Plasticizers and inhibition of leukocyte function in vitro.

OBJECTIVES: To evaluate the influence of the plasticizer metabolites of di(2-ethylhexyl)phthalate (DEHP), mono(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH), and phthalic acid (PA) on various immune functions of polymorphonuclear blood leukocytes (PMNL) and monocytes (MN). MEHP, 2-EH, and PA are the main hydrolysis products of DEHP. Since DEHP is leached out of the plastic matrix, patients on hemodialysis and continuous ambulatory peritoneal dialysis are exposed to considerable amounts of DEHP and its metabolites. SETTING: Teaching hospital, Department of Nephrology. PARTICIPANTS: Ten healthy volunteers. MEASUREMENTS: After incubation of leukocytes in solutions with different plasticizer concentrations, oxidative respiratory metabolism was determined by luminol-enhanced chemiluminescence (CL) after stimulation with phorbol myristate acetate (PMA). Furthermore, superoxide (O2-) generation was measured by cytochrome c reduction. RESULTS: At pH 5.4, a dose-dependent decrease of luminol-enhanced CL response was found in all assays. For MEHP and PA the level of significance was reached at 10 mg/L and 1 mg/L, respectively. Superoxide generation by PMNL and MN at pH 5.4 was also suppressed by MEHP and PA. At pH 7.4, only a slight suppression of oxidative metabolism at higher concentrations was observed. After incubation of the cells in a solution containing all DEHP metabolites (MEHP, PA, and 2-EH), a significant suppressive effect of CL at pH 5.4 could be observed at final plasticizer concentrations of 0.5 mg/L. CONCLUSIONS: A dose-dependent impairment of leukocyte oxidative metabolism at a low pH could be demonstrated. The suppressive effect was particularly marked after incubation of the cells in solutions containing a mixture of the main plasticizers. At pH 5.4, we observed a slight alteration even at concentrations very close to those that could be found in commercially available peritoneal dialysis fluids. These results might point toward a possible synergistic detrimental effect of the different DEHP metabolites on leukocyte function, with possible clinical relevance.

Low-dose intradermal versus intramuscular hepatitis B vaccination in patients with end-stage renal failure. A preliminary study.

Patients with end-stage renal disease (ESRD) are at high risk of hepatitis B infection. Only 50-60% of the patients respond adequately to the routinely performed intramuscular (i.m.) hepatitis B vaccination. We examined whether low dose intradermal (i.d.) application of the vaccine is equivalent to regular i.m. administration. Thirty-two patients with ESRD of different etiologies were investigated at the onset of dialysis treatment [11 patients on continuous ambulatory peritoneal dialysis (CAPD) and 21 patients on hemodialysis (HD)]. Patients were vaccinated at month 0, 1, 3 and 6 with either 40 micrograms HBs Ag (2 ml Engerix B, 14 patients) i.m. or with 10 micrograms HBsAg (0.5 ml Engerix B, 18 patients) i.d. The i.m. vaccination was applied in the deltoid muscle, while for i.d. vaccination the vaccine was injected into the skin of the deltoid region. Six weeks after the last vaccination anti-HBs titers were measured. 61% (11 patients) of the patients vaccinated i.d. and 64% (9 patients) of the patients vaccinated i.m. developed protective titers. Neither the height of the titers nor the proportion of patients responding to the vaccination differed significantly between the two vaccination schedules. No difference regarding the height of titers achieved or the rate of seroconversion could be found when CAPD and HD patients were analyzed separately. Only minor side effects have been observed. According to these preliminary data i.d. hepatitis B vaccination in patients with ESRD may be equivalent to i.m. administration of the vaccine. Given equivalency i.d. vaccination may be a cost-saving alternative to i.m. vaccination (only a quarter of the dose of i.m. administered vaccine is needed) with a good practicability (vaccination can be performed during HD) and a low rate of side effects.

Propafenone in a usual dose produces severe side-effects: the impact of genetically determined metabolic status on drug therapy.

