This present study aims to investigate if P9605, an ethanolic extract of PIPER CUBEBA L, exhibits... more This present study aims to investigate if P9605, an ethanolic extract of PIPER CUBEBA L, exhibits anti-estrogenic and anti-inflammatory properties. We found that P9605 significantly inhibited growth induced by beta-estradiol in MCF-7, a human breast cancer cell line. It inhibited aromatase activity, which is responsible for transforming androgens into estrogens. Competitive binding assays also indicated P9605 binding to both human recombinant estrogen a and beta receptors. Furthermore, this extract inhibited the activities of cyclo-oxygenases (COX-1 and COX-2) and 5-lipo-oxygenase (5-LOX), also it attenuated the induction of interleukin 6 (IL-6) in differentiated THP-1 cells stimulated by lipopolysaccharide (LPS). Taken together with our previous results, P9605 possesses anti-androgenic, anti-estrogenic and anti-inflammatory properties. These results support the potential use of P9605 in phytotherapy against benign prostatic hyperplasia (BPH).
In vitro and in vivo studies suggest that extracts of St John's wort (Hyp... more In vitro and in vivo studies suggest that extracts of St John's wort (Hypericum perforatum, L .; SJWE) interact with various drugs, by enhancing their elimination, due to induction of intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), the gene product of multidrug resistance gene 1 (MDR1/ABCB1). The aim of our study was to identify the major constituents responsible for this induction and their relative importance. Therefore, plant extracts were investigated that vary in these constituents with respect to their effect on mRNA expression of MDR1/CYP3A4. First, different pure constituents of Hypericum perforatum L . were investigated. Secondly, diverse SJWE with different concentrations of hyperforin, quercitrin and hypericin were investigated. The concentrations of hyperforin, hypericin, and quercitrin in the plant extracts were determined by HPLC, and an "artificial extract" containing the same mixture of these constituents was investigated. Different plant extracts, pure constituents or "artificial extracts" were applied to the human colon carcinoma-derived cell line (LS180) and the induction of MDR1 and CYP3A4 expression was analyzed by quantitative RT-PCR. MDR1 and CYP3A4 mRNA expression were both induced by single constituents of SJW such as hypericin and hyperforin in a concentration of 10 microM. Additionally, CYP3A4 mRNA expression was induced by quercitrin. SJW extracts containing hyperforin induced significantly MDR1 mRNA expression, whereas no CYP3A4 induction was observed after treatment with any of the investigated SJWE. These effects could be mimicked by "artificial extracts" containing the same compositions of hyperforin, hypericin and quercitrin as the plant extracts.
Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vi... more Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vitro cell culture model of the blood-brain barrier. The present study describes the influence of cell-culture conditions on tight junctions, filamentous-actin cytoskeleton, and expression of ATP-binding cassette (ABC) transporters in primary cell cultures of porcine BCEC. Astrocyte as well as C6 glioma-conditioned cell culture medium was used in combination with retinoic acid, dexamethasone, cyclic adenosine monophosphate (cAMP) analogs, or 1,25dihydroxyvitamin D 3 . It was shown that C6-conditioned medium led to a reorganization of filamentous actin and to an improved staining of zonula occludens-associated protein-1 (ZO-1). Further optimization of these culture conditions was achieved with cAMP analogs and dexamethasone. Retinoic acid, as well as 1,25-dihydroxyvitamin D 3 , did not improve cellular tight junctions as judged by filamentous actin, ZO-1 rearrangement, and transcellular electrical resistance (TER) measurements. However, these morphological changes did not influence the paracellular permeability of the extracellular marker sucrose. Expression of ABC transporters such as P-glycoprotein, multidrug resistance-associated protein-1 (MRP1), and MRP2 were compared by measuring messenger RNA (mRNA) levels in whole-brain tissue, isolated brain capillaries, and cultured cells. In freshly isolated BCEC, mRNA levels of MRP2 and P-glycoprotein dropped by two-to sevenfold, respectively, whereas MRP1 mRNA levels were slightly increased. During cell culture, mRNA levels of MRP1 and MRP2 decreased by up to fivefold, while P-glycoprotein levels remained constant. These results were unaltered by different cellculture conditions. In conclusion, the present study suggests that paracellular permeability, as well as mRNA expression of the studied ABC transporters in primary cultures, of porcine BCEC are insensitive toward changes in cell-culture conditions.
