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T Mettang

Publications and source records attributed to T Mettang.

At least 19 recordsLinked to original sources
PubMed2001

P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin.

Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Sustaining continuous ambulatory peritoneal dialysis after herniotomy.

Controversy still exists as to whether peritoneal dialysis (PD) treatment can be safely continued after herniotomy. Many nephrologists withhold PD treatment for several weeks after herniotomy for fear of dialysate leakage and hernia recurrence. Here, we report on 9 patients (2 women, 7 men) in whom herniotomy was performed for umbilical (n = 3), inguinal (n = 5), or cicatricial hernia (n = 2), or for open processus vaginalis (n = 2). Surgery was performed according to the Lichtenstein method with insertion of a polypropylene mesh and ligation of the hernia sac. In all patients, PD treatment was paused for the day of surgery and for 1-3 days postoperatively, depending on residual renal function. Over the next several days, low-volume (1.0-1.5 L), high-frequency (6 per day) exchanges were started. The patient's original PD regimen was gradually reinstated over the next 2-4 weeks. All patients recovered rapidly, with no uremia or dialysis-related complications. Particularly, no leakage and no hernia recurrence could be observed 3 months thereafter. None of the patients had to be hemodialyzed intercurrently. In conclusion, continuing a modified regimen of CAPD treatment after herniotomy seems to be safe, with excellent patient comfort.

Adult↗
PubMed2000

Stimulated IFNgamma and IL-10 secretion of blood mononuclear cells in patients on renal replacement therapies show different secretion patterns.

Infection is still a leading cause of morbidity and mortality in patients on renal replacement therapy (RRT). Although the role of the immune system is of great importance, little is known about the influence of the mode of RRT to the preferential excretions of regulator cytokines of mononuclear cells. Therefore, we investigated the stimulated IFNgamma (Th1) and IL-10 (Th2) secretions of mononuclear cells from patients on RRT. Blood was drawn from 10 controls, 15 patients on hemodialysis (HD), 15 on peritoneal dialysis (PD), and 10 after kidney transplantation (Tx). The cells were separated, and phytohemagglutinine (PHA) was added for stimulation. After 0, 6, and 24 h, IFNgamma and IL-10 (pg/ml) were measured by enzyme-linked immunosorbent assay. IFNgamma secretion was significantly enhanced 6 (p < 0.001) and 24 h (p = 0.002) after stimulation in all groups (in mean +/- SEM). The analysis of the subgroups 6 h after adding PHA showed significant differences (p = 0.0239) with the lowest IFNgamma in Tx (16 +/- 5) and the highest in PD (79 +/- 30). For IL-10, secretion was enhanced in all groups 6 h after stimulation (p < 0.0116). The lowest secretions were seen in HD (18 +/- 8) and controls (27 +/- 9); the highest secretions were in Tx (98 +/- 20) and PD (57 +/- 12). The differences between HD and Tx (p < 0.01) and HD versus PD (p = 0.05) were significant. The stimulated cytokine secretion of blood mononuclear cells is preserved with RRT. The modes of RRT could influence the pattern of cytokine secretion. Surprisingly, the cells from patients on PD showed enhanced IL-10 secretion compared to HD. Presumably, this is due to the chronic contact of peritoneal dialysis fluids with monocytes and the lymphatic system in PD.

Adult↗
PubMed2000

A new lactate-based, plasticizer-free, neutral peritoneal dialysis fluid provided in a two-compartment system: effect on peripheral leukocyte function.

BACKGROUND: A new neutral peritoneal dialysis fluid (PDF; Balance) provided in a two-compartment bag (pH 7.4, no plasticizers, minimal glucose degradation products - GDP) was investigated in comparison with a neutral control (Hanks' balanced salt solution with gelatin 0.1%) and other PDFs with standard properties and plasticizers (Andy plus, pH 5.2, GDP), plasticizer free (stay safe, pH 5.2, GDP), and in addition plasticizer free after sterile filtration instead of heat sterilization (pH 5.2) regarding the function of peripheral blood leukocytes. METHODS: Blood was drawn from 12 volunteers, and blood monocytes (MN) and polymorphonuclear leukocytes (PMNL) were collected. The cells were incubated for 30 min in control medium and the PDFs: glucose 1.5% (83 mmol/l) and 4.25% (238 mmol/l). Respiratory burst of cells was evaluated by chemiluminescence and superoxide (SO) generation after stimulation with phorbol myristate acetate. RESULTS: In comparison with the control medium, incubation of MN in the two-compartment PDF showed preservation of respiratory burst. In contrast, the incubation of MN in standard PDF and plasticizer-free PDF showed impaired functions. The same was found for PMNL. SO anion measurement in MN and PMNL after incubation in the new two-compartment PDF also showed preservation of cell function in comparison with the control medium. The incubation of PMNL in standard PDF and plasticizer-free PDF with a high glucose content showed depressed SO anion generation. CONCLUSIONS: These in vitro data demonstrate a better preservation of in vitro phagocyte function with adaptation of pH and reduction of glucose, GDP, and plasticizers in PDFs. The best results are achieved with the two-compartment, lactate-based neutral PDF.

