Pharmacokinetics of continuous subcutaneous insulin infusion

Summary One of the reasons for the variability of blood glucose regulation in Type 1 (insulin-dependent) diabetic patients is the huge variation in subcutaneous absorption of intermediate-acting insulin. We have investigated the variation in insulin absorption during continuous subcutaneous insulin infusion in eight such patients. The content of insulin in the subcutaneous tissue was measured using ¹²⁵I-labelled insulin. The concentration of free serum insulin and blood glucose was followed from 1 h before and from 7 h after breakfast on two consecutive days. The amount of insulin absorbed during 24 h differed in all cases by less than 3% from the daily insulin dose given by the pumps. Mean insulin absorption rates and mean free insulin concentration showed peak values 30–90 min after meal bolus injections; this was sufficient to maintain near-normal blood glucose. Mean free serum insulin correlated strongly with disappearance of insulin from the subcutaneous tissue (r=0.98). From the insulin absorption rates and free insulin concentrations during basal constant insulin infusion, the half-time of serum insulin was calculated as 6 min. Compared with the known large variability in the absorption of intermediate-acting insulin, continuous subcutaneous insulin infusion offers a precise and reproducible way of insulin administration resulting in post-prandial serum insulin peaks sufficient to maintain near-normal blood glucose levels. The half-time of serum insulin during subcutaneous infusion corresponds to values for intravenous infusion given in the literature, indicating that local degradation of insulin in subcutaneous tissue is of minor importance.     

Left ventricular dysfunction in Churg-Strauss syndrome

Churg-Strauss syndrome is a rare disorder characterized by hypereosinophilia and a systemic vasculitis occurring inpatients with asthma and allergic rhinitis. Vasculitis commonly affects the lungs, the heart, the skin, and the peripheral nervous system. Cardiac involvement is characterized by acute and constrictive pericarditis, myocarditis and endocarditis, as well as ischemic cardiomyopathy. Endomyocardial fibrosis similar to Loeffler's syndrome has been rarely described. In the presented case, a 43 year old man with a history of allergy and asthma suffered from increasing dyspnea, fever, pulmonary infiltates and cardiomyopathy. Laboratory studies were notable for marked hypereosinophilia. In a bronchoscopic lavage and transbronchial biopsy eosinophilic infiltrates accompanied by vasculitis were found, Churg-Strauss syndrome was diagnosed. Echocardiogram showed endomyocardial deposits in the apex of the right ventricle, right ventricular function was normal particular in the basal segments. The left ventricle was slightly enlarged and left ventricular function was impaired. The diastolic mitral in-flow showed a restrictive pattern. Additionally, a pericardial effusion was observed without signs of tamponade. The patient received corticosteroids, cyclophosphamide and cardiomyopathy-specific therapy and showed a marked improvement after 4 months.     

BCG lymphadenitis in an HIV-infected child 9.5 years after vaccination

Complications of Bacillus Calmette-Guerin (BCG) vaccination have been reported in immunocompetent as well as in immunocompromised individuals. Severe and/or late complications have been associated with impairment of cell-mediated immunity. A case of BCG lymphadenitis in a vertically infected HIV-positive boy 9.5 years after vaccination is presented. The vaccination was performed within the first week of life, the HIV status of the mother being unknown. When the boy was 2.5 years old, his HIV infection was diagnosed after his mother had died from AIDS. At that time his CD4 count was 739 cells/microL. In the course of the following years, his CD4 count declined steadily, until it reached a low of about 20 cells/microL at the age of 5.5 years. He was troubled with recurring respiratory infections and one incidence of severe pancreatitis. Apart from that, he was in stable condition and led a more or less normal life. At the age of 9.5 years he developed lymphadenitis in his left axilla. The node was examined via biopsy, and the appropriate tests showed an infection with Mycobacterium bovis BCG variety. The CD4 count at that time was 16 cells/microL, polymerase chain reaction showed 220,000 RNA copies/mL. There were no signs of dissemination. Antitubercular agents were administered, and an antiretroviral combination therapy was started. The patient was discharged from the hospital after approximately 2 months. After an uneventful period of 9 months, the boy, still on antitubercular medicine, exhibited a secreting fistula in his left axilla, again due to Mycobacterium bovis, BCG variety. The fistulous tissue was removed surgically, and the antitubercular treatment was given intravenously for almost 3 months before being changed to an oral application. In addition, the antiretroviral regimen was completely exchanged. The case presented illustrates that there is a risk of very late complications in HIV-infected individuals, even when they are vaccinated when they are asymptomatic newborns. Although the risk seems low, one has to be aware of the problem because timely treatment is probably essential to prevent dissemination of the infection. Late complications of BCG vaccinations are most likely to be detected in countries with high medical standards, where HIV-infected children are surviving for longer periods of time.     