British Journal of Clinical Pharmacology, Sep 1, 2000
Aims To investigate the effect of acute P-glycoprotein inhibition by the multidrugresistance (MDR... more Aims To investigate the effect of acute P-glycoprotein inhibition by the multidrugresistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Methods In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO 2 , blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h. Results The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically signi®cant increase in the AUC and C max of M3G (11.8 and 8.3%, respectively). The t K and t max were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not signi®cantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (E max 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a signi®cant decrease in systolic blood pressure (E min x9 mmHg), and a trend for a fall in diastolic blood pressure (E min x14.5 mmHg) and respiratory rate (E min x1.8 breathemin x1 ). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a signi®cant increase in PCO 2 (E max 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination. Conclusions Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic pro®le of morphine in a clinically signi®cant manner.
Neue therapeutische Optionen der hochaktiven antiretroviralen Therapie (HAART) haben die Morbidit... more Neue therapeutische Optionen der hochaktiven antiretroviralen Therapie (HAART) haben die Morbidität und Mortalität von HIV-infizierten Patienten deutlich gesenkt, so dass nun vermehrt die altersspezifischen Erkrankungen manifest werden, wie z.B. kardiovaskuläre Erkrankungen. Zusätzlich verursacht die HIV-Erkrankung selber eine gewisse kardiovaskuläre Morbidität. Aus diesem Grund gewinnt die Behandlung der kardiovaskulären Symptome eine zunehmende Bedeutung. Die Pharmakotherapie dieser HIV-positiven Patienten ist sehr komplex, da sie durch eine Polypharmazie aus Medikamenten mit einem hohen Interaktionspotential geprägt ist.
Several antibiotics show significant pharmacokinetic interactions when they are given orally conc... more Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C max) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C max , lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C max , V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.
Aims Somatostatin analogues (e.g. vapreotide) are used for treatment of acromegaly, endocrine tum... more Aims Somatostatin analogues (e.g. vapreotide) are used for treatment of acromegaly, endocrine tumours and variceal bleeding. The pharmacodynamic effects of vapreotide have, however, not been documented in the gastrointestinal tract. The aim of this study was to investigate the effects of continuous vapreotide administration on gastric acidity, gallbladder contraction and hormone release. Methods Ten healthy males participated in this randomised, placebo‐controlled, double‐blind, crossover trial. A constant vapreotide (or placebo) infusion (1.5 mg day−1 s.c.) was given for 7 days with a portable pump. Intragastric pH was monitored on days 2 and 7. Gallbladder volume was sonographically assessed and the maximal ejection fraction was calculated. In addition basal and postprandial plasma levels of gastrin and cholecystokinin (CCK) were measured. Results After an initial increase in the median 24 h intragastric pH to a value of 2.6 on day 2, vapreotide’s effect on pH decreased: (day 7: m...
Background Membrane lipids have an important function in the brain as they not only provide a phy... more Background Membrane lipids have an important function in the brain as they not only provide a physical barrier segregating the inner and outer cellular environments, but are also involved in cell signaling. It has been shown that the lipid composition effects membrane fluidity which affects lateral mobility and activity of membrane-bound receptors. Methods Since changes in cellular membrane properties are considered to play an important role in the development of depression, the effect of St. John’s wort extract Ze 117 on plasma membrane fluidity in peripheral blood mononuclear cells (PBMC) was investigated using fluorescence anisotropy measurements. Changes in fatty acid residues in phospholipids after treatment of cortisol-stressed [1 μM] PBMCs with Ze 117 [10–50 µg/ml] were analyzed by mass spectrometry. Results Cortisol increased membrane fluidity significantly by 3%, co-treatment with Ze 117 [50 µg/ml] counteracted this by 4.6%. The increased membrane rigidity by Ze 117 in cort...