Adult↗
PubMed2000

Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein.

Verapamil is subject to extensive oxidative metabolism mediated by cytochrome P450 enzymes with less than 5% of an oral dose being excreted unchanged in urine. Furthermore, verapamil is known to be a potent inhibitor of P-glycoprotein function. There is evidence from in vivo investigations that some verapamil metabolites might be actively transported. The aim of the present study was to investigate P-glycoprotein-mediated transport and inhibition properties of verapamil and its metabolites norverapamil, D-620, D-617, and D-703. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1-P-glycoprotein). Inhibition of P-glycoprotein-mediated transport by these compounds was determined using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, significant differences between basal-to-apical and apical-to-basal apparent permeability coefficients were observed for D-617 and D-620 in all P-glycoprotein-expressing cell monolayers, indicating that both are P-glycoprotein substrates. In contrast, no P-glycoprotein-dependent transport was found for verapamil, norverapamil, and D-703 in Caco-2 cells and for D-703 in L-MDR1 cells. Moreover, verapamil, norverapamil, and D-703 inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 1.1, 0.3, and 1.6 microM, respectively, whereas D-617 and D-620 did not (at concentrations up to 100 microM). We conclude that verapamil phase I metabolites exhibit different P-glycoprotein substrate and inhibition characteristics, with the N-dealkylated metabolites D-617 and D-620 being P-glycoprotein substrates and norverapamil and D-703 being inhibitors of P-glycoprotein function, which may influence P-glycoprotein-dependent drug disposition and elimination.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

[Severe nephrotic syndrome with reversible acute kidney failure in lupus-associated membranous nephropathy].

HISTORY AND CLINICAL FINDINGS: A 20 year old, previously healthy woman presented with a four week history of progressive oedema of the legs and the eyelids and a weight gain of 10 kg. INVESTIGATIONS: Biochemical tests revealed a nephrotic syndrome with a protein-loss in urine of 13.6 g/24 hours and a serum-albumin of 1.2 g/dl. Serological tests showed positive response for antinuclear antibodies, anti-double-stranded-DNA antibodies and cardiolipin antibodies. Renal histology revealed a lupus-associated diffuse membranous nephropathy (WHO-type Vd). DIAGNOSIS, TREATMENT AND COURSE: We first started a treatment regimen with oral steroids and intravenous loop-diuretics without improvement of the nephrotic syndrome. Two weeks after initial presentation the patient developed dialysis-dependent, acute renal failure. Having excluded a renal vein-thrombosis and the transition to diffuse proliferative form of the glomerulonephritis we suggested a nephrotic etiology of the acute renal failure. We initiated cyclophosphamide pulse-therapy which led to dramatic improvement of the nephrotic syndrome after the first cycle with reduction of protein-loss to 6 g/24 hours. Concurrently renal function recovered and treatment with hemodialysis could be stopped after 3 weeks. CONCLUSION: Acute renal failure in nephrotic syndrome has also to be considered in an acute form of a membranous lupus nephritis. Renal recovery is much better when acute renal failure is caused by nephrotic syndrome.

Acute Kidney Injury↗
PubMed1999

Effects of L-carnitine on leukocyte function and viability in hemodialysis patients: A double-blind randomized trial.

