Acute tolerance to furosemide diuresis in humans. Pharmacokinetic-pharmacodynamic modeling

Furosemide, 40 mg, was given to eight healthy volunteers as an i.v. dose and as oral doses (tablet and solution) with and without food intake. The urine and plasma were sampled frequently and analyzed on their content of furosemide (high-performance liquid chromatography). The urine flow and chloride excretion rate were used as measures of the effect. In spite of a 3-fold difference (28 vs. 9 mg/8 hr, P less than .001) in the cumulative urinary excretion of furosemide between i.v. and postprandial oral administration, no significant difference in the diuretic effect was found (2-2.2 liters/8 hr). The drug excretion-response curves showed parallel shifts depending on mode of administration of furosemide. Clockwise hysteresis, indicating acute tolerance development to the diuretic effect, was seen after the oral doses after food intake. This within-dose development of tolerance was modeled with an extended Hill equation. The tolerance development seems to have a near relationship to acute volume depletion (inadequate substitution of urine losses), probably activating some intrarenal mechanism for extracellular fluid volume preservation. Thus, the time course of furosemide excretion, as well as the degree of renal compensation, determine the renal sensitivity to furosemide. This has important implications for the proper design and interpretation of studies of the excretion-response relationship of diuretics.     

The Living Conditions of Children with Shared Residence – the Swedish Example

Among children with separated parents, shared residence – i.e., joint physical custody where the child is sharing his or her time equally between two custodial parents’ homes – is increasing in many Western countries and is particularly common in Sweden. The overall level of living among children in Sweden is high; however, the potential structural differences between children in various post-separation family arrangements have not been sufficiently studied. Potential risks for children with shared residence relate to the daily hassles and stress when having two homes. This study aims at investigating the living conditions of children with shared residence compared with children living with two custodial parents in the same household and those living with one custodial parent, respectively. Swedish national survey data collected from children aged 10–18 years (n ≈ 5000) and their parents were used. The outcomes were grouped into: Economic and material conditions, Social relations with parents and peers, Health and health behaviors, Working conditions and safety in school and in the neighborhood, and Culture and leisure time activities. Results from a series of linear probability models showed that most outcomes were similar for children with shared residence and those living with two custodial parents in the same household, while several outcomes were worse for children living with one parent. However, few differences due to living arrangements were found regarding school conditions. This study highlights the inequalities in the living conditions of Swedish children, with those living with one parent having fewer resources compared with other children.     

Response to furosemide during dehydration with and without naproxen pretreatment of kidney donors and renal transplant recipients

Summary The response to 40 mg furosemide p.o. in 6 healthy kidney donors and 6 renal transplant recipients with and without naproxen pretreatment has been studied. No volume replacement was given in order to study the development of tolerance. The subjects showed an average dehydration of 1.5 kg · 6 h^–1.While mean creatinine clearance was equal in patients and donors (76 vs 80 ml/min), renal furosemide clearance was significantly lower in the patients (47 vs 81 ml/min; P<0.05). The patients also excreted a smaller fraction of the dose in the urine (5.7 vs 7.8 mg/6 h; P<0.05). As the overall renal sensitivity was similar in the two groups, the natriuretic response was correspondingly smaller in transplant recipients as compared to donors.Within the observation period of 6 h after dosing, acute tolerance developed in the donors and in 4 of the 6 patients, as shown by clockwise hysteresis in the dose (urine furosemide excretion rate)-response (natriuresis) curves. Pretreatment with naproxen reduced renal sensitivity to furosemide (right shift of the dose response curve) in all the donors but in only 2 of the patients.In both groups acute tolerance was less pronounced after naproxen, which may indicate involvement of the prostaglandin system in the development of acute tolerance. The results may also indicate regeneration of sympathetic nerves with functional capacity in at least some renal transplants, or that other mechanisms of salt regulation compensate for loss of sympathetic nerve activity.     