We report the case of an elderly lady presenting with dizziness, a head injury resulting from a fall and bradycardia. Propafenone 150 mg t.i.d. had been prescribed for atrial fibrillation with tachyarrhythmia, induced by hyperthyroidism, 18 months earlier. A toxic concentration of parent propafenone, and no 5-hydroxy metabolite, was detected in a plasma sample. Symptoms disappeared after the discontinuation of propafenone. The poor metaboliser (PM) phenotype of sparteine/debrisoquine was assumed and subsequently confirmed by phenotyping (sparteine test) and genotyping (allele-specific polymerase chain reaction). The PM phenotype is common in European populations, with a prevalence of about 7%. If drugs with narrow therapeutic ranges undergo genetically polymorphic metabolism, toxicity may arise even with recommended doses. Individualization of doses is required to avoid adverse effects.

Epidermal Langerhans cells in uremic patients on hemodialysis or continuous ambulatory peritoneal dialysis.

Skin biopsies of 33 uremic patients-13 patients on continuous ambulatory peritoneal dialysis (CAPD), 12 on hemodialysis (HD), 8 patients with end-stage renal disease (ESRD) before initiation of dialysis treatment-and 10 healthy volunteers were investigated to determine the number of Langerhans cells (LC) by light microscopy after staining for S-100 protein. The epidermal LC count was significantly lower in patients on CAPD (mean: 62.9 LC/mm2; p = 0.027) and patients on HD (mean: 30.4 LC/mm2; p = 0.0015) compared to controls (mean: 110.1 LC/mm2) and uremic patients before initiation of dialysis treatment (mean: 122.6 LC/mm2). The difference between LC counts of CAPD and HD patients did not reach statistical significance (p = 0.057). There was no relation between LC count and age (p = 0.057) or epidermal width (p = 0.26). No statistically significant correlation could be demonstrated between duration of dialysis and LC count (r = -0.33, p = 0.10). LC counts of CAPD patients with diabetes mellitus (n = 7) were not significantly different from those of nondiabetics (n = 6; p = 0.77). LC counts seem to be normal in uremic patients before dialysis treatment. The reduction in LC density in the skin of dialysis patients may contribute to immunodeficiency of uremic patients on regular dialysis treatment.

Pharmacokinetics, bioavailability, metabolism and acute and chronic antihypertensive effects of nitrendipine in patients with chronic renal failure and moderate to severe hypertension.

1. The pharmacokinetics, bioavailability, metabolism and antihypertensive effects of nitrendipine have been studied in 12 patients with impaired renal function and moderate to severe hypertension. The drug was administered simultaneously by the i.v. [13C4] and oral (commercial tablet 20 mg) routes. 2. No differences in the pharmacokinetic parameters were observed between the two routes of administration. The systemic clearance after i.v. administration in patients with renal impairment (18.2 +/- 6.1 ml min-1 kg-1) was similar to that observed in healthy volunteers. Despite complete absorption of drug from the tablet the bioavailability of the parent compound was 21.2 +/- 12.5%. Cumulative urinary excretion of nitrendipine metabolites was correlated with the creatinine clearance (r = 0.946). 3. Significant reductions in mean arterial blood pressure (mean: 23.6%) at the end of the nitrendipine infusion and after oral administration of 20 mg (mean: 17.5%) were observed. The blood pressure lowering effect of nitrendipine could be correlated within individuals with serum nitrendipine concentrations using a log linear model. 4. Following 4 weeks of therapy an average dose of 77 mg nitrendipine day-1 was required to achieve a systolic blood pressure below 160 mm Hg or a diastolic blood pressure below 90 mm Hg. The reduction in blood pressure during multiple dosing was related to the nitrendipine steady-state concentration. There was a significant relationship between the nitrendipine bioavailability and the dose required for sufficient blood pressure control. 5. No accumulation of nitrendipine caused by impaired renal function was observed during multiple dosing. Thus, no reduction of the nitrendipine dose in patients with renal impairment is necessary.

Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells.

Fifty-four uremic patients (26 patients were maintained on continuous ambulatory peritoneal dialysis [CAPD] and 28 on hemodialysis [HD]) were screened for pruritus and plasma histamine. 50% of the patients on CAPD and 64.3% of patients on HD complained of current itching. The extent of itch, assessed by a score, was not significantly different between HD and CAPD patients. Plasma histamine levels showed no significant difference between CAPD and HD patients and no correlation between plasma histamine level and the extent of pruritus could be demonstrated. In six patients on CAPD and 9 patients on HD plasma histamine levels were determined before and three months after initiation of dialysis treatment; no substantial change could be observed. In some patients skin biopsies were obtained from the gluteal region in order to determine the number of skin mast cells. The number of mast cells did not show a significant difference between controls (n = 12), uremic patients before initiation of dialysis treatment (n = 8), patients on CAPD (n = 11) and patients on HD (n = 13). There was no relationship between the level of plasma histamine, the number of skin mast cells and the extent of pruritus in uremic patients.

