Paracetamol disposition in renal allograft recipients.

OBJECTIVE: To evaluate the disposition of paracetamol in renal allograft recipients. METHOD: Eight fasting renal allograft recipients were given 1 g soluble paracetamol orally. RESULTS: Paracetamol was absorbed rapidly, and the mean plasma half-life from 2 h to 8 h was 2.6 +/- 0.5 h. After that, disappearance of paracetamol from the plasma was slower. Both the glucuronide and sulphate conjugates of paracetamol had slow elimination half-lives of 15.1 +/- 8.8 h and 26.2 +/- 14.6 h, and there were residual amounts of both conjugates in the plasma at 24 h. The renal clearances of both conjugates were low (21 +/- 14.2 ml/min and 32.4 +/- 31.4 ml/min) and there was a significant negative correlation between total amount of paracetamol recovered in the urine in 24 h and serum creatinine (r = -0.89, P<0.01). CONCLUSION: Paracetamol disposition is abnormal in renal allograft recipients and seems to relate to abnormal renal function in these patients.

Experimental exposure of llamas (Lama glama) to Brucella abortus: humoral antibody response.

Positive antibody reactions to brucella were observed in the sera of four llamas receiving Brucella abortus Strain 19 subcutaneously at 2-3 weeks post-exposure (PE) using five of eight conventional brucella serologic tests and an ISU-ELISA. Positive brucella antibody reactions were detected in sera of four llamas exposed by intraocular instillation (IOI) of 1.02x10(8) (high dose) B. abortus Strain 2308 at 16-35 days PE using seven of eight serologic tests or an ISU-ELISA. Brucella antibody was also detected in sera of four llamas exposed by IOI of 9x10(5) (low dose) B. abortus using each of four agglutination tests, Complement Fixation test, PCFIA, the rivanol test and the ISU-ELISA at 16-35 days PE. Positive reactions were observed using the Card test, BAPA, SPT, STT, the rivanol test, the PCFIA, and the ISU-ELISA on sera collected on days 42-70 PE, except on one llama, given the low dose; that llama was negative on the PCFIA on day 42. Positive or suspicious reactions were not detected in sera of controls, receiving saline subcutaneously, using the routine tests, with the exception of the CFT. The B. abortus Strain 2308 was isolated from tissues of seven of eight llamas exposed to virulent B. abortus Strain 2308.

Recombinant erythropoietin improves cognitive function in patients maintained on chronic ambulatory peritoneal dialysis.

Psychometric performance was studied in 17 patients maintained on CAPD. Nine patients treated with rHuEpo performed a battery of psychometric tests before treatment (haemoglobin mean (SD) 6.8 (0.8) g/dl) and after partial correction of anaemia (haemoglobin 9.0 (1.0) g/dl). The same battery of psychometric tests was administered to eight patients (haemoglobin 7.7 (0.7) g/dl), matched with the treatment group for age, duration of dialysis and social class, who did not receive rHuEpo. The National Adult Reading Test was used in all patients to estimate the premorbid IQ (the peak cognitive level attained before any cognitive deterioration). In the rHuEpo-treated group current IQ, measured by a short form of the Wechsler Adult Intelligence Scale--Revised, improved by a mean of 7.2 points (P < 0.01) and approached estimated premorbid levels, while in the control group an improvement by 0.3 points was not significant. Concentration and speed of information processing were assessed by the Paced Auditory Serial Addition Task and also improved in the treatment group (P < 0.05). Memory, assessed by the Rey Auditory Verbal Learning Test, tended to improve in the treatment group with amelioration of anaemia, although only the improvement in delayed recall was significant. No overall change was seen in either group in the time taken to complete the Trail Making Test (part A). These results are consistent with our earlier findings in haemodialysis patients, indicating that anaemia makes a reversible contribution to uraemic cognitive dysfunction.

The disposition of paracetamol and its conjugates during multiple dosing in patients with end-stage renal failure maintained on haemodialysis.

The disposition of oral paracetamol (1.0 g 3 times daily for 10 days) was studied in 6 patients with end-stage renal failure (creatinine clearance < 5 ml x min-1) maintained on haemodialysis 2 or 3 times per week. Blood was sampled daily for 10 days. The time of sampling depended on whether the patients were dialysed in the morning or afternoon but was always within 5 h of the last dose of paracetamol. On dialysis days samples were taken at the start of the session. The mean plasma concentration of paracetamol was 6.8 mg x l-1 after the first 24 h and subsequently varied little throughout the 10 days. Apparent steady-state plasma concentrations of 60.0 mg x l-1 and 54.5 mg x l-1 were reached for the glucuronide and sulphate conjugate of paracetamol respectively by the 2nd day of treatment with little variation throughout the remainder of the study. These steady-state concentrations of paracetamol glucuronide and sulphate were much lower than predicted. The steady-state plasma concentrations of the retained cysteine and mercapturate conjugates of paracetamol were low (5.7 and 3.7 mg x l-1, respectively) and there was no evidence of accumulation of these potentially toxic metabolites. It is not clear why regular dosing with paracetamol in haemodialysis patients did not cause the accumulation of paracetamol glucuronide or sulphate as predicted. There may be enterohepatic elimination of retained paracetamol conjugates or depletion of substrates such as inorganic sulphate during chronic dosing.

