the nasal bioavailability of the peptide was in the order of 15 and 10% in rats and rabbits, respectively. The absorption could be improved by addition of a variety of absorption enhancers to the nasal preparation. The beta-cyclodextrin derivative, dimethyl-beta-cyclodextrin (DM beta CD) at a concentration of 5% (w/v) improved the absorption in rats about 5 fold from 13 +/- 4% (mean +/- s.d.) for administration of the peptide alone to 65 +/- 21%, and in rabbits 1 to 2 fold, from 10 +/- 6% to 17 +/- 8%. 3. The increased permeability of the rat nasal mucosa for Org2766 caused by DM beta CD in rats reversed substantially within 1 h. However, the nasal absorption had not yet completely returned to the level without enhancer. 4. S.c. administered Org2766 accelerated the functional recovery from peripheral nerve damage in rats. However, the peptide did not facilitate nerve repair following i.n. administration with DM beta CD, in spite of the fact that Org2766 was well absorbed. I.v. injection of Org2766 was also ineffective.

Absorption↗
PubMed1992

Intranasal administration of estradiol in combination with progesterone to oophorectomized women: a pilot study.

A pilot study was done to investigate the pharmacokinetics and acceptability of an intranasal 17 beta-estradiol/progesterone formulation. This formulation contained dimethyl-beta-cyclodextrin as a solubilizer and absorption enhancer of the steroid hormones. The study was performed in four oophorectomized and hysterectomized patients. After nasal delivery of 0.34 mg estradiol and 0.85 mg progesterone, concentration-time curves of progesterone, estradiol and its metabolite estrone were established. Rapid absorption of progesterone and estradiol was demonstrated. Progesterone peak-levels (3.9-6.7 nmol/l) exceeded the levels which are found in the follicular phase of the menstrual cycle, but did not reach the levels of the luteal phase. Comparison with an earlier reported study in which only estradiol was administered shows that the addition of progesterone does not alter the absorption and pharmacokinetics of estradiol. The nasal formulation was well accepted by the four patients and no adverse effects were noted.

Administration, Intranasal↗
PubMed1992

Influence of levocabastine suspension on ciliary beat frequency and mucociliary clearance.

The effects of levocabastine, a new fast-acting, highly potent H1-antagonist, on nasal ciliary epithelial function were investigated in an in vitro and in vivo study. In the in vitro study, a suspension of levocabastine in Locke-Ringer solution was applied to 10 bioptic specimens of ciliated human adenoid tissue. Each specimen was exposed to the test solution for 60 min. Ciliary beat frequency (CBF) was recorded with a photoelectric recording device at 10-min intervals. There were small, insignificant decreases in CBF, which were minimal compared to that observed with ciliotoxic agents. In the in vivo study, 8 healthy volunteers were given, intranasally, one droplet of the levocabastine suspension. Mucociliary transit time (MTT) was measured by placing a saccharin particle drenched in indigo carmine in the nose just below the top of the concha and measuring the time until appearance of the dye in the pharyngeal cavity. No statistically significant differences were found in the MTT before and after application of the levocabastine suspension. The studies thus indicate that nasally administered levocabastine does not interfere with ciliary beat frequency and mucociliary function.

Adenoids↗
PubMed1991

Intranasal estradiol administration to oophorectomized women.

An open, dose-finding study into the effects of a new intranasal 17 beta-estradiol formulation using dimethyl-beta-cyclodextrin as a solubilizer was conducted in nine hysterectomized and oophorectomized patients with symptoms of estrogen deficiency. After nasal delivery of 0.34 mg estradiol in three patients, concentration-time curves of estradiol in serum and its metabolite estrone in plasma were established. High initial estradiol serum levels were found in the order of 5 nmol/l. Estrone/estradiol ratios were below unity, whereas, in contrast, estrone/estradiol ratios after oral administration of estradiol are known to exceed unity. Biological activity, as reflected by suppression of FSH and LH, was manifest. In nine patients symptoms of estrogen deficiency were assessed by a questionnaire. After 3 and 6 months of treatment, a clinically and statistically significant decrease (P less than 0.01) of the total score according to this questionnaire was found compared to the beginning of the study. Thus nasal delivery of estradiol using this cyclodextrin formulation has potential for further clinical evaluation.

Administration, Intranasal↗
PubMed1991

The nasal mucociliary clearance: relevance to nasal drug delivery.

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.

Administration, Intranasal↗
PubMed1991

Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats.

The absorption enhancing effect of alpha-, beta-, and gamma-cyclodextrin (CD), dimethyl-beta-cyclodextrin (DM beta CD), and hydroxypropyl-beta-cyclodextrin (HP beta CD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DM beta CD to the insulin solution resulted in a high bioavailability, 108.9 +/- 36.4% (mean +/- SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% alpha-CD gave rise to an insulin bioavailability of 27.7 +/- 11.5% (mean +/- SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the alpha-CD-containing solution as compared to the DM beta CD preparation. The other CDs, HP beta CD (5%), beta-CD (1.8%), and gamma-CD (5%), did not have significant effects on nasal insulin absorption. DM beta CD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DM beta CD is a potent enhancer of nasal insulin absorption in rats.

Absorption↗
PubMed1990

Nasal absorption enhancement of 17 beta-estradiol by dimethyl-beta-cyclodextrin in rabbits and rats.