Background Membrane lipids have an important function in the brain as they not only provide a phy... more Background Membrane lipids have an important function in the brain as they not only provide a physical barrier segregating the inner and outer cellular environments, but are also involved in cell signaling. It has been shown that the lipid composition effects membrane fluidity which affects lateral mobility and activity of membrane-bound receptors. Methods Since changes in cellular membrane properties are considered to play an important role in the development of depression, the effect of St. John’s wort extract Ze 117 on plasma membrane fluidity in peripheral blood mononuclear cells (PBMC) was investigated using fluorescence anisotropy measurements. Changes in fatty acid residues in phospholipids after treatment of cortisol-stressed [1 μM] PBMCs with Ze 117 [10–50 µg/ml] were analyzed by mass spectrometry. Results Cortisol increased membrane fluidity significantly by 3%, co-treatment with Ze 117 [50 µg/ml] counteracted this by 4.6%. The increased membrane rigidity by Ze 117 in cort...
The characterization of naturally occurring variations in the human genome has evoked an immense ... more The characterization of naturally occurring variations in the human genome has evoked an immense interest during recent years. Variations known as biallelic Single-Nucleotide Polymorphisms (SNPs) have become increasingly popular markers in molecular genetics because of their wide application both in evolutionary relationship studies and in the identification of susceptibility to common diseases. We have addressed the issue of SNP genotype determination by investigating variations within the Renin–Angiotensin–Aldosterone System (RAAS) using pyrosequencing, a real-time pyrophosphate detection technology. The method is based on indirect luminometric quantification of the pyrophosphate that is released as a result of nucleotide incorporation onto an amplified template. The technical platform employed comprises a highly automated sequencing instrument that allows the analysis of 96 samples within 10 to 20 minutes. In addition to each studied polymorphic position, 5–10 downstream bases we...
Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorva... more Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin,¯uvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b). 2 P-gp modulation was studied by a¯uorimetric assay and confocal microscopy by means of R123 eux and uptake experiments, respectively. 3 Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid,¯uvastatin and pravastatin did not show a signi®cant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest anities for P-gp and results were comparable for both methods. 4 In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition tō uorimetric assay is a sensitive tool to study P-gp anity in drug screening that is especially useful for early phases of drug development.
A 22-year-old woman ingested 5.4 g of colloidal bismuth subcitrate (CBS) in a suicide attempt. Af... more A 22-year-old woman ingested 5.4 g of colloidal bismuth subcitrate (CBS) in a suicide attempt. After ingestion, she presented with Fanconi's syndrome and acute renal failure to our unit. On the third day after ingestion, she was anuric. Ulcerations of both tonsils were observed 8 days after intoxication. Sodium-2,3-dimercapto-1-propanesulfonate (DMPS) is shown to be an effective chelating agent of heavy metal intoxications, but it has only a small effect on elimination of bismuth salts in patients with renal insufficiency without hemodialysis. In our case, we initiated hemodialysis and intravenous treatment with DMPS 60 hours after intoxication. By repeated measurements of bismuth concentrations in serum and dialyzed fluid, we showed its successful elimination. Serum bismuth level decreased from 640 microg/L to 15 microg/L within 6 days. With elimination of bismuth, renal function improved, and tonsil ulcerations healed. Hemodialysis was discontinued on day 14. Follow-up examination 6 weeks later showed normal renal function. Clinicians should be aware that acute renal failure and tonsil ulcerations can occur after CBS intoxication. Generally, acute renal failure caused by CBS intoxication is reversible. Treatment with the chelating agent DMPS in combination with hemodialysis is highly effective in reducing the serum bismuth level in patients with acute renal failure.
Lidocaine has been used for spinal anesthesia since 1948, seemingly without causing concern. Howe... more Lidocaine has been used for spinal anesthesia since 1948, seemingly without causing concern. However, during the last 10 years, a number of reports have appeared implicating lidocaine as a possible cause of neurologic complications after spinal anesthesia. Follow-up of patients who received uncomplicated spinal anesthesia revealed that some of them developed pain in the lower extremities-transient neurologic symptoms (TNS). In this study, we sought to compare the frequency of 1) TNS and 2) neurologic complications after spinal anesthesia with lidocaine with that after other local anesthetics.
