Biomedical subjects

H Laufen

Publications and source records attributed to H Laufen.

At least 37 records · Page 2Linked to original sources

PubMed1995

Serial gadolinium-enhanced magnetic resonance imaging in patients with multiple sclerosis treated with mitoxantrone.

Serial gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) was used to monitor the effect of mitoxantrone in ten patients with rapidly deteriorating multiple sclerosis (MS). MRI was performed as a baseline and thereafter at 1, 3, 6, 9, 12 and 24 months. The total number of Gd-enhancing lesions diminished from 169 at baseline to 10 after 1 year and to 5 after 2 years. This reduction and the percentage of follow-up MRI studies showing no Gd enhancement were more pronounced than in other MRI studies of the natural course of MS. Measured with quantitative neurological scales, only one patient showed deterioration after 2 years; nevertheless, the changes in MRI were much more marked than those observed clinically. Serial Gd-MRI therefore, seems necessary for documenting efficacy in future therapeutic trials.

Adult↗

PubMed1995

Pharmacokinetic optimization of the treatment of oral candidiasis with fluconazole: studies with a suspension.

An open crossover study was performed in 12 healthy subjects to investigate the pharmacokinetics in saliva and plasma of a 100 mg oral dose of fluconazole, administered as either a capsule or as a suspension, the latter being used to rinse the mouth and retained for 2 min before being swallowed. In terms of fluconazole plasma concentrations the capsule and the suspension were essentially bioequivalent. While the saliva concentrations of fluconazole after capsule administration reached their peak at 3.0 +/- 0.8 micrograms/ml 4 h after dosage, administration of the suspension resulted in a mean peak concentration of 551.1 +/- 425.6 micrograms/ml 5 min after ingestion. The saliva concentrations decreased gradually after ingestion of the suspension, but were higher for 4 h than the corresponding levels from the capsule. The area under the curve (AUC) from 0 to 96 h of fluconazole in saliva was 227.7 +/- 73.8 h micrograms/ml after the suspension, compared to 123.5 +/- 25.5 h micrograms/ml after the capsule, indicating that the total drug exposure to the oral mucosa by the salivary route was enhanced more than 80% with use of the suspension. Four h after administration of the suspension, saliva and plasma concentrations of fluconazole were in equilibrium, at a saliva: plasma ratio of around 1.2. Taken together, the present results suggest that the treatment of oral candidiasis with fluconazole may be optimized by use of an oral suspension, as this delivers pharmacologically active levels of the drug to the site of infection by both topical and systemic routes.

Adult↗

PubMed1994

Enantioselective gas chromatographic assay with electron-capture detection for amlodipine in biological samples.

A sensitive enantioselective gas chromatographic assay has been developed for amlodipine, 2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine, a calcium channel blocking therapeutic agent. The assay involves conversion of the (+)-(R)- and (-)-(S)-enantiomers of amlodipine into their acyl derivatives with the chiral reagent (+)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (Mosher's reagent). Peak separation after chromatography of the diastereomers was larger than 85%, and the lower limit of detection in blood plasma was 0.02 ng/ml for each enantiomer. The method has been used for the measurement of amlodipine enantiomers in human, rat and dog plasma, and in various organs of the rat.

Adult↗

PubMed1994

Enantioselective disposition of oral amlodipine in healthy volunteers.

Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the Cmax and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with--and thus highly predictive for--the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers.

Administration, Oral↗

PubMed1994

Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole.

