Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer.

The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).

Modelling the pharmacokinetics of tramadol: on the difference between CYP2D6 extensive and poor metabolizers.

In this work we propose a mathematical model for the kinetics of tramadol, a synthetic opioid commonly used for treating moderate to severe pain. This novel theoretical framework could result in an objective criterion on how to adjust the assigned dose, depending on the genetic polymorphisms of CYP2D6. The model describes the coupled dynamics of tramadol and the metabolite O-desmethyltramadol. The effect of diffusion of the drug in the blood is here accounted for and we further hypothesize the existence of a time delay in the process of chemical translation from tramadol into metabolites. The system of coupled differential equations is solved numerically and the free parameters adjusted so to interpolate the experimental time series for the intravenous injection setting. Theoretical curves are shown to reproduce correctly the experimental profiles obtained from clinical trials. This enables in turn to extract an estimate of the metabolization rate. A difference in metabolization rate between CYP2D6 poor and extensive metabolizers is also found, and the stereoselectivity in the O-demethylation of tramadol highlighted. Our results allow one to quantify the dose of (+)-tramadol (resp. (-)-tramadol) administered to poor or extensive metabolizers, if the same effect is sought. The latter is here quantified through the blood concentration of (+)-metabolites (resp. (-)-metabolites).

Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol.

OBJECTIVE: Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. METHODS: With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double-blind, placebo-controlled, 4-way crossover study by use of experimental pain models. RESULTS: With paroxetine pretreatment, the area under the plasma concentration-time curve (AUC) of (+)- and (-)-tramadol was increased (37% [P = .001] and 32% [P = .002], respectively), and the corresponding AUCs of(+)- and (-)-M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)-M1 and (-)-M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus -84 kPa (95% CI, - 492 to -32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, -4.2 cm x s (95% CI, -6.8 to -1.9 cm x s) versus -0.4 cm x s (-1.4 to 1.4 cm x s) (P = .002); and discomfort, -4.7 cm (95% CI, -10.6 to -2.8 cm) versus 0.5 cm (-0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, -2.2 cm x s (95% CI, -3.7 to -0.4 cm x s) (P = .036, compared with placebo/tramadol); and discomfort, -2.0 cm (95% CI, -5.6 to -1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect. CONCLUSIONS: It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests.

Effect of an acute oral lithium intake on urinary Aquaporin-2 in healthy humans with and without simultaneous stimulation with hypertonic saline infusion.

OBJECTIVE: Animal experiments have shown that lithium interferes with the formation of Aquaporin-2 in the distal renal tubuli. The effect of lithium on formation of renal water channels has not been studied in healthy humans. The aim of this study was to test the hypotheses that a single oral dose of lithium will reduce the formation of water channels both with and without stimulation with hypertonic saline infusion, and that this effect can be detected by measurement of urinary excretion of Aquaporin-2 (u-AQP2). METHODS: In healthy subjects, Study 1 (n = 11) and Study 2 (n = 12), urine was collected in 6 and 7 periods between 08.00 and 14.00, respectively, and blood samples were drawn at 30- to 60-min intervals. The study medication was given at 09.00; u-AQP2 was determined by radioimmunoassay. RESULTS: In Study 1 neither u-AQP2 nor urinary output were significantly changed by lithium. In Study 2, u-AQP2 was increased by hypertonic saline infusion in parallel with an increase in arginine vasopressin. At the end of the study, u-AQP2 was increased by 30% with placebo but only by 13% with the 600 mg lithium dose, and urinary output was significantly higher after 600 mg lithium than after placebo and 300 mg lithium. CONCLUSIONS: U-AQP2 was not significantly changed after a single oral dose of lithium. The antidiuretic response to hypertonic saline infusion was reduced when lithium was given. It is suggested that lithium increases urinary output by inhibiting trafficking of renal water channels in healthy humans.

Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in dialysis patients, renal transplant recipients and healthy controls.

It has been suggested that infection with Chlamydia pneumoniae plays a role in the development and maintenance of atherosclerosis based on differences in the prevalence of antibodies against Chlamydia pneumoniae in patients with and without atherosclerotic lesions and on the presence of bacteria in atherosclerotic lesions. It is well known that patients undergoing chronic dialysis treatment and renal transplant recipients have a considerably increased risk of cardiovascular disease. In this study it is hypothesized that patients with these conditions have a higher prevalence of Chlamydia pneumoniae DNA in the white cells of the peripheral blood. Blood samples from 196 dialysis patients, 114 renal transplant recipients and 342 healthy controls were analysed with an in-house nested polymerase chain reaction (nPCR) and tested for the presence of Chlamydia pneumoniae DNA. The prevalence of Chlamydia pneumoniae DNA was significantly higher in dialysis patients (16.3%) than in healthy controls (8.5%, p < 0.01), whereas no significant difference was found between the prevalence in renal transplant recipients (9.6%) and healthy controls. The prevalence was not related to gender or age in either group, and it was the same in diabetics and non-diabetics. Dialysis patients have a higher prevalence of Chlamydia pneumoniae DNA than healthy controls. The lower prevalence of Chlamydia pneumoniae DNA in renal transplant recipients than in dialysis patients may be due to selection of dialysis patients with few or no cardiovascular complications for renal transplantation. Our results are consistent with the hypothesis that Chlamydia pneumoniae is associated with the pathogenesis of atherosclerosis.