Multifactorial genesis of enhanced platelet aggregability in patients with nephrotic syndrome.

Platelet aggregation, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF 4) release and thromboxane B2 (TxB2) formation in stimulated platelet-rich plasma were investigated in 13 patients with nephrotic syndrome who had normal serum creatinine levels (creatinine clearance greater than 70 ml/min/1.73 m2). In contrast to 13 sex- and age-matched controls, spontaneous platelet aggregation only occurred in patients with nephrotic syndrome with correlation to serum albumin and plasma fibrinogen levels. The EC50 (estimated concentration of aggregating agent to cause half maximum velocity of primary aggregation) for ADP and collagen and threshold concentration of arachidonic acid (threshold AA) were decreased in patients with nephrotic syndrome, reflecting a hyperaggregable state. In patients with nephrotic syndrome EC50 ADP values were significantly correlated to serum albumin, serum cholesterol and plasma fibrinogen, however, EC50 collagen or threshold AA did not correlate to these parameters. Plasma beta-TG levels were increased in patients, whereas plasma PF 4 levels were not significantly changed in patients compared to controls. In vitro TxB2 formation was elevated in patients only after stimulation with AA. Nevertheless, after stimulation with collagen and ADP, TxB2 formation was unchanged in patients compared to controls. Platelet hyperaggregability in nephrotic patients was confirmed in our study. However, unchanged thromboxane B2 formation after collagen stimulus as well as missing correlations between EC50 collagen or threshold AA and serum albumin were contradictory to the hypothesis that enhanced AA availability due to hypoalbuminemia is responsible for platelet hyperaggregability. Platelet hyperaggregability in terms of EC50 ADP being associated with serum albumin levels as well as to serum cholesterol and plasma fibrinogen indicate a multifactorial genesis.

Pulmonary disease due to Mycobacterium xenopi in a renal allograft recipient: report of a case and review.

A 39-year-old man with pulmonary disease due to Mycobacterium xenopi is described. He had received prednisone and azathioprine for 5 years and prednisone in combination with cyclosporin A for 1 year in an effort to prevent rejection of his renal transplant. Shortly after the renal allograft was removed because of chronic rejection, the patient developed dyspnea and a decrease in vitality. He had no history of preexisting lung disease. A chest roentgenogram showed multiple nodular infiltrates in both lungs. M. xenopi was cultured from three sputum samples. The organism was susceptible to isoniazid, streptomycin, ethambutol, rifampin, pyrazinamide, and ethionamide. The patient was treated successfully with isoniazid, ethambutol, and rifampin for 3 months and with isoniazid in combination with rifampin for an additional 9 months, while he was maintained on continuous ambulatory peritoneal dialysis (CAPD). The literature on mycobacterial disease, especially in renal transplant recipients and patients on CAPD, is reviewed.

Treatment of peritonitis in continuous ambulatory peritoneal dialysis (CAPD) with intraperitoneal cefazolin and gentamicin.

Between 1983 and 1988 57 peritonitis episodes in an unselected patient population were initially treated with intraperitoneal cefazolin and gentamicin. The loading dose consisted of 500 mg cefazolin/L dialysate and 40 mg gentamicin/L dialysate. The maintenance dosage was 125 mg cefazolin and 8 mg gentamicin per liter dialysate. Forty-five (78.9%) patients were primarily cured with this regimen (responder group = RG). Twelve patients (21.1%) did not respond to the initial therapy (nonresponder group = NG). Eight peritonitis episodes in the NG (14.0% of all patients) were caused by tunnel infections and 2 by diverticulitis (3.5%). The cure rate in patients without tunnel infection or bowel disease was 95.7%. A relapse occurred in 2 patients (3.5%). Duration of therapy was assessed by daily white blood cell count (WBC) in the effluent and treatment was discontinued when the WBC was less than 100/microliters for 3 days. The mean duration of therapy with cefazolin and gentamicin was 8.1 days in the RG and 6.0 days in the NG. Nonresponders were subsequently treated with a modified antibiotic regimen on an average 11.9 days.