The influence of food on the pharmacokinetics of the triazole antimycotics fluconazole and itraconazole was investigated in a randomised, parallel group, single dose study in 24 healthy subjects. Each group took either a 100 mg capsule of fluconazole or a 100 mg capsule of itraconazole, pre-prandially or after a light meal or a full meal, in a three-way crossover design. Gastric and intestinal pH were measured with a co-administered radiotelemetric pH capsule, and gastric emptying time of the capsule (GET) was taken as the maximum gastric residence time of drug and food. The plasma AUC and Cmax of itraconazole were significantly different under the various conditions and the mean AUC was greatest after the full meal. The bioavailability (90% confidence intervals) of itraconazole relative to that after the full meal, was 54% (41-77%) on an empty stomach and 86% (65-102%) after a light meal. The criteria for bioequivalence were not attained. In contrast, the bioavailability (90% CI) of fluconazole relative to the full meal was 110% pre-prandially (100-115%) and 102% after the light meal (88-103%), and the criteria for bioequivalence were attained. Itraconazole absorption was promoted by low stomach pH, long gastric retention time and a high fat content of the coadministered meal, whereas the pharmacokinetics of fluconazole was relatively insensitive to physiological changes in the gastrointestinal tract.

Administration, Oral↗

PubMed1994

The influence of gastric pH on the pharmacokinetics of fluconazole: the effect of omeprazole.

AIDS patients may have achlorhydria, a condition that could result in drug malabsorption, especially of antifungals. The effect of a reduction in the production of gastric acid on the pharmacokinetics of the antimycotic fluconazole after a single 100 mg dose was investigated in a randomized two-way crossover study with 12 healthy volunteers. Gastric acid production was reduced by pretreatment with 20 mg omeprazole/day over a period of 7 days; pH and gastric emptying times were measured by a radiotelemetering pH capsule. Omeprazole pretreatment significantly raised the median gastric pH (from pH 1.1 to pH 4.7, p < 0.0001), but had no significant influence on gastric emptying time of the pH capsule (median = 4.3 vs 4.9 hours). The pharmacokinetics of fluconazole were unchanged; plasma parameters were Cmax = 2.04 micrograms/ml, tmax = 4.08 h and AUC = 98.91 h micrograms/ml after the omeprazole treatment, compared to 2.06 microliters/ml, 3.92 hours and 97.29 h micrograms/ml, respectively. The median bioavailability ratio of fluconazole before and after omeprazole treatment was 1.00. It is inferred that there is no interference of omeprazole with the plasma pharmacokinetics of fluconazole. The findings suggest that changes in gastric pH, as in patients with AIDS or those being treated with anti-ulcer drugs, should not influence the pharmacokinetics of fluconazole.

Administration, Oral↗

PubMed1994

Influence of concomitant food intake on the gastrointestinal absorption of fluconazole and itraconazole in Japanese subjects.

The effect of food intake on the pharmacokinetics of orally administered fluconazole or itraconazole was investigated in a single-dose randomized two-way crossover study in Japanese subjects. 100-mg capsules of fluconazole or itraconazole were given to two parallel groups, each of 12 male and female volunteer subjects, and plasma concentrations of the antimycotics were determined by specific assays. Gastric pH and gastric emptying times were measured by coadministration of a radiotelemetric pH capsule. Intersubject variations in drug plasma concentrations were found to be much higher with itraconazole than with fluconazole. The coefficient of variation of the AUC (0-72) after food amounted to +/- 62% for itraconazole and +/- 16% for fluconazole. The consumption of a heavy breakfast significantly delayed the tmax of both drugs by approximately two hours (p < 0.05). This effect was accompanied by a significant prolongation of gastric emptying times (p < 0.0001). Food intake had essentially no effect on the absorbed amounts of fluconazole. The median relative bioavailability (postprandial vs fasting) based on AUC (0-72) was f = 0.99, with an individual range from 0.72 to 1.15. The corresponding Cmax ratio was 1.04 (range 0.91-1.17). The effect of food on the bioavailability of itraconazole was highly variable: it ranged from marked reductions (f = 0.35) to large increases (f = 3.74) of the AUC (0-72), at a median ratio of f = 1.23. The Cmax ratios postprandial vs fasting ranged between 0.27 and 5.71 (median = 1.04). It is concluded that food had an unpredictable effect on the extent of itraconazole absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Distribution of orally administered azithromycin in various blood compartments.