Influence of training habits on exercise-induced changes in plasma atrial and brain natriuretic peptide and urinary excretion of aquaporin-2 in healthy man.

The purpose of this study was to quantify the influence of training habits on the changes in plasma atrial natriuretic peptide (ANP), plasma brain natriuretic peptide (BNP) and urine aquaporin-2 (u-AQP2) during exercise by studying trained and untrained healthy subjects. Eleven trained subjects (7 males, 4 females) and 10 untrained subjects (8 males, 2 females) performed a maximal aerobic exercise test. ANP and BNP were determined every 3 min and at maximum exercise by radioimmunoassay (RIA), and u-AQP2 was determined before and after the exercise test by RIA. The absolute increase in ANP during exercise was higher in the trained subjects (trained subjects: 5.6 pmol/L; untrained subjects: 2.4 pmol/L, p < 0.05) and was positively correlated to ANP at rest (p < 0.03). The maximum absolute increase in BNP during exercise was the same in the two groups (trained subjects: 0.5 pmol/L; untrained subjects: 0.6 pmol/L, NS) and tended to correlate positively with resting BNP in the trained subjects (p = 0.07). Exercise did not change u-AQP2 excretion in either trained subjects (rest: 372 ng/mmol creatinine; exercise: 314 ng/mmol creatinine, NS) or untrained subjects (rest: 263 ng/mmol creatinine; exercise: 338 ng/mmol creatinine, NS). The absolute increase in ANP during exercise was higher in trained subjects than in untrained subjects and was positively correlated to ANP at rest. This might reflect the normal cardiovascular adaptation to exercise. The increase in BNP during exercise was unrelated to training habits. Training habits did not affect the u-AQP2 excretion during exercise.

Effect of water deprivation and hypertonic saline infusion on urinary AQP2 excretion in healthy humans.

Arginine vasopressin (AVP) mediates water transport in the renal collecting ducts by forming water channels of aquaporin-2 (AQP2) in the apical plasma membrane. AQP2 is excreted in human urine. We wanted to test the hypothesis that urinary excretion of AQP2 (u-AQP2) reflects the effect of AVP on the renal collecting ducts during water deprivation and hypertonic saline infusion in healthy subjects. Fifteen healthy subjects underwent a 24-h period of fluid restriction. Urine and blood samples were collected at timed intervals. Fifteen healthy subjects were given 7 ml/kg 3% hypertonic saline infusion for 30 min. Urine and blood samples were collected at timed intervals. During fluid restriction, the u-AQP2 rate increased from 3.9 (25th percentile: 3.1; 75th percentile: 5.2) to 7.6 (5.9-9.1; P < 0.001) ng/min, and the plasma AVP (p-AVP) level increased from 0.5 (0.4-0.6) to 3 (1.7-3.3) pmol/l. There was a positive correlation between the maximum change in u-AQP2 rate and the maximum change in p-AVP (r = 0.57, P < 0.03). During the infusion study, u-AQP2 rate was at maximum 90 min after the infusion [baseline: 4.5 ng/min (3.5-4.8); 90 min: 5 ng/min (4.5-6.0) P < 0.02]. p-AVP increased from 1.0 (0.9-1.1) to 1.5 (1.2-1.8; P < 0.002) pmol/l. There was a positive correlation between the maximum change in u-AQP2 rate and the maximum change in p-AVP (r = 0.83; P < 0.0001). It can be concluded that p-AVP and u-AQP2 are increased during thirst and hypertonic saline infusion and that u-AQP2 reflects the action of AVP on the collecting ducts.

Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus.

