Risk factors between analgesic use and chronic nephropathy in Thailand.

Analgesic abuse is common in Thailand. Heavy use of analgesic may also increase risk of chronic nephropathy. However, the extent of this risk remains unclear. We carried out a case-control study in three referral hospitals. A total of 84 patients with newly diagnosed of chronic tubulointerstitial nephritis were enrolled as cases. Two control groups were randomly selected, 192 from hospitalized patients who had no renal disease and serum creatinine below 1.2 mg/dl and 166 from relatives of friends visiting the hospitals. Both cases and controls were interviewed by a standardized pre-coded questionnaire to obtain histories of analgesic use before diagnosis of renal disease. On multiple logistic regression analysis, patients whose estimated lifetime use of acetaminophen of 1,000 g or more had an increased risk of chronic nephropathy compared with non-users, the odds ratio (OR) was 5.9 (95% confidence interval (CI) 1.3-25.6, hospital controls) and OR = 5.8 (95% CI 1.04-31.9, visitor controls). Also, uses of aspirin showed a similar relationship. Patients who used aspirin 1,000 g or more per lifetime had higher risk of chronic nephropathy when compared to non-users, the odds ratio were 7.1 (95% CI 2.0-25.8, hospital controls) and 20.4 (95% CI 2.4-174.2) for visitor controls. These data indicate that analgesic abuse increased risk of chronic nephropathy in Thailand.

Fetal viability and fetal growth after prolonged uterine contractions induced by progesterone withdrawal in late pregnancy in rats.

The hypothesis that sustained uterine contractile activity is the direct cause of fetal death after progesterone withdrawal in late pregnancy in rats was investigated. Pregnant rats were subjected to progesterone withdrawal on day 15 of pregnancy by injecting 2 mg mifepristone (RU 486) kg-1 or by ovariectomy with oestradiol replacement (200 ng day-1). Uterine contractile activity (force and frequency) at 4 h, but not at 2 h, in rats injected with mifepristone was significantly higher than in rats injected with vehicle. The contractile activity in mifepristone-treated rats remained higher than in control rats, at 12, 24 and 48 h. Fetal viability 36 h after mifepristone injection, when uterine contractions had lasted for 32 h, was not significantly different from fetal viability in rats injected with vehicle, but at 42 h after mifepristone injection, fetal viability was significantly reduced. In ovariectomized rats, uterine contractile activity at 12, 24, 36 and 48 h, but not at 8 h, was significantly greater than in ovariectomized rats with progesterone replacement (4 mg day-1). Fetal viability at 42 h after the operation, when uterine contractions had lasted for 30 h, was not significantly reduced, but it was significantly reduced at 48 h. When ovariectomized rats had been left to develop uterine contractions for a period before progesterone was injected, deprivation of progesterone and prolonged uterine contractions for about 30 h did not reduce fetal viability or fetal growth determined on day 18, but it did so 3 days later, on day 21. Administration of 5 mg isoxuprine kg-1 twice a day, which suppressed uterine contractions, improved fetal viability in ovariectomized rats at the earlier stage, but not at the later stage. Nevertheless, isoxuprine did improve fetal growth at the later stage in these ovariectomized rats. It is concluded that increased uterine contractile activity sustained for 32 h or less does not reduce fetal viability, but longer periods of contraction may be the cause of fetal death.

Uterine contractile activity in rats induced by mifepristone (RU 486) in relation to changes in concentrations of prostaglandins E-2 and F-2 alpha.

Pregnant rats were injected with mifepristone (RU 486) on Day 15 of pregnancy. The force and frequency of uterine contractions, recorded by a microballoon technique, were significantly greater at 12, 24 and 36 h in treated than in control rats (11.9 +/- 1.9 vs. 8.9 +/- 1.2 units, 17.7 +/- 3.0 vs. 10.5 +/- 2.3 units and 16.8 +/- 2.9 vs. 8.8 +/- 1.8 units for force and 51.3 +/- 9.1 vs. 29.4 +/- 3.8/h, 35.4 +/- 6.4 vs. 22.1 +/- 4.9/h and 35.6 +/- 3.2 vs. 24.6 +/- 4.6/h for frequency, respectively). There was no significant difference in concentrations of prostaglandin (PG) E-2 or PGF-2 alpha between treated and control rats at 12 h and 24 h after injection. At 36 h, 7 of 12 rats were aborting and uterine PG concentrations in these were significantly greater than in the others (1.5 +/- 0.2 vs. 0.9 +/- 0.2 ng PGE-2/g and 38.6 +/- 19.2 vs. 16.9 +/- 5.4 ng PGF-2 alpha/g), but there was no significant difference between control and treated rats that were not aborting. Concentrations of PGE-2 and PGF-2 alpha were significantly higher at 48 h when abortion had occurred in all animals (6.5 +/- 2.6 vs. 2.4 +/- 1.7 ng PGE-2/g and 30.4 +/- 8.9 vs. 9.3 +/- 5.6 ng PGF-2 alpha/g). Thus, the increase in uterine contractile activity induced by mifepristone preceded significant changes in concentrations of PGE-2 and PGF-2 alpha in the uterus and so could not have been caused by these changes.

Critical progesterone requirement for maintenance of pregnancy in ovariectomized rats.

The minimum progesterone concentration required to maintain the pregnancy was studied by varying doses of progesterone given subcutaneously to rats ovariectomized on Day 8 of pregnancy. Injecting 3 mg progesterone plus 200 ng oestradiol benzoate daily provided serum progesterone values between 25.4 +/- 7.0 and 35.2 +/- 6.2 ng/ml throughout Days 10-19 which were significantly lower than normal levels (P less than 0.05), but resulted in 93.6% of fetal survival on Day 19 which was not significantly different from 93.3% in the control group. Injecting 2 mg progesterone plus 200 ng oestradiol benzoate daily gave progesterone values between 13.2 +/- 4.6 and 19.0 +/- 6.2 ng/ml and could not maintain fetal viability to Day 19 (14.2%, P less than 0.05 compared with control group). Critical times to supplement progesterone in rats ovariectomized on Day 8 or Day 15 were studied by varying the time of progesterone implantation after ovariectomy. Progesterone implants were administered 8, 12 and 24 h after ovariectomy on Day 8 and 24, 36 and 48 h after ovariectomy on Day 15. On Day 8, progesterone replacement could be delayed to 8 h but not 12 h, while on Day 15, progesterone replacement could be delayed up to 36 h but not 48 h after ovariectomy without affecting fetal survival.

Dosing regimen of gentamicin during intermittent peritoneal dialysis.

The peritoneal clearance of gentamicin was studied in 11 chronic uremic patients who undergoing intermittent peritoneal dialysis. Gentamicin was significantly removed by peritoneal dialysis with a clearance value of 9.75 +/- 3.78 ml/min. The serum half life was 14.08 +/- 3.57 hr, a value significantly less than that of non dialysed end stage renal disease patients. The mean apparent volume of distribution of the drug in these patients was about 27% of body weight. The derived value for gentamicin peritoneal clearance and volume of distribution can be used to calculate maintenance dose during intermittent peritoneal dialysis. In order to achieve the peak level of 8 micrograms/ml, supplementary dose compensated for the loss during peritoneal dialysis is approximately 40% of loading dose 0.8 mg/kg every 12 hours.