4-Heptanone is a metabolite of the plasticizer di(2-ethylhexyl) phthalate (DEHP) in haemodialysis patients.

BACKGROUND: There is an ongoing discussion about the risks of di(2-ethylhexyl) phthalate (DEHP) exposure for the general population as well as for specific subgroups in various medical settings. Haemodialysis patients certainly belong to the group with the highest exposure taking into account the repeated treatments over a long period of time. Many studies have shown that DEHP metabolites are more active with regard to cellular responses than DEHP itself. Although 4-heptanone has been shown to be a DEHP metabolite in rats, this has never been tested in humans. On the other hand, 4-heptanone was reported to be associated with diabetes mellitus. METHODS: After establishing analytical methods for all postulated metabolites, we analysed (i) plasma samples from 50 patients on haemodialysis and 50 controls; (ii) urine samples from 100 diabetic patients and 100 controls; and (iii) urine samples from 10 controls receiving DEHP intravenously. RESULTS: 4-Heptanone concentrations in urine did not differ between controls (128.6+/-11.4 micro g/l, mean+/- SEM) and diabetic patients (131.2+/-11.6 micro g/l) but were significantly elevated in plasma from haemodialysis patients (95.9+/-9.6 micro g/l) compared with controls (10.4+/-0.5 micro g/l). Exposure to DEHP led to a significant increase (P<0.001) of the metabolite 4-heptanone and all the proposed intermediates in urine of healthy persons within 24 h. CONCLUSIONS: These studies show that 4-heptanone is not associated with diabetes but is a major DEHP metabolite in humans. Studies concerning the toxicity of DEHP in haemodialysis patients and other highly exposed groups should therefore include 4-heptanone together with DEHP and its primary metabolites mono(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol.

Clinical trials for drugs against diabetic neuropathy: can we combine scientific needs with clinical practicalities?

Diabetic neuropathy is a chronic progressive disease accounting for considerable morbidity and reduced quality of life among patients with diabetes. Accumulating evidence suggests that the clinical and neurophysiological markers used to assess neuropathy not only predict the development of neuropathic foot ulceration, one of the most common causes for hospital admission and lower limb amputations, but are also predictors of increased mortality in diabetic patients. In addition to metabolic control, drug treatment of both incipient and clinically manifest diabetic neuropathy will be necessary for the years to come. Because 1-2% of the whole population in western societies may be affected, the search for effective drug treatment is not only a very important goal for the patient suffering from diabetic neuropathy and for the practicing physician, but also an economic task for both the health care systems and pharmaceutical companies. The validity of inferences about the clinical consequences of the use of any given agent to induce a specific pharmacologic effect will depend not only on the extent to which it affects the targeted biological phenomenon, but also on the extent to which all of the actions of the agent have been defined and the extent to which all affect the entire organism, alone and in concert. The ultimate test of the usefulness of a drug or device depends on the determination of outcomes, ideally in randomized clinical trials (RCTs) of sufficient scope and duration. The efficacy and safety of a variety of drugs based on the different pathogenetic hypotheses proposed have been evaluated in RCTs since the 1970s. However, the quality of RCTs published between 1981 and 1992 that evaluated the effects of medical treatment in diabetic polneuropathy was poor. Adequate designs for RCTs in diabetic neuropathy must consider the following criteria: type and stage of neuropathy, homogeneity of the study population, outcome measures (neurophysiological markers, intermediate clinical end points, ultimate clinical outcomes, quality of life), natural history, sample size, study duration, reproducibility of neurophysiological and intermediate end points, nonspecific effects of treatment, measures of treatment effect, the extent to which the overall trail result applies to individual patients (external validity), and the reporting of the RCTs. Trials focusing preferentially on patients with mild or moderate early stages of neuropathy over long periods of 3-5 years aimed at slowing or prevention, rather than reversal, using end point measures that have clinical and prognostic significance are most likely to produce meaningful results.