Search PubMed⌕ Search

Biomedical subjects

M Müller

Publications and source records attributed to M Müller.

At least 613 records · Page 34Linked to original sources
PubMed1998

[The effect of food on theophylline absorption].

The possible influence of the food and fat content of meals on the bioavailability and pharmacokinetics of a 350 mg sustained release theophylline (CAS 58-55-9) preparation (Bronchoretard) was investigated after single dose oral administration to 18 volunteers in a randomised 3-way crossover design. The treatments investigating administration of the test preparation in a fasting state, after a standard meal and after a high-caloric fat evening meal, according to commonly applied rules, were shown to be equivalent with respect to the extent of bioavailability (AUC) and the observed maximal concentration (Cmax). Pharmacokinetic parameters describing sustained release characteristics were not changed to any relevant degree. As expected, the co-administration of food resulted in a physiologically determined delay in absorption, which is probably not therapeutically relevant during long-term administration.

Adult↗
PubMed1998

[Absorption profile and absolute bioavailability of a theophylline sustained-release preparation].

In a single-dose crossover study with 16 healthy male nonsmoking volunteers the absorption profile and absolute bioavailability of the sustained release pellets contained in all dosage strengths of Bronchoretard (100, 200, 350, 500 mg anhydrous theophylline) were investigated. One capsule (500 mg theophylline) was given after an evening meal. The reference treatment consisted of an i.v. infusion over 8 h in a total dosage of 350 mg theophylline. Plasma concentration-time profiles were evaluated for 72 h after dosing, respectively start of infusion. Theophylline was measured by high-performance liquid chromatography (HPLC). Absorption profiles (Wagner-Nelson) were derived and the absolute bioavailability was calculated. For the sustained release pellets a liberation/absorption of zero order for 12 h could be noted; the dose-corrected mean absolute bioavailability was 88%. The assumptions of an investigation on absolute bioavailability are discussed and the limitations on generalizability resulting therefrom.

Adolescent↗
PubMed1998

[In vivo verification of in vitro release specifications of a theophylline sustained-release preparation].

Especially in drugs with a narrow therapeutic range, "within product bioequivalence" i.e. "batch-to-batch bioequivalence" should be scrutinized. Therefore, pharmacokinetics and bioavailability of to batches at the upper and lower in vitro specification range as well as a batch representing the middle of the specification range was evaluated in an in vivo bioequivalence study. An open, randomized, 3-way crossover, multiple dose study in 18 healthy, male volunteers was selected for this purpose. Bioequivalence regarding rate (Cmax ss; t75%Cmax) and extent (AUCss) of absorption could be established for both extreme batches at the lower and upper in vitro specification range. Additionally both batches proved to be bioequivalent compared to the batch in the middle of the in vitro specification range. As a result, reproducible concentration-time profiles can be guaranteed for all batches of this sustained release theophylline (CAS 58-55-9) preparation. Furthermore, pharmacokinetic characteristics of all three batches meet the quality criteria defined for sustained release theophylline preparations, guaranteeing optimal concentration/time profiles for the therapy of asthma.

Adult↗
PubMed1998

[Pharmacokinetics of a theophylline sustained-release formulation after single and twice daily dosage].

Sustained release theophylline (CAS 58-55-9) preparations may be dosed once or alternatively twice-a-day, depending on the intention of a theophylline therapy. A once-a-day dosage regimen is considered appropriate in patients with nocturnal asthma attacks, whereas a twice-a-day regimen is advantageous for guaranteeing bronchodilatation and to control the underlying inflammatory disease. Therefore, pharmacokinetic characteristics of both modes of administration were evaluated in a randomised, two-way crossover study in 18 female and male elderly volunteers under multiple-dose conditions. The shape of the pharmacokinetic profiles showed the expected and pronounced differences, while the extent of absorption was bioequivalent. Twice daily administration decreased the nocturnal maximum concentration and at the same time increased the minimum concentration. At the expense of the nocturnal excess, the peak-trough fluctuations (PTF) were reduced from 92.1% to 39.5%. Plateau times of 11.4 h and 20.2 h were achieved with both modes of administration. As for theophylline with its narrow therapeutic range, high quality sustained release preparations distinguish themselves by long plateau times and small peak-trough fluctuations such as those observed with the preparation under investigation. When using this preparation, therapeutic concentrations necessary for safety and efficacy are assured under either a once- or a twice-daily dosing regimen.

Aged↗
PubMed1998

[Pharmacokinetics of a new fluid theophylline sustained-release drug form. Microcapsules in a sachet].