Effects of 10 days of endurance exercise training on the suppression of whole body and regional lipolysis by insulin

The aim of this study was to evaluate in premenopausal women (10 sedentary obese women) the effects of 10 days of exercise on the suppression of whole body and regional lipolysis by insulin. Lipolysis was determined using 2H5-glycerol infusion and microdialysis of sc adipose tissue during a two-stage hyperinsulinemic-euglycemic clamp [10 (LO) and 20 (MO) mU/m x min]. Microdialysis probes were positioned in abdominal and femoral sc adipose tissue to monitor interstitial glycerol and blood flow. Basal plasma glycerol was 86.7 +/-17.0 and 100.3 +/- 19.8 micromol/L before and after training, respectively (P < 0.05). Plasma glycerol was suppressed to a greater extent after [to 47 +/- 5% (LO) and 42 +/- 5% (MO) of basal] than before [to 62 +/- 8% (LO) and 55 +/- 8% (MO) of basal] training. The rate of appearance of glycerol was suppressed to 49 +/- 7% and 40 +/- 5% of basal during LO and to 38 +/- 5% and 30 +/- 4% of basal during MO (P < 0.05) before and after training, respectively. There were no differences in the suppression of lipolysis in abdominal as well as femoral sc adipose tissue as evidenced by similar reductions in dialysate glycerol levels before and after training in each of these tissues. The results indicate that the antilipolytic response to insulin can be improved through endurance exercise training. Intraabdominal adipose tissue or skeletal muscle may be the site of improved antilipolytic response to insulin after training, as improvement was not evident in abdominal or femoral sc adipose tissue.     

Flottierender Riesenthrombus im offenen Foramen ovale Diagnose mittels transösophagealer Echokardiographie

Zusammenfassung Die Diagnose eines flottierenden Thrombus in einem offenen Foramen ovale wird selten gestellt. Wir berichten über einen Patienten, bei dem aufgrund des dringenden Verdachtes auf eine Pulmonalembolie eine trans?sophageale Echokardiographie (TEE) durchgeführt wurde. Mit Hilfe der TEE konnte der Verdacht der Pulmonalembolie erh?rtet werden. Als überraschungsbefund fand sich jedoch im rechten und linken Vorhof ein langer, wurmf?rmiger, sehr mobiler Thrombus, der im offenen Foramen ovale eingekeilt war. Der Patient wurde aufgrund dieser Diagnose unverzüglich einem chirurgischem Eingriff unterzogen, wobei sich der TEE-Befund best?tigte und ein 19 cm langer Thrombus entfernt wurde. Mit Hilfe der TEE konnte der Riesenthrombus erkannt und einer entsprechenden Therapie zugeführt werden, wodurch Komplikationen, wie das Auftreten einer neuerlichen Pulmonalembolie oder einer paradoxen Embolie, verhindert werden konnten. Eingegangen: 10. August 1998 Akzeptiert: 12. August 1998     

Protection from arabinofuranosylcytosine and n-mustard-induced myelotoxicity using hemoregulatory peptide pGlu-Glu-Asp-Cys-Lys monomer and dimer

We have previously shown that the synthetic peptide pGlu-Glu-Asp-Cys-Lys (pEEDCK monomer) inhibits the cytostatic drug-induced proliferation of hematopoietic stem cells CFU-S. Keeping CFU-S quiescent by pEEDCK treatment renders them insensitive to cycle-specific cytostatic drugs and leads to reduced toxicity. Here we show that pEEDCK application during repeated (twice) administration of clinically relevant (nonlethal) 1-beta-D-arabinofuranosylcytosine (Ara-C) doses reduced the percentage of CFU-S in S-phase from 60%-70% to 25%-30% and led to a sustained stem cell number in the bone marrow (BM), whereas unprotected mice had lost about 75% of their CFU-S population. Owing to its cysteine content, the pEEDCK monomer is easily oxidized. The resulting dimer (pEEDCK)2 is a potent stimulator of hematopoiesis. As we show, it can be used for postchemotherapy acceleration of hematologic recovery, similar to the use of recombinant hematopoietic growth factors. A single injection of 30 micrograms/kg pEEDCK monomer to mice 2 hours before the second Ara-C injection retarded onset of neutropenia (by 2 to 3 days) and improved recovery after depression. The quantitative degree of neutropenia was not changed. Postchemotherapy (Ara-C administered twice, followed by N-mustard) infusion of the stimulatory (pEEDCK)2 dimer (1.4 micrograms/kg/d) produced a 4.6-fold increase of progenitor levels (6.7 CFU-GM/1,000 BM cells v 1.45 CFU-GM/1,000 in normal mice) 2 days after the end of the cytostatic treatment when CFU-GM were not detectable in unprotected mice. This increase was followed after several days by strongly elevated granulocyte counts, which remained high for approximately 1 week. Up to 75% of the peripheral leukocytes were mature polymorphonuclear leukocytes (PMN) during this phase. Ara-C (twice) and monomer treatment as above followed by dimer infusion resulted in the complete protection of hematopoiesis. Mice treated with the protective pEEDCK monomer plus stimulatory dimer did not develop the leukocyte depression noted in unprotected animals. The inhibitory monomer appears to keep the stem cell population numerically and qualitatively intact, thus providing optimum target cell conditions for the subsequent stimulator (dimer) treatment. Our results show that the hemoregulatory peptide monomer and dimer can be used for improving the hematologic status of mice treated with clinically relevant doses of cytostatic drugs (antimetabolite and alkylating, alone and in combination). Combining both peptides can prevent occurrence of neutropenia completely. Both peptides can be obtained easily by chemical synthesis and are also active on human cells. They are thus highly promising candidates for application as multilevel hemoprotectors in cancer chemotherapy.