Recombinant erythropoietin improves cognitive function in chronic haemodialysis patients.

Psychometric performance was studied on two occasions in 18 chronic haemodialysis patients. Nine patients treated with rHuEpo performed a battery of psychometric tests before treatment, haemoglobin [mean (SD)] 5.8 (0.6) g/dl and after partial correction of anaemia, haemoglobin 9.3 (1.28) g/dl. The same battery of psychometric tests was administered on two occasions to nine patients (haemoglobin 7.3 (1.2) g/dl) matched with the treatment group for age, educational status and social class, who did not receive rHuEpo. In the rHuEpo-treated group, IQ, measured by the Wechsler Adult Intelligence Scale-Revised, improved by a mean of 8.7 points (P less than 0.01), while in the control group an improvement by a mean of 2.5 points was not significant. Comparison between the groups of the change in IQ score was significant (P = 0.04). There was no change in the mean scores obtained in either group for the other psychometric tests administered including the Paced Auditory Serial Addition Test, Rey auditory verbal learning, and Borkowski verbal fluency test. These results indicate that anaemia makes a reversible contribution to uraemic cognitive dysfunction.

Effect of treatment mode on the natural history of acquired cystic disease of the kidney in patients on renal replacement therapy.

The natural history of acquired cystic disease of the kidney has been investigated in a long-term follow-up study of patients on renal replacement therapy. A cohort of 145 end-stage renal failure patients was initially investigated with ultrasonography to determine the degree of cystic change. Seventy-three patients were available for follow up a minimum of 3 years later. The grade of cystic disease progressed in dialysis patients and progression was more marked in haemodialysis patients than patients maintained on CAPD. Patients with functioning renal transplants did not show progression of cystic change and in two patients regression was seen. Nine patients maintained on chronic dialysis at the time of initial ultrasound subsequently received renal grafts, and three of these patients had evidence of regression of cystic change on follow-up scanning. After 3 years follow-up a single haemodialysis patient had evidence of a solid lesion in a cystic kidney and this has not progressed during a further 12 months of follow-up. Acquired cystic disease of the kidney is a progressive disease in chronic dialysis patients. However, over a follow-up period of 3 years, patients with functioning renal grafts do not show similar progression. The incidence of solid renal tumours has been shown to be low.

The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure.

We have compared the disposition of oral paracetamol (1.0 g t.d.s. for 10 days) in 6 healthy volunteers and 6 conservatively-managed patients with chronic renal failure (mean plasma creatinine 451 mumol.l-1). Blood was sampled daily for 10 days before the morning dose of paracetamol. Each day the pretreatment plasma concentrations of paracetamol were higher in the renal failure patients than in the volunteers, with mean values over the 10 days of 3.1 and 1.1 mg.l-1 respectively. The mean daily plasma concentrations of the sulphate and glucuronide conjugates of paracetamol were markedly higher in the renal failure group and apparent steady-state concentrations of about 25 and 85 mg.l-1 were reached on the 2nd and 6th days respectively. The mean steady-state plasma concentrations of the glucuronide conjugate on the 7th to 10th days of treatment were positively correlated with the plasma creatinine concentration (r = 0.97), but this relationship did not hold for the sulphate conjugate. Cysteine and mercapturate conjugates could only be detected in one patient. Predictions of steady-state concentrations based on previous studies with single doses of paracetamol in renal failure patients were remarkably accurate for the glucuronide but not for the sulphate conjugate. These results are consistent with some extra-renal elimination of retained paracetamol conjugates in patients with chronic renal failure, with limited regeneration of the parent compound. The sulphate metabolite did not accumulate as predicted, possibly because of depletion of inorganic sulphate.

Paracetamol disposition and metabolite kinetics in patients with chronic renal failure.

The disposition of paracetamol following an oral dose of 1.0 g was compared in 10 healthy volunteers, 7 patients with moderate chronic renal failure and 6 patients with end stage renal failure on maintenance haemodialysis. Paracetamol absorption was normal in the patients with renal failure. The mean plasma half-life of paracetamol from 2 to 8 h was similar in the 3 groups (2.1 to 2.3 h) but from 8 to 24 h it disappeared much more slowly in the renal failure patients (half-life 11.7 compared with 4.9 h in the healthy volunteers). Plasma concentrations of paracetamol glucuronide and sulphate conjugates were greatly increased in the patients with moderate renal failure and the mean plasma half-lives were 30.5 and 21.8 h respectively compared with about 3 h in the healthy volunteers. Plasma concentrations of these metabolites were even higher in the dialysis patients and there was no significant fall over 24 h. The cysteine and mercapturic acid conjugates of paracetamol could only be measured in plasma in the patients with renal failure and concentrations were very low. The fractional urinary recovery of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates was similar in healthy volunteers and patients with moderate renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Observations on diagnostic tests for paratuberculosis in a deer herd.

Paratuberculosis was diagnosed in a herd of 62 fallow deer (Dama dama) and 38 sika deer (Cervus nipon) maintained in an animal park in Ohio. A comparison was made of delayed-type hypersensitivity responses, results of in vitro lymphocyte immunostimulation tests, and isolation of Mycobacterium paratuberculosis on fecal culture in 19 deer.