A new sustained release theophylline (CAS 58-55-9) formulation was especially designed for the elderly and children. Microcapsules of theophylline, administered as a suspension in water, proved to be a suitable dosage form for a clientele with impaired or difficult deglutition. Pharmacokinetic characteristics of 2 batches at the lower (T1) and upper (T2) in vitro dissolution specification range of this new formulation and a pellet formulation (R) as a comparator were evaluated in an open, randomised, 3-way, multiple dose, crossover study with an asymmetric dosage regimen of 400 mg and 200 mg theophylline. Smooth and safe plasma concentrations with a high and long-lasting plateau were achieved with this new formulation. Plateau times which are independent of the asymmetric dosage regimen ranged from 16.4 h (T1) to 13.8 h (T2) and could therefore cover sufficient time of the dosage interval. Maximum plasma levels of 9.6 micrograms/ml and 10.0 micrograms/ml were attained 6.6 and 6.1 h after dosing of T1 and T2, coinciding perfectly with the time of the critical morning dip at 2-6 a.m. With a nocturnal excess of 15.5% (T1) and 17.9% (T2), this circadian-tailored asymmetric dosage regimen proved to take into account the chronopathology of asthma and the chronopharmacokinetics of theophylline sustained release preparations. Bioequivalence of all 3 formulations compared with each other with regard to rate (Cmax ss) and extent (AUCss) of absorption could be established for the 2 batches at the upper and lower in vitro specification range and for both batches of the new formulation compared to the reference. All in all, the safety and efficacy of this new liquid sustained release theophylline preparation could be established. Furthermore, in vitro specifications were justified according to current EC guidelines.

Aged↗
PubMed1998

Activity and expression of the multidrug resistance proteins MRP1 and MRP2 in acute myeloid leukemia cells, tumor cell lines, and normal hematopoietic CD34+ peripheral blood cells.

To develop a functional assay for the activity of the multidrug resistance protein 1 (MRP1), we tested whether carboxyfluorescein (CF) was specifically transported by MRP and whether this transport pump could be specifically blocked by the leukotriene D4 receptor antagonist MK-571. The activity and expression of MRP1 were studied in several tumor cell lines and in leukemic blasts from patients with acute myeloid leukemia (AML). In the MRP1-overexpressing cell line GLC4/ADR and the MRP1-transfected cell line S1(MRP), MK-571 inhibited CF efflux with high factors [45.9+/-5.8 (mean+/-SD) and 14.4+/-3.2, respectively; n=3; efflux-blocking factors are defined as the ratio of the median fluorescence in presence or absence of MK-571] compared with their MRP1 low-expressing counterparts GLC4 (11.5+/-2.7) and S1 (2.8+/-0.4). In 15 AML cases, the CF efflux-blocking factors of MK-571 varied between 1.9 and 5.2. A good correlation was found between MRP1 protein expression and CF efflux-blocking factors of MK-571 (P=0.013, r=0.39). Besides MRP1, MRP2 was demonstrated with reverse transcription-PCR in 40% of the cases. In contrast to the cell lines, MK-571 also inhibited rhodamine 123 (Rh123) efflux in AML samples. On the other hand, PSC833, a P-glycoprotein specific inhibitor, did not modulate the CF efflux but is efficient in blocking Rh123 efflux. This study demonstrates that AML blasts express MRP1 and MRP2 and that MRP1 activity can be determined by a flow cytometric assay using CF and MK-571.

ATP-Binding Cassette Transporters↗
PubMed1998

Comparison of human telomerase RNA and telomerase activity in urine for diagnosis of bladder cancer.

New, noninvasive methods for the early detection of urothelial carcinomas of the urinary bladder are needed for the diagnosis, follow-up, and screening of patients with bladder cancer. Detection of the enzyme telomerase in urine could offer these new diagnostic possibilities. The standard technique for detecting telomerase activity is the telomeric repeat amplification protocol (TRAP assay). Because of the instability of the ribonucleoprotein telomerase in an aggressive medium, such as urine, investigations conducted to date have yielded nonuniform or even contradictory findings. This study compares the detection of human telomerase RNA (hTR) by reverse transcriptase-PCR (RT-PCR) with detection of telomerase activity by the TRAP assay in the diagnosis of urothelial carcinoma of the urinary bladder. Sedimented cells obtained from urine of 30 patients with urothelial carcinoma, 15 patients with benign urological disorders, 3 patients as part of follow-up for malignant disease, and 20 healthy subjects were examined for the presence of hTR and for telomerase activity (TRAP). In patients with bladder cancer, telomerase activity was detected by the TRAP assay in only 2 of 30 specimens (7%). However, increased levels of hTR were detected by RT-PCR in 25 of the same 30 cases (83%). For patients with benign urological disorders, such as urolithiasis or urinary tract infections, hTR was detected in samples obtained from 4 of 15 patients (27%). Low hTR expression levels were found in 15% of the healthy controls. The detection of hTR by RT-PCR represents a promising new method for detecting malignant cells in urine.