A new formulation for nasal administration containing 17 beta-estradiol (E2) with dimethyl-beta-cyclodextrin (DM beta C) as a solubilizer and absorption enhancer is described. Nasal administration of this E2-DM beta C formulation gave a significantly higher E2 absorption than an E2 suspension in both rabbits and rats. Relative to an intravenous injection of the E2-DM beta C formulation, absolute bioavailabilities of 94.6 and 67.2% were calculated for the nasal E2-DM beta C formulation in rabbits and rats, respectively. Differences in bioavailability may have resulted from differences in experimental animal conditions. The effects on human nasal ciliary activity of the E2-DM beta C formulation were studied with an in vitro method. The formulation was found to exert only a minor effect on ciliary beat frequency. Thus, nasal delivery of E2, using a cyclodextrin inclusion formulation, may have potential for clinical application, e.g., in the therapy of postmenopausal disorders.

Absorption↗
PubMed1990

Effects of absorption enhancers on human nasal tissue ciliary movement in vitro.

Sodium taurodihydrofusidate (STDHF) is one of the most promising absorption enhancers for nasal delivery of peptide drugs. Drugs and additives in nasal formulations should not interfere with the self-cleaning capacity of the nose by the ciliary epithelium. Measured in vitro on human adenoid tissue with a photoelectric method, STDHF was found to induce ciliostasis at concentrations of 0.3% (w/v) and higher. STDHF (0.3%) is less ciliostatic than laureth-9 (0.3%) or deoxycholate (0.3%). Glyco- and taurocholate (0.3%) show only very mild effects on nasal ciliary movement. Human insulin (1%) has no ciliostatic potency in vitro, whereas a combination of human insulin (1%) and STDHF (1%) is ciliostatic but not as potent as STDHF (1%) alone.

Absorption↗
PubMed1990

The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers.

The pharmacokinetics after oral, intramuscular and rectal administration of artemisinin, a new potent antimalarial drug, to healthy volunteers has been examined. The study was set-up as a four-way cross-over design with a wash-out period of one week between the test days. In ten volunteers artemisinin concentrations in serum were monitored using a reversed phase HPLC assay with UV detection after derivatization. After oral administration, artemisinin was rapidly but incompletely absorbed, the mean absorption time was 0.78 h and the bioavailability relative to the intramuscularly injected suspension in oil 32%. The mean residence time of the latter (10.6 h) was 3 times that of the oral formulation (3.4 h). This seems to enable a twice daily dosage regimen for the intramuscular oil injection, while the oral formulation necessitates a more frequent dosing interval. After intramuscular injection and rectal administration of an aqueous suspension, very low and variable artemisinin concentrations in serum were observed, probably indicating a poor and erratic absorption.

Administration, Oral↗
PubMed1989

Absorption enhancement of intranasally administered insulin by sodium taurodihydrofusidate (STDHF) in rabbits and rats.

The enhancement of nasal insulin absorption by sodium taurodihydrofusidate (STDHF) was studied in rabbits and rats. Using identical nasal formulations remarkable interspecies differences were observed. The fusidate derivative at 1% (w/v) enhanced nasal insulin bioavailability from 0.9 to 5.2% and from 0.3 to 18.0% in rabbits and rats, respectively. In both species the insulin formulations with STDHF resulted in strong hypoglycemic responses. Coadministration with the trypsin inhibitor aprotinin tended further to increase insulin bioavailability in rats and decrease insulin bioavailability in rabbits; however, these aprotinin effects were not statistically significant. Addition of the aminopeptidase inhibitor bacitracin to the STDHF containing formulation did not have any effect on insulin bioavailability in rats. Hence, STDHF is a potent enhancer of nasal insulin absorption, probably both by facilitating insulin transport through the nasal mucosa and possibly also by inhibiting enzymatic degradation. Further, interspecies differences and, experimental animal conditions can greatly affect nasal drug absorption.

Administration, Intranasal↗
PubMed1987

Plasma protein binding of digitoxin and some other drugs in renal disease.

Plasma protein binding of most acidic drugs is decreased in uraemia, whereas the binding of basic drugs is usually unchanged or decreased. Decreased protein binding in patients with renal disease mainly relates to drugs binding to albumin. Digitoxin binds to a specific site on the albumin molecule. Conflicting reports exist on digitoxin-protein binding in patients with renal disease. In ten patients with end-stage renal disease treated with haemodialysis we found only a slightly increased free fraction of digitoxin. A heparin-induced increase of the free fraction of digitoxin during haemodialysis has been reported. However, this increase was caused by the generation of non-esterified fatty acids in vitro. If this in vitro lipolysis was blocked, no increase of free digitoxin could be detected. Alterations of digitoxin-protein binding in uraemic patients during haemodialysis and during the intervals between haemodialysis treatments are small.

Blood Proteins↗
PubMed1987

The influence of drugs on nasal ciliary movement.

Drugs in nasal preparations, for local use as well as for systemic use, should not interfere with the self-cleaning capacity of the nose, effectuated by the ciliary epithelium. Many drugs and additives, however, have a negative effect on nasal ciliary function. Examples of ciliotoxic agents are lipophilic and mercuric preservatives, local anesthetics, antihistamines, propranolol, and absorption enhancers such as the bile salts. Cholinergic drugs and beta-adrenergic drugs exert a ciliostimulatory effect. It is the purpose of this review to summarize the present knowledge of ciliotoxicity of drugs and additives and to give recommendations for the use of ciliofriendly drugs in nasal preparations.

Cilia↗
PubMed1987

The metabolism and biopharmaceutics of spironolactone in man.

Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.

Aged↗