The concentrations of azithromycin in whole blood, plasma, erythrocytes and polymorphonuclear leucocytes (PMNLs) were measured in 6 healthy volunteers following the last administration of a three-day regimen of 500 mg once daily. Marked enrichment of azithromycin was observed in PMNLs; the drug concentration amounted to 119 +/- 31 (SD) mg/l 6 hours after the administration. Twelve days thereafter 42 +/- 10 mg/l azithromycin was still measured in the PMNLs, although the drug was no longer demonstrable in plasma (< 0.02 mg/l). The elimination of azithromycin from the PMNLs (half-life 210 +/- 69 hours) was clearly slower than the elimination from plasma (half-life 93 +/- 70 hours). The maximal concentrations of azithromycin in plasma (0.64 +/- 0.27 mg/l) and erythrocytes (0.17 +/- 0.06 mg/l) were much lower and occurred earlier (tmax = 3 hours) than those observed in the PMNLs. The enrichment factor for azithromycin in PMNLs relative to plasma came to 177 +/- 92 at 3 hours or 1814 +/- 706 at 120 hours after the last administration. In a parallel in vitro study, the effect of accumulation of azithromycin in PMNLs on the intracellular survival of ingested staphylococci was investigated. At subinhibitory extracellular concentrations of azithromycin as low as 0.03 mg/l (MIC = 1 mg/l), a significant reduction in bacterial viability was observed, thus demonstrating antibacterial activity of the intracellularly enriched antibiotic.

Administration, Oral↗

PubMed1994

Pharmacological comparison of the stereoisomers of glyceryl-1-nitrate.

The enantiomers of glyceryl-1-nitrate, a metabolite of glyceryl trinitrate, were pharmacologically characterized in vitro and in animals. In the Langendorff heart (l) G-1-N was double as potent as (d) G-1-N with respect to the enhancement of coronary flow. The two enantiomers showed almost the same dose-response curves in rabbit aortic strips contracted with phenylephrine. In the same model there were no enantiospecific differences in the development of cross-tolerance to glyceryl-trinitrate. In anaesthetized rabbits, intravenous (l) G-1-N reduced the blood pressure slightly more than (d) G-1-N, while in the conscious dog the blood pressure lowering effect of (d) G-1-N was greater and had a much longer duration (4-6 versus 2 h) than that of (l)G-1-N. The differences in dogs are probably explained by enantiospecific pharmacokinetics: (d) G-1-N had higher plasma levels and showed a longer half-life of elimination than (l) G-1-N (more than 5 h versus 2.7 h). Both enantiomers enhanced the rate of survival after acute coronary ligature in rats with a tendency to higher long-term survival rates after the (d) form.

Administration, Oral↗

PubMed1994

Neurological and neuropsychiatric dysfunction in primary Sjögren's syndrome.

In a prospective clinical investigation of 20 patients with primary Sjögren's syndrome (SS), neurological complications, not attributable to other diseases were detected in 14 patients (= 70%). Dysfunction of the peripheral nervous system (PNS) was nearly twice as frequent as central nervous system (CNS) complications. PNS involvement was dominated by symmetric sensory neuropathies, carpal tunnel syndromes, cranial nerve palsies (above all trigeminal sensory neuropathy) and pupillary dysfunction. CNS impairment was represented by cortical atrophy (n = 4), hemiparesis (n = 1) and aseptic meningitis (n = 1). Though CNS complications were rare, psychometric testing revealed diminished cognitive capacity in 14 patients. In addition to the characteristic sicca syndrome patients suffered from musculoskeletal pain and recurring abnormal sensation which frequently lead to the misdiagnosis of functional disorders. Additionally the frequent occurrence of psychiatric symptoms such as nervosity and depression support the impression of a psychosomatic pattern with no organic basis.

Adult↗

PubMed1993

Comparison of the pharmacokinetics of three-day and five-day regimens of azithromycin in plasma and urine.

