Dent's disease: identification of a novel mutation in the renal chloride channel CLCN5.

Dent's disease is an inherited tubulopathy caused by a mutation in the CLCN5 chloride channel gene. It is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis or nephrocalcinosis, rickets and eventual-progressive renal failure. Onset of clinical symptoms show a great variability, making a diagnosis at an early stage of the disease often difficult. Given the variably clinical picture, genetic analysis can provide a reliable method to confirm the diagnosis. Here, we report on the case of a patient with progressive renal failure showing signs of a tubular lesion and symptoms of Dent's disease. Although this rare disease was suspected by means of the clinical features, it was genetic analysis that confirmed the diagnosis and revealed a novel mutation in the CLCN5 gene.

Biapenem pharmacokinetics in healthy volunteers and in patients with impaired renal function.

Biapenem (CAS 120410-24-4) is a new broad spectrum antibiotic agent from the group of carbapenem antibiotics. Results of a pharmacokinetic study in eight volunteers, 17 patients with variant degrees of renal impairment and in addition 13 haemodialysis patients, both on (n = 8) and off dialysis (n = 5), are reported. A single dose of 500 mg biapenem was administered i.v. over 30 min; blood and urine samples were collected up to 24 h post infusion in volunteers and up to 48 h in patients. Concentrations were determined by microbiological assay using the cup plate method. The tolerance was good. The renal function in patients was determined using single shot 51chromium-EDTA clearance. The calculation of pharmacokinetic parameters was performed non-compartmentally as well as based on an open two-compartment model. Although the compound is eliminated extrarenally in considerable amounts (approximately 46% in volunteers), an important prolonged elimination in renal dysfunction was found. This was mainly due to decreased renal elimination but also partly due to decreased extrarenal clearance. A dose reduction factor (DRF) is calculated derived from the ratio of the areas under the serum concentration curve (AUC), in normal and impaired renal function. Dosage suggestions are made. The compound is eliminated considerably by haemodialysis. It is therefore recommended that biapenem is given after haemodialysis or in double the dose on haemodialysis days.

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers.

OBJECTIVE: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. RESULTS: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC0-infinity 12.6 micrograms.h.ml-1) in comparison with healthy volunteers (AUC0-infinity 39.3 micrograms.h.ml-1). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free Cmax (5.0 vs. 2.6 ng/ml) but similar free AUC0-infinity (0.13 vs. 0.11 microgram.h.ml-1) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemodialysis. CONCLUSION: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound nonsteroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free Cmax value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable.

Pharmacokinetics of azithromycin in normal and impaired renal function.

Plasma and urine levels of 12 healthy subjects and 30 patients with renal insufficiency of different degrees were examined after oral administration of four 250 mg capsules azithromycin (total daily dose 1,000 mg). The concentrations were determined by cup plate method. The pharmacokinetic parameters were determined model-dependent and noncompartmentally. Neither the area under the plasma concentration curve nor the distribution volume in steady state (16 l/kg body weight) nor the maximal plasma concentration were significantly affected by renal insufficiency. Thus the dosage regimen of azithromycin in renal impairment may (and should) be the same as in patients with normal renal function. The nonrenal clearance is not affected by renal insufficiency, but the concentration of the substance in the tubular lumen (the "tubular load") may be increased.

The Demers atrial catheter: experience with a single-lumen silicone catheter as short- and long-term access for hemodialysis.

The Demers catheter is a silicone atrial catheter with a dacron cuff used as short- and long-term access for hemodialysis. It was implanted in 316 patients between January 1, 1987 through May 31, 1991. Data on these implantations were retrospectively analyzed and are reported here. Follow-up and analysis was possible in 404 of 417 Demers catheter implantations. The mean age of patients in this study was 61 years. For short-term use (< 91 days) 153 catheters were implanted in 135 patients, for long-term use (> 90 days) 251 catheters in 181 patients. The median life span of all 404 catheters was 87 days. The median life span for long-term use was 150 days (2-1302) per catheter and 220 days (92-1717) per patient. Catheter malfunction (arterial blood flow < 200 ml) was encountered every 876 days in the running time of the catheter. Twenty percent (n = 80) of the catheters were explanted because of complications. These included 42 cases of catheter malfunction and 22 cases of infection.

[Antibiotic therapy in general practice]. / Antibiotikatherapie in der Praxis.