Diabetic nephropathy is one of the leading causes of end-stage renal disease. We examined whether ACE inhibitor treatment may have a nephroprotective effect in normotensive insulin-dependent diabetic patients without microalbuminuria and with normal glomerular filtration rate (GFR), and whether any effect was associated with the ACE genotype. In a prospective double-blind randomized study, normotensive patients with type 1 diabetes mellitus with normal serum creatinine and no microalbuminuria were treated with either placebo or perindopril, an ACE inhibitor. Urine albumine/creatinine ratio (ACR), mean blood pressure (MBP) and index of glomerular filtration rate (GFR) based on S-creatinine were determined. ACE genotype was determined by electrophoresis. ACR was higher in the placebo group than in the perindopril group after 4 months, and continued to increase during the study period. After 36 months of observation, ACR in the placebo group was 1.7+/-1.1 mg/mmol, and 0.6+/-0.2 mg/mmol in the ACE-inhibitor-treated group (p<0.001, Mann-Whitney test). During treatment, a significant increase in ACR in the placebo group (p=0.007), Wilcoxon matched paired test) was observed. There were no differences between the groups regarding MBP or GFR. The nephroprotective effects of ACE inhibitor treatment was not associated with the ACE genotype (II, ID, DD).

Effect of an acute oral ibuprofen intake on urinary aquaporin-2 excretion in healthy humans.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase and thereby block the prostaglandin (PG) synthesis in the kidneys. In animals, PG interferes with the formation of aquaporin 2 in the distal renal tubules. The purpose was to measure the effect of ibuprofen on urinary excretion of aquaporin-2 (u-AQP2), urinary output, urinary osmolality (u-osm) and plasma concentration of vasopressin (AVP) in a dose-response study using placebo and ibuprofen 600mg and 1200mg. In 12 healthy subjects, urine was collected in 6 periods between 07.00 h and 13.00 h, and blood samples were drawn at 60-min intervals. The study medication was given 10 h and 1 h before the study. U-AQP2 and AVP were determined by radioimmunoassays. U-AQP2 decreased 33% in the placebo group and increased 47% in the ibuprofen groups. There was a highly significant difference between the placebo group, on the one hand, and the ibuprofen groups, on the other. There was a small but significant increase in AVP in the placebo group and the 600 mg ibuprofen group, but not in the 1200 mg ibuprofen group. Urinary output was at maximum after 2 h, with a 394%, 1020% and 714% increase for placebo, 600 mg ibuprofen and 1200 mg ibuprofen, respectively. U-osm decreased during the experiment in all three groups. Inhibition of renal prostaglandin synthesis by ibuprofen affects the distal part of the nephron by increasing u-AQP2. This increase was not related to changes in AVP, urinary output or urinary osmolality. We suggest that the increased excretion of AQP2 can be explained by an increase in the ratio of AQP2 that is shed into the urine because the endocytic retrieval of AQP2 from the apical membrane is impaired. This could not be revealed by changes in the osmoregulatory system by the low doses of ibuprofen used in the present study.

Staphylococcus aureus carriage in adult peritoneal dialysis patients and their spouses.

OBJECTIVE: We hypothesized that carriage of Staphylococcus aureus among continuous ambulatory peritoneal dialysis (CAPD) patients was influenced by their spouses. Furthermore, this carrier status was compared to previous Staph. aureus peritonitis episodes in order to identify the influence of Staph. aureus carriage on peritonitis rate. DESIGN: A combined prospective surveillance study (Staph. aureus carriage) and retrospective chart review (Staph. aureus peritonitis). SETTING: A single peritoneal dialysis unit in a county hospital. PATIENTS AND METHODS: Cultures from patients (n = 32) and spouses (n = 16) were obtained twice, with a 1-month interval, from the anterior nares, the umbilical, and one groin area. All positive cultures were phage typed. Retrospective chart review of all episodes of Staph. aureus peritonitis among the patients was carried out. RESULTS: Twelve of 32 patients (37.5%) and 5 of 16 spouses (31%) evaluated were carriers. Half of the spouses of patients who were Staph. aureus carriers, were also carriers, as opposed to 20% of spouses of noncarrier patients (p = 0.30). Patients and spouses always shared the same phage type. Among patients, Staph. aureus was found in the nose only (n = 9), in all three regions (n = 2), and extranasally only (n = 1). If only one nasal culture was used to establish carriage, the sensitivity and negative predictive value would be 92% and 95%, respectively. A trend toward a higher incidence (p = 0.062) of Staph. aureus peritonitis was found among carriers (patients), 0.37 versus 0.28 peritonitis episode/dialysis-year. CONCLUSIONS: Only one positive nasal culture was necessary when carriage of Staph. aureus was to be established. Staph. aureus carriage was found more often in patients who had previously suffered from Staph. aureus peritonitis. The phage types isolated remained fairly constant, and the patients and spouses often had the same carrier state and shared the same phage types, although transmission does not always take place.

Etoposide: more effective and less bone-marrow toxic than standard immunosuppressive therapy in systemic vasculitis?

In two patients suffering from ANCA-positive systemic vasculitis (one from Wegener's granulomatosis, the other from microscopic polyangiitis), who were both resistant to or could not tolerate standard immunosuppressive therapy, complete clinical and biochemical remission was obtained within few months, treating with cyclic etoposide. Etoposide therapy was found to be significantly less bone marrow toxic than standard immunosuppressive therapy.

