[Progress in the field of medical devices for diabetes]. / Ontwikkelingen op het gebied van diabeteshulpmiddelen.

In the eighties major improvements were made in insulin injection and home blood glucose monitoring. However, in the nineties further improvements were rather disappointing. Despite considerable effort, non-invasive, continuous monitoring glucose sensors are still not ready for marketing. It will take 10-20 years before 'closed-loop systems' will appear, with the amount of insulin released by the pump adjusted automatically on the basis of the measuring results of a permanently implanted blood glucose sensor. Islet cell transplantation, if possible in a way that abolishes the need to take immunosuppressive medicines, is still under development. The number of people suffering from diabetes in the Netherlands is estimated to increase from about 285,400 in 1999 to about 400,000 in 2020. The costs of medical devices for diabetes will probably double in 2020. However, increased costs for devices may improve the quality of life and may result in decreased expenditure in other parts of health care by reducing the long-term complications.

Clinical pharmacokinetics of dapsone.

Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to 100mg, but varies from 50 to 400mg in the treatment of other dermatological disorders. In malaria prophylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly haematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. Alcoholic liver disease decreases the protein binding of dapsone; coeliac disease and dermatitis herpetiformis may delay its oral absorption and severe leprosy has been reported to affect the extent of absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Sex differences in the absorption of dapsone after intramuscular injection.

A trial was performed with a long-acting dapsone (DDS) injection, consisting of an aqueous suspension of dapsone crystals, in doses of 900 mg and 1200 mg. Forty-one Ethiopian leprosy patients, 13 women and 28 men, participated in the study. There appeared to be a large discrepancy in the serum concentration curves of dapsone between men and women. Following injection of 900 mg dapsone in men, a peak of 2.28 +/- 1.06 micrograms/ml (mean +/- S.D.) was observed in the first week. After two weeks the serum concentrations had fallen to 0.42 +/- 0.29 micrograms/ml, and after four weeks they fell to 0.11 +/- 0.09 micrograms/ml. Following injection in women, the curves were smooth with a peak in the first week of only 1.04 +/- 0.40 micrograms/ml, while the serum concentrations after four weeks were still 0.42 +/- 0.23 micrograms/ml. The differences between the mean curves of men and women were statistically significant (p less than 0.001). The 1200 mg dapsone injections were only given to men. The explanation of the sex difference in intramuscular absorption can probably be found in the differences in the thickness of gluteal fat in men and women. In these Ethiopian leprosy patients, the non-protein-bound fraction of dapsone comprised 17 +/- 4%. In saliva, 19.5 +/- 7.0% of the dapsone level in serum was found. Methemoglobin levels were raised but did not reach levels of clinical importance. No other significant side effects were observed.

Intramuscular injection of dapsone in therapy for leprosy: a new approach.

Dapsone is the drug of first choice in the treatment of leprosy. Although the oral route of administration has been mostly used, recent studies of patient compliance revealed that only about 50% of the tables received by the patients are actually taken. It is generally assumed that irregular self-medication favors the development of dapsone resistance. The need for a more reliable route of administration led us to investigate the possibility of an i.m. dapsone depot injection. To achieve effective blood levels for 3-4 weeks, suspensions of large dapsone particles in an aqueous vehicle were made. In a trial with 20 leprosy patients in Nigeria, injection of 900 mg dapsone i.m. as a mixture of particle sizes less than 90 micrometer (20%) and 90-125 micrometer (80%) resulted in a serum level above 0.5 microgram/ml for 18 +/- 5 days with a mean peak concentration of 3.1 +/- 0.9 microgram/ml (n = 10). Injection of 1200 mg of the same particle-size mixture led to peak concentrations of 2.7 +/- 1.0 microgram/ml and maintenance of the level above 0.5 microgram/ml for 25 +/- 3 days (n = 5). After injection of 1200 mg (particle size less than 90 micrometer), serum levels were kept above 0.5 microgram/ml for 21 +/- 5 days with a maximum concentration of 3.9 +/- 1.2 microgram/ml (n = 5). Serum levels were measured using a rapid non-extractive HPLC method. The injections were very well tolerated. Due to these encouraging results, the dosage and formulation will be further optimized.