Excess morbidity and mortality among long-term hemodialysis patients because of infectious complications is partly caused by an impairment of cellular immune defense. We hypothesized this impairment is related to an abnormal carnitine metabolism also present in these patients. In a double-blind, randomized, placebo-controlled trial, we investigated the effect of L-carnitine on phagocytic function and viability of blood leukocytes in 17 patients undergoing maintenance hemodialysis. After an observation period of 1 month, the patients received either 10 mg/kg of L-carnitine or placebo intravenously at the end of each hemodialysis session over a period of 4 months. Leukocyte oxidative metabolism was measured by means of luminol-enhanced chemiluminescence and superoxide generation after stimulation with Staphylococcus aureus or phorbol myristate acetate. Killing capacity and phagocytosis of radiolabeled staphylococci were determined. A lactate dehydrogenase (LDH) release test was applied to assess cell viability. We were unable to show an effect of L-carnitine on phagocytic function and viability in vivo. Several clinical parameters were observed during the trial. No statistically significant differences concerning dialysis-related morbidity, anemia, or reduction of blood urea nitrogen and creatinine levels were detected. Additionally, we tested the effect of L-carnitine on phagocytic function after in vitro incubation of blood leukocytes, which also showed no changes. LDH release was decreased, indicating an improved viability of these cells. The latter results were found after in vitro incubation of cells, but could not be confirmed in vivo. In summary, we could not show beneficial effects of L-carnitine administration in hemodialysis patients for the dosage and duration of treatment stated, either on phagocytic function and viability or on the clinical and biochemical parameters observed.

Adult↗
PubMed1999

Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis.

BACKGROUND: Conjugation with glucuronic acid represents the major route of biotransformation of morphine. The glucuronides morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are eliminated via the kidneys. Therefore, chronic renal failure should affect the disposition of M3G and M6G. Numerous patients undergoing long-term continuous ambulatory peritoneal dialysis (CAPD) require pain treatment with morphine. There are only limited data available about the disposition of morphine and its active metabolites M6G and M3G in patients on CAPD. We therefore investigated the pharmacokinetics of morphine and its metabolites in CAPD patients. METHODS: This was a single intravenous dose pharmacokinetic study in 10 CAPD patients (1 female, 9 male, age 31-69 years). Morphine-hydrochloride (Mo) (10 mg) was administered intravenously. Serum, urine, and dialysate samples were collected during 24 h. GC-MS-MS and HPLC-MS methods were used to quantify respectively morphine and morphine glucuronides. RESULTS: While systemic clearance of morphine (1246+/-240 ml/min) was in the range observed in patients with normal kidney function, both M3G and M6G showed substantial accumulation. The area under the concentration-time curve (AUC) ratio of M3G:Mo (33.4+/-7.1) and of M6G:Mo (12.2+/-3.2) was 5.5 and 13.5 times higher than in patients with normal kidney function. Renal clearances of morphine, M3G, and M6G (morphine 3.0+/-2.5 ml/min; M3G 3.9+/-2.2 ml/min; M6G 3.6+/-2.2 ml/min) and dialysate clearances (morphine 4.1+/-1.3 ml/min; M3G 3.2+/-0.7 ml/min; M6G 3.0+/-0.8 ml/min) were extremely low. Therefore the accumulation of M6G and M3G is readily explained by kidney failure which is not compensated by CAPD. CONCLUSION: Accumulation of M3G and M6G is due to the substantially lowered clearance by residual renal function and peritoneal dialysis. In view of the accumulation of potential active metabolites, subsequent investigations have to assess the frequency of side-effects in patients on CAPD.

Adult↗
PubMed1999

Phthalic acid is the main metabolite of the plasticizer di(2-ethylhexyl) phthalate in peritoneal dialysis patients.

Di(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer in polyvinyl chloride (PVC) plastics, and is therefore a major constituent of continuous ambulatory peritoneal dialysis (CAPD) bags. Because DEHP is not chemically bound, it leaches out of the plastic matrix. Recently, we found that leukocyte function in vitro is impaired by a mixture of metabolites of DEHP. In the present study, we investigated the metabolism of DEHP in patients on CAPD. The study group consisted of 10 stable patients, on CAPD for at least 6 months, using a plasticizer-containing PVC PD system [ANDY Plus (Fresenius Medical Care, Bad Homburg, Germany)]. Effluent dialysate and urine samples were collected over 24 hours, and a 10 mL blood sample was drawn. Concentrations of DEHP and its metabolites mono(2-ethylhexyl) phthalate (MEHP), phthalic acid (PA), and 2-ethylhexanol (2-EH) were determined in urine, dialysate, and serum using gas chromatography/mass spectrometry. Additionally, the degree of glucuronidation of the phthalic acid esters in urine were determined. In serum, dialysate, and urine, PA was the predominant metabolite of DEHP (0.205 +/- 0.067 mg/L, 0.284 +/- 0.180 mg/L, and 1.34 +/- 1.00 mg/L, respectively), but concentrations of MEHP were low (0.0100 +/- 0.0056 mg/L, 0.022 +/- 0.008 mg/L, 0.011 +/- 0.0064 mg/L, respectively). Urinary MEHP was glucuronidated to approximately 15%. PA was 35% eliminated as a glucuronide. Unlike healthy subjects, PD patients do not eliminate DEHP mainly in the form of MEHP or MEHP metabolites. They further break these compounds down to PA. The fact that concentrations of PA in urine exceed by far the respective serum concentrations indicates that PA is secreted by the kidney. Further research on the toxicological aspects of plasticizers in uremic patients should take these findings into account.

