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In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flow-dependent and membrane-limited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.

Objective: To examine the indications for prescription and possibilities for withdrawal of loop diuretics in community-dwelling patients aged 75 years or older, as reported by their general practitioners (GPs)., Methods: Analysis of dispensary data to identify patients aged 75 years or older using loop diuretics on 1 February 1996. Questionnaires were sent to the GPs of these patients to inquire about the indications for loop diuretic prescription and the necessity for continuation. We subsequently determined loop diuretic prescription rates in the survey population over the next 9 months., Setting: A panel of nine Dutch community pharmacies., Results: Questionnaires were returned for 338 out of 667 patients (50.7%) using loop diuretics on 1 February 1996. Reported indications for loop diuretic use were heart failure in 223 patients (66.0%), hypertension in 35 patients (10.4%), and a combination of both in 23 patients (6.8%). Loop diuretics were used for ankle edema in 27 patients (8.0%) and for unknown reasons in another 27 patients (8.0%). Continuation of treatment was considered unnecessary by GPs in 66 out of 338 patients (19.5%). However, prescription rates for these 66 patients in the following months were no different from rates for the remaining 272 patients. Loop diuretics were still prescribed to 47 of 66 patients (71.2%) after 12 weeks, and to 26 patients (39.4%) after 36 weeks., Conclusions: GPs reported substantial opportunities for withdrawal of loop diuretics in patients over 75 years of age, but this did not influence actual prescription rates in these patients. Future studies should explore means of facilitating withdrawal of these medications in this population.

The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F + T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men. A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC480) F2.58 micrograms.h.ml-1; F + T 2.46 micrograms.h.ml-1; FT 1.97 micrograms.h.ml-1. There was a significant reduction in the AUC480 of plasma triamterene (F + T 204.9 micrograms.h.l-1; FT 130.2 micrograms.h.l-1). Sodium excretion after F + T and FT was more pronounced than after F (F + T 302 mmol; FT 311 mmol; F259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F + T as well as after FT (F 121 mmol; F + T 104 mmol; FT 107 mmol). It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.

In an open triple crossover study in 8 patients with essential hypertension, the possibility has been investigated of whether the blood pressure lowering effect of hydrochlorothiazide 50 mg once daily was attenuated by co-administration for 4 weeks of ibuprofen 400 mg t.i.d., diclofenac 25 mg t.i.d. or sulindac 200 mg b.i.d. Only a slight, statistically nonsignificant change was found, with the exception of a significant increase in systolic blood pressure after 4 weeks treatment with ibuprofen. There was considerable variation in the blood pressure response during treatment with all three NSAIDs, with slight rises in blood pressure in 13 out of 24 periods. Body weight increased significantly on treatment both with ibuprofen and diclofenac, whereas the increase on sulindac was less and was transient. No significant change was found in various biochemical parameters, including plasma electrolytes, plasma renin activity (PRA), aldosterone, albumin and creatinine, in haematocrit or in the 24-h urinary excretion of sodium and potassium. The sole exception was a decrease in PRA during ibuprofen treatment. From these observations it is concluded that ibuprofen and diclofenac differ from sulindac in their interaction with the diuretic action of hydrochlorothiazide. It appears that all three NSAIDs can safely be combined with hydrochlorothiazide in hypertensive patients, but blood pressure should be monitored carefully when an NSAID are added.

A simple and reliable HPLC method for the determination of tienilic acid ((TA) Selacryn, Selcryn, Diflurex, Ticrynafen) and its alcoholic metabolite in plasma and urine has been developed. In 8 healthy adult volunteers the plasma and urinary levels of tienilic acid and its alcoholic metabolite, and plasma and urinary levels of sodium, creatinine and uric acid were measured after oral administration of tienilic acid 250 mg. The pharmacokinetic parameters found differed only slightly from those reported in the literature, as there was faster absorption and a shorter half-life. TA is probably excreted by a saturable renal tubular transport mechanism. The pharmacodynamic effects of tienilic acid developed quickly, the uricosuric effect being very impressive and the natriuretic effect moderate. These effects disappeared in about 8 h. An inverse relationship was found between the starting plasma uric acid level in an individual and the maximal uric acid clearance - the higher the plasma uric acid level, the lower was the maximum effect. Plasma tienilic acid level and natriuretic effect were correlative within individuals and intra-individually (p less than 0.05). Urinary tienilic acid level and natriuretic effect were correlated, too (p less than 0.05 to p less than 0.001), but only intraindividually. No correlation between drug level and uricosuric effect was found.