Antibiotic therapy only makes sense if a bacterial infection exists. Strategies are discussed how viral infections--the most important reason of fever in general practise--can be differed from bacterial infections. Of special importance is e.g. CRP which only rises in case of a bacterial infection. Its decline shows that therapy is successful and that the antibiotic therapy can be discontinued. If the location of the infection is known (e.g. urinary tract), one can expect certain microorganisms and their sensitivity to antibiotics. With this kind of "calculated therapy" the use of "wrong" antibiotics can be minimized. The antibiotics which can be employed in general practise are discussed by terms of effectiveness, side effects, and price in relation to their indications and contraindications.

Nonrenal clearance and tubular load in renal failure.

Twelve studies on the pharmacokinetics of various antibiotics (11 beta-lactams, 1 quinolone) in renal failure were re-examined on a meta-level. It was found that besides the expected (and obvious) decrease of renal clearance in impaired renal function, the nonrenal clearance (CLNR) also decreased: in terminal renal insufficiency, CLNR was approximately only half the value found in healthy subjects. A possible explanation for this could be the uremic intoxication and the resulting disturbance of the metabolic processes. Though the absolute value decreases, nonrenal clearance in renal failure is a relevant part of the total elimination: the ratio nonrenal to total elimination doubled and was even more. Furthermore, the amount of substances eliminated per nephron was found to increase. The ratio "renal clearance/glomerular filtration rate", the tubular load, increased as well. This might have positive effects (exceptionally high concentrations of antibiotics at important sites in kidney infections) but also negative consequences (higher tubular toxicity depending on the concentration).

Pharmacokinetics of teicoplanin in hemodialysis patients.

As only insufficient knowledge about the dosage of teicoplanin in hemodialysis patients exists, a clinical trial was performed on 26 patients. An initial dose of 800 mg teicoplanin, followed by doses of 400 mg on day 8 and day 15, was administered. In addition to the common clinical parameters (fever, white blood cell count, C-reactive protein), the plasma concentrations of this substance were determined. The HLTterm was 159 +/- 35 h, the Vss 104 +/- 25 1/100 kg and the CLtot 5.3 +/- 1.3 ml/min. It could be shown that the dosage regimen mentioned above produced long-lasting and highly effective levels, sufficiently surpassing the MICs of the expected bacteria (streptococci and staphylococci). The easily administered substance showed no adverse side effects, based on clinical criteria. The above-mentioned therapy nearly always resulted in success according to clinical criteria. Therefore, and due to its easy administration, it seems advantageous to start treatment with teicoplanin in hemodialysis patients obviously suffering from bacterial infections.

Cefpodoxime proxetil in patients with endstage renal failure on hemodialysis.

The blood levels of cefpodoxime of 16 hemodialysis patients were monitored after a single oral of Cefpodoxime proxetil with a Cefpodixime-equivalent of 200 mg dose. Eight patients were on dialysis during the period of observation, while the other eight patients were observed during a non-dialysis period. During hemodialysis the cefpodoxime levels were determined before and after the capillary dialyzer. It became apparent that hemodialysis patients have considerably higher and longer-lasting concentrations than patients with normal kidney function. The area under the curve is about seven times greater. Cefpodoxime is thus apparently eliminated to a great extent renally. The concentration levels before capillary dialyzer are noticeably higher than those after capillary dialyzer, so that it can be assumed that cefpodoxime is being dialyzed: the area under the curve of the eight patients observed during hemodialysis was about 50% less than that of the patients observed while not on hemodialysis. Based on the pharmacokinetic data gathered, simulations of the course of concentration were made which took into consideration the clinical circumstances (normal period of dosage administration and dialysis). According to these simulations one can recommend a loading dose of 200 mg and thereafter a dose of 100 mg 12 h later followed by 100 mg every 24 h. This will result in an average concentration of 2 mg/l and never falling below 1.5 mg/l. With this schedule all bacteria considered to be sensitive can be reached. Cefpodoxime proxetil thereby ensures a simple and effective therapy of bacterial infections in hemodialysis patients.

Age dependence of therapy result and risk in the treatment of arterial hypertension?