Humans↗
PubMed1998

Transdermal penetration of diclofenac after multiple epicutaneous administration.

OBJECTIVE: To test whether therapeutic diclofenac concentrations are attained in skeletal muscle tissue beneath the application site of an epicutaneously administered diclofenac foam formulation. METHODS: Diclofenac foam (5%) was administered epicutaneously at the thigh 80 mg/200 cm2 twice daily for a period of 7 days in healthy volunteers (n=12). On Day 8, 2 microdialysis probes were inserted into skeletal muscle tissue beneath the application site and an 80 mg dose was administered epicutaneously. Concentration versus time profiles in plasma and skeletal muscle were followed for 10 hours. RESULTS: Concentration versus time profiles were obtained for plasma and interstitial muscle fluid in all experiments. Mean Cmax in plasma was 18.75+/-4.97 ng/ml. Corresponding interstitial concentrations in skeletal muscle were significantly higher, 219.68+/-66.36 ng/ml (p=0.01). Plasma concentrations were not correlated to tissue concentrations (r=-0.08). CONCLUSION: There is significant direct penetration of diclofenac into skeletal muscle following multiple epicutaneous administration. However, the concentration attained in individual subjects is not predictable and may be strongly influenced by individual skin properties.

Administration, Cutaneous↗
PubMed1998

[Foot reflexology: an intervention study].

The study's goal was to test if foot reflexology (FR) affects well-being, voiding, bowel movements, pain and/or sleep in women who underwent an abdominal operation. 130 subjects were randomized into three groups. For five days they were exposed to 15 minutes of FR, foot/leg massage (FM) or talking respectively. Results show that women in the FR group were more able to void without problems, after the indwelling catheter had been removed, than did women in the comparison groups. There was also a tendency in the FR-group for the indwelling catheter to be removed earlier than in the other groups. In comparison, the FR-subjects slept worse than the others. FM showed significant results in subjective measurements of well-being, pain and sleep.

Adult↗
PubMed1998

Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung.

The transmembrane receptor (RAGE) of advanced glycation endproducts (AGEs), is abundantly present in the lung. Although the interaction of AGEs and RAGE plays an important role in vasculopathies, particularly in diabetes, the lung is not a classical target organ of diabetes. Thus, the role of RAGE in the lung is still obscure. This study sought to precisely localise RAGE in the lungs of rat and human by immunohistochemistry, double immunofluorescence and immunoelectron microscopy using a polyclonal antiserum developed against human recombinant RAGE. Anti-RAGE immunoreactivity was prominent in alveolar epithelial type I pneumocytes, while it was absent from type II pneumocytes and capillary endothelium. Cell type specificity was demonstrated by colocalisation with well established cell markers. Quantitative immunoelectron microscopy of cryo-substituted, Lowicryl-embedded rat and human specimens demonstrated a unique labelling pattern of RAGE in that it selectively localised to the basal cell membrane of type I pneumocytes. Labelling pattern was independent of the mode of fixation. Equivalent labelling densities were calculated from a fibrotic rat lung 3 months after irradiation. This highly selective localisation of RAGE to the basal face of type I pneumocytes and its absence from capillary endothelium might explain the resistance of the lung to typical diabetic complications.

Animals↗
PubMed1998

The role of p53 and the CD95 (APO-1/Fas) death system in chemotherapy-induced apoptosis.

To explore the pathway of p53 dependent cell death, we investigated if p53 dependent apoptosis following DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated cell lines of solid human tumors upon treatment with clinically relevant chemotherapeutic drugs known to act via p53 accumulation. Treatment with these cytotoxic drugs led to an upregulation of both, the CD95 receptor (CD95) and the CD95L (CD95L). Induction of the CD95L occurred in p53 wild-type (wt), p53 mutant (mt) and in cell lines lacking p53 altogether (p53-/-). Thus, the regulation of the CD95L in response to chemotherapeutic drugs clearly involves p53 independent mechanisms. Most importantly, upregulation of CD95 occurred only in cell lines with wild-type p53, thereby strongly increasing the responsiveness towards CD95 mediated apoptosis. Thus, upregulation of the CD95 receptor seems to be dependent on intact wild-type p53. Apoptosis was mediated by cleavage of the receptor proximal caspase, caspase-8 (FLICE/MACH). Caspase-8 cleavage was observed, independent of the p53 status of the tumor cells and irrespective whether or not apoptosis was dependent on the CD95 system. Hence, additional effector pathways besides CD95/CD95L signaling are likely to contribute to drug-induced apoptosis.