In an open crossover study, the pharmacokinetics of three-day and five-day regimens of azithromycin were compared. Fourteen healthy volunteers received oral doses of azithromycin once-daily, over three days (500 mg/day) and over five days (500 mg on day 1, followed by 250 mg/day on days 2-5). Plasma and urine concentrations were determined by HPLC. Azithromycin was found to be absorbed rapidly on the first and the last days of both regimens, with mean Tmax ranging between 2.5-3 h. On day 1, peak plasma concentrations were 0.37 mg/L and 0.31 mg/L, respectively, with three- and five-day regimens, and increased to 0.42 mg/L on the last day of the three-day regimen, but decreased to 0.18 mg/L at the end of the five-day regimen. Similarly, the AUC0-24 increased from 1.30 to 1.88 h.mg/L during the three-day regimen, and decreased from 1.24 to 0.80 h.mg/L on the five-day regimen. After absorption, azithromycin was distributed rapidly; the respective half-lives were 2.4 h and 2.2 h with the three-day and five-day regimens. Thereafter, a polyphasic decline of plasma concentrations was observed; the average half-lives between 8-48 h after administration were 27.9 h (three-day regimen) and 35.8 h (five-day regimen). In urine, 5.5% (three-day regimen) and 4.6% (five-day regimen) of the total dose was found as unchanged azithromycin over a 12-day period. The observed pharmacokinetics of azithromycin with both regimens conformed with the known pharmacokinetic behaviour of the drug. The treatment-related differences seen in the plasma concentrations were as expected from the different dosage schedules.

Administration, Oral↗

PubMed1993

Levels of fluconazole in serum, stratum corneum, epidermis-dermis (without stratum corneum) and eccrine sweat.

The distribution in the skin of orally active antifungals and other drugs claimed to be active in the treatment of skin diseases is of major importance, but to date has been studied only rarely. In the present study the distribution of fluconazole in stratum corneum, epidermis-dermis (without stratum corneum), eccrine sweat and serum was studied in human male volunteers after dosages of 50 mg daily for 12 days and 150 mg once weekly for 2 weeks. In the present study high levels of fluconazole were found especially in the stratum corneum. At a dose of 50 mg once daily the concentration of fluconazole after 12 days was 73.0 micrograms/g and 7 days after cessation of treatment the concentration was still 5.8 micrograms/g. At the 150 mg once a week dose the concentration 7 days after the second dose was still 7.1 micrograms/g in stratum corneum indicating that medication once a week may be effective in the treatment of dermatomycoses. High concentrations, all above the serum concentrations, were also seen in sweat and epidermis/dermis. These results indicate that fluconazole is delivered to the stratum corneum, where it is accumulated, through sweat and by direct diffusion through the dermis-epidermis. These pharmacokinetic results indicate that the drug should be very effective in the treatment of dermatomycoses. An extremely high concentration of the drug in the stratum corneum combined with concentrations from 2.93 to 4.62 micrograms/g in the rest of the epidermis and dermis is important in the treatment of these diseases.

Adult↗

PubMed1993

Uptake and subcellular distribution of azithromycin in human phagocytic cells. Demonstration of the antibiotic in neutrophil polymorphonuclear leucocytes and monocytes by autoradiography and electron microscopy.

Azithromycin (CAS 83905-01-5), a new azalide antibiotic, reached high concentrations in alveolar macrophages obtained from patients. Uptake of [14C] azithromycin by macrophages resulted in an intracellular/extracellular concentration ratio of approximately 634 after 90 min incubation. Electron microscopic autoradiography provided visual evidence for the marked uptake and localization of [3H] azithromycin in human neutrophils and monocytes isolated from healthy volunteers. Quantitative analysis of the autoradiographs showed the distribution of azithromycin over the various compartments of the phagocytic cells.

Autoradiography↗

PubMed1992

Equivalence of a high-performance liquid chromatographic assay and a bioassay of azithromycin in human serum samples.

