F. W. J. Gribnau

Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance

Objectives. To assess the value of treatment with continuous intravenous infusion of furosemide (F) in patients with refractory congestive heart failure.

Mechanisms of drug transfer across the human placenta.

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.

DIURETIC EFFICIENCY OF FUROSEMIDE DURING CONTINUOUS ADMINISTRATION VERSUS BOLUS INJECTION IN HEALTHY VOLUNTEERS

Furosemide delivery rate in the nephron has been reported to be one of the major determinants of diuretic response. In a randomized, crossover double‐blind study in eight healthy volunteers, we tested this hypothesis by comparing continuous intravenous infusion of furosemide (infusion rate, 4 mg/hr) during 8 hours after administration of an intravenous loading dose of 8 mg (total dose, 40 mg) with an intravenous bolus injection of 40 mg furosemide. During the study days subjects were rehydrated with isovolumetric amounts of fluid. Mean total urinary volume (Vur), sodium (UNa), potassium, and chloride excretion after 8 and 24 hours were significantly greater after treatment with continuous furosemide infusion when compared with bolus injection, whereas total urinary furosemide excretion showed no differences (Vur bolus versus Vur infusion, 5270 versus 6770 ml/8 hours; UNa bolus versus UNa infusion, 314 versus 430 mmol/8 hours; both p < 0.001). These findings strongly support the concept of the furosemide delivery rate into the nephron as a determinant of diuretic efficiency.

A double blind comparative study of sulphasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulphasalazine.

In a double blind, single observer, 48 week study the effects of sulphasalazine (2 g daily) and hydroxychloroquine (400 mg daily months 0-6, thereafter 200 mg daily) were compared in 60 patients with definite or classical rheumatoid arthritis. They had not been treated previously with second line drugs. The onset of response with sulphasalazine was earlier than with hydroxychloroquine. After 48 weeks a comparison of the treatments showed no statistically significant differences in disease activity variables. Adverse reaction was the main reason for withdrawal in the sulphasalazine group and lack of efficacy in the hydroxychloroquine group. All adverse reactions, one being agranulocytosis after eight weeks of sulphasalazine treatment, appeared in the first three months of treatment and were completely reversible.

Furosemide kinetics and dynamics in aged patients

Furosemide (F) is frequently used by elderly persons. We wanted to know whether age‐related changes in the disposition or the effect of F occurred and whether these changes could be predicted or explained. Kinetics and diuretic effects were studied after intravenous F injection in geriatric patients (70 to 93 yr of age). The changes in kinetics were as follows: slightly enlarged volume of distribution (0.16 ± 0.04 l) inversely related to serum albumin, diminished total body clearance (73 ± 27 ml/min), decreased renal clearance (40 ± 18 ml/min), and prolonged elimination t½ (180 ± 87 min). F effects were unchanged only if the decreased renal delivery of F and the decreased glomerular filtration rate were taken into account. Renal F clearance correlated best with endogenous creatinine clearance (FCC) and with F effects. Only ECC and plasma creatinine turned out to be useful patient characteristics to predict all F effects. Many drugs have an increased effect in elderly persons if a standard dose is used, based on the attainment of higher free plasma levels. In the case of F, however, the effects are decreased because they depend on decreased glomerular filtration of electrolytes and water and on decreased renal F secretion. These decreases are in part age dependent and in part disease dependent.

Specimen handling and high-performance liquid chromatographic determination of furosemide

A simple high-performance liquid chromatographic method to measure furosemide in plasma and urine is described. Furosemide fluoresces best, but is unstable, at acidic pH and is subject to photochemical degradation. These factors were analysed and the results prompted changes in previously described methods. All specimens were very carefully protected from light; extraction and acidification were done with acetic acid instead of hydrochloric acid. With these precautions no 4-chloro-5-sulphamoylanthranilic acid was found in biological specimens. The main metabolite was furosemide glucuronide (20% of furosemide excretion). Sensitivity was 0.1 and 0.5 microgram/ml for plasma and urine, respectively. The applicability of our method for furosemide studies is demonstrated.

Transcutaneous absorption of naproxen gel.

SummaryThe 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.

Risk factors of second-line antirheumatic drugs in rheumatoid arthritis

treatment of patients with rheumatoid arthritis (RA). Unlike nonsteroidal antiinllammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs) are assumed to influence the disease process and to slow the progression of joint damage. Sometimes they induce a remission of the disease. An important restriction in applying DMARDs is that drug treatment must be abandoned in patients because of inefficacy or serious side effects. Several studies have shown that about 70% of patients stop treatment within 2 years.lm6 Another feature of DMARDs is the delayed onset of action which varies from 6 to 12 weeks or longer. In this period of persisting disease activity, the development of irreversible joint damage continues. Knowledge of factors predicting response to DMARDs could improve the risk-benefit ratio of exposing patients to such treatment. Until recently only a few factors predictive of DMARD efficacy have been described. For example, the presence of the HLA-DR3 antigen has been related to good results from parenteral gold treatment.’ However, no such relation was found in other studies.‘,’ With respect to side effects, many risk factors have been described. Risk factors associated with genetics,’ pharmacokinetics,* immunologic variab1es,3 and others will be reviewed.4 Side effects caused by overdose and commonly known hazards and contraindications, such as renal impairment and drug interactions, are not discussed. RISK FACTORS RELATED TO GENETICS

Diuretic Usage and Withdrawal Patterns in a Dutch Geriatric Patient Population

OBJECTIVES: To describe diuretic usage and withdrawal patterns in a population of very old geriatric patients and to evaluate the long‐term probability of remaining free from diuretic therapy after withdrawal.

Superior efficacy of new medicines

PurposeTo provide an overview of and discuss newly authorised medicines with an improved efficacy.MethodsThis analysis focussed on new medicines with an improved efficacy based on the results of randomised active control trials. Information on comparative efficacy was obtained from the European Medicines Agency European Public Assessment Reports.ResultsBetween 1999 and 2005 we identified 122 new medicines with a new active substance. Of these, 13 (10%) were shown to be superior to already available medicines in terms a statistically significant difference in primary clinical endpoints.ConclusionsA proven advantage in efficacy at an early stage of drug development is the exception rather than the rule. The absence of evidence demonstrating differences between medicines does not necessarily mean that there are no actual differences. Optimal pharmacotherapy would benefit from more comparative research in the development of new medicines. The results of comparative trials need to be critically evaluated for their specific value in clinical practice. To this end, prescription data may be helpful.