Antineoplastic Agents↗
PubMed1997

Detection of a single base exchange in PCR-amplified DNA fragments using agarose gel electrophoresis containing bisbenzimide-PEG.

Using PCR fragments of known sequences derived from isolates of two related fungal species, simple submarine electrophoresis in agarose gels containing a bisbenzimide-PEG conjugate (H.A.-Yellow) has been shown to be capable of distinguishing DNA fragments 567 bp long which differ by as little as a single base change. However, only changes affecting bisbenzimide binding sites (which consist of at least four consecutive A/T bases) alter mobility; other changes are ineffective. A second ligand (H.A.-Red) with high G/C specificity is suggested which may be as effective in detecting other sequence changes.

Bisbenzimidazole↗
PubMed1997

[Spontaneous remission of an amiodarone-induced pulmonary lesion].

Amiodarone is an effective class-III antiarrhythmic agent. However, during long term therapy 1-10% of patients develop severe adverse pulmonary reactions, which are potentially life threatening. We report the case of a patient who developed dyspnoea and extensive pulmonary infiltrates compatible with amiodarone-associated interstitial lung disease following 6 months of treatment with amdiodarone (300 mg daily) for atrial flutter. On discontinuation of amiodarone treatment the infiltrates impressively resolved almost completely within 8 weeks, without administration of corticosteroids.

Amiodarone↗
PubMed1997

Dynamical aspects of the EEG in different psychopathological states in an interview situation: a pilot study.

Dynamical brain states can be characterized by non-linear measures of EEG. The present study shows that critical transitions, i.e., abrupt changes from one dynamic pattern of neural mass activity to another one, may be detected by abrupt variations in local chaoticity. Using an ambulatory device, EEG was recorded from 10 patients with a schizophrenic and two patients with an affective disorder during a series of 25-min interviews. Dynamical aspects, in particular, phase transitions in the EEG-dynamics of the EEG were characterized by means of a measure that continuously estimates the chaoticity of the EEG signal and is thus related to its predictability. Results indicate simpler dynamics of the EEG time series in paranoid-hallucinatory patients, while at the same time these patients tended to exhibit more abrupt transitions/unit of time between different dynamical EEG states. Such sudden phase transitions in brain activity were significantly enhanced prior to expressions of thought disorders that were detected by the interviewer and an observer in the conversation, compared with time periods during the interview without such symptoms.

Adult↗
PubMed1997

Mechanisms for high methoxymorpholino doxorubicin cytotoxicity in doxorubicin-resistant tumor cell lines.

Methoxymorpholino doxorubicin (MMRDX) is an anthracycline analogue that is able to overcome tumor cell resistance to classical anthracyclines. Mechanisms for increased MMRDX cytotoxicity were analyzed in a small cell lung carcinoma cell line (GLC4), its 300-fold doxorubicin-resistant and multidrug resistance-associated protein (MRP)-over-expressing subline (GLC4/ADR), an ovarian carcinoma cell line (A2780) and its 100-fold doxorubicin resistant and P-glycoprotein (P-gp)-overexpressing subline A2780AD. Cross-resistance, measured with the MTT assay at MMRDX concentration resulting in 50% growth inhibition, was 1.8-fold in GLC4/ADR and 4.5-fold in A2780AD compared to their respective parental cell lines. Cellular MMRDX accumulation was equal in GLC4 and GLC4/ADR and 2-fold lower in A2780AD compared to A2780. Doxorubicin fluorescence was analyzed with confocal laser scan microscopy. Fluorescence was nuclear in sensitive, and cytoplasmic in resistant, cell lines, while MMRDX fluorescence was found in the nucleus in all cell lines. Pre-incubation with the MRP blocker MK 571 restored in GLC4/ADR cells the nuclear doxorubicin fluorescence pattern, as observed in GLC4 cells. MMRDX, thus, can largely overcome cross-resistance in these P-gp- and MRP-overexpressing doxorubicin-resistant cell lines. Our results suggest that MMRDX is not a substrate for MRP-mediated resistance.

Antibiotics, Antineoplastic↗