Pharmacokinetics and pharmacodynamics of nitrendipine in healthy subjects and patients with kidney and liver disease.

Nitrendipine [3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate] is a calcium antagonist with a dihydropyridine structure that has a great structural resemblance to nifedipine. Instead of a methyl group in position 3, it has an ethyl group and the NO2 group is in the meta instead of in the ortho position. These minor structural differences have a pronounced impact with respect to both the pharmacokinetics and pharmacodynamics of nitrendipine as compared to nifedipine. Based on equimolar plasma concentrations, nitrendipine is on average three times more potent than nifedipine with regard to the reduction of peripheral vascular resistance, arterial blood pressure, and increased leg blood flow. The terminal half-life is on average 8 h, and thus substantially longer than the terminal half-life of 2-3 h for nifedipine. Despite its almost complete absorption, bioavailability is on average 15-25% and shows great interindividual variability ranging from 7 to 40%. The systemic plasma clearance of the drug is on average 18 ml/min/kg and thus approaches the liver blood flow. In patients with liver cirrhosis, the half-life is prolonged to 19.6 h, the total plasma clearance is decreased by 50%, and the bioavailability is more than doubled to 54%. No data are available if liver disease alters the pharmacodynamic response of the drug. Kidney disease has some effect on the disposition of the drug. Systemic clearance is not changed but the terminal elimination half-life is slightly prolonged to 10.5 h. This increase in half-life is due to an increased volume of distribution. Bioavailability, which is 21.2%, is not grossly altered in renal failure.

Prevention of coronary platelet aggregation with a phosphodiesterase inhibitor RX-RA 69.

The formation and prevention of coronary platelet thrombi (CPT) was studied in a modified Folts model in 23 anaesthetized dogs. The left circumflex coronary artery was acutely damaged and narrowed until resting flow started to fall. Spontaneous sharp decrease of flow indicated the acute formation of CPT. Intravenous infusion of 30 ng/kg/min of PGI2 prevented the formation of CTP. The effect lasted 3-7 min after termination of the infusion. RX-RA 69 a potent inhibitor of platelet phosphodiesterase (IC50 of 1 X 10(-9) mol/1) inhibited the formation of CPT for 9 and 18 min when 60 and 120 micrograms/kg were administered i.v. The results demonstrate that platelet aggregation induced by acute damage of the vascular wall can be inhibited by a potent PDE inhibitor.

Formation and elimination of prostacyclin metabolites in the cat in vivo as determined by radioimmunoassay of unextracted plasma.

Using newly develop radioimmunoassay for 6-keto-prostaglandin F1 alpha and 6,15-diketo-13,14-dihydro-prostaglandin F1 alpha, the plasma concentrations of these two prostacyclin derivatives were measured in anaesthetized cats. After the administration of angiotensin II, which releases prostacyclin into the circulation, concentrations of both derivatives rose simultaneously, the major immunoreactivity being 6,15-diketo-13,14-dihydro-prostaglandin F1 alpha. Angiotensin II-induced prostacyclin release was not caused by vasoconstriction alone, since comparable vasopressor responses to noradrenaline and vasopressin were not accompanied by increases in prostacyclin plasma levels. Injection of exogenous prostacyclin resulted in a shortlasting peak of 6-keto-prostaglandin F 1 alpha, which rapidly declined (t 1/2: 1.29-1.52 min). 6,15-diketo-13,14-dihydro-prostaglandin F1 alpha appeared with an t 1/2 of 0.48-1.38 min and was eliminated with a t 1/2 of 8.0-9.0 min. Due to its longer half-life in the circulation 6,15-diketo-13,14-dihydro-prostaglandin F 1 alpha again was the predominant derivative after 3 min. These data suggest that in vivo prostacyclin is mainly inactivated by the 15-hydroxy-PG-dehydrogenase-, delta 13-reductase-pathway, rather than by hydrolysis. Therefore, 6,15-diketo-13,14-dihydro-prostaglandin F1 alpha seems to be a better indicator of prostacyclin plasma levels than 6-keto-prostaglandin F1 alpha, although under certain conditions the additional determinations of this product of hydrolysis can be valuable.