In an open multicenter study, 2,012 patients with mild to moderate essential hypertension were treated for 8 weeks with the beta1-selective blocker bisoprolol. A total of 570 general practitioners participated in this study. A total of 1,597 patients whose resting diastolic blood pressure (DBP) ranged from 95 to 115 mm Hg were considered eligible for this study. Patients received one tablet of bisoprolol (5 mg) o.d. for the first 4 weeks. In patients not responding satisfactorily to treatment, the dose could be increased to 10 mg o.d. for the following 4 weeks. A total of 1,201 patients were evaluated for efficacy and all 2,012 patients were evaluated for tolerability. After 4 weeks of therapy, mean systolic blood pressure (SBP) was lowered significantly from 170+/-15 to 151+/-14 mm Hg, and mean DBP was lowered from 104+/-5 to 92+/-7 mm Hg. A further 4-week treatment lowered the blood pressure even more: mean SBP from 151+/-14 to 144+/-13 mm Hg and mean DBP from 92+/-7 to 88+/-7 mm Hg. The total extent of both SBP and DBP reduction was equal in all age groups and showed no dependency of the initial blood pressure value. At the end of the study. the responder rate was 94.9% in patients aged under 60 years, and 90.6% in patients aged over 60 years. The age group 31-40 years showed the highest responder rate (97.5%). After 8 weeks of treatment, 69.5% of the patients were still on 5 mg of bisoprolol and 27.6% on 10 mg of bisoprolol. Of all 2,012 patients, 11.6% reported side effects such as vertigo, fatigue. gastrointestinal disturbances, and headache. The incidence of adverse drug reactions was highest in the age group 31-40 years. Bisoprolol proved in this study to be an effective and safe antihypertensive agent when given to patients with mild to moderate hypertension for 8 weeks.

Pharmacokinetics of aspoxicillin in subjects with normal and impaired renal function.

The pharmacokinetics of aspoxicillin [2S,5R,6R)-6-[(2R)-2-[(2R)-2-amino-3-(methylcarbamoyl)propionam ido]-2- (p-hydroxyphenyl)acetamido]penicillanic acid) in 10 subjects with normal kidney function and in 20 patients suffering from impaired renal function were examined after an i.v. short-term infusion of 4 g for a period of 20 min. In contrast to available semi-synthetic penicillins, aspoxicillin shows a slightly longer half-life elimination. As the substance is mainly excreted renally, the areas under the curve (AUC) are larger in cases of impaired renal function. Mathematical correlations can be established between the AUC and the renal function parameters creatinine and glomerular filtration rate. Dosage reduction factors are then derived which allow appropriate dosages to be established for the substances under examination. Dosages for differing degrees of impaired renal function are given in tables. Since sufficiently high and long-lasting urine levels are achieved, it is reasonable to use aspoxicillin as treatment of urinary tract infections in patients suffering from end-stage renal failure.

Pharmacokinetics of pefloxacin in normal and impaired renal function.

Ten healthy young volunteers (mean age 28 years) and 24 patients (mean age 54 years) suffering from various degrees of chronic renal failure received an infusion of 400 mg pefloxacin (1-ethyl-6-fluoro-1, 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid) over 30 min. The blood and urine levels of pefloxacin and of the two metabolites pefloxacin-N-oxide and norfloxacin were determined using the HPLC method. Blood levels were taken after periods of 0, 60, 120, 180, 360, 600, 720, 1440, 2880, 3360 min, and in patients suffering from renal insufficiency also after 4320 min. The urine was collected and analyzed during the periods of 0-2, 2-4, 4-10 (12) h and then in longer periods up to 72 h. In all subjects, the glomerular filtration rate (GFR, by chrome-51-EDTA) and the plasma creatinine level were determined. Effective levels against bacteria lying in pefloxacin's spectrum can be found in the plasma for about 1.5 days and in the urine for about 2.5 days. Patients suffering from chronic renal failure have pefloxacin plasma levels which beyond 24 h are higher than in healthy persons. This can be explained by both: impaired renal and extrarenal elimination. The volume of distribution of the volunteer and the patient group does not differ significantly. Therapeutic urine levels could be found in patients up to 48 h after end of infusion. Even in patients requiring regular hemodialysis, therapeutic urine levels were found up to 24 h (if urine could be produced at all). The substance therefore is a suitable remedy for urinary infections in dialysis patients as well.(ABSTRACT TRUNCATED AT 250 WORDS)