Chromatography, Gas↗
PubMed1998

Severe thrombocytopenia and response to corticosteroids in a case of nephropathia epidemica.

Nine days after working in the woods, a previously healthy 32-year-old man fell seriously ill. His symptoms included high fever, chills, diffuse myalgia, severe headache, and back pain. On the fifth day of onset of symptoms, blood tests showed creatinine levels of 5.4 mg/dL accompanied by marked proteinuria. After admission to the hospital, a diagnosis of nephropathia epidemica (NE) caused by Puumala virus was made using solid-phase enzyme-linked immunosorbent assay (ELISA). The patient gradually recovered renal function without requiring dialysis. However, he surprisingly experienced a sharp decline in platelet count to a minimum of 2,000/microL with concomitant occurrence of petechiae and conjunctival hemorrhage. Prednisolone was initiated, resulting in a swift rise in platelets. Six days later, when the medication was withdrawn, a sharp decrease in platelets recurred. The steroids were then readministered for the next 3 months, thus reestablishing a stable platelet count. The immediate rise of platelets after administration of prednisolone supports the pathophysiological view of hantavirus infection as an immunologically mediated disease. Corticosteroids in the treatment of hantavirus-associated thrombocytopenia might need further systematic evaluation.

Adult↗
PubMed1997

In vitro effects of glucose polymer-containing peritoneal dialysis fluids on phagocytic activity.

Commercially available peritoneal dialysis fluids (PDFs) are known to impair peritoneal cellular defense mechanisms. We have investigated the influence of glucose polymer-containing PDFs on phagocytic function in vitro. Polymorphonuclear neutrophils (PMNLs) and monocytes (MNs) from 10 continuous ambulatory peritoneal dialysis patients and 10 healthy donors were incubated in PDFs containing either 7.5% icodextrin (glucose polymer) or 1.5% glucose at original pH and pH 7.4. Chemiluminescence response and H202 production were measured following stimulation with preopsonized Staphylococcus epidermidis or phorbol myristate acetate. Phagocytosis of radiolabeled bacteria and killing capacity of the cells were determined. A comparison of the impact of glucose polymer versus glucose-containing solutions at their original pH on the oxidative metabolism of the cells showed a highly significant difference (P < 0.0001) in favor of glucose polymers for H202 production of PMNLs (7.78 +/- 4.5 nmol cytochrome C reduction/10(6) cells/min v 1.11 +/- 0.67 nmol cytochrome C reduction/10(6) cells/min) and MNs (7.66 +/- 3.6 nmol cytochrome C reduction/10(6) cells/min v 1.29 +/- 0.86 nmol cytochrome C reduction/10(6)cells/min). Correspondingly, PMNLs and MNs incubated in glucose polymers showed a significantly higher chemiluminescence response irrespective of the stimulant used (P < 0.0001). Applying the killing assay on PMNLs also revealed a significantly higher percentage of inactivated bacteria (45.5% +/- 11.0% v 29.2% +/- 15.5%; P < 0.05). After adjustment of pH to 7.4, a significant difference could only be found for H202 production of PMNLs in favor of glucose polymers (16.73 +/- 6.98 nmol cytochrome C reduction/10(6) cells/min v 11.65 +/- 5.37 nmol cytochrome C reduction/10(6) cells/min; P < 0.05). In addition, we compared the glucose-polymer solution to an otherwise equally composed equiosmolar solution that contained 0.274% glucose instead of glucose polymers. No significant differences were detected with any of the tests applied. Our data suggest that glucose polymer solutions are comparatively less suppressive to phagocytic function than currently used glucose-containing PDFs. This effect may be attributed to the low osmolarity of these solutions.

Adult↗