The kinetics of naproxen was studied in healthy volunteers after cutaneous application of gels containing 5 and 10% of the drug. Bioavailability was estimated from serum concentration and cumulative urinary metabolite excretion data, both determined up to 96 hours after drug administration. The mean bioavailability after the 10% gel was 1.1% (serum data) and 1.0% (urine data), and after the 5% gel it was 2.1% (serum data) and 1.8% (urine data). Despite the small amount of naproxen absorbed, a potential pharmacological effect, due to cutaneous accumulation of the drug following topical administration, may be suggested from the course of the serum concentration-time curves.

Fifty-two patients with rheumatoid arthritis were studied in a single blind trial comparing aurothioglucose and auranofin. The duration of the study was 52 weeks. Twenty-six patients, 13 in each treatment group, dropped out during the first year of treatment. The main reason for discontinuing treatment with aurothioglucose was adverse reactions and, in the auranofin group, lack of efficacy. In those patients who continued therapy the results of treatment were comparable; patients on aurothioglucose improved slightly more than auranofin treated patients, although the difference was not statistically significant.

Serum gold concentrations were measured in rheumatoid arthritis patients during chronic treatment with the orally adsorbable gold compound auranofin. In agreement with data in the literature, the highest serum gold concentration was reached after 16 weeks of treatment with 6 mg auranofin daily. A striking finding in this study was that thereafter the serum gold concentrations did not appear to plateau but declined gradually. Statistically this resulted in a significantly lower concentration after one year as compared with week 16 (p less than 0.05, paired t-test). It is suggested that a shift from protein bound gold to cell-bound gold might be the explanation.

A 12-week double-blind randomized drug trial followed by an open extension period of 36 weeks was carried out in 38 male patients with ankylosing spondylitis (AS) to compare the efficacy and safety of diflunisal (500 mg twice daily) and phenylbutazone (200 mg twice daily). Both drugs proved to be effective in improving the severity of symptoms associated with AS, and this improvement was maintained throughout the open extension period. Initially diflunisal had a more pronounced and rapid analgesic action, whereas phenylbutazone was more effective in increasing axial mobility. During the study 9 patients dropped out: 3 in each treatment group due to side effects and 1 in each group due to lack of efficacy; another patient was lost to follow-up. The two drugs were similarly safe as judged by the occurrence of adverse clinical effects, mainly gastrointestinal. This study again demonstrates the value of phenylbutazone in AS but, taking into account the possible haematological side effects, the use of other NSAIDs is stressed. Diflunisal is an alternative capable of improving the painful stiffness associated with AS.

Radiographic films of 40 patients participating in a single centre patient blind study of auranofin versus aurothioglucose were evaluated in a random order by one reader. The two treatment groups were comparable with respect to number of erosions and total radiographic score at the start of the study. Only in the auranofin-treated patients was a statistically significant increase in the mean number of new erosions (p less than 0.001 at 6 months and p less than 0.01 at 12 months treatment, paired t-test) as well as in the total radiographic score (p less than 0.01 at 6 and 12 months treatment, paired t-test) observed. Results of this study confirm that parenteral gold compounds do retard radiographic progression of joint destruction in the treatment of rheumatoid arthritis. The effects on radiographic progression shown in this study are in agreement with other reports which, based on clinical and biochemical parameters, have shown that auranofin is somewhat less effective than the injectible gold salts.