Continuous venovenous haemodialysis: a three-pump system.

A simple three-pump-based system for the performance of continuous venovenous haemodialysis is described. The method employs access to the circulation via a double-lumen catheter, and by means of a standard extracorporeal peristaltic pump the blood is circulated through a haemofiltration filter. Standard solutions for peritoneal dialysis are administered in a single-pass manner countercurrent to the blood flow. To control the dialysate flow through the filter, two separate pumps designed for intravenous infusion are used. Anticoagulation is achieved by means of continuous heparin infusion. This three-pump system is effective in controlling the fluid balance and the level of azotemia. Furthermore, this system makes haemodialysis possible in spite of severe haemodynamic instability. The system is easy to use and inexpensive. 3 patients participated in the study.

Long-term prognosis in idiopathic membranoproliferative glomerulonephritis.

The following results were obtained in a long-term follow-up investigation including 37 patients who suffered from idiopathic membranoproliferative glomerulonephritis. The mean follow-up period was 51 months (median 32 months). 1) Renal survival was 35% at 5 years and 16% at 10 years. 2) Univariate analysis indicated significant (p < or = 0.10) association between poor prognosis and the two following parameters a) high age b) elevated blood pressure. 3) Using a Cox-analysis including a) gender b) age at kidney biopsy c) square of age (age age) at biopsy d) presence of nephrotic syndrome e) presence of elevated blood pressure, the following p-values were found: 0.56; 0.02; 0.04; 0.50; 0.09. Thus at the 10% level age, the square of age and elevated blood pressure were significant and independently associated with poor prognosis.

[Peritonitis among patients treated with continuous ambulatory peritoneal dialysis]. / Peritonitis blandt patienter behandlet med kontinuerlig ambulant peritonealdialyse.

A retrospective study of 51 consecutive patients treated with continuous ambulatory peritoneal dialysis (CAPD) during a total of 736 months is presented. Forty-one episodes of peritonitis were found. Thirty-three patients did not experience peritonitis. One patient had six episodes of peritonitis. The time to first and second episode of peritonitis was 487 days (16.2 months) and 1005 days (33.5 months) respectively. The incidence of peritonitis was 0.67 episodes per patient-year, and was not influenced by either sex, diabetes or previous abdominal surgery. The time to the first episode of peritonitis was equal in patients suffering from one vs two or more episodes of peritonitis. Two patients suffered from tunnel infection. Initial treatment with vancomysin and gentamycin (before knowing the results of microbiological culturing) was adequate in 90% of the peritonitis episodes. Sterile peritonitis was found in 12% of the cases. No relapse of peritonitis was observed. Six patients suffered from eleven cases of reinfection. An optimal surgical strategy as well as vancomycin plus gentamicin treatment of peritonitis are advised when a reduction in infection rates is required

Ultrasound-guided renal biopsy with biopsy gun technique--efficacy and complications.

One hundred and thirty-one ultrasound-guided renal biopsies performed in 127 patients with automated spring-loaded biopsy technique were evaluated. Adequate tissue for histologic diagnosis was obtained in 92% of the procedures (94% of the patients). The mean glomerular yield was 16.8 glomeruli. Complications were seen in 21% of the patients, 18% having minor and 3% having major complications. Patients with severe hypertension had significantly more complications than the rest of the patients. The rate of complications in patients who had 3 or 4 biopsy passes was not increased compared to patients who had one or 2 biopsy passes. Thus, this study indicates that the risk of complications and the safety of the procedure is not influenced by increasing the number of biopsy passes in order to obtain representative specimens.

[Short and long term prognosis of acute renal failure requiring dialysis. An analysis of 419 consecutive patients]. / Kort- og langtidsprognose ved akut dialysekraevende nyresvigt. En analyse af 419 konsekutive patienter.

To describe the relationship between morbidity, mortality, and year of admission we studied 419 patients with acute dialysis-requiring renal failure. Effects of various follow-up periods and stratification on main prognostic factors were evaluated. There was a significantly higher (p < 0.001) number of organ failures/patient during the second six-year period compared with the first six-year period. Early (day 90) mortality was 46% and unchanged during the period. Estimated five year survival rate (95% confidence limits) was 52% (44-60) in patients with a medical etiology, and 28% (20-36) in patients with a surgical etiology. Prognosis was dependent on the severity and progression of the underlying disease process. Changed censoring time and stratification were important tools for enhancing the yield of information from the study. Time(s) and method(s) of risk scoring, stratification(s) of patients, time(s) of censorship, and method of statistical analysis should be identical when comparing results of treatment for acute renal failure from different centres.