A randomized comparative study of highly purified follicle stimulating hormone and human menopausal gonadotrophin for ovarian hyperstimulation in an oocyte donation programme

A randomized comparative study of highly purified human follicle-stimulatinghormone (FSH-HP), administered s.c, and human menopausal gonadotrophin(HMG), administered i.m., was carried out in 41 volunteer oocytedonors. The response to ovarian hyperstimulation was similarin both groups. One cycle in both groups was cancelled. Thenumber of oocytes recovered was 16.0 ± 7.9 (mean ±SD) following stimulation with 32.8 ± 103 ampoules ofFSH-HP (n = 19) over 12.3 ± 1.7 days. Following stimulationwith 29.8 ± 10.6 ampoules of HMG over 11.5 ± 1.6days, the number of oocytes collected was 18.4 ± 12.7(n = 20). The oocyte recipients were allocated 9.2 ±3.6 oocytes in the FSH-HP group (n = 33) and 9.6 ± 4.6oocytes in the HMG group (n = 37). The fertilization rate (2PN/cell)was significantly higher in the HMG group (48%, 170/355) thanin the FSH-HP group (36%, 109/304) (P < 0.01). The numberof embryos transferred per recipient was 2.0 ± 0.4 inthe FSH-HP and 2.0 ± 03 in the HMG group. The pregnancyrate per embryo transfer was 25% in the FSH-HP (5/20) and 26%(8/31) in the HMG group. Fertile donors with body mass index£25 made up a poor responder group to s.c FSH-HP, possiblyindicating reduced absorption of the drug.     

Is 125I iothalamate an ideal marker for glomerular filtration?

The triiodinated angiographic contrast medium, iothalamate, has (usually labelled 125I) been used extensively as a marker for glomerular filtration. We have studied the renal handling of 125I iothalamate (IOT) in vivo and in vitro in several species. In renal cortical slices from chicken, rabbit, rat, and monkey, the tissue-to-medium ratio of IOT was twice that of 51Cr-EDTA (EDTA) at 37 degrees C; a difference that was abolished at 0 degree C and markedly reduced by added o-iodohippurate or iodipamide. In five chickens the steady-state renal clearance of IOT (CIOT) was twice (P less than 0.05) that of EDTA (CEDTA) or 3H inulin (C1); a difference that was abolished by administration of 100 mg/kg/hr of novobiocin, an organic anion transport inhibitor. CEDTA was similar to C1 before as well as after transport inhibition. Utilizing the Sperber technique the mean apparent tubular excretion fraction (ATEF) of IOT was 8%, while that of EDTA was 1% (P less than 0.01; N = 10). After novobiocin coinfusion (new steady-state) ATEFIOT was significantly reduced (P less than 0.01) and not different from that of EDTA (-1%). In the same animals the total urinary recovery of IOT was 84 and 57% (P less than 0.01) before and after novobiocin, respectively, while corresponding values for EDTA was unchanged by the inhibitor. In seven rats the renal extraction of IOT was reduced from 29 to 17% (P less than 0.05) by coinfusion of probenecid (5 mg/kg/hr). Corresponding extractions were 82 to 34% (P less than 0.005) and 22% (unchanged) for PAH and EDTA, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomized trial of the Gyne T 380 and Gyne T 380 Slimline Intrauterine Copper devices

To facilitate manufacture and insertion of the Gyne T 380 IUD, design changes were instituted. Copper collars were seated flush at the ends of the horizontal crossbar of the device. A randomized study of the Gyne T 380 Slimline, the new design, was undertaken in comparison with the standard Gyne T 380. A total of 996 women were enrolled, with 698 Slimline insertions and 298 of the standard Gyne T. No statistically significant difference in ease of insertion or in performance was detected between the models. At one year, the pregnancy rate of each model was below 0.5 per 100 and the continuation rate was 79-80 per 100. Pelvic inflammatory disease or endometritis was found in one percent of subjects in the first year. This is the seventh multicenter randomized study of a collared T IUD with 380 mm2 of copper surface. In all seven, the one-year gross pregnancy rate has been 1.2 per 100 or lower.     

Steady state pharmacokinetics of trimethoprim 300 mg once daily in healthy volunteers assessed by two independent methods

Summary The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healty volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations >4 µg/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 µg/ml (range 3.1–9.5 µg/ml); the minimum value was 1.5 µg/ml (range 0.6–2.9 µg/ml). The mean AUC_ss was 77 µg/ml · h and the mean plasma clearance_ss was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7–15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 µg/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 µmol/l, probably due to competitive inhibition of the tubular secretion of creatinine.