The chemokine interleukin (IL)-8 is a cytokine involved in neutrophil attraction and activation a... more The chemokine interleukin (IL)-8 is a cytokine involved in neutrophil attraction and activation and elevated levels have been observed in intestinal inflammation. Anti-inflammatory activities have been attributed to green tea or its major constituent (-)-epigallocatechin gallate (EGCG). In this study, we investigated the effects of a defined green tea extract (GTE) or EGCG on basal or IL-1beta-induced IL-8 expression and secretion in the human gastrointestinal epithelial cell line Caco-2. mRNA expression levels were determined by quantitative RT-PCR. GTE significantly induced IL-8 mRNA expression, which was not mediated indirectly via an induction of IL-1beta mRNA expression. EGCG only exerted a weak although significant induction of IL-8 mRNA expression at the highest concentration. Intracellular and extracellular protein levels were analyzed by an enzyme-linked immunosorbent assay. GTE and EGCG significantly decreased secreted IL-8 concentrations. Determination of intracellular and secreted IL-8 concentrations after 24 h, 48 h, and 72 h of incubation suggested that GTE specifically inhibited IL-8 secretion while inducing DE NOVO synthesis of IL-8. The IL-1beta-mediated increase of IL-8 secretion was significantly inhibited by GTE in a dose-dependent manner. At the highest concentration, GTE inhibited IL-1beta-induced IL-8 secretion to a similar extent as found for brefeldin A, an inhibitor of vesicular transport. These results suggest that GTE may exert an anti-inflammatory activity in enterocytes, which may be useful for the treatment of intestinal inflammation.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999
Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but... more Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake ( P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulat...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2000
Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the... more Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the mechanisms are unclear. We therefore tested the hypothesis that alimentary CCK (CCK-A) receptors mediate the interaction of CCK with an appetizer on food intake in humans. CCK octapeptide (CCK-8, 0.75 μg infused over 10 min) or saline (placebo) with concomitant infusions of saline (placebo) or loxiglumide, a specific CCK-A antagonist, was infused into 16 healthy men with use of a double-blind, four-period design. All subjects received a standard 400-ml appetizer (amounting to 154 kcal) but were free to eat and drink thereafter as much as they wished. The effect of these infusions on feelings of hunger and satiety and on food intake was quantified. CCK-8 induced a reduction in calorie intake ( P < 0.05) compared with saline. Furthermore, a decrease in hunger feelings ( P < 0.05, saline-CCK-8 vs. all other treatments) and an increase in fullness were observed. These effects were ant...
This present study aims to investigate if P9605, an ethanolic extract of PIPER CUBEBA L, exhibits... more This present study aims to investigate if P9605, an ethanolic extract of PIPER CUBEBA L, exhibits anti-estrogenic and anti-inflammatory properties. We found that P9605 significantly inhibited growth induced by beta-estradiol in MCF-7, a human breast cancer cell line. It inhibited aromatase activity, which is responsible for transforming androgens into estrogens. Competitive binding assays also indicated P9605 binding to both human recombinant estrogen a and beta receptors. Furthermore, this extract inhibited the activities of cyclo-oxygenases (COX-1 and COX-2) and 5-lipo-oxygenase (5-LOX), also it attenuated the induction of interleukin 6 (IL-6) in differentiated THP-1 cells stimulated by lipopolysaccharide (LPS). Taken together with our previous results, P9605 possesses anti-androgenic, anti-estrogenic and anti-inflammatory properties. These results support the potential use of P9605 in phytotherapy against benign prostatic hyperplasia (BPH).
In vitro and in vivo studies suggest that extracts of St John&amp;amp;amp;amp;#39;s wort (Hyp... more In vitro and in vivo studies suggest that extracts of St John&amp;amp;amp;amp;#39;s wort (Hypericum perforatum, L .; SJWE) interact with various drugs, by enhancing their elimination, due to induction of intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), the gene product of multidrug resistance gene 1 (MDR1/ABCB1). The aim of our study was to identify the major constituents responsible for this induction and their relative importance. Therefore, plant extracts were investigated that vary in these constituents with respect to their effect on mRNA expression of MDR1/CYP3A4. First, different pure constituents of Hypericum perforatum L . were investigated. Secondly, diverse SJWE with different concentrations of hyperforin, quercitrin and hypericin were investigated. The concentrations of hyperforin, hypericin, and quercitrin in the plant extracts were determined by HPLC, and an &amp;amp;amp;amp;quot;artificial extract&amp;amp;amp;amp;quot; containing the same mixture of these constituents was investigated. Different plant extracts, pure constituents or &amp;amp;amp;amp;quot;artificial extracts&amp;amp;amp;amp;quot; were applied to the human colon carcinoma-derived cell line (LS180) and the induction of MDR1 and CYP3A4 expression was analyzed by quantitative RT-PCR. MDR1 and CYP3A4 mRNA expression were both induced by single constituents of SJW such as hypericin and hyperforin in a concentration of 10 microM. Additionally, CYP3A4 mRNA expression was induced by quercitrin. SJW extracts containing hyperforin induced significantly MDR1 mRNA expression, whereas no CYP3A4 induction was observed after treatment with any of the investigated SJWE. These effects could be mimicked by &amp;amp;amp;amp;quot;artificial extracts&amp;amp;amp;amp;quot; containing the same compositions of hyperforin, hypericin and quercitrin as the plant extracts.
Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vi... more Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vitro cell culture model of the blood-brain barrier. The present study describes the influence of cell-culture conditions on tight junctions, filamentous-actin cytoskeleton, and expression of ATP-binding cassette (ABC) transporters in primary cell cultures of porcine BCEC. Astrocyte as well as C6 glioma-conditioned cell culture medium was used in combination with retinoic acid, dexamethasone, cyclic adenosine monophosphate (cAMP) analogs, or 1,25dihydroxyvitamin D 3 . It was shown that C6-conditioned medium led to a reorganization of filamentous actin and to an improved staining of zonula occludens-associated protein-1 (ZO-1). Further optimization of these culture conditions was achieved with cAMP analogs and dexamethasone. Retinoic acid, as well as 1,25-dihydroxyvitamin D 3 , did not improve cellular tight junctions as judged by filamentous actin, ZO-1 rearrangement, and transcellular electrical resistance (TER) measurements. However, these morphological changes did not influence the paracellular permeability of the extracellular marker sucrose. Expression of ABC transporters such as P-glycoprotein, multidrug resistance-associated protein-1 (MRP1), and MRP2 were compared by measuring messenger RNA (mRNA) levels in whole-brain tissue, isolated brain capillaries, and cultured cells. In freshly isolated BCEC, mRNA levels of MRP2 and P-glycoprotein dropped by two-to sevenfold, respectively, whereas MRP1 mRNA levels were slightly increased. During cell culture, mRNA levels of MRP1 and MRP2 decreased by up to fivefold, while P-glycoprotein levels remained constant. These results were unaltered by different cellculture conditions. In conclusion, the present study suggests that paracellular permeability, as well as mRNA expression of the studied ABC transporters in primary cultures, of porcine BCEC are insensitive toward changes in cell-culture conditions.
British Journal of Clinical Pharmacology, Sep 1, 2000
Aims To investigate the effect of acute P-glycoprotein inhibition by the multidrugresistance (MDR... more Aims To investigate the effect of acute P-glycoprotein inhibition by the multidrugresistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Methods In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO 2 , blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h. Results The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically signi®cant increase in the AUC and C max of M3G (11.8 and 8.3%, respectively). The t K and t max were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not signi®cantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (E max 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a signi®cant decrease in systolic blood pressure (E min x9 mmHg), and a trend for a fall in diastolic blood pressure (E min x14.5 mmHg) and respiratory rate (E min x1.8 breathemin x1 ). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a signi®cant increase in PCO 2 (E max 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination. Conclusions Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic pro®le of morphine in a clinically signi®cant manner.
Neue therapeutische Optionen der hochaktiven antiretroviralen Therapie (HAART) haben die Morbidit... more Neue therapeutische Optionen der hochaktiven antiretroviralen Therapie (HAART) haben die Morbidität und Mortalität von HIV-infizierten Patienten deutlich gesenkt, so dass nun vermehrt die altersspezifischen Erkrankungen manifest werden, wie z.B. kardiovaskuläre Erkrankungen. Zusätzlich verursacht die HIV-Erkrankung selber eine gewisse kardiovaskuläre Morbidität. Aus diesem Grund gewinnt die Behandlung der kardiovaskulären Symptome eine zunehmende Bedeutung. Die Pharmakotherapie dieser HIV-positiven Patienten ist sehr komplex, da sie durch eine Polypharmazie aus Medikamenten mit einem hohen Interaktionspotential geprägt ist.
Several antibiotics show significant pharmacokinetic interactions when they are given orally conc... more Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C max) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C max , lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C max , V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.