Two sensitive methods for the determination of the azalide antibiotic azithromycin in human serum were compared. High-performance liquid chromatography (HPLC) and a microbiological assay were simultaneously applied to 768 serum samples obtained in a clinical study. There was excellent agreement between the azithromycin concentrations measured by HPLC and by the bioassay. The correlation coefficient for the two methods was r2 = 0.96. The precision and the sensitivity of the methods were found to be very similar.

Azithromycin↗

PubMed1992

Treatment of multiple sclerosis with mitoxantrone.

Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.

Adult↗

PubMed1992

Relative bioavailability of carbinoxamine and phenylpropanolamine from a retard suspension after single dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylpropanolamine (PP, CAS 14838-15-4) after single dose administration of a retard suspension (Rhinopront), containing a resinate as sustained-release agent, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects who received the two formulations according to a standard crossover design with a one-week wash-out. Blood samples were obtained up to 24 h post-dose. PP and CA were assayed in the plasma samples by gas chromatography with electron-capture detection and HPLC with coulometric detection, respectively. The pharmacokinetic results indicated sustained release of the two active principles with the retard suspension: CA appeared in plasma at a much slower rate than with the solution, a 30% lower Cmax being reached after 8.0 h instead of 3.0 h post-dose. For PP, Cmax was 23% lower and occurred 3.0 post-dose instead of 1.5 h with the solution. The extent of absorption of the two drugs, as assessed by AUC (0-24 h), was slightly smaller with the retard suspension than with the aqueous solution. However, the test/reference ratio remained within 95% confidence intervals of 80-87% and 88-98% for CA and PP, respectively, indicating bioequivalence of the two formulations. A simulation of the plasma levels during repeated administration indicated that dosing with the retard suspension at 12-h intervals should yield the same steady-state plasma levels as a 5 times daily administration of a divided dose of the aqueous solution, for both drugs.

Adult↗

PubMed1992

Bioavailability and metabolism of isosorbide dinitrate from a transdermal spray.

The plasma pharmacokinetics of isosorbide dinitrate (ISDN), isosorbide-2-nitrate (IS-2-N) and isosorbide-5-nitrate (IS-5-N) were investigated in 12 healthy volunteers after a single cutaneous administration of 60 mg ISDN (CAS 87-33-2) in the form of a solution sprayed onto the skin (TD Spray Iso Mack), in comparison with an intravenous infusion of 5 mg ISDN. After the intravenous dose, the apparent steady state volume of ISDN distribution came to 179.9 l, total body clearance was 3.14 l min-1, and terminal half-life was 79 min, on average. The transdermal absorption resulted in an average peak plasma concentration of 6.9 ng ISDN ml-1 at 5 h after the administration. ISDN concentrations between 1 and 5 ng ml-1 were maintained over at least 15 h. On average, 16.5% of the topically applied ISDN reached the systemic circulation. Total variations in Cmax (CV = 47.9%) and AUC (CV = 36.0%) of transdermal ISDN were similar to those usually observed after oral ISDN.

Administration, Cutaneous↗

PubMed1992

Subcellular distribution and antifungal effects of fluconazole in human phagocytic cells. Demonstration of the antifungal agent in neutrophil polymorphonuclear leucocytes and monocytes by autoradiography and electron micrography.

Electron microscopic autoradiography was used to demonstrate the presence of [3H] fluconazole (CAS 86386-73-4) in neutrophils and monocytes isolated from volunteers. Quantitative analysis of the autoradiographs showed significant accumulation of fluconazole in both phagocytic cells. The distribution of fluconazole was equal in the different intracellular compartments such as cytoplasm and nucleus. Fluconazole (20 micrograms/ml) induced ultrastructural changes in Candida albicans cells which had been phagocytized by neutrophils or monocytes (macrophages) in vitro. Particularly, changes in the plasma membrane and in the cytoplasmic structure of the intraphagocytic yeast cells were observed electron microscopically.

Antifungal Agents↗