Aims Somatostatin analogues (e.g. vapreotide) are used for treatment of acromegaly, endocrine tum... more Aims Somatostatin analogues (e.g. vapreotide) are used for treatment of acromegaly, endocrine tumours and variceal bleeding. The pharmacodynamic effects of vapreotide have, however, not been documented in the gastrointestinal tract. The aim of this study was to investigate the effects of continuous vapreotide administration on gastric acidity, gallbladder contraction and hormone release. Methods Ten healthy males participated in this randomised, placebo‐controlled, double‐blind, crossover trial. A constant vapreotide (or placebo) infusion (1.5 mg day−1 s.c.) was given for 7 days with a portable pump. Intragastric pH was monitored on days 2 and 7. Gallbladder volume was sonographically assessed and the maximal ejection fraction was calculated. In addition basal and postprandial plasma levels of gastrin and cholecystokinin (CCK) were measured. Results After an initial increase in the median 24 h intragastric pH to a value of 2.6 on day 2, vapreotide’s effect on pH decreased: (day 7: m...
Background Membrane lipids have an important function in the brain as they not only provide a phy... more Background Membrane lipids have an important function in the brain as they not only provide a physical barrier segregating the inner and outer cellular environments, but are also involved in cell signaling. It has been shown that the lipid composition effects membrane fluidity which affects lateral mobility and activity of membrane-bound receptors. Methods Since changes in cellular membrane properties are considered to play an important role in the development of depression, the effect of St. John’s wort extract Ze 117 on plasma membrane fluidity in peripheral blood mononuclear cells (PBMC) was investigated using fluorescence anisotropy measurements. Changes in fatty acid residues in phospholipids after treatment of cortisol-stressed [1 μM] PBMCs with Ze 117 [10–50 µg/ml] were analyzed by mass spectrometry. Results Cortisol increased membrane fluidity significantly by 3%, co-treatment with Ze 117 [50 µg/ml] counteracted this by 4.6%. The increased membrane rigidity by Ze 117 in cort...
Background Membrane lipids have an important function in the brain as they not only provide a phy... more Background Membrane lipids have an important function in the brain as they not only provide a physical barrier segregating the inner and outer cellular environments, but are also involved in cell signaling. It has been shown that the lipid composition effects membrane fluidity which affects lateral mobility and activity of membrane-bound receptors. Methods Since changes in cellular membrane properties are considered to play an important role in the development of depression, the effect of St. John’s wort extract Ze 117 on plasma membrane fluidity in peripheral blood mononuclear cells (PBMC) was investigated using fluorescence anisotropy measurements. Changes in fatty acid residues in phospholipids after treatment of cortisol-stressed [1 μM] PBMCs with Ze 117 [10–50 µg/ml] were analyzed by mass spectrometry. Results Cortisol increased membrane fluidity significantly by 3%, co-treatment with Ze 117 [50 µg/ml] counteracted this by 4.6%. The increased membrane rigidity by Ze 117 in cort...
The characterization of naturally occurring variations in the human genome has evoked an immense ... more The characterization of naturally occurring variations in the human genome has evoked an immense interest during recent years. Variations known as biallelic Single-Nucleotide Polymorphisms (SNPs) have become increasingly popular markers in molecular genetics because of their wide application both in evolutionary relationship studies and in the identification of susceptibility to common diseases. We have addressed the issue of SNP genotype determination by investigating variations within the Renin–Angiotensin–Aldosterone System (RAAS) using pyrosequencing, a real-time pyrophosphate detection technology. The method is based on indirect luminometric quantification of the pyrophosphate that is released as a result of nucleotide incorporation onto an amplified template. The technical platform employed comprises a highly automated sequencing instrument that allows the analysis of 96 samples within 10 to 20 minutes. In addition to each studied polymorphic position, 5–10 downstream bases we...
Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorva... more Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin,¯uvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b). 2 P-gp modulation was studied by a¯uorimetric assay and confocal microscopy by means of R123 eux and uptake experiments, respectively. 3 Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid,¯uvastatin and pravastatin did not show a signi®cant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest anities for P-gp and results were comparable for both methods. 4 In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition tō uorimetric assay is a sensitive tool to study P-gp anity in drug screening that is especially useful for early phases of drug development.
A 22-year-old woman ingested 5.4 g of colloidal bismuth subcitrate (CBS) in a suicide attempt. Af... more A 22-year-old woman ingested 5.4 g of colloidal bismuth subcitrate (CBS) in a suicide attempt. After ingestion, she presented with Fanconi&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s syndrome and acute renal failure to our unit. On the third day after ingestion, she was anuric. Ulcerations of both tonsils were observed 8 days after intoxication. Sodium-2,3-dimercapto-1-propanesulfonate (DMPS) is shown to be an effective chelating agent of heavy metal intoxications, but it has only a small effect on elimination of bismuth salts in patients with renal insufficiency without hemodialysis. In our case, we initiated hemodialysis and intravenous treatment with DMPS 60 hours after intoxication. By repeated measurements of bismuth concentrations in serum and dialyzed fluid, we showed its successful elimination. Serum bismuth level decreased from 640 microg/L to 15 microg/L within 6 days. With elimination of bismuth, renal function improved, and tonsil ulcerations healed. Hemodialysis was discontinued on day 14. Follow-up examination 6 weeks later showed normal renal function. Clinicians should be aware that acute renal failure and tonsil ulcerations can occur after CBS intoxication. Generally, acute renal failure caused by CBS intoxication is reversible. Treatment with the chelating agent DMPS in combination with hemodialysis is highly effective in reducing the serum bismuth level in patients with acute renal failure.
Lidocaine has been used for spinal anesthesia since 1948, seemingly without causing concern. Howe... more Lidocaine has been used for spinal anesthesia since 1948, seemingly without causing concern. However, during the last 10 years, a number of reports have appeared implicating lidocaine as a possible cause of neurologic complications after spinal anesthesia. Follow-up of patients who received uncomplicated spinal anesthesia revealed that some of them developed pain in the lower extremities-transient neurologic symptoms (TNS). In this study, we sought to compare the frequency of 1) TNS and 2) neurologic complications after spinal anesthesia with lidocaine with that after other local anesthetics.
The chemokine interleukin (IL)-8 is a cytokine involved in neutrophil attraction and activation a... more The chemokine interleukin (IL)-8 is a cytokine involved in neutrophil attraction and activation and elevated levels have been observed in intestinal inflammation. Anti-inflammatory activities have been attributed to green tea or its major constituent (-)-epigallocatechin gallate (EGCG). In this study, we investigated the effects of a defined green tea extract (GTE) or EGCG on basal or IL-1beta-induced IL-8 expression and secretion in the human gastrointestinal epithelial cell line Caco-2. mRNA expression levels were determined by quantitative RT-PCR. GTE significantly induced IL-8 mRNA expression, which was not mediated indirectly via an induction of IL-1beta mRNA expression. EGCG only exerted a weak although significant induction of IL-8 mRNA expression at the highest concentration. Intracellular and extracellular protein levels were analyzed by an enzyme-linked immunosorbent assay. GTE and EGCG significantly decreased secreted IL-8 concentrations. Determination of intracellular and secreted IL-8 concentrations after 24 h, 48 h, and 72 h of incubation suggested that GTE specifically inhibited IL-8 secretion while inducing DE NOVO synthesis of IL-8. The IL-1beta-mediated increase of IL-8 secretion was significantly inhibited by GTE in a dose-dependent manner. At the highest concentration, GTE inhibited IL-1beta-induced IL-8 secretion to a similar extent as found for brefeldin A, an inhibitor of vesicular transport. These results suggest that GTE may exert an anti-inflammatory activity in enterocytes, which may be useful for the treatment of intestinal inflammation.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999
Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but... more Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake ( P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulat...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2000
Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the... more Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the mechanisms are unclear. We therefore tested the hypothesis that alimentary CCK (CCK-A) receptors mediate the interaction of CCK with an appetizer on food intake in humans. CCK octapeptide (CCK-8, 0.75 μg infused over 10 min) or saline (placebo) with concomitant infusions of saline (placebo) or loxiglumide, a specific CCK-A antagonist, was infused into 16 healthy men with use of a double-blind, four-period design. All subjects received a standard 400-ml appetizer (amounting to 154 kcal) but were free to eat and drink thereafter as much as they wished. The effect of these infusions on feelings of hunger and satiety and on food intake was quantified. CCK-8 induced a reduction in calorie intake ( P < 0.05) compared with saline. Furthermore, a decrease in hunger feelings ( P < 0.05, saline-CCK-8 vs. all other treatments) and an increase in fullness were observed. These effects were ant...
